Functional impact of global rare copy number variation in autism spectrum disorders.

Authors: Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger Jr JI, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C.

The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.

Biological, clinical and population relevance of 95 loci for blood lipids.

Authors: Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee JY, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, Zee RY, Wright AF, Witteman JC, Wilson JF, Willemsen G, Wichmann HE, Whitfield JB, Waterworth DM, Wareham NJ, Waeber G, Vollenweider P, Voight BF, Vitart V, Uitterlinden AG, Uda M, Tuomilehto J, Thompson JR, Tanaka T, Surakka I, Stringham HM, Spector TD, Soranzo N, Smit JH, Sinisalo J, Silander K, Sijbrands EJ, Scuteri A, Scott J, Schlessinger D, Sanna S, Salomaa V, Saharinen J, Sabatti C, Ruokonen A, Rudan I, Rose LM, Roberts R, Rieder M, Psaty BM, Pramstaller PP, Pichler I, Perola M, Penninx BW, Pedersen NL, Pattaro C, Parker AN, Pare G, Oostra BA, O'Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, Meitinger T, McPherson R, McCarthy MI, McArdle W, Masson D, Martin NG, Marroni F, Mangino M, Magnusson PK, Lucas G, Luben R, Loos RJ, Lokki ML, Lettre G, Langenberg C, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, Kronenberg F, König IR, Khaw KT, Kaprio J, Kaplan LM, Johansson A, Jarvelin MR, Cecile J W Janssens A, Ingelsson E, Igl W, Kees Hovingh G, Hottenga JJ, Hofman A, Hicks AA, Hengstenberg C, Heid IM, Hayward C, Havulinna AS, Hastie ND, Harris TB, Haritunians T, Hall AS, Gyllensten U, Guiducci C, Groop LC, Gonzalez E, Gieger C, Freimer NB, Ferrucci L, Erdmann J, Elliott P, Ejebe KG, Döring A, Dominiczak AF, Demissie S, Deloukas P, de Geus EJ, de Faire U, Crawford G, Collins FS, Chen YD, Caulfield MJ, Campbell H, Burtt NP, Bonnycastle LL, Boomsma DI, Boekholdt SM, Bergman RN, Barroso I, Bandinelli S, Ballantyne CM, Assimes TL, Quertermous T, Altshuler D, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Adair LS, Taylor HA Jr, Borecki IB, Gabriel SB, Wilson JG, Holm H, Thorsteinsdottir U, Gudnason V, Krauss RM, Mohlke KL, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE, Rotter JI, Boerwinkle E, Strachan DP, Mooser V, Stefansson K, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, van Duijn CM, Peltonen L, Abecasis GR, Boehnke M, Kathiresan S.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Altered hippocampal morphology in unmedicated patients with major depressive illness.

Authors: Bearden CE, Thompson PM, Avedissian C, Klunder AD, Nicoletti M, Dierschke N, Brambilla P, Soares JC.

Despite converging evidence that major depressive illness is associated with both memory impairment and hippocampal pathology, findings vary widely across studies and it is not known whether these changes are regionally specific. Here we acquired brain magnetic resonance images from 31 unmedicated patients with major depressive disorder (MDD; mean age 39.2+/11.9; 77% female) and 31 demographically comparable controls. Three-dimensional parametric mesh models were created to examine localized alterations of hippocampal morphology. Although global volumes did not differ between groups, statistical mapping results revealed that in MDD patients, more severe depressive symptoms were associated with greater left hippocampal atrophy, particularly in CA1 subfields and the subiculum. However, previous treatment with atypical antipsychotics was associated with a trend toward larger left hippocampal volume. Our findings suggest effects of illness severity on hippocampal size, as well as a possible effect of past history of atypical antipsychotic treatment, which may reflect prolonged neuroprotective effects. This possibility awaits confirmation in longitudinal studies.

Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in Major Depressive Disorder: Results of the BRITE-MD study.

Authors: Leuchter AF, Cook IA, Marangell LB, Gilmer WS, Burgoyne KS, Howland RH, Trivedi MH, Zisook S, Jain R, McCracken JT, Fava M, Iosifescu D, Greenwald S

Patients with Major Depressive Disorder (MDD) may not respond to antidepressants for 8 weeks or longer. A biomarker that predicted treatment effectiveness after only 1 week could be clinically useful. We examined a frontal quantitative electroencephalographic (QEEG) biomarker, the Antidepressant Treatment Response (ATR) index, as a predictor of response to escitalopram, and compared ATR with other putative predictors. Three hundred seventy-five subjects meeting DSM-IV criteria for MDD had a baseline QEEG study. After 1 week of treatment with escitalopram, 10 mg, a second QEEG was performed, and the ATR was calculated. Subjects then were randomly assigned to continue with escitalopram, 10 mg, or change to alternative treatments. Seventy-three evaluable subjects received escitalopram for a total of 49days. Response and remission rates were 52.1% and 38.4%, respectively. The ATR predicted both response and remission with 74% accuracy. Neither serum drug levels nor 5HTTLPR and 5HT2a genetic polymorphisms were significant predictors. Responders had larger decreases in Hamilton Depression Rating Scale (Ham-D(17)) scores at day 7 (P=0.005), but remitters did not. Clinician prediction based upon global impression of improvement at day 7 did not predict outcome. Logistic regression showed that the ATR and early Ham-D(17) changes were additive predictors of response, but the ATR was the only significant predictor of remission. Future studies should replicate these results prior to clinical use.

Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder

Authors: Altshuler LL, Abulseoud OA, Foland-Ross L, Bartzokis G, Chang S, Mintz J, Hellemann G, Vinters HV.

Altshuler LL, Abulseoud OA, Foland-Ross L, Bartzokis G, Chang S, Mintz J, Hellemann G, Vinters HV. Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord 2010: 12: 541-549. (c) 2010 The Authors. Journal compilation (c) 2010 John Wiley & Sons A/S. Objectives: Several magnetic resonance imaging studies have found changes in amygdala volumes in adults with mood disorders. The cellular basis for these changes has not been explored in detail. Specifically, it is not known whether differences in the density and/or volume of neurons or glial cells contribute to tissue volume changes seen on magnetic resonance images. Methods: Postmortem amygdala samples were obtained from the Stanley Foundation Neuropathology Consortium from subjects diagnosed with bipolar disorder (n = 10), major depressive disorder (n = 11), and schizophrenia (n = 9), and from normal controls (n = 14). Samples were first stained with glial fibrillary acidic protein (GFAP) and counter-stained with hematoxylin to ascertain neuron and glia (astrocyte) densities. Results: No significant differences in neuronal densities were found between groups. However, a reduction in the density of GFAP immunoreactive astrocytes was observed in the amygdala of subjects with major depressive disorder compared to the bipolar disorder, schizophrenia, and normal control postmortem samples. Conclusions: A decrease in density of GFAP immunoreactive astrocytes in the amygdala of depressed subjects is consistent with prior histologic reports and might contribute to amygdala volume reductions reported in several in vivo neuroimaging studies.

Effects of ApoE4 and maternal history of dementia on hippocampal atrophy

Authors: Andrawis JP, Hwang KS, Green AE, Kotlerman J, Elashoff D, Morra JH, Cummings JL, Toga AW, Thompson PM, Apostolova LG.

We applied an automated hippocampal segmentation technique based on adaptive boosting (AdaBoost) to the 1.5 T magnetic resonance imaging (MRI) baseline and 1-year follow-up data of 243 subjects with mild cognitive impairment (MCI), 96 with Alzheimer's disease (AD), and 145 normal controls (NC) scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). MCI subjects with positive maternal history of dementia had smaller hippocampal volumes at baseline and at follow-up, and greater 12-month atrophy rates than subjects with negative maternal history. Three-dimensional maps and volumetric multiple regression analyses demonstrated a significant effect of positive maternal history of dementia on hippocampal atrophy in MCI and AD after controlling for age, ApoE4 genotype, and paternal history of dementia, respectively. ApoE4 showed an independent effect on hippocampal atrophy in MCI and AD and in the pooled sample.

A genomewide scan for common alleles affecting risk for autism.

Authors: Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu S, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, Hallmayer J.

While autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1,558 rigorously defined ASD families for one million single nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P<5x10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P<5x10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2, and TAF1C.

n-Type Organic Semiconductors in Organic Electronics.

Authors: Anthony JE, Facchetti A, Heeney M, Marder SR, Zhan X.

Organic semiconductors have been the subject of intensive academic and commercial interest over the past two decades, and successful commercial devices incorporating them are slowly beginning to enter the market. Much of the focus has been on the development of hole transporting, or p-type, semiconductors that have seen a dramatic rise in performance over the last decade. Much less attention has been devoted to electron transporting, or so called n-type, materials, and in this paper we focus upon recent developments in several classes of n-type materials and the design guidelines used to develop them.

Hippocampal, caudate, and ventricular changes in Parkinson's disease with and without dementia.

Authors: Apostolova LG, Beyer M, Green AE, Hwang KS, Morra JH, Chou YY, Avedissian C, Aarsland D, Janvin CC, Larsen JP, Cummings JL, Thompson PM.

Parkinson's disease (PD) has been associated with mild cognitive impairment (PDMCI) and with dementia (PDD). Using radial distance mapping, we studied the 3D structural and volumetric differences between the hippocampi, caudates, and lateral ventricles in 20 cognitively normal elderly (NC), 12 cognitively normal PD (PDND), 8 PDMCI, and 15 PDD subjects and examined the associations between these structures and Unified Parkinson's Disease Rating Scale (UPDRS) Part III:motor subscale and Mini-Mental State Examination (MMSE) performance. There were no hippocampal differences between the groups. 3D caudate statistical maps demonstrated significant left medial and lateral and right medial atrophy in the PDD vs. NC, and right medial and lateral caudate atrophy in PDD vs. PDND. PDMCI showed trend-level significant left lateral caudate atrophy vs. NC. Both left and right ventricles were significantly larger in PDD relative to the NC and PDND with posterior (body/occipital horn) predominance. The magnitude of regionally significant between-group differences in radial distance ranged between 20-30% for caudate and 5-20% for ventricles. UPDRS Part III:motor subscale score correlated with ventricular enlargement. MMSE showed significant correlation with expansion of the posterior lateral ventricles and trend-level significant correlation with caudate head atrophy. Cognitive decline in PD is associated with anterior caudate atrophy and ventricular enlargement. 2010 Movement Disorder Society.

3D PIB and CSF biomarker associations with hippocampal atrophy in ADNI subjects.

Authors: Apostolova LG, Hwang KS, Andrawis JP, Green AE, Babakchanian S, Morra JH, Cummings JL, Toga AW, Trojanowski JQ, Shaw LM, Jack CR Jr, Petersen RC, Aisen PS, Jagust WJ, Koeppe RA, Mathis CA, Weiner MW, Thompson PM; Alzheimer's Disease Neuroimaging Initiative.

Cerebrospinal fluid (CSF) measures of Ab and tau, Pittsburgh Compound B (PIB) imaging and hippocampal atrophy are promising Alzheimer's disease biomarkers yet the associations between them are not known. We applied a validated, automated hippocampal labeling method and 3D radial distance mapping to the 1.5T structural magnetic resonance imaging (MRI) data of 388 ADNI subjects with baseline CSF Ab(42), total tau (t-tau) and phosphorylated tau (p-tau(181)) and 98 subjects with positron emission tomography (PET) imaging using PIB. We used linear regression to investigate associations between hippocampal atrophy and average cortical, parietal and precuneal PIB standardized uptake value ratio (SUVR) and CSF Ab(42), t-tau, p-tau(181), t-tau/Ab(42) and p-tau(181)/Ab(42). All CSF measures showed significant associations with hippocampal volume and radial distance in the pooled sample. Strongest correlations were seen for p-tau(181), followed by p-tau(181)/Ab(42) ratio, t-tau/Ab(42) ratio, t-tau and Ab(42). p-tau(181) showed stronger correlation in ApoE4 carriers, while t-tau showed stronger correlation in ApoE4 noncarriers. Of the 3 PIB measures the precuneal SUVR showed strongest associations with hippocampal atrophy. Copyright © 2010. Published by Elsevier Inc.

Automated 3D mapping of baseline and 12-month associations between three verbal memory measures and hippocampal atrophy in 490 ADNI subjects.

Authors: Apostolova LG, Morra JH, Green AE, Hwang KS, Avedissian C, Woo E, Cummings JL, Toga AW, Jack CR Jr, Weiner MW, Thompson PM; Alzheimer’s Disease Neuroimaging Initiative.

We used a previously validated automated machine learning algorithm based on adaptive boosting to segment the hippocampi in baseline and 12-month follow-up 3D T1-weighted brain MRIs of 150 cognitively normal elderly (NC), 245 mild cognitive impairment (MCI) and 97 DAT ADNI subjects. Using the radial distance mapping technique, we examined the hippocampal correlates of delayed recall performance on three well-established verbal memory tests - ADAScog delayed recall (ADAScog-DR), the Rey Auditory Verbal Learning Test -DR (AVLT-DR) and Wechsler Logical Memory II-DR (LM II-DR). We observed no significant correlations between delayed recall performance and hippocampal radial distance on any of the three verbal memory measures in NC. All three measures were associated with hippocampal volumes and radial distance in the full sample and in the MCI group at baseline and at follow-up. In DAT we observed stronger left-sided associations between hippocampal radial distance, LM II-DR and ADAScog-DR both at baseline and at follow-up. The strongest linkage between memory performance and hippocampal atrophy in the MCI sample was observed with the most challenging verbal memory test - the AVLT-DR, as opposed to the DAT sample where the least challenging test the ADAScog-DR showed strongest associations with the hippocampal structure. After controlling for baseline hippocampal atrophy, memory performance showed regionally specific associations with hippocampal radial distance in predominantly CA1 but also in subicular distribution.

3D comparison of low, intermediate, and advanced hippocampal atrophy in MCI.

Authors: Apostolova LG, Thompson PM, Green AE, Hwang KS, Zoumalan C, Jack CR Jr, Harvey DJ, Petersen RC, Thal LJ, Aisen PS, Toga AW, Cummings JL, Decarli CS.

We applied the hippocampal radial atrophy mapping technique to the baseline and follow-up magnetic resonance image data of 169 amnestic mild cognitive impairment (MCI) participants in the imaging arm of the Alzheimer's Disease Cooperative Study MCI Donepezil/Vitamin E trial. Sixty percent of the subjects with none to mild hippocampal atrophy rated with the visual medial temporal atrophy rating scale (MTA score < 2) and 33.8% of the subjects with moderate to severe (MTA >/= 2) hippocampal atrophy converted to Alzheimer's disease (AD) during 3-year follow-up. MTA >/= 2 showed a trend for greater left sided hippocampal atrophy versus MTA < 2 groups at baseline (P(corrected) = 0.08). Higher MTA scores were associated with progressive atrophy of the subiculum and the CA1-3 subregions. The MTA < 2 group demonstrated significant bilateral atrophy progression at follow-up (left P(corrected) = 0.008; right P(corrected) = 0.05). Relative to MTA < 2 nonconverters, MTA < 2 converters showed further involvement of the subiculum and CA1 and additional involvement of CA2-3 at follow-up. Right CA1 atrophy was significantly associated with conversion to dementia (for 1 mm greater right CA1 radial distance subjects had 50% reduced hazard for conversion). Greater CA1 and subicular atrophy can be demonstrated early and is predictive of future conversion to AD, whereas CA2-3 involvement becomes more evident as the disease progresses. Hum Brain Mapp.

3D comparison of low, intermediate, and advanced hippocampal atrophy in MCI.

Authors: Apostolova LG, Thompson PM, Green AE, Hwang KS, Zoumalan C, Jack CR Jr, Harvey DJ, Petersen RC, Thal LJ, Aisen PS, Toga AW, Cummings JL, Decarli CS.

The article to which this erratum refers was published in Hum Brain Mapp 2010, DOI: 10.1002/hbm.20905. © 2010 Wiley-Liss, Inc.

Alkynylated Aceno[2,1,3]thiadiazoles.

Authors: Appleton AL, Miao S, Brombosz SM, Berger NJ, Barlow S, Marder SR, Lawrence BM, Hardcastle KI, Bunz UH.

Enlarged acenothiadiazoles, which are easily prepared, display attractive optical and electrochemical properties. The annulation of thiadiazole to anthracene gives a stable material with optical properties similar to those of substituted pentacenes.

Diffusion tensor imaging reliably differentiates patients with schizophrenia from healthy volunteers.

Authors: Ardekani BA, Tabesh A, Sevy S, Robinson DG, Bilder RM, Szeszko PR.

The objective of this research was to determine whether fractional anisotropy (FA) and mean diffusivity (MD) maps derived from diffusion tensor imaging (DTI) of the brain are able to reliably differentiate patients with schizophrenia from healthy volunteers. DTI and high resolution structural magnetic resonance scans were acquired in 50 patients with schizophrenia and 50 age- and sex-matched healthy volunteers. FA and MD maps were estimated from the DTI data and spatially normalized to the Montreal Neurologic Institute standard stereotactic space. Individuals were divided randomly into two groups of 50, a training set, and a test set, each comprising 25 patients and 25 healthy volunteers. A pattern classifier was designed using Fisher's linear discriminant analysis (LDA) based on the training set of images to categorize individuals in the test set as either patients or healthy volunteers. Using the FA maps, the classifier correctly identified 94% of the cases in the test set (96% sensitivity and 92% specificity). The classifier achieved 98% accuracy (96% sensitivity and 100% specificity) when using the MD maps as inputs to distinguish schizophrenia patients from healthy volunteers in the test dataset. Utilizing FA and MD data in combination did not significantly alter the accuracy (96% sensitivity and specificity). Patterns of water self-diffusion in the brain as estimated by DTI can be used in conjunction with automated pattern recognition algorithms to reliably distinguish between patients with schizophrenia and normal control subjects. Hum Brain Mapp.

Moderators, mediators, and other predictors of risperidone response in children with autistic disorder and irritability.

Authors: Arnold LE, Farmer C, Kraemer HC, Davies M, Witwer A, Chuang S, DiSilvestro R, McDougle CJ, McCracken J, Vitiello B, Aman MG, Scahill L, Posey DJ, Swiezy NB.

The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritability in autistic disorder. This paper explores moderators and mediators of this effect. METHOD: Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results. RESULTS: Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5'-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo. CONCLUSION: The benefit-risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems nonspecifically predict better outcome. Mineral interactions with risperidone deserve further study.

Long-term benefits of short-term quality improvement interventions for depressed youths in primary care.

Authors: Asarnow JR, Jaycox LH, Tang L, Duan N, LaBorde AP, Zeledon LR, Anderson M, Murray PJ, Landon C, Rea MM, Wells KB.

Quality improvement programs for depressed youths in primary care settings have been shown to improve 6-month clinical outcomes, but longer-term outcomes are unknown. The authors examined 6-, 12-, and 18-month outcomes of a primary care quality improvement intervention. METHOD: Primary care patients 13-21 years of age with current depressive symptoms were randomly assigned to a 6-month quality improvement intervention (N=211) or to treatment as usual enhanced with provider training (N=207). The quality improvement intervention featured expert leader teams to oversee implementation of the intervention; clinical care managers trained in cognitive-behavioral therapy for depression to support patient evaluation and treatment; and support for patient and provider choice of treatments. RESULTS: The quality improvement intervention, relative to enhanced treatment as usual, lowered the likelihood of severe depression (Center for Epidemiological Studies Depression Scale score > or =24) at 6 months; a similar trend at 18 months was not statistically significant. Path analyses revealed a significant indirect intervention effect on long-term depression due to the initial intervention improvement at 6 months. CONCLUSIONS: In this randomized effectiveness trial of a primary care quality improvement intervention for depressed youths, the main effect of the intervention on outcomes was to decrease the likelihood of severe depression at the 6-month outcome assessment. These early intervention-related improvements conferred additional long-term protection through a favorable shift in illness course through 12 and 18 months

Future Research on Psychotherapy Practice in Usual Care.

Authors: Audrey Burnam M, Hepner KA, Miranda J.

Efficiency of working memory encoding in twins discordant for schizophrenia.

Authors: Bachman P, Kim J, Yee CM, Therman S, Manninen M, Lönnqvist J, Kaprio J, Huttunen MO, Näätänen R, Cannon TD.

It has been proposed that patients with schizophrenia and some of their relatives suffer from reduced neurocognitive efficiency, increasing their sensitivity to experimental task demands. The present study evaluated such a possibility during performance of a working memory task by schizophrenia patients and their co-twins along with a healthy control sample. Electrophysiological data were obtained from sets of nine twin pairs (monozygotic and dizygotic pairs collapsed) discordant for a diagnosis of schizophrenia and from nine matched healthy control twin pairs, during administration of a variable-load spatial working memory task. Event-related potentials (ERPs) were measured immediately after memory set onset and during a delay period. For correctly performed trials, slow-wave ERP activity measured during the late stimulus encoding and delay periods exhibited a significant Diagnostic Group-by-Memory Load interaction, with schizophrenia patients showing a differentially strong load effect. Patients' co-twins displayed an intermediate level of load sensitivity while healthy controls showed no significant load effect. These results support an inefficiency model of neurocognitive dysfunction in schizophrenia, a pattern that appears to be related to the pathogenesis and inheritance of the disorder. Furthermore, this inefficiency appeared during the late stimulus encoding stage of working memory functioning, possibly reflecting disruptions in stimulus representation consolidation

A Randomized C ommunity-based Intervention Trial Comparing Faith Community Nurse Referrals to Telephone-Assisted Physician Appointments for Health Fair Participants with Elevated Blood Pressure.

Authors: Baig AA, Mangione CM, Sorrell-Thompson AL, Miranda JM.

To measure the effect of faith community nurse referrals versus telephone-assisted physician appointments on blood pressure control among persons with elevated blood pressure at health fairs. METHODS: Randomized community-based intervention trial conducted from October 2006 to October 2007 of 100 adults who had an average blood pressure reading equal to or above a systolic of 140 mm Hg or a diastolic of 90 mm Hg obtained at a faith community nurse-led church health event. Participants were randomized to either referral to a faith community nurse or to a telephone-assisted physician appointment. The average enrollment systolic blood pressure (SBP) was 149 +/- 14 mm Hg, diastolic blood pressure (DBP) was 87 +/- 11 mm Hg, 57% were uninsured and 25% were undiagnosed at the time of enrollment. RESULTS: The follow-up rate was 85% at 4 months. Patients in the faith community nurse referral arm had a 7 +/- 15 mm Hg drop in SBP versus a 14 +/- 15 mm Hg drop in the telephone-assisted physician appointment arm (p = 0.04). Twenty-seven percent of the patients in the faith community nurse referral arm had medication intensification compared to 32% in the telephone-assisted physician appointment arm (p = 0.98). CONCLUSIONS: Church health fairs conducted in low-income, multiethnic communities can identify many people with elevated blood pressure. Facilitating physician appointments for people with elevated blood pressure identified at health fairs confers a greater decrease in SBP than referral to a faith community nurse at four months.

Assessing underwater noise levels during pile-driving at an offshore windfarm and its potential effects on marine mammals.

Authors: Bailey H, Senior B, Simmons D, Rusin J, Picken G, Thompson PM.

Marine renewable developments have raised concerns over impacts of underwater noise on marine species, particularly from pile-driving for wind turbines. Environmental assessments typically use generic sound propagation models, but empirical tests of these models are lacking. In 2006, two 5MW wind turbines were installed off NE Scotland. The turbines were in deep (>40m) water, 25km from the Moray Firth Special Area of Conservation (SAC), potentially affecting a protected population of bottlenose dolphins. We measured pile-driving noise at distances of 0.1 (maximum broadband peak to peak sound level 205dB re 1muPa) to 80km (no longer distinguishable above background noise). These sound levels were related to noise exposure criteria for marine mammals to assess possible effects. For bottlenose dolphins, auditory injury would only have occurred within 100m of the pile-driving and behavioural disturbance, defined as modifications in behaviour, could have occurred up to 50km away.

Electronic and Optical Properties of 4H-Cyclopenta[2,1-b:3,4-b']bithiophene Derivatives and Their 4-Heteroatom-Substituted Analogues: A Joint Theoretical and Experimental Comparison (dagger).

Authors: Barlow S, Odom SA, Lancaster K, Getmanenko YA, Mason R, Coropceanu V, Brédas JL, Marder SR.

The electronic and optical properties of 2,6-dialkyl and 2,6-bis(5-alkyl-2-thienyl) derivatives of the fused-ring systems 4H-cyclopenta[2,1-b:3,4-b']bithiophene, 4,4-di-n-hexyl-4H-cyclopenta[2,1-b:3,4-b']bithiophene, 4H-cyclopenta[2,1-b:3,4-b']bithiophene-4-one, 4-alkyl and 4-aryldithieno[3,2-b:2',3'-d]pyrrole, 4-phenyldithieno[3,2-b:2',3'-d]phosphole, 4-phenyldithieno[3,2-b:2',3'-d]phosphole 4-oxide, dithieno[3,2-b:2',3'-d]thiophene, dithieno[3,2-b:2',3'-d]thiophene 4-oxide, and dithieno[3,2-b:2',3'-d]thiophene 4,4-dioxide have been compared to those of the analogous unbridged 5,5'-substituted 2,2'-bithiophene derivatives using electrochemistry, UV-visible absorption and emission spectroscopy, and DFT and TD-DFT calculations. The planarization in the fused-ring compounds means that the methylene-bridged cyclopentabithiophenes are more readily oxidized than their unbridged bithiophene analogues. In each case, the bridging group (X) lies on a nodal plane of the HOMO; accordingly, within each series of fused-ring compounds, electrochemical oxidation potentials and calculated ionization potentials depend primarily on the inductive donor/acceptor strength of the bridging group. On the other hand, significant LUMO coefficients can be found on X groups with pi-donor or acceptor properties; accordingly, the electrochemical reduction potentials, calculated electron affinities, and the energies of the HOMO-->LUMO optical transitions depend on both inductive and mesomeric donor and acceptor strengths. In particular, within the 2,6-bis(5-alkyl-2-thienyl) series, increasingly electron-withdrawing bridging groups lead to a bathochromic shift and weakening of the low-energy absorption band relative to that of methylene- or pi-donor-bridged examples and also to a loss of vibronic structure, with the compound that has the strongest pi-accepting bridge of those examined (X = CO) showing a particularly low-energy and weak band. The fluorescence of acceptor-bridged compounds exhibits greater Stokes shifts and a loss of vibronic structure relative to those of methylene- or pi-donor-bridged analogues, with the carbonyl-bridged derivative showing no observable fluoresence. These results can be related to increasing localization of the LUMO on the core and toward the bridging group, leading to increased charge-transfer character for the first excited state. The radical cations of some examples have been generated by chemical oxidation and investigated using visible-NIR and ESR spectroscopy and DFT and TD-DFT calculations. The absorption spectra of the radical cations of the 2,6-bis(5-alkyl-2-thienyl) compounds are generally similar to those previously reported for quaterthiophene derivatives, while the hyperfine couplings obtained from ESR spectra are consistent with delocalization of the unpaired electron over both the core and terminal thienyl rings of the pi system.

Prevalent Iron Metabolism Gene Variants Associated with Increased Brain Ferritin Iron in Healthy Older Men.

Authors: Bartzokis G, Lu PH, Tishler TA, Peters DG, Kosenko A, Barrall KA, Finn JP, Villablanca P, Laub G, Altshuler LL, Geschwind DH, Mintz J, Neely E, Connor JR.

Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimer's disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinson's disease, where it has been reported to contribute to younger age at onset in men. The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76. The iron content of ferritin molecules (ferritin iron) in the brain was measured with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. 47% of the sample carried neither genetic variant (IRON-) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI compared to IRON- men (p=0.013). This genotype effect was not observed in women who, as expected, had lower FDRI than men. This is the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men. Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases.

Neurocognitive and Neuroimaging Predictors of Clinical Outcome in Bipolar Disorder.

Authors: Bearden CE, Woogen M, Glahn DC.

Historically, bipolar disorder has been conceptualized as a disease involving episodic rather than chronic dysfunction. However, increasing evidence indicates that bipolar disorder is associated with substantial inter-episode psychosocial and vocational impairment. Here we review the contributions of neurocognitive deficits and structural and functional neuroanatomic alterations to the observed functional impairments. In particular, compelling evidence now suggests that neurocognitive impairments, particularly in the areas of attention, processing speed, and memory, are associated with functional outcome. Although investigation of the neural correlates of functional disability in bipolar disorder is only in its nascent stages, preliminary evidence suggests that white matter abnormalities may be predictive of poor outcome. A better understanding of the relationship between neurocognitive and neuroimaging assays and functional outcome has the potential to improve current treatment options and provide targets for new treatment strategies in bipolar disorder.

5. Mol Psychiatry. 2010 Sep 14. [Epub ahead of print] Abuse of amphetamines and structural abnormalities in the brain.

Authors: Berman S, Kuczenski R, McCracken JT, London ED.

Phenomics: building scaffolds for biological hypotheses in the post-genomic era.

Authors: Bilder RM

The Neuropsychology of Schizophrenia Circa 2009

Authors: Bilder RM

A serotonin transporter gene polymorphism predicts peripartum depressive symptoms in an at-risk psychiatric cohort.

Authors: Binder EB, Jeffrey Newport D, Zach EB, Smith AK, Deveau TC, Altshuler LL, Cohen LS, Stowe ZN, Cubells JF.

Peripartum major depressive disorder (MDD) is a prevalent psychiatric disorder with potential detrimental consequences for both mother and child. Despite its enormous health care relevance, data regarding genetic predictors of peripartum depression are sparse. The aim of this study was to investigate associations of the serotonin-transporter linked polymorphic region (5-HTTLPR) genotype with peripartum MDD in an at-risk population. METHODS: Two hundred and seventy four women with a prior history of MDD were genotyped for 5-HTTLPR and serially evaluated in late pregnancy (gestational weeks 31-40), early post-partum (week 1-8) and late post-partum (week 9-24) for diagnosis of a current major depressive episode (MDE) and depressive symptom severity. RESULTS: 5-HTTLPR S-allele carrier status predicted the occurrence of a MDE in the early post-partum period only (OR=5.13, p=0.017). This association persisted despite continued antidepressant treatment. CONCLUSIONS: The 5-HTTLPR genotype may be a clinically relevant predictor of early post-partum depression in an at-risk population. OBJECTIVE: Peripartum major depressive disorder is a prevalent psychiatric disorder with potential detrimental consequences for both mother and child. Despite its enormous health care relevance, data regarding genetic predictors of peripartum depression are sparse. The aim of this study was to investigate associations of the serotonin-transporter linked polymorphic region (5-HTTLPR) genotype with peripartum MDD in an at-risk population

Abnormal hippocampal shape in offenders with psychopathy

Authors: Boccardi M, Ganzola R, Rossi R, Sabattoli F, Laakso MP, Repo-Tiihonen E, Vaurio O, Könönen M, Aronen HJ, Thompson PM, Frisoni GB, Tiihonen J.

Posterior hippocampal volumes correlate negatively with the severity of psychopathy, but local morphological features are unknown. The aim of this study was to investigate hippocampal morphology in habitually violent offenders having psychopathy. Manual tracings of hippocampi from magnetic resonance images of 26 offenders (age: 32.5 +/- 8.4), with different degrees of psychopathy (12 high, 14 medium psychopathy based on the Psychopathy Checklist Revised), and 25 healthy controls (age: 34.6 +/- 10.8) were used for statistical modelling of local changes with a surface-based radial distance mapping method. Both offenders and controls had similar hippocampal volume and asymmetry ratios. Local analysis showed that the high psychopathy group had a significant depression along the longitudinal hippocampal axis, on both the dorsal and ventral aspects, when compared with the healthy controls and the medium psychopathy group. The opposite comparison revealed abnormal enlargement of the lateral borders in both the right and left hippocampi of both high and medium psychopathy groups versus controls, throughout CA1, CA2-3 and the subicular regions. These enlargement and reduction effects survived statistical correction for multiple comparisons in the main contrast (26 offenders vs. 25 controls) and in most subgroup comparisons. A statistical check excluded a possible confounding effect from amphetamine and polysubstance abuse. These results indicate that habitually violent offenders exhibit a specific abnormal hippocampal morphology, in the absence of total gray matter volume changes, that may relate to different autonomic modulation and abnormal fear-conditioning. Hum Brain Mapp, 2009. (c) 2009 Wiley-Liss, Inc.

Heritability of Nonalcoholic Fatty Liver Disease

Authors: Brouwers MC, van Greevenbroek MM, Cantor RM.

Laboratory of Vascular Metabolism and Biology, Department of Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands

A Non-Conservative Lagrangian Framework for Statistical Fluid Registration???SAFIRA.

Authors: Brun CC, Lepore N, Pennec X, Chou Y, Lee AD, de Zubicaray G, McMahon K, Wright MJ, Gee JC, Thompson PM.

In this paper, we used a non-conservative Lagrangian mechanics approach to formulate a new statistical algorithm for fluid registration of 3D brain images. This algorithm is named SAFIRA, acronym for Statistically-Assisted Fluid Image Registration Algorithm. A non-statistical version of this algorithm was implemented [9], where the deformation was regularized by penalizing deviations from a zero rate of strain. In [9], the terms regularizing the deformation included the covariance of the deformation matrices () and the vector fields (q). Here we used a Lagrangian framework to re-formulate this algorithm, showing that the regularizing terms essentially allow non-conservative work to occur during the flow. Given 3D brain images from a group of subjects, vector fields and their corresponding deformation matrices are computed in a first round of registrations using the non-statistical implementation. Covariance matrices for both the deformation matrices and the vector fields are then obtained and incorporated (separately or jointly) in the non-conservative terms, creating four versions of SAFIRA. We evaluated and compared our algorithms performance on 92 3D brain scans from healthy monozygotic and dizygotic twins; 2D validations are also shown for corpus callosum shapes delineated at midline in the same subjects. After preliminary tests to demonstrate each method, we compared their detection power using tensor-based morphometry (TBM), a technique to analyze local volumetric differences in brain structure. We compared the accuracy of each algorithm variant using various statistical metrics derived from the images and deformation fields. All these tests were also run with a traditional fluid method, which has been quite widely used in TBM studies. The versions incorporating vector-based empirical statistics on brain variation were consistently more accurate than their counterparts, when used for automated volumetric quantification in new brain images. This suggests the advantages of this approach for largescale neuroimaging studies.

The FDA-NIMH-MATRICS Guidelines for Clinical Trial Design of Cognitive-Enhancing Drugs: What Do We Know 5 Years Later?

Authors: Buchanan RW, Keefe RS, Umbricht D, Green MF, Laughren T, Marder SR.

The Food and Drug Administration (FDA)-National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) clinical trial guidelines for cognitive-enhancing drugs in schizophrenia and the MATRICS Consensus Cognitive Battery (MCCB) were designed to facilitate novel compound development in the treatment of cognitive impairments. Several studies have recently utilized the FDA-NIMH-MATRICS guidelines and MCCB and allow an evaluation of the feasibility of guideline implementation and MCCB performance. In light of the study results, we would recommend the following inclusion criteria revisions-(1) clinical status and symptom inclusion criteria: maximum allowed score for hallucinations and delusions should be increased from moderate to moderately severe and the negative symptom criterion should be dropped in phase 2 studies; (2) antipsychotic medication inclusion criteria: first-generation antipsychotics should be allowed, but only in the context of no concomitant anticholinergic agents and minimal extrapyramidal symptoms, and antipsychotic polypharmacy should be allowed in the absence of pertinent pharmacokinetic or pharmacodynamic considerations; and (3) people who use illicit substances should not be allowed in phase 1B or 2A proof-of-concept studies but may be included in phase 2B and 3 studies in which proof of effectiveness and generalizability of results become more important goals. These revisions are recommended to enhance recruitment while maintaining sufficient methodological rigor to ensure the validity of study results. The MCCB has been shown to have excellent psychometric characteristics, including reliability for multisite clinical trials, clinical relevance for real-world functioning, and possible sensitivity to behavioral treatment, and should continue to serve as the standard outcome measure for cognitive enhancement studies in schizophrenia.

Bipolar disorder and pregnancy: maintaining psychiatric stability in the real world of obstetric and psychiatric complications.

Authors: Burt VK, Bernstein C, Rosenstein WS, Altshuler LL.

Dr. Burt has served as consultant or adviser to, or on the speakers bureau of, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Noven Pharmaceuticals, Takeda Pharmaceuticals, and Wyeth-Ayerst. Dr. Altshuler has served on the advisory boards of or received research support or honoraria from Abbott, Forest Laboratories, and Glaxo-SmithKline. The other authors report no financial relationships with commercial interests.

Clinical and subthreshold panic disorder.

Authors: Bystritsky A, Kerwin L, Niv N, Natoli JL, Abrahami N, Klap R, Wells K, Young AS.

Background: Panic disorder (PD) is a highly prevalent and disabling condition, and subthreshold cases may be even more prevalent. This study examined psychiatric comorbidities, work functioning, and health-care utilization of individuals with subthreshold panic. The purpose of this study was to add to the accumulating evidence of significant comorbidity and disability associated with subthreshold PD. Methods: Data are drawn from the Health Care for Communities study, a national household survey of the United States' adult, civilian, noninstitutionalized population (N=9585). Data assessing psychiatric disorders, employment and work productivity, and health-care utilization were collected. Seven categories of panic and subthreshold panic were created. Results: The prevalence of clinical and subthreshold panic in the general population was 40%. Subthreshold panic was associated with increased odds of several comorbid disorders, including depression, dysthymia, psychosis, generalized anxiety disorder, bipolar disorder, and alcohol and drug use disorders. Subthreshold panic was also associated with greater likelihood of health-care service utilization but not with the intensity of mental health services. Conclusion: Psychiatric comorbidities and health-care utilization are common among patients with subthreshold panic. The relationship between varying degrees of panic symptomology and other mental health problems and indices of functioning impairment warrants further investigation. These results inform further research focusing on the course of subthreshold PD and its impact on quality of life. Depression and Anxiety 0:1-9, 2009. (c) 2009 Wiley-Liss, Inc

Treatment history in the psychosis prodr ome: characteristics of the North American Prodrome Longitudinal Study Cohort.

Authors: Cadenhead KS, Addington J, Cannon T, Cornblatt B, McGlashan T, Perkins D, Seidman L, Tsuang M, Walker E, Woods S, Heinssen R.

Aim: Early identification and better characterization of the prodromal phase of psychotic illness can lead to targeted treatment and, perhaps, prevention of many of the devastating effects of a first psychotic episode. The primary aim of this manuscript is to describe the treatment histories of a large cohort of individuals who entered into one of seven prodromal research programs in a North American Prodrome Longitudinal Study consortium. Methods: Treatment histories from 372 clinical high-risk subjects are described along with demographic, symptom, diagnostic and functional variables that may have contributed to treatment decisions for this group of individuals. Results: Of all subjects included, 82.1% had received psychosocial and/or pharmacologic treatment prior to entry. Psychosocial interventions were more common in the attenuated psychotic syndrome prodromal sample, especially those with more negative, disorganized or general symptoms and more impaired functioning. Psychotropic medication had been administered to individuals with a history of Axis I disorders. Conclusions: Given the many potential clinical presentations, treatments and ethical issues connected with the psychosis-risk syndrome, it is not surprising that clinicians administered a broad range of interventions to study participants prior to their entry into the various research programs. Those individuals with milder and non-specific symptoms were more likely to have received psychosocial treatments, whereas those with more severe symptoms received pharmacologic intervention. Clinical treatment research is needed that addresses the complexities of these psychosis-risk states and helps to specify appropriate treatment at different stages of the psychosis prodrome.

Candidate Gene Studies in the GWAS Era: The MET Proto-Oncogene, Neurocognition, and Schizophrenia.

Authors: Cannon TD.

Dr. Cannon has served as a consultant to Rules-Based Medicine. Dr. Freedman has reviewed this editorial and found no evidence of influence from this relationship

Prioritizing GWAS Results: A Review of Statistical Methods and Recommendations for Their Application.

Authors: Cantor RM, Lange K, Sinsheimer JS.

Genome-wide association studies (GWAS) have rapidly become a standard method for disease gene discovery. A substantial number of recent GWAS indicate that for most disorders, only a few common variants are implicated and the associated SNPs explain only a small fraction of the genetic risk. This review is written from the viewpoint that findings from the GWAS provide preliminary genetic information that is available for additional analysis by statistical procedures that accumulate evidence, and that these secondary analyses are very likely to provide valuable information that will help prioritize the strongest constellations of results. We review and discuss three analytic methods to combine preliminary GWAS statistics to identify genes, alleles, and pathways for deeper investigations. Meta-analysis seeks to pool information from multiple GWAS to increase the chances of finding true positives among the false positives and provides a way to combine associations across GWAS, even when the original data are unavailable. Testing for epistasis within a single GWAS study can identify the stronger results that are revealed when genes interact. Pathway analysis of GWAS results is used to prioritize genes and pathways within a biological context. Following a GWAS, association results can be assigned to pathways and tested in aggregate with computational tools and pathway databases. Reviews of published methods with recommendations for their application are provided within the framework for each approach.

Twelve-month meta bolic declines in probable Alzheimer's disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical region-of-interest: Findings from the Alzheimer's disease neuroimaging initiative.

Authors: Chen K, Langbaum JB, Fleisher AS, Ayutyanont N, Reschke C, Lee W, Liu X, Bandy D, Alexander GE, Thompson PM, Foster NL, Harvey DJ, de Leon MJ, Koeppe RA, Jagust WJ, Weiner MW, Reiman EM; The Alzheimer's Disease Neuroimaging Initiative.

Alzheimer's disease (AD) is characterized by specific and progressive reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose (CMRgl), some of which may precede the onset of symptoms. In this report, we describe twelve-month CMRgl declines in 69 probable AD patients, 154 amnestic mild cognitive impairment (MCI) patients, and 79 cognitively normal controls (NCs) from the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM). We introduce the use of an empirically predefined statistical region-of-interest (sROI) to characterize CMRgl declines with optimal power and freedom from multiple comparisons, and we estimate the number of patients needed to characterize AD-slowing treatment effects in multi-center randomized clinical trials (RCTs). The AD and MCI groups each had significant twelve-month CMRgl declines bilaterally in posterior cingulate, medial and lateral parietal, medial and lateral temporal, frontal and occipital cortex, which were significantly greater than those in the NC group and correlated with measures of clinical decline. Using sROIs defined based on training sets of baseline and follow-up images to assess CMRgl declines in independent test sets from each patient group, we estimate the need for 66AD patients or 217 MCI patients per treatment group to detect a 25% AD-slowing treatment effect in a twelve-month, multi-center RCT with 80% power and two-tailed alpha=0.05, roughly one-tenth the number of the patients needed to study MCI patients using clinical endpoints. Our findings support the use of FDG PET, brain-mapping algorithms and empirically pre-defined sROIs in RCTs of AD-slowing treatments.

GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA 5) as a risk gene for schizophrenia.

Authors: Chen X, Lee G, Maher BS, Fanous AH, Chen J, Zhao Z, Guo A, van den Oord E, Sullivan PF, Shi J, Levinson DF, Gejman PV, Sanders A, Duan J, Owen MJ, Craddock NJ, O'Donovan MC, Blackman J, Lewis D, Kirov GK, Qin W, Schwab S, Wildenauer D, Chowdari K, Nimgaonkar V, Straub RE, Weinberger DR, O'Neill FA, Walsh D, Bronstein M, Darvasi A, Lencz T, Malhotra AK, Rujescu D, Giegling I, Werge T, Hansen T, Ingason A, Nöethen MM, Rietschel M, Cichon S, Djurovic S, Andreassen OA, Cantor RM, Ophoff R, Corvin A, Morris DW, Gill M, Pato CN, Pato MT, Macedo A, Gurling HM, McQuillin A, Pimm J, Hultman C, Lichtenstein P, Sklar P, Purcell SM, Scolnick E, St Clair D, Blackwood DH, Kendler KS.

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values 0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.Molecular Psychiatry advance online publication, 14 September 2010; doi:10.1038/mp.2010.96.

Efficiency of static and computer adaptive short forms compared to full-length measures of depressive symptoms.

Authors: Choi SW, Reise SP, Pilkonis PA, Hays RD, Cella D.

Short-form patient-reported outcome measures are popular because they minimize patient burden. We assessed the efficiency of static short forms and computer adaptive testing (CAT) using data from the Patient-Reported Outcomes Measurement Information System (PROMIS) project. METHODS: We evaluated the 28-item PROMIS depressive symptoms bank. We used post hoc simulations based on the PROMIS calibration sample to compare several short-form selection strategies and the PROMIS CAT to the total item bank score. RESULTS: Compared with full-bank scores, all short forms and CAT produced highly correlated scores, but CAT outperformed each static short form in almost all criteria. However, short-form selection strategies performed only marginally worse than CAT. The performance gap observed in static forms was reduced by using a two-stage branching test format. CONCLUSIONS: Using several polytomous items in a calibrated unidimensional bank to measure depressive symptoms yielded a CAT that provided marginally superior efficiency compared to static short forms. The efficiency of a two-stage semi-adaptive testing strategy was so close to CAT that it warrants further consideration and study.

Evaluation of the Brief Problem Checklist: Child and caregiver interviews to measure clinical progress.

Authors: Chorpita BF, Reise S, Weisz JR, Grubbs K, Becker KD, Krull JL.

To support ongoing monitoring of child response during treatment, we sought to develop a brief, easily administered, clinically relevant, and psychometrically sound measure. Method: We first developed child and caregiver forms of a 12-item Brief Problem Checklist (BPC) interview by applying item response theory and factor analysis to Youth Self-Report (YSR; Achenbach & Rescorla, 2001) and Child Behavior Checklist (CBCL;Achenbach & Rescorla, 2001) data for a sample of 2,332 youths. These interviews were then administered weekly via telephone to an ethnically diverse clinical sample of 184 boys and girls 7-13 years of age and their caregivers participating in outpatient treatment, to examine psychometric properties and feasibility. Results: Internal consistency and test-retest reliability were excellent, and factor analysis yielded 1 internalizing and 1 externalizing factor. Validity tests showed large and significant correlations with corresponding scales on paper-and-pencil administrations of the CBCL and YSR as well as with diagnoses obtained from a structured diagnostic interview. Discriminant validity of the BPC interviews was supported by low correlations with divergent criteria. Longitudinal data for the initial 6 months of treatment demonstrated that the BPC significantly predicted change on related measures of child symptoms. Estimates obtained from random coefficient growth models showed generally higher slope reliabilities for the BPC given weekly relative to the CBCL and YSR given every 3 months. Conclusions: Given their combination of brevity and psychometric strength, the child and caregiver BPC interviews appear to be a promising strategy for efficient, ongoing assessment of clinical progress during the course of treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

Ventricular maps in 804 ADNI subjects: correlations with CSF biomarkers and clinical decline.

Authors: Chou YY, Leporé N, Saharan P, Madsen SK, Hua X, Jack CR, Shaw LM, Trojanowski JQ, Weiner MW, Toga AW, Thompson PM; Alzheimer's Disease Neuroimaging Initiative.

Ideal biomarkers of Alzheimer's disease (AD) should correlate with accepted measures of pathology in the cerebrospinal fluid (CSF); they should also correlate with, or predict, future clinical decline, and should be readily measured in hundreds to thousands of subjects. Here we explored the utility of automated 3D maps of the lateral ventricles as a possible biomarker of AD. We used our multi-atlas fluid image alignment (MAFIA) method, to compute ventricular models automatically, without user intervention, from 804 brain MRI scans with 184 AD, 391 mild cognitive impairment (MCI), and 229 healthy elderly controls (446 men, 338 women; age: 75.50 +/- 6.81 [SD] years). Radial expansion of the ventricles, computed pointwise, was strongly correlated with current cognition, depression ratings, Hachinski Ischemic scores, language scores, and with future clinical decline after controlling for any effects of age, gender, and educational level. In statistical maps ranked by effect sizes, ventricular differences were highly correlated with CSF measures of Abeta(1-42), and correlated with ApoE4 genotype. These statistical maps are highly automated, and offer a promising biomarker of AD for large-scale studies. 2010 Elsevier Inc. All rights reserved.

Using a community partnered participatory research approach to implemen t a randomized controlled trial: planning community partners in care.

Authors: Chung B, Jones L, Dixon EL, Miranda J, Wells K; Community Partners in Care Steering Council.

Quality improvement (QI) for depression in primary care can reduce disparities in outcomes. We describe how community-partnered participatory research was used to design Community Partners in Care, a randomized trial of community engagement to activate a multiple-agency network versus support for individual agencies to implement depression QI in underserved communities.

A unique adolescent response to reward prediction errors.

Authors: Cohen JR, Asarnow RF, Sabb FW, Bilder RM, Bookheimer SY, Knowlton BJ, Poldrack RA.

Previous work has shown that human adolescents may be hypersensitive to rewards, but it is not known which aspect of reward processing is responsible for this. We separated decision value and prediction error signals and found that neural prediction error signals in the striatum peaked in adolescence, whereas neural decision value signals varied depending on how value was modeled. This suggests that heightened dopaminergic prediction error responsivity contributes to adolescent reward seeking.

Decoding developmental differences an d individual variability in response inhibition through predictive analyses across individuals.

Authors: Cohen JR, Asarnow RF, Sabb FW, Bilder RM, Bookheimer SY, Knowlton BJ, Poldrack RA.

Response inhibition is thought to improve throughout childhood and into adulthood. Despite the relationship between age and the ability to stop ongoing behavior, questions remain regarding whether these age-related changes reflect improvements in response inhibition or in other factors that contribute to response performance variability. Functional neuroimaging data shows age-related changes in neural activity during response inhibition. While traditional methods of exploring neuroimaging data are limited to determining correlational relationships, newer methods can determine predictability and can begin to answer these questions. Therefore, the goal of the current study was to determine which aspects of neural function predict individual differences in age, inhibitory function, response speed, and response time variability. We administered a stop-signal task requiring rapid inhibition of ongoing motor responses to healthy participants aged 9-30. We conducted a standard analysis using GLM and a predictive analysis using high-dimensional regression methods. During successful response inhibition we found regions typically involved in motor control, such as the ACC and striatum, that were correlated with either age, response inhibition (as indexed by stop-signal reaction time; SSRT), response speed, or response time variability. However, when examining which variables neural data could predict, we found that age and SSRT, but not speed or variability of response execution, were predicted by neural activity during successful response inhibition. This predictive relationship provides novel evidence that developmental differences and individual differences in response inhibition are related specifically to inhibitory processes. More generally, this study demonstrates a new approach to identifying the neurocognitive bases of individual differences.

Quantitative in vivo evidence for broad regional gradients in the timing of white matter maturation during adolescence.

Authors: Colby JB, Van Horn JD, Sowell ER.

A fundamental tenet in the field of developmental neuroscience is that brain maturation generally proceeds from posterior/inferior to anterior/superior. This pattern is thought to underlie the similar timing of cognitive development in related domains, with the dorsal frontal cortices - important for decision making and cognitive control - the last to fully mature. While this caudal to rostral wave of structural development was first qualitatively described for white matter in classical postmortem studies, and has been discussed frequently in the developmental neuroimaging literature and in the popular press, it has never been formally demonstrated continuously and quantitatively across the whole brain with magnetic resonance imaging (MRI). Here we use diffusion imaging to map developmental changes in the white matter in 32 typically-developing individuals age 5-28years. We then employ a novel meta-statistic that is sensitive to the timing of this developmental trajectory, and use this integrated strategy to both confirm these long-postulated broad regional gradients in the timing of white matter maturation in vivo, and demonstrate a surprisingly smooth transition in the timing of white matter maturational peaks along a caudal-rostral arc in this cross-sectional sample. These results provide further support for the notion of continued plasticity in these regions well into adulthood, and may provide a new approach for the investigation of neurodevelopmental disorders that could alter the timing of this typical developmental sequence.

Child/Adolescent Anxiety Multimodal Study (CAMS): rationale, design, and methods.

Authors: Compton SN, Walkup JT, Albano AM, Piacentini JC, Birmaher B, Sherrill JT, Ginsburg GS, Rynn MA, McCracken JT, Waslick BD, Iyengar S, Kendall PC, March JS.

To present the design, methods, and rationale of the Child/Adolescent Anxiety Multimodal Study (CAMS), a recently completed federally-funded multi-site randomized placebo-controlled trial that examined the relative efficacy of cognitive-behavior therapy (CBT), sertraline (SRT), and their combination (COMB) against pill placebo (PBO) for the treatment of separation (SAD) and generalized anxiety disorders (GAD) and social phobia (SoP) in children and adolescents. METHOD: Following a brief review of the acute outcomes of the CAMS trial, as well as the psychosocial and pharmacologic treatment literature for pediatric anxiety disorders, the design and methods of the CAMS trial will be described. RESULTS: CAMS was a six-year, six-site, randomized controlled trail. Four hundred eighty-eight (N=488) children and adolescents (ages 7-17 years) with DSM-IV-TR diagnoses of SAD, GAD, or SoP were randomly assigned to one of four treatment groups: CBT, SRT, COMB, or PBO. Assessments of anxiety symptoms, safety, and functional outcomes, as well as putative mediators and moderators of treatment response were completed in an explicitly multi-measure, multi-informant fashion. Manual-based therapies, trained clinicians and independent evaluators were used to ensure treatment and assessment fidelity. A multi-layered administrative structure with representation from all sites facilitated cross-site coordination of the protocol and quality assurance. CONCLUSIONS: CAMS offers a model for clinical trials methods applicable to psychosocial and psychopharmacological comparative treatment trials. CAMS also provided a large-scale examination of the relative and combined efficacy and safety of the best evidenced-based psychosocial (CBT) and pharmacologic (SSRI) treatments to date for the most commonly occurring pediatric anxiety disorders. CAMS utilized state-of-the-art methods and rigorous cross-site quality controls. Primary and secondary results of CAMS will hold important implications for informing practice-relevant decisions regarding the initial treatment of youth with anxiety disorders

Engagement of large-scale networks is related to individual differences in inhibitory control.

Authors: Congdon E, Mumford JA, Cohen JR, Galvan A, Aron AR, Xue G, Miller E, Poldrack RA.

Understanding which brain regions regulate the execution, and suppression, of goal-directed behavior has implications for a number of areas of research. In particular, understanding which brain regions engaged during tasks requiring the execution and inhibition of a motor response provides insight into the mechanisms underlying individual differences in response inhibition ability. However, neuroimaging studies examining the relation between activation and stopping have been inconsistent regarding the direction of the relationship, and also regarding the anatomical location of regions that correlate with behavior. These limitations likely arise from the relatively low power of voxelwise correlations with small sample sizes. Here, we pooled data over five separate fMRI studies of the Stop-signal task in order to obtain a sufficiently large sample size to robustly detect brain/behavior correlations. In addition, rather than performing mass univariate correlation analysis across all voxels, we increased statistical power by reducing the dimensionality of the data set using independent component analysis and then examined correlations between behavior and the resulting component scores. We found that components reflecting activity in regions thought to be involved in stopping were associated with better stopping ability, while activity in a default-mode network was associated with poorer stopping ability across individuals. These results clearly show a relationship between individual differences in stopping ability in specific activated networks, including regions known to be critical for the behavior. The results also highlight the usefulness of using dimensionality reduction to increase the power to detect brain/behavior correlations in individual differences research. Copyright © 2010 Elsevier Inc. All rights reserved.

Co-Occurrence of ADHD and High IQ: A Case Series Empirical Study.

Authors: Cordeiro ML, Farias AC, Cunha A, Benko CR, Farias LG, Costa MT, Martins LF, McCracken JT.

The validity of a diagnosis of ADHD in children with a high intelligence quotient (IQ) remains controversial. Using a multidisciplinary approach, rigorous diagnostic criteria, and worldwide-validated psychometric instruments, we identified a group of children attending public schools in southern Brazil for co-occurrence of high IQ and ADHD. Method: Students attending public schools, in the first to fifth grades, were referred to our Research Center for behavioral and/or learning difficulties. These children completed clinical, psychiatric, psychological, and pedagogical evaluations for assessment of IQ, ADHD, learning, and other emotional or behavioral disorders. Results: Fifteen of the participants were identified to have a full-scale IQ >/= 120. Data show that 10 of these high-IQ children met the DSM-IV criteria diagnosis for ADHD combined type, 5 met criteria for current oppositional-defiant disorder, 2 had current major depression, and 2 had a learning disorder. Here we present the results as a case series. Conclusion: Our data support the hypothesis that ADHD is a valid diagnosis in children with high IQs. (J. of Att. Dis. 2010; XX(X) 1-XX).

Cha llenges and methods in developmental neuroimaging.

Authors: Crone EA, Poldrack RA, Durston S.

Psychophysiological prodromal signs of schizophrenic relapse: A pilot study.

Authors: Dawson ME, Schell AM, Rissling A, Ventura J, Subotnik KL, Nuechterlein KH.

Do physiological changes occur shortly prior to psychotic relapse in schizophrenia outpatients? We addressed this question in a group of schizophrenia outpatients by measuring changes in symptoms and changes in activation of the sympathetic nervous system, as indexed by changes in skin conductance level (SCL), on a biweekly basis for between one and two years. All six outpatients exhibited heightened SCL within two weeks prior to relapse or exacerbation, compared to SCL proceeding continued remission. These results shed light on the psychotic relapse process and are consistent with neural diathesis-stress models of schizophrenia.

Meeting the Challenges of Neuroimaging Genetics.

Authors: de Zubicaray GI, Chiang MC, McMahon KL, Shattuck DW, Toga AW, Martin NG, Wright MJ, Thompson PM.

As research encompassing neuroimaging and genetics gains momentum, extraordinary information will be uncovered on the genetic architecture of the human brain. However, there are significant challenges to be addressed first. Not the least of these challenges is to accomplish the sample size necessary to detect subtle genetic influences on the morphometry and function of the healthy brain. Aside from sample size, image acquisition and analysis methods need to be refined in order to ensure optimum sensitivity to genetic and complementary environmental influences. Then there is the vexing issue of interpreting the resulting data. We describe how researchers from the east coast of Australia and the west coast of America have embarked upon a collaboration to meet these challenges using data currently being collected from a large-scale twin study, and offer some opinions about future directions in the field.

Efficient, Distributed and Interactive Neuroimaging Data Analysis Using the LONI Pipeline.

Authors: Dinov ID, Van Horn JD, Lozev KM, Magsipoc R, Petrosyan P, Liu Z, Mackenzie-Graham A, Eggert P, Parker DS, Toga AW.

The LONI Pipeline is a graphical environment for construction, validation and execution of advanced neuroimaging data analysis protocols (Rex et al., 2003). It enables automated data format conversion, allows Grid utilization, facilitates data provenance, and provides a significant library of computational tools. There are two main advantages of the LONI Pipeline over other graphical analysis workflow architectures. It is built as a distributed Grid computing environment and permits efficient tool integration, protocol validation and broad resource distribution. To integrate existing data and computational tools within the LONI Pipeline environment, no modification of the resources themselves is required. The LONI Pipeline provides several types of process submissions based on the underlying server hardware infrastructure. Only workflow instructions and references to data, executable scripts and binary instructions are stored within the LONI Pipeline environment. This makes it portable, computationally efficient, distributed and independent of the individual binary processes involved in pipeline data-analysis workflows. We have expanded the LONI Pipeline (V.4.2) to include server-to-server (peer-to-peer) communication and a 3-tier failover infrastructure (Grid hardware, Sun Grid Engine/Distributed Resource Management Application API middleware, and the Pipeline server). Additionally, the LONI Pipeline provides three layers of background-server executions for all users/sites/systems. These new LONI Pipeline features facilitate resource-interoperability, decentralized computing, construction and validation of efficient and robust neuroimaging data-analysis workflows. Using brain imaging data from the Alzheimer's Disease Neuroimaging Initiative (Mueller et al., 2005), we demonstrate integration of disparate resources, graphical construction of complex neuroimaging analysis protocols and distributed parallel computing. The LONI Pipeline, its features, specifications, documentation and usage are available online (

Treatment of Resista nt Depression in Adolescents (TORDIA): Week 24 Outcomes.

Authors: Emslie GJ, Mayes T, Porta G, Vitiello B, Clarke G, Wagner KD, Asarnow JR, Spirito A, Birmaher B, Ryan N, Kennard B, Debar L, McCracken J, Strober M, Onorato M, Zelazny J, Keller M, Iyengar S, Brent D.

Objective The purpose of this study was to report on the outcome of participants in the Treatment of Resistant Depression in Adolescents (TORDIA) trial after 24 weeks of treatment, including remission and relapse rates and predictors of treatment outcome. Method Adolescents (ages 12-18 years) with selective serotonin reuptake inhibitor (SSRI)-resistant depression were randomly assigned to either a medication switch alone (alternate SSRI or venlafaxine) or a medication switch plus cognitive-behavioral therapy (CBT). At week 12, responders could continue in their assigned treatment arm and nonresponders received open treatment (medication and/or CBT) for 12 more weeks (24 weeks total). The primary outcomes were remission and relapse, defined by the Adolescent Longitudinal Interval Follow-Up Evaluation as rated by an independent evaluator. Results Of 334 adolescents enrolled in the study, 38.9% achieved remission by 24 weeks, and initial treatment assignment did not affect rates of remission. Likelihood of remission was much higher (61.6% versus 18.3%) and time to remission was much faster among those who had already demonstrated clinical response by week 12. Remission was also higher among those with lower baseline depression, hopelessness, and self-reported anxiety. At week 12, lower depression, hopelessness, anxiety, suicidal ideation, family conflict, and absence of comorbid dysthymia, anxiety, and drug/alcohol use and impairment also predicted remission. Of those who responded by week 12, 19.6% had a relapse of depression by week 24. Conclusions Continued treatment for depression among treatment-resistant adolescents results in remission in approximately one-third of patients, similar to adults. Eventual remission is evident within the first 6 weeks in many, suggesting that earlier intervention among nonresponders could be important.

New approaches to structu ral and functional imaging in focal epilepsy.

Authors: Engel J Jr, Akhtari M, Bragin A, Fried I, Ogren JA, Staba RJ, Salamon N, Thompson PM.

Manganese in chil dren with attention-deficit/hyperactivity disorder: relationship with methylphenidate exposure.

Authors: Farias AC, Cunha A, Benko CR, McCracken JT, Costa MT, Farias LG, Cordeiro ML.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder that affects children worldwide. The etiology of ADHD is complex and not fully understood. Earlier studies associated elevated levels of manganese (Mn) with learning problems, attention deficits, and ADHD. Furthermore, it has also been shown that the dopamine (DA) system, the primary site of action of pharmacological ADHD treatments, is influenced by high levels of Mn. Recent studies have suggested that Mn accumulates in dopaminergic neurons via the presynaptic dopamine transporter (DAT). A role for altered functioning of the dopaminergic system in the etiology of ADHD has been well established through neurochemical, neurophysiological, imaging, and genetics studies. Methylphenidate (MPH) is a psychostimulant commonly used to manage ADHD symptoms. The pharmacotherapeutic effect of MPH occurs primarily through its action of inhibiting DAT, and thus increasing dopamine, as well as other catecholamines, at the synapse. We assessed a group of children with ADHD and matched control children without psychopathology attending public schools in a southern Brazilian city and reported elevated serum concentrations of Mn in treatment-naïve children with ADHD compared to normal controls. Interestingly, children with ADHD receiving concurrent MPH showed no difference in Mn serum levels versus controls. We then prospectively assessed the impact of naturalistic treatment with MPH and determined that Mn concentrations were significantly reduced from baseline values following MPH exposure.

Inverted face processing in body dysmorphic disorder.

Authors: Feusner JD, Moller H, Altstein L, Sugar C, Bookheimer S, Yoon J, Hembacher E.

Individuals with body dysmorphic disorder (BDD) are preoccupied with perceived defects in appearance. Preliminary evidence suggests abnormalities in global and local visual information processing. The objective of this study was to compare global and local processing in BDD subjects and healthy controls by testing the face inversion effect, in which inverted (upside-down) faces are recognized more slowly and less accurately relative to upright faces. Eighteen medication-free subjects with BDD and 17 matched, healthy controls performed a recognition task with sets of upright and inverted faces on a computer screen that were either presented for short duration (500 ms) or long duration (5000 ms). Response time and accuracy rates were analyzed using linear and logistic mixed effects models, respectively. Results indicated that the inversion effect for response time was smaller in BDD subjects than controls during the long duration stimuli, but was not significantly different during the short duration stimuli. Inversion effect on accuracy rates did not differ significantly between groups during either of the two durations. Lesser inversion effect in BDD subjects may be due to greater detail-oriented and piecemeal processing for long duration stimuli. Similar results between groups for short duration stimuli suggest that they may be normally engaging configural and holistic processing for brief presentations. Abnormal visual information processing in BDD may contribute to distorted perception of appearance; this may not be limited to their own faces, but to others' faces as well. Copyright © 2010 Elsevier Ltd. All rights reserved.

Selective corticostriatal dysfunction in schizophrenia: Examination of motor and cognitive skill learning.

Authors: Foerde K, Poldrack RA, Khan BJ, Sabb FW, Bookheimer SY, Bilder RM, Guthrie D, Granholm E, Nuechterlein KH, Marder SR, Asarnow RF

It has been suggested that patients with schizophrenia have corticostriatal circuit dysfunction (Carlsson & Carlsson, 1990). Skill learning is thought to rely on corticostriatal circuitry and different types of skill learning may be related to separable corticostriatal loops (Grafton, Hazeltine, & Ivry, 1995; Poldrack, Prabhakaran, Seger, & Gabrieli, 1999). The authors examined motor (Serial Reaction Time task, SRT) and cognitive (Probabilistic Classification task, PCT) skill learning in patients with schizophrenia and normal controls. Development of automaticity was examined, using a dual task paradigm, across three training sessions. Patients with schizophrenia were impaired at learning on the PCT compared to controls. Performance gains of controls occurred within the first session, whereas patients only improved gradually and never reached the performance level of controls. In contrast, patients were not impaired at learning on the SRT relative to controls, suggesting that patients with schizophrenia may have dysfunction in a specific corticostriatal subcircuit. (PsycINFO Database Record (c) 2008 APA, all rights reserved).

Avoidant personality disorder symptoms in first-degree relatives of schizophrenia patients predict performance on neurocognitive measures: The UCLA family study.

Authors: Fogelson DL, Asarnow RA, Sugar CA, Subotnik KL, Jacobson KC, Neale MC, Kendler KS, Kuppinger H, Nuechterlein KH.

Whether avoidant personality disorder symptoms are related to neurocognitive impairments that aggregate in relatives of schizophrenics is unknown. We report the relationship between avoidant personality disorder symptoms and neurocognitive performance in the first-degree relatives of probands with schizophrenia. 367 first-degree relatives of probands with schizophrenia and 245 relatives of community controls were interviewed for the presence of avoidant personality symptoms and symptoms of paranoid and schizotypal personality disorders and administered neurocognitive measures. Relationships between neurocognitive measures and avoidant symptoms were analyzed using linear mixed models. Avoidant dimensional scores predicted performance on the span of apprehension (SPAN), 3-7 Continuous Performance Test (3-7 CPT), and Trail Making Test (TMT-B) in schizophrenia relatives. These relationships remained significant on the SPAN even after adjustment for paranoid or schizotypal dimensional scores and on the TMT-B after adjustment for paranoid dimensional scores. Moreover, in a second set of analyses comparing schizophrenia relatives to controls there were significant or trending differences in the degree of the relationship between avoidant symptoms and each of these neurocognitive measures even after adjustments for paranoid and schizotypal dimensional scores. The substantial correlation between avoidant and schizotypal symptoms suggests that these personality disorders are not independent. Avoidant and in some cases schizotypal dimensional scores are significant predictors of variability in these neurocognitive measures. In all analyses, higher levels of avoidant symptoms were associated with worse performance on the neurocognitive measures in relatives of schizophrenia probands. These results support the hypothesis that avoidant personality disorder may be a schizophrenia spectrum phenotype

Independent contributions of cognitive functioning and social risk factors to symptoms of ADHD in two nordic populations-based cohorts.

Authors: Forssman L, Bohlin G, Lundervold AJ, Taanila A, Heiervang E, Loo S, Jarvelin MR, Smalley S, Moilanen I, Rodriguez A.

This study examined independent contributions of executive functioning (EF), state regulation (SR), and social risk factors to symptom dimensions of attention deficit hyperactivity disorder (ADHD) in two cohorts, which included 221 Norwegian children and 294 Finnish adolescents. Independent contributions of EF and SR were shown in the Norwegian cohort and EF contributed independently in the Finnish cohort. When controlling for each symptom dimension, cognitive functioning and social risk factors were differentially associated with inattention and hyperactivity/impulsivity symptoms. The results show the need to include both social risk factors and cognitive functioning to obtain a better understanding of ADHD symptoms.

A Randomized Controlled Study of Parent-assisted Children's Friendship Training with Children having Autism Spectrum Disorders.

Authors: Frankel F, Myatt R, Sugar C, Whitham C, Gorospe CM, Laugeson E.

This study evaluated Children's Friendship Training (CFT), a manualized parent-assisted intervention to improve social skills among second to fifth grade children with autism spectrum disorders. Comparison was made with a delayed treatment control group (DTC). Targeted skills included conversational skills, peer entry skills, developing friendship networks, good sportsmanship, good host behavior during play dates, and handling teasing. At post-testing, the CFT group was superior to the DTC group on parent measures of social skill and play date behavior, and child measures of popularity and loneliness, At 3-month follow-up, parent measures showed significant improvement from baseline. Post-hoc analysis indicated more than 87% of children receiving CFT showed reliable change on at least one measure at post-test and 66.7% after 3 months follow-up

Erratum to: A Randomized Controlled Study of Parent-assisted Children's Friendship Training with Children having Autism Spectrum Disorders.

Authors: Frankel F, Myatt R, Sugar C, Whitham C, Gorospe CM, Laugeson E.

Mothers' reports of play dates and observation of school playground behavior of children having high-functioning autism spectrum disorders.

Authors: Frankel FD, Gorospe CM, Chang YC, Sugar CA.

Children with high-functioning autism spectrum disorders (ASD) are generally included with typically developing peers at school. They have difficulties interacting with peers on the school playground. Previous literature suggests that having play dates in the home may be related to better peer acceptance at school. Methods  This study examines the relationship between mother-reported play date frequency and amount of conflict, and peer interaction observed on the school playground for a sample of 27 boys and 4 girls meeting structured interview and observation criteria for ASD. Measures of intellectual functioning, adaptive behavior, and social skills were included in a stepwise regression analysis to account for their impact on relationships between maternal play date reports, general peer acceptance at school (as rated by the child's teacher) and observations of school playground behavior. Results  Results revealed that children with autism spectrum disorders who had more play dates in their home tended to spend a greater amount of time engaged in behaviors such as mutual offering of objects, conversing and other turn-taking activities with peers on the school playground. They also received more positive responses to their overtures from peers. These relationships remained highly significant even after accounting for other demographic, general social, and cognitive variables. Conclusions  The present results suggest that play date frequency is strongly related to school playground behavior. Owing to the design of this study, future research must assess whether play dates in the home promote better peer relationships on the playground or the reverse. In either case, the assessment of play dates, as well as observation of spontaneous unsupervised social interactions, are important outcome measures to consider in social skills interventions for children with high-functioning ASD.

The clinical use of structural MRI in Alzheimer disease.

Authors: Frisoni GB, Fox NC, Jack CR Jr, Scheltens P, Thompson PM.

Structural imaging based on magnetic resonance is an integral part of the clinical assessment of patients with suspected Alzheimer dementia. Prospective data on the natural history of change in structural markers from preclinical to overt stages of Alzheimer disease are radically changing how the disease is conceptualized, and will influence its future diagnosis and treatment. Atrophy of medial temporal structures is now considered to be a valid diagnostic marker at the mild cognitive impairment stage. Structural imaging is also included in diagnostic criteria for the most prevalent non-Alzheimer dementias, reflecting its value in differential diagnosis. In addition, rates of whole-brain and hippocampal atrophy are sensitive markers of neurodegeneration, and are increasingly used as outcome measures in trials of potentially disease-modifying therapies. Large multicenter studies are currently investigating the value of other imaging and nonimaging markers as adjuncts to clinical assessment in diagnosis and monitoring of progression. The utility of structural imaging and other markers will be increased by standardization of acquisition and analysis methods, and by development of robust algorithms for automated assessment.

Progress and promise of attention-deficit hyperactivity disorder pharmacogenetics.

Authors: Froehlich TE, McGough JJ, Stein MA.

One strategy for understanding variability in attention-deficit hyperactivity disorder (ADHD) medication response, and therefore redressing the current trial-and-error approach to ADHD medication management, is to identify genetic moderators of treatment. This article summarizes ADHD pharmacogenetic investigative efforts to date, which have primarily focused on short-term response to methylphenidate and largely been limited by modest sample sizes. The most well studied genes include the dopamine transporter and dopamine D(4) receptor, with additional genes that have been significantly associated with stimulant medication response including the adrenergic alpha(2A)-receptor, catechol-O-methyltransferase, D(5) receptor, noradrenaline (norepinephrine) transporter protein 1 and synaptosomal-associated protein 25 kDa. Unfortunately, results of current ADHD pharmacogenetic studies have not been entirely consistent, possibly due to differences in study design, medication dosing regimens and outcome measures. Future directions for ADHD pharmacogenetics investigations may include examination of drug-metabolizing enzymes and a wider range of stimulant and non-stimulant medications. In addition, researchers are increasingly interested in going beyond the individual candidate gene approach to investigate gene-gene interactions or pathways, effect modification by additional environmental exposures and whole genome approaches. Advancements in ADHD pharmacogenetics will be facilitated by multi-site collaborations to obtain larger sample sizes using standardized protocols. Although ADHD pharmacogenetic efforts are still in a relatively early stage, their potential clinical applications may include the development of treatment efficacy and adverse effect prediction algorithms that incorporate the interplay of genetic and environmental factors, as well as the development of novel ADHD treatments.

Base-Catalyzed Halogen Dance Reaction and Oxidative Coupling Sequence as a Convenient Method for the Preparation of Dihalo-bisheteroarenes.

Authors: Getmanenko YA, Tongwa P, Timofeeva TV, Marder SR.

A one-pot preparation of the 2,2'-dibromo-1,1'-bisheteroarenes 3a-d from bromo-heteroarenes utilizing the sequence of the base-catalyzed halogen dance (BCHD) reaction and CuCl(2)-promoted oxidative coupling of the in situ formed alpha-lithio-beta-halo-heteroarenes 2a-d provides a convenient access to precursors for the preparation of tricyclic heteroaromatic cores. The structures of 3a,b,d, 6, and 9 were confirmed by single-crystal X-ray analysis, and dibromides 3a and 3b were used for the preparation of dithieno-[2,3-b:3',2'-d]-pyrrole 10a and its selenophene analogue 10b, respectively.

Neural Components Underlying Behavioral Flexibility in Human Reversal Learning.

Authors: Ghahremani DG, Monterosso J, Jentsch JD, Bilder RM, Poldrack RA.

The ability to flexibly respond to changes in the environment is critical for adaptive behavior. Reversal learning (RL) procedures test adaptive response updating when contingencies are altered. We used functional magnetic resonance imaging to examine brain areas that support specific RL components. We compared neural responses to RL and initial learning (acquisition) to isolate reversal-related brain activation independent of cognitive control processes invoked during initial feedback-based learning. Lateral orbitofrontal cortex (OFC) was more activated during reversal than acquisition, suggesting its relevance for reformation of established stimulus-response associations. In addition, the dorsal anterior cingulate (dACC) and right inferior frontal gyrus (rIFG) correlated with change in postreversal accuracy. Because optimal RL likely requires suppression of a prior learned response, we hypothesized that similar regions serve both response inhibition (RI) and inhibition of learned associations during reversal. However, reversal-specific responding and stopping (requiring RI and assessed via the stop-signal task) revealed distinct frontal regions. Although RI-related regions do not appear to support inhibition of prepotent learned associations, a subset of these regions, dACC and rIFG, guide actions consistent with current reward contingencies. These regions and lateral OFC represent distinct neural components that support behavioral flexibility important for adaptive learning.

Subsyndromal depressive symptoms after symptomatic recovery from mania are associa ted with delayed functional recovery.

Authors: Gitlin MJ, Mintz J, Sokolski K, Hammen C, Altshuler LL.

This study examined whether the presence of subsyndromal depressive symptoms predicted functional recovery after an acute manic episode. METHOD: Subjects with bipolar I disorder (according to the Structured Clinical Interview for DSM-IV) who, at the time of symptomatic recovery from an acute manic or hypomanic episode, had a concomitant functional recovery (n = 52) were compared on demographic variables and mood symptoms to those who had symptomatically recovered but not functionally recovered (n = 33). Demographic and mood variables were examined in the nonfunctionally recovered group to assess predictors of time to functional recovery. The primary functional outcome measure used was the Life Functioning Questionnaire, a 5-minute, gender-neutral self-report scale to measure role function in 4 domains: workplace, duties at home, leisure time with family, and leisure time with friends. Participants in the study were recruited from July 2000 through February 2005. RESULTS: Depressive symptoms, even at a subsyndromal level, were significantly associated with persisting functional impairment after symptomatic recovery from a manic episode (P < .02). Subsyndromal depressive symptoms also significantly predicted a slower time to functional recovery over the next 9 months (P = .006). CONCLUSION: The presence of even mild subsyndromal depressive symptoms may interfere with functional recovery in patients with bipolar disorder after symptomatic recovery from a manic or hypomanic episode. © Copyright 2010 Physicians Postgraduate Press, Inc.

Fronto-temporal dysregulation in asymptomatic bipolar I patients: A paired associate functional MRI study.

Authors: Glahn DC, Robinson JL, Tordesillas-Gutierrez D, Monkul ES, Holmes MK, Green MJ, Bearden CE.

Bipolar disorder is associated with persistent declarative memory disturbances, but the neural basis of these deficits is not well understood. We used fMRI to investigate brain activity during performance on a face-name paired associate task, which allows for the dissociation of encoding and recall-related memory processes. Fifteen clinically remitted bipolar I disorder patients and 24 demographically matched healthy comparison subjects were scanned during task performance. At the voxel level, bipolar patients showed reduced cortical activation, relative to controls, in multiple task-related brain regions during encoding. During recognition, bipolar patients under-activated left hippocampal and parahippocampal regions, despite adequate task performance. Region of interest analyses indicated that, during encoding, bipolar patients had greater bilateral dorsolateral prefrontal (DLPFC) activity than healthy subjects. In contrast, during recognition patients showed hypo-activation relative to controls in the right, but not the left, DLPFC. Although hippocampal activity did not differ between groups during encoding, bipolar patients failed to activate hippocampal regions to the same extent as healthy subjects during recognition. Finally, while better task performance was associated with recognition-related hippocampal activity in healthy subjects, bipolar patients showed an inverse relationship between task performance and hippocampal activity. Remitted bipolar patients over-engaged dorsolateral prefrontal regions when learning face-name pairs, but relative hypoactivation in both prefrontal and medial temporal regions during recognition. These findings suggest a neural basis for the long-term memory deficits consistently observed in patients with bipolar disorder; further, as these patterns appear in symptomatically remitted patients, they are unlikely to be an artifact of mood symptoms. Hum Brain Mapp.

Mapping gray matter development: Implications for typical development and vulnerability to psychopathology.

Authors: Gogtay N, Thompson PM.

Recent studies with brain magnetic resonance imaging (MRI) have scanned large numbers of children and adolescents repeatedly over time, as their brains develop, tracking volumetric changes in gray and white matter in remarkable detail. Focusing on gray matter changes specifically, here we explain how earlier studies using lobar volumes of specific anatomical regions showed how different lobes of the brain matured at different rates. With the advent of more sophisticated brain mapping methods, it became possible to chart the dynamic trajectory of cortical maturation using detailed 3D and 4D (dynamic) models, showing spreading waves of changes evolving through the cortex. This led to a variety of time-lapse films revealing characteristic deviations from normal development in schizophrenia, bipolar illness, and even in siblings at genetic risk for these disorders. We describe how these methods have helped clarify how cortical development relates to cognitive performance, functional recovery or decline in illness, and ongoing myelination processes. These time-lapse maps have also been used to study effects of genotype and medication on cortical maturation, presenting a powerful framework to study factors that influence the developing brain.

Depressive symptoms and their social contexts: A qualitative sytematic literature review of contextual interventions.

Authors: Gottlieb L, Waitzkin H, Miranda J.

Numerous observational studies demonstrate associations between social context and depressive symptoms, yet few intervention trials exist in this arena. AIMS: This review examines intervention trials that explore the impact of contextual change on depressive symptoms. METHODS: Electronic literature databases of PubMed and PsycINFO, bibliographies of retrieved articles and the publicly available internet were searched for English-language articles published between 1997 and 2008. Peer-reviewed studies were eligible for inclusion if they reported contextual interventions and depressive symptoms measures in adult populations without other significant underlying medical or psychological illness. In total, 2,128 studies met search term criteria. Of these, 13 studies meeting inclusion criteria were classified by type of intervention. Qualitative synthesis was used to interpret the mental health impact of contextual interventions. RESULTS: The interventions focused on employment, housing, poverty, parenting and violence. Eight of these studies reported a decrease in depressive symptoms and/or psychological distress in intervention groups. Interventions varied in focus, length of follow-up and measures of depressive symptoms. CONCLUSIONS: Contextual interventions for the prevention and treatment of depressive symptoms and psychological distress can be effective, though very limited data exist in this field. Policy implications include a greater emphasis on improving context to decrease depression and other mental disorders

Relationships between perceptions of the family environ ment and of negative life events in recent-onset schizophrenia patients.

Authors: Gretchen-Doorly D, Detore NR, Ventura J, Hellemann G, Subotnik KL, Nuechterlein KH.

Atypical EEG Beta Asymmetry in Adults with ADHD.

Authors: Hale TS, Smalley SL, Walshaw PD, Hanada G, Macion J, McCracken JT, James, McGough J, Loo SK.

Abnormal brain laterality (ABL) is well established in ADHD. However, its clinical specificity and association to cognitive and clinical symptoms is not yet understood. Previous studies indicate increased right hemisphere (RH) contribution in both ADHD and reading impaired samples. The current study investigates whether this ABL characteristic occurs in adults with ADHD absent comorbid language impairment. Methods: EEG beta asymmetry was compared in 35 adult ADHD subjects and 104 controls during rest and active cognition. Group differences in beta asymmetry were then further evaluated for association to linguistic and attentional abilities, as well as association to beta asymmetry measures across different brain regions. Results: Adults with ADHD showed pronounced rightward beta asymmetry (p=.00001) in inferior parietal regions (P8-P7) during a continuous performance task (CPT) that could not be attributed to linguistic ability. Among ADHD subjects only, greater rightward beta asymmetry at this measure was correlated with better CPT performance. Furthermore, this measure showed a lack of normal association (i.e., observed in controls) to left-biased processing in temporal-parietal (TP8-TP7) brain regions important for higher order language functions. Conclusion: Adult ADHD involves abnormally increased right-biased contribution to CPT processing that could not be attributed to poor language ability. This appears to also involve abnormal recruitment of LH linguistic processing regions and represents an alternative, albeit less effective, CPT processing strategy. These findings suggest different pathophysiologic mechanisms likely underlie RH biased processing in ADHD and reading impaired samples. Copyright © 2010. Published by Elsevier Ltd.

Design of Polymethine Dyes with Large Third-Order Optical Nonlinearities and Loss Figures of Merit.

Authors: Hales JM, Matichak J, Barlow S, Ohira S, Yesudas K, Brédas JL, Perry JW, Marder SR.

All-optical switching applications require materials with large third-order nonlinearities and low nonlinear optical losses. We present a design approach that involves enhancing the real part of the third-order polarizability (gamma) of cyanine-like molecules through incorporation of polarizable chalcogen atoms into terminal groups, while controlling the molecular length to obtain favorable one- and two-photon absorption resonances that lead to suitably low optical loss and appreciable dispersion enhancement of Re(gamma). We implement this strategy in a soluble bis(selenopyrylium) heptamethine dye that exhibits a real part of gamma that is exceptionally large throughout the wavelength range used for telecommunications, and an imaginary part of gamma, a measure of nonlinear loss, that is two orders-of-magnitude smaller. This combination is critical in enabling low-power and high-contrast optical switching.

Robust discrimination between self and non-self neurites requires thousands of Dscam1 isoforms

Authors: Hattori D, Chen Y, Matthews BJ, Salwinski L, Sabatti C, Grueber WB, Zipursky SL.

Down Syndrome cell adhesion molecule (Dscam) genes encode neuronal cell recognition proteins of the immunoglobulin superfamily. In Drosophila, Dscam1 generates 19,008 different ectodomains by alternative splicing of three exon clusters, each encoding half or a complete variable immunoglobulin domain. Identical isoforms bind to each other, but rarely to isoforms differing at any one of the variable immunoglobulin domains. Binding between isoforms on opposing membranes promotes repulsion. Isoform diversity provides the molecular basis for neurite self-avoidance. Self-avoidance refers to the tendency of branches from the same neuron (self-branches) to selectively avoid one another. To ensure that repulsion is restricted to self-branches, different neurons express different sets of isoforms in a biased stochastic fashion. Genetic studies demonstrated that Dscam1 diversity has a profound role in wiring the fly brain. Here we show how many isoforms are required to provide an identification system that prevents non-self branches from inappropriately recognizing each other. Using homologous recombination, we generated mutant animals encoding 12, 24, 576 and 1,152 potential isoforms. Mutant animals with deletions encoding 4,752 and 14,256 isoforms were also analysed. Branching phenotypes were assessed in three classes of neurons. Branching patterns improved as the potential number of isoforms increased, and this was independent of the identity of the isoforms. Although branching defects in animals with 1,152 potential isoforms remained substantial, animals with 4,752 isoforms were indistinguishable from wild-type controls. Mathematical modelling studies were consistent with the experimental results that thousands of isoforms are necessary to ensure acquisition of unique Dscam1 identities in many neurons. We conclude that thousands of isoforms are essential to provide neurons with a robust discrimination mechanism to distinguish between self and non-self during self-avoidance.

Development of a Clinician Report Measure to Assess Psychotherapy for Depression in Usual Care Settings.

Authors: Hepner KA, Azocar F, Greenwood GL, Miranda J, Burnam MA.

Although mental health policy initiatives have called for quality improvement in depression care, practical tools to describe the quality of psychotherapy for depression are not available. We developed a clinician-report measure of adherence to three types of psychotherapy for depression-cognitive behavioral therapy, interpersonal therapy, and psychodynamic therapy. A total of 727 clinicians from a large, national managed behavioral health care organization responded to a mail survey. The measure demonstrated good psychometric properties, including appropriate item-scale correlations, internal consistency reliability, and a three-factor structure. Our results suggest that this questionnaire may be a promising approach to describing psychotherapy for depression in usual care.

Usual Care Psychotherapy for Depression in a Large Managed Behavioral Health Organization.

Authors: Hepner KA, Greenwood GL, Azocar F, Miranda J, Burnam MA.

Evidence-based psychotherapies to treat depression are available, yet it remains unknown the extent to which these practices are used in routine care for depression. Using survey and administrative data, we sought to describe usual care psychotherapy for depression for adult patients receiving care through a large, managed behavioral health care organization. Data from 420 patients receiving psychotherapy for depression and 159 of their therapists provide evidence that some practitioners are using evidence-based psychotherapy techniques for depression, but also demonstrate the need for improved tools to monitor and improve quality of psychotherapy in usual care.

Comparing 3 T and 1.5 T MRI for tracking Alzheimer's disease progression with tensor-based morphometry.

Authors: Ho AJ, Hua X, Lee S, Leow AD, Yanovsky I, Gutman B, Dinov ID, Leporé N, Stein JL, Toga AW, Jack CR Jr, Bernstein MA, Reiman EM, Harvey DJ, Kornak J, Schuff N, Alexander GE, Weiner MW, Thompson PM; the Alzheimer's Disease Neuroimaging Initiative

A key question in designing MRI-based clinical trials is how the main magnetic field strength of the scanner affects the power to detect disease effects. In 110 subjects scanned longitudinally at both 3.0 and 1.5 T, including 24 patients with Alzheimer's Disease (AD) [74.8 +/- 9.2 years, MMSE: 22.6 +/- 2.0 at baseline], 51 individuals with mild cognitive impairment (MCI) [74.1 +/- 8.0 years, MMSE: 26.6 +/- 2.0], and 35 controls [75.9 +/- 4.6 years, MMSE: 29.3 +/- 0.8], we assessed whether higher-field MR imaging offers higher or lower power to detect longitudinal changes in the brain, using tensor-based morphometry (TBM) to reveal the location of progressive atrophy. As expected, at both field strengths, progressive atrophy was widespread in AD and more spatially restricted in MCI. Power analysis revealed that, to detect a 25% slowing of atrophy (with 80% power), 37 AD and 108 MCI subjects would be needed at 1.5 T versus 49 AD and 166 MCI subjects at 3 T; however, the increased power at 1.5 T was not statistically significant (alpha = 0.05) either for TBM, or for SIENA, a related method for computing volume loss rates. Analysis of cumulative distribution functions and false discovery rates showed that, at both field strengths, temporal lobe atrophy rates were correlated with interval decline in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), mini-mental status exam (MMSE), and Clinical Dementia Rating sum-of-boxes (CDR-SB) scores. Overall, 1.5 and 3 T scans did not significantly differ in their power to detect neurodegenerative changes over a year. Hum Brain Mapp, 2009. (c) 2009 Wiley-Liss, Inc.

The effects of physical activity, education, and body mass index on the aging brain.

Authors: Ho AJ, Raji CA, Becker JT, Lopez OL, Kuller LH, Hua X, Dinov ID, Stein JL, Rosano C, Toga AW, Thompson PM.

Normal human aging is accompanied by progressive brain tissue loss and cognitive decline; however, several factors are thought to influence brain aging. We applied tensor-based morphometry to high-resolution brain MRI scans to determine whether educational level or physical activity was associated with brain tissue volumes in the elderly, particularly in regions susceptible to age-related atrophy. We mapped the 3D profile of brain volume differences in 226 healthy elderly subjects (130F/96M; 77.9 +/- 3.6 SD years) from the Cardiovascular Health Study-Cognition Study. Statistical maps revealed the 3D profile of brain regions whose volumes were associated with educational level and physical activity (based on leisure-time energy expenditure). After controlling for age, sex, and physical activity, higher educational levels were associated with approximately 2-3% greater tissue volumes, on average, in the temporal lobe gray matter. After controlling for age, sex, and education, greater physical activity was associated with approximately 2-2.5% greater average tissue volumes in the white matter of the corona radiata extending into the parietal-occipital junction. Body mass index (BMI) was highly correlated with both education and physical activity, so we examined BMI as a contributing factor by including physical activity, education, and BMI in the same model; only BMI effects remained significant. This is one of the largest MRI studies of factors influencing structural brain aging, and BMI may be a key factor explaining the observed relationship between education, physical activity, and brain structure. Independent contributions to brain structure could not be teased apart as all these factors were highly correlated with one another. Hum Brain Mapp, 2010. (c) 2010 Wiley-Liss, Inc.

Obesity is linked with lower brain volume in 700 AD and MCI patients.

Authors: Ho AJ, Raji CA, Becker JT, Lopez OL, Kuller LH, Hua X, Lee S, Hibar D, Dinov ID, Stein JL, Jack CR Jr, Weiner MW, Toga AW, Thompson PM; Cardiovascular Health Study; ADNI.

Obesity is associated with lower brain volumes in cognitively normal elderly subjects, but no study has yet investigated the effects of obesity on brain structure in patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD). To determine if higher body mass index (BMI) is associated with brain volume deficits in cognitively impaired elderly subjects, we analyzed brain magnetic resonance imaging (MRI) scans of 700 MCI or AD patients from 2 different cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Cardiovascular Health Study-Cognition Study (CHS-CS). Tensor-based morphometry (TBM) was used to create 3-dimensional maps of regional tissue excess or deficits in subjects with MCI (ADNI, n = 399; CHS-CS, n = 77) and AD (ADNI, n = 188; CHS, n = 36). In both AD and MCI groups, higher body mass index was associated with brain volume deficits in frontal, temporal, parietal, and occipital lobes; the atrophic pattern was consistent in both ADNI and CHS populations. Cardiovascular risk factors, especially obesity, should be considered as influencing brain structure in those already afflicted by cognitive impairment and dementia. Copyright © 2010 Elsevier Inc. All rights reserved.

A commonly carried allele of the obesity- related FTO gene is associated with reduced brain volume in the healthy elderly.

Authors: Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Stephan DA, Decarli CS, Dechairo BM, Potkin SG, Jack CR Jr, Weiner MW, Raji CA, Lopez OL, Becker JT, Carmichael OT, Thompson PM; the Alzheimer's Disease Neuroimaging Initiative.

A recently identified variant within the fat mass and obesity-associated (FTO) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes-these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

Sex and age differences in atrophic rates: an ADNI study with n= 1368 MRI scans.

Authors: Hua X, Hibar DP, Lee S, Toga AW, Jack CR Jr, Weiner MW, Thompson PM; Alzheimer's Disease Neuroimaging Initiative.

We set out to determine factors that influence the rate of brain atrophy in 1-year longitudinal magnetic resonance imaging (MRI) data. With tensor-based morphometry (TBM), we mapped the 3-dimensional profile of progressive atrophy in 144 subjects with probable Alzheimer's disease (AD) (age: 76.5 +/- 7.4 years), 338 with amnestic mild cognitive impairment (MCI; 76.0 +/- 7.2), and 202 healthy controls (77.0 +/- 5.1), scanned twice, 1 year apart. Statistical maps revealed significant age and sex differences in atrophic rates. Brain atrophic rates were about 1%-1.5% faster in women than men. Atrophy was faster in younger than older subjects, most prominently in mild cognitive impairment, with a 1% increase in the rates of atrophy and 2% in ventricular expansion, for every 10-year decrease in age. TBM-derived atrophic rates correlated with reduced beta-amyloid and elevated tau levels (n = 363) at baseline, baseline and progressive deterioration in clinical measures, and increasing numbers of risk alleles for the ApoE4 gene. TBM is a sensitive, high-throughput biomarker for tracking disease progression in large imaging studies; sub-analyses focusing on women or younger subjects gave improved sample size requirements for clinical trials. 2010 Elsevier Inc. All rights reserved.

Mapping Alzheimer's Disease Progression in 1309 MRI Scans: Power Estimates for Different Inter-Scan Intervals.

Authors: Hua X, Lee S, Hibar DP, Yanovsky I, Leow AD, Toga AW, Jack CR Jr, Bernstein MA, Reiman EM, Harvey DJ, Kornak J, Schuff N, Alexander GE, Weiner MW, Thompson PM; the Alzheimer's Disease Neuroimaging Initiative.

Neuroimaging centers and pharmaceutical companies are working together to evaluate treatments that might slow the progression of Alzheimer's disease (AD), a common but devastating late-life neuropathology. Recently, automated brain mapping methods, such as tensor-based morphometry (TBM) of structural MRI, have outperformed cognitive measures in their precision and power to track disease progression, greatly reducing sample size estimates for drug trials. In the largest TBM study to date, we studied how sample size estimates for tracking structural brain changes depend on the time interval between the scans (6-24 months). We analyzed 1,309 brain scans from 91 probable AD patients (age at baseline: 75.4+/-7.5 years) and 189 individuals with mild cognitive impairment (MCI; 74.6+/-7.1 years), scanned at baseline, 6, 12, 18, and 24 months. Statistical maps revealed 3D patterns of brain atrophy at each follow-up scan relative to the baseline; numerical summaries were used to quantify temporal lobe atrophy within a statistically-defined region-of-interest. Power analyses revealed superior sample size estimates over traditional clinical measures. Only 80, 46, and 39 AD patients were required for a hypothetical clinical trial, at 6, 12, and 24 months respectively, to detect a 25% reduction in average change using a two-sided test (alpha=0.05, power=80%). Correspondingly, 106, 79, and 67 subjects were needed for an equivalent MCI trial aiming for earlier intervention. A 24-month trial provides most power, except when patient attrition exceeds 15-16%/year, in which case a 12-month trial is optimal. These statistics may facilitate clinical trial design using voxel-based brain mapping methods such as TBM.

A Brief Cognitive Assessment Tool for Schizophrenia: Construction of a Tool for Clinicians.

Authors: Hurford IM, Marder SR, Keefe RS, Reise SP, Bilder RM.

Cognitive impairment in schizophrenia is often severe, enduring, and contributes significantly to chronic disability. But clinicians have difficulty in assessing cognition due to a lack of brief instruments. We evaluated whether a brief battery of cognitive tests derived from larger batteries could generate a summary score representing global cognitive function. Using data from 3 previously published trials, we calculated the corrected item-total correlations (CITCs) or the correlation of each test with the battery total score. We computed the proportion of variance that each test shares with the global score excluding that test (R(t)(2)=CITC(2)) and the variance explained per minute of administration time for each test (R(t)(2)/min). The 3 tests with the highest R(t)(2)/min were selected for the brief battery. The composite score from the trail making test B, category fluency, and digit symbol correlated .86 with the global score of the larger battery in 2 of the studies and correlated between .73 and .82 with the total battery scores excluding these 3 tests. A Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) using the above 3 tests can be administered in 10-11 min. The full batteries of the larger studies have administration times ranging from 90 to 210 min. Given prior research suggesting that a single factor of global cognition best explains the pattern of cognitive deficit in schizophrenia, an instrument like B-CATS can provide clinicians with meaningful data regarding their patients' cognitive function. It can also serve researchers who want an estimate of global cognitive function without requiring a full neuropsychological battery.

Response to distress in infants at risk for autism: a prospective longitud inal study.

Authors: Hutman T, Rozga A, Delaurentis AD, Barnwell JM, Sugar CA, Sigman M.

Background: Infants and preschoolers with ASD show impairment in their responses to other people's distress relative to children with other developmental delays and typically developing children. This deficit is expected to disrupt social interactions, social learning, and the formation of close relationships. Response to distress has not been evaluated previously in infants with ASD earlier than 18 months of age. Methods: Participants were 103 infant siblings of children with autism and 55 low-risk controls. All children were screened for ASD at 36 months and 14 were diagnosed with ASD. Infants' responsiveness to distress was evaluated at 12, 18, 24, and 36 months. An examiner pretended to hit her finger with a toy mallet and infants' responses were video-recorded. Attention to the examiner and congruent changes in affect were coded on four-point Likert scales. Results: Cross-sectional and longitudinal analyses confirm that the ASD group paid less attention and demonstrated less change in affect in response to the examiner's distress relative to the high-risk and low-risk participants who were not subsequently diagnosed with ASD. Group differences remained when verbal skills and general social responsiveness were included in the analytic models. Conclusions: Diagnostic groups differ on distress response from 12 to 36 months of age. Distress-response measures are predictive of later ASD diagnosis above and beyond verbal impairments. Distress response is a worthwhile target for early intervention programs.

A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia.

Authors: Ingason A, Giegling I, Cichon S, Hansen T, Rasmussen HB, Nielsen J, Jürgens G, Muglia P, Hartmann AM, Strengman E, Vasilescu C, Mühleisen TW, Djurovic S, Melle I, Lerer B, Möller HJ, Francks C, Pietiläinen OP, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Walshe M, Vassos E, Di Forti M, Murray R, Bonetto C, Tosato S; GROUP Investigators, Cantor RM, Rietschel M, Craddock N, Owen MJ, Peltonen L, Andreassen OA, Nöthen MM, St Clair D, Ophoff RA, Odonovan M, Collier D, Werge T, Rujescu D.

The Abelson helper integration site 1 (AHI1) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium (LD) mapping, and subsequent replication of the association in an independent sample. Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3,907 affected and 7,429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4,496 affected and 18,920 controls. Both the replication study of new samples and the meta-analysis show evidence for significant overrepresentation of all tested alleles in patients compared with controls (meta-analysis; P=8.2x10(-5)-1.7x10(-3), common OR=1.09-1.11). The region contains two genes, AHI1and C6orf217, and both genes - as well as the neighbouring phosphodiesterase 7B (PDE7B) - may be considered candidates for involvement in the genetic aetiology of schizophrenia.

Update on the magnetic res onance imaging core of the Alzheimer's disease neuroimaging initiative.

Authors: Jack CR Jr, Bernstein MA, Borowski BJ, Gunter JL, Fox NC, Thompson PM, Schuff N, Krueger G, Killiany RJ, Decarli CS, Dale AM, Carmichael OW, Tosun D, Weiner MW; Alzheimer's Disease Neuroimaging Initiative.

Functions of the Alzheimer's Disease Neuroimaging Initiative (ADNI) magnetic resonance imaging (MRI) core fall into three categories: (1) those of the central MRI core laboratory at Mayo Clinic, Rochester, Minnesota, needed to generate high quality MRI data in all subjects at each time point; (2) those of the funded ADNI MRI core imaging analysis groups responsible for analyzing the MRI data; and (3) the joint function of the entire MRI core in designing and problem solving MR image acquisition, pre-processing, and analyses methods. The primary objective of ADNI was and continues to be improving methods for clinical trials in Alzheimer's disease. Our approach to the present ("ADNI-GO") and future ("ADNI-2," if funded) MRI protocol will be to maintain MRI methodological consistency in the previously enrolled "ADNI-1" subjects who are followed up longitudinally in ADNI-GO and ADNI-2. We will modernize and expand the MRI protocol for all newly enrolled ADNI-GO and ADNI-2 subjects. All newly enrolled subjects will be scanned at 3T with a core set of three sequence types: 3D T1-weighted volume, FLAIR, and a long TE gradient echo volumetric acquisition for micro hemorrhage detection. In addition to this core ADNI-GO and ADNI-2 protocol, we will perform vendor-specific pilot sub-studies of arterial spin-labeling perfusion, resting state functional connectivity, and diffusion tensor imaging. One of these sequences will be added to the core protocol on systems from each MRI vendor. These experimental sub-studies are designed to demonstrate the feasibility of acquiring useful data in a multicenter (but single vendor) setting for these three emerging MRI applications.

Genetic influences on brain asymmetry: A DTI study of 374 twins and siblings.

Authors: Jahanshad N, Lee AD, Barysheva M, McMahon KL, de Zubicaray GI, Martin NG, Wright MJ, Toga AW, Thompson PM.

Brain asymmetry, or the structural and functional specialization of each brain hemisphere, has fascinated neuroscientists for over a century. Even so, genetic and environmental factors that influence brain asymmetry are largely unknown. Diffusion tensor imaging (DTI) now allows asymmetry to be studied at a microscopic scale by examining differences in fiber characteristics across hemispheres rather than differences in structure shapes and volumes. Here we analyzed 4 Tesla DTI scans from 374 healthy adults, including 60 monozygotic twin pairs, 45 same-sex dizygotic pairs, and 164 mixed-sex DZ twins and their siblings; mean age: 24.4 years +/- 1.9SD). All DTI scans were nonlinearly aligned to a geometrically-symmetric, population-based image template. We computed voxel-wise maps of significant asymmetries (left/right differences) for common diffusion measures that reflect fiber integrity (fractional and geodesic anisotropy; FA, GA and mean diffusivity, MD). In quantitative genetic models computed from all same-sex twin pairs (N=210 subjects), genetic factors accounted for 33% of the variance in asymmetry for the inferior fronto-occipital fasciculus, 37% for the anterior thalamic radiation, and 20% for the forceps major and uncinate fasciculus (all L > R). Shared environmental factors accounted for around 15% of the variance in asymmetry for the cortico-spinal tract (R > L) and about 10% for the forceps minor (L > R). Sex differences in asymmetry (men > women) were significant, and were greatest in regions with prominent FA asymmetries. These maps identify heritable DTI-derived features, and may empower genome-wide searches for genetic polymorphisms that influence brain asymmetry. Copyright © 2010. Published by Elsevier Inc.

Population Pharmacokinetics of Perphenazine in Schizophrenia Patients From CATIE: Impact of Race and Smoking.

Authors: Jin Y, Pollock BG, Coley K, Miller D, Marder SR, Florian J, Schneider L, Lieberman J, Kirshner M, Bies RR.

The goal of the study was to characterize population pharmacokinetics (PPK) for perphenazine in patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). Patients (n = 156) received 8 to 32 mg of perphenazine daily for 14 to 600 days for a total of 421 plasma concentrations measurements. Nonlinear mixed-effects modeling was used to determine PPK characteristics of perphenazine. One- and 2-compartment models with various random effect implementations and mixture distributions were evaluated. Objective function values and goodness-of-fit plots were used as model selection criteria. Age, weight, sex, race, smoking, and concomitant medications were evaluated as covariates. A 1-compartment linear model with proportional error best described the data. The population mean clearance and volume of distribution for perphenazine were 483 L/h and 18 200 L, respectively. Race and smoking status had significant impacts on perphenazine clearance estimates. In addition, the estimated population mean clearance was 48% higher in nonsmoking African Americans than in nonsmoking other races (512 L/h vs 346 L/h). Active smokers eliminated perphenazine 159 L/h faster than nonsmokers in each race. Clearances for smoking African Americans versus smokers in other races were 671 L/h versus 505 L/h, respectively.

Work through the valley: do.

Authors: Jones L, Wells K, Meade B, Forge N, Lucas-Wright A, Jones F, Young-Brinn A, Jones A, Norris K.

Much of the work for a community-partnered participatory research (CPPR) initiative is done in committees that operate under the principles of CPPR and the vision of the partnership, while implementing the action plans of the initiative. Action plans are developed in work group meetings and sponsored events that engage the community in discussion about programs or new policy directions. This article provides detailed recommendations for conducting meetings, completing assignments, and running events as the main body of work.

Celebrate victory.

Authors: Jones L, Wells K, Meade B.

The promise of a community-partnered participatory research (CPPR) initiative to build capacity and reinforce assets is realized through a fully implemented Victory stage. This article reviews the process to plan for victory by including its goals in the main action plans and reviews several key activities that comprise the main accomplishments, which might include products for the community and scientific articles and presentations that are co-authored and co-presented; as well as partnered conferences and reflection retreats on major accomplishments and transitions. Because dealing with conflict is an important part of the work of projects in general and of developing victories, this article also reviews strategies to turn conflicts into celebrations of growth that can set the stage for the next phase of partnership development as well as for further partnered research

The vision, valley, and victory of community engagement.

Authors: Jones L, Wells K, Norris K, Meade B, Koegel P.

This chapter provides an overview of Community-Partnered Participatory Research (CPPR) and introduces the articles in this special issue. CPPR is a model to engage community and academic partners equally in an initiative to benefit the community while contributing to science. This article reviews the history of the partnership of community and academic institutions that developed under the leadership of Healthy African American Families. Central to the CPPR model is a framework of community engagement that includes and mobilizes the full range of community and academic stakeholders to work collaboratively. The three stages of CPPR (Vision, Valley and Victory) are reviewed, along with the organization and purpose of the guidebook presented as articles in this issue.

Trauma, Depression, and Comorbid PTSD/Depression in a Community Sample of Latina Immigrants.

Authors: Kaltman S, Green BL, Mete M, Shara N, Miranda J

Trauma exposure is frequently overlooked as a risk factor for psychiatric morbidity among studies with Latinos. The purpose of this study was to examine the relationships among trauma history, immigration-related factors, and mental health status among Latina immigrants. The current study used baseline data from a randomized clinical trial for the treatment of depression (Miranda et al., 2006) of 64 women with comorbid PTSD and depression, 69 with depression-only, and 61 with no Axis I mental disorder. Sixty-four percent of the sample was Central American and 75% percent reported trauma exposure. Multinomial logit analysis suggested fewer years in the US was associated with worse mental health status. Having a non-married marital status was also associated with worse mental health. Reporting four or more types of traumatic events was associated with an increase in the probability of comorbidity. These findings have important implications for future research and clinical practice.

A multicenter, randomized, double-blind, placebo-controlled, 16-week study of adjunctive aripiprazole for schizophrenia or schizoaffective disorder inadequately treated with quetiapine or risperidone monotherapy.

Authors: Kane JM, Correll CU, Goff DC, Kirkpatrick B, Marder SR, Vester-Blokland E, Sun W, Carson WH, Pikalov A, Assunção-Talbott S.

Combining antipsychotics is common practice in the treatment of schizophrenia. This study investigated aripiprazole adjunctive to risperidone or quetiapine for treating schizophrenia and schizoaffective disorder. METHOD: In this multicenter, double-blind, 16-week, placebo-controlled study conducted at 43 American sites from July 2006 to October 2007, patients with chronic, stable schizophrenia or schizoaffective disorder diagnosed with DSM-IV-TR were randomly assigned to receive aripiprazole (2-15 mg/d) or placebo in addition to a stable regimen of quetiapine (400-800 mg/d) or risperidone (4-8 mg/d). The primary outcome measure was the mean change from baseline to endpoint (week 16, last observation carried forward) in the Positive and Negative Syndrome Scale (PANSS) total score. RESULTS: 323 subjects being treated with either risperidone (n = 177) or quetiapine (n = 146) were randomly assigned to receive adjunctive aripiprazole (n = 168) or placebo (n = 155). Baseline characteristics were similar (mean PANSS total score: aripiprazole, 74.5; placebo, 75.9) except for history of suicide attempts (aripiprazole, 27%; placebo, 40%). Nearly 70% of subjects in each arm completed the trial. Adjunctive aripiprazole and placebo groups were similar in the mean change from baseline to endpoint in the PANSS total score (aripiprazole, -8.8; placebo, -8.9; P = .942). The incidence of treatment-emergent adverse events was similar between groups. Mean changes in Simpson-Angus Scale, Abnormal Involuntary Movement Scale, and Barnes Akathisia Rating Scale scores were not statistically significantly different. Adjunctive aripiprazole was associated with statistically significantly greater decreases in mean serum prolactin levels from baseline than was adjunctive placebo (-12.6 ng/mL for aripiprazole vs -2.2 ng/mL for placebo; P < .001), an effect that was seen in the risperidone subgroup (-18.7 ng/mL vs -1.9 ng/mL; P < .001) but not in the quetiapine subgroup (-3.01 ng/mL vs +0.15 ng/mL; P = .104). CONCLUSIONS: The addition of aripiprazole to risperidone or quetiapine was not associated with improvement in psychiatric symptoms but was generally safe and well tolerated. Further research is warranted to explore whether antipsychotic combination therapy offers benefits to particular patient populations-for example, in cases of hyperprolactinemia. TRIAL REGISTRATION: Identifier: NCT00325689. Copyright 2009 Physicians Postgraduate Press, Inc.

Variance component model to account for sample structure in genome-wide association studies.

Authors: Kang HM, Sul JH, Service SK, Zaitlen NA, Kong SY, Freimer NB, Sabatti C, Eskin E.

Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA. [2] Center for Computational Medicine and Bioinformatics, The University of Michigan Medical School, Ann Arbor, Michigan, USA. [3] These authors contributed equally to this work. Although genome-wide association studies (GWASs) have identified numerous loci associated with complex traits, imprecise modeling of the genetic relatedness within study samples may cause substantial inflation of test statistics and possibly spurious associations. Variance component approaches, such as efficient mixed-model association (EMMA), can correct for a wide range of sample structures by explicitly accounting for pairwise relatedness between individuals, using high-density markers to model the phenotype distribution; but such approaches are computationally impractical. We report here a variance component approach implemented in publicly available software, EMMA eXpedited (EMMAX), that reduces the computational time for analyzing large GWAS data sets from years to hours. We apply this method to two human GWAS data sets, performing association analysis for ten quantitative traits from the Northern Finland Birth Cohort and seven common diseases from the Wellcome Trust Case Control Consortium. We find that EMMAX outperforms both principal component analysis and genomic control in correcting for sample structure

Collaborative depression care: history, evolution and ways to enhance dissemination and sustainability.

Authors: Katon W, Unützer J, Wells K, Jones L.

OBJECTIVE: To describe the history and evolution of the collaborative depression care model and new research aimed at enhancing dissemination. METHOD: Four keynote speakers from the 2009 NIMH Annual Mental Health Services Meeting collaborated in this article in order to describe the history and evolution of collaborative depression care, adaptation of collaborative care to new populations and medical settings, and optimal ways to enhance dissemination of this model. RESULTS: Extensive evidence across 37 randomized trials has shown the effectiveness of collaborative care vs. usual primary care in enhancing quality of depression care and in improving depressive outcomes for up to 2 to 5 years. Collaborative care is currently being disseminated in large health care organizations such as the Veterans Administration and Kaiser Permanente, as well as in fee-for-services systems and federally funded clinic systems of care in multiple states. New adaptations of collaborative care are being tested in pediatric and ob-gyn populations as well as in populations of patients with multiple comorbid medical illnesses. New NIMH-funded research is also testing community-based participatory research approaches to collaborative care to attempt to decrease disparities of care in underserved minority populations. CONCLUSION: Collaborative depression care has extensive research supporting the effectiveness of this model. New research and demonstration projects have focused on adapting this model to new populations and medical settings and on studying ways to optimally disseminate this approach to care, including developing financial models to incentivize dissemination and partnerships with community populations to enhance sustainability and to decrease disparities in quality of mental health care.

Report From the Working Group Conference on Multisite Trial Design for Cognitive Remediation in Schizophrenia.

Authors: Keefe RS, Vinogradov S, Medalia A, Silverstein SM, Bell MD, Dickinson D, Ventura J, Marder SR, Stroup TS.

The National Institute of Mental Health (NIMH)-Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Project and related efforts have stimulated the initiation of several studies of pharmacologic treatments for cognitive impairment in schizophrenia. Cognitive remediation may provide an excellent platform for the provision of new learning opportunities and the acquisition of new skills for patients who are engaged in pharmacologic trials to improve cognition. However, it is not clear how a cognitive remediation intervention would be employed in multisite clinical trials. A meeting of experts on cognitive remediation and related methodological topics was convened to address the feasibility and study design issues for the development of a multisite trial of cognitive remediation in schizophrenia called the Cognitive Remediation in the Schizophrenia Trials Network study. This report details the findings from this meeting, which included the following 4 conclusions. (1) A multisite trial of a cognitive remediation intervention using a network of diverse research sites would be of great scientific value. (2) Various interventions could be employed for this multisite trial. (3) Programs that do not address key motivational and interpersonal aspects of cognitive remediation may benefit from supplementation with "bridging groups" that allows patients to meet with others and to apply their newly acquired cognitive skills to everyday life. (4) Before a multisite efficacy trial is initiated, a pilot study could demonstrate the feasibility of conducting a trial using a cognitive remediation intervention.

Clinical characteristics of anxiety disord ered youth.

Authors: Kendall PC, Compton SN, Walkup JT, Birmaher B, Albano AM, Sherrill J, Ginsburg G, Rynn M, McCracken J, Gosch E, Keeton C, Bergman L, Sakolsky D, Suveg C, Iyengar S, March J, Piacentini J.

Reports the characteristics of a large, representative sample of treatment-seeking anxious youth (N=488). Participants, aged 7-17 years (mean 10.7 years), had a principal DSM-IV diagnosis of separation anxiety disorder (SAD), generalized anxiety disorder (GAD), or social phobia (SP). Although youth with a co-primary diagnosis for which a different disorder-specific treatment would be indicated (e.g., major depressive disorder, substance abuse) were not included, there were few other exclusion criteria. Participants and their parent/guardian underwent an extensive baseline assessment using a broad array of measures capturing diagnostic status, anxiety symptoms and severity, and areas of functional impairment. Means and standard deviations of the measures of psychopathology and data on diagnostic status are provided. The sample had moderate to severe anxiety disorder and was highly comorbid, with 55.3% of participants meeting criteria for at least one non-targeted DSM-IV disorder. Anxiety disorders in youth often do not present as a single/focused disorder: such disorders in youth overlap in symptoms and are highly comorbid among themselves.

Inhibitory motor control in response stopping and response switching.

Authors: Kenner NM, Mumford JA, Hommer RE, Skup M, Leibenluft E, Poldrack RA.

While much is known about the neural regions recruited in the human brain when a dominant motor response becomes inappropriate and must be stopped, less is known about the regions that support switching to a new, appropriate, response. Using functional magnetic resonance imaging with two variants of the stop-signal paradigm that require either stopping altogether or switching to a different response, we examined the brain systems involved in these two forms of executive control. Both stopping trials and switching trials showed common recruitment of the right inferior frontal gyrus, presupplementary motor area, and midbrain. Contrasting switching trials with stopping trials showed activation similar to that observed on response trials (where the initial response remains appropriate and no control is invoked), whereas there were no regions that showed significantly greater activity for stopping trials compared with switching trials. These results show that response switching can be supported by the same neural systems as response inhibition, and suggest that the same mechanism of rapid, nonselective response inhibition that is thought to support speeded response stopping can also support speeded response switching when paired with execution of the new, appropriate, response.

High Energy Density Nanocomposites Based on Surface-Modified BaTiO(3) and a Ferroelectric Polymer.

Authors: Kim P, Doss NM, Tillotson JP, Hotchkiss PJ, Pan MJ, Marder SR, Li J, Calame JP, Perry JW.

The dielectric permittivity and electric breakdown strength of nanocomposites comprising poly(vinylidene fluoride-co-hexafluoro propylene) and phosphonic acid surface-modified BaTiO(3) nanoparticles have been investigated as a function of the volume fraction of nanoparticles. The mode of binding of pentafluorobenzylphosphonic acid on the BaTiO(3) particles was investigated using infrared and (31)P solid-state nuclear magnetic resonance spectroscopy, and the phosphonic acid was found to form well ordered, tightly bound monolayers. The effective permittivity of nanocomposites with low volume fractions (<50%) was in good agreement with standard theoretical models, with a maximum relative permittivity of 35. However, for nanoparticle volume fractions of greater than 50%, the effective permittivity was observed to decrease with increasing nanoparticle volume fraction, and this was correlated with an increase in porosity of the spin-coated nanocomposite films. The dielectric breakdown strength was also found to decrease with increasing volume fraction of the BaTiO(3) nanoparticles, with an abrupt decrease observed around 10% and a gradual decrease for volume fractions of 20-50%. Comparison of these results with model calculations, using statistical particle packing simulations and effective medium theory for the permittivity and breakdown strength, indicates the important roles of nanoparticle percolation and porosity of the nanocomposites on the dielectric properties. The measured energy density at a field strength of 164 V/mum, well below the breakdown strength, increased to a value of 3.2 J/cm(3) as the nanoparticle volume fraction is increased to 50%, roughly in line with the trend of the permittivity. The calculated maximum energy densities indicate maximal extractable energy (7-8 J/cm(3) at 1 kHz) for two different particle volume fractions, as a result of the interplay of the dependencies of permittivity and breakdown strength on volume fraction.

HARDI denoising: variational regularization of the spherical apparent diffusion coefficient sADC

Authors: Kim Y, Thompson PM, Toga AW, Vese L, Zhan L.

We denoise HARDI (High Angular Resolution Diffusion Imaging) data arising in medical imaging. Diffusion imaging is a relatively new and powerful method to measure the 3D profile of water diffusion at each point. This can be used to reconstruct fiber directions and pathways in the living brain, providing detailed maps of fiber integrity and connectivity. HARDI is a powerful new extension of diffusion imaging, which goes beyond the diffusion tensor imaging (DTI) model: mathematically, intensity data is given at every voxel and at any direction on the sphere. However, HARDI data is usually highly contaminated with noise, depending on the b-value which is a tuning parameter preselected to collect the data. Larger b-values help to collect more accurate information in terms of measuring diffusivity, but more noise is generated by many factors as well. So large b-values are preferred, if we can satisfactorily reduce the noise without losing the data structure. We propose a variational method to denoise HARDI data by denoising the spherical Apparent Diffusion Coefficient (sADC), a field of radial functions derived from the data. We use vectorial total variation regularization, an L1 data fidelity term and the logarithmic barrier function in the minimization. We present experiments of denoising synthetic and real HARDI data.


Authors: Kim Y, Thompson PM, Vese LA.

In this work, we wish to denoise HARDI (High Angular Resolution Diffusion Imaging) data arising in medical brain imaging. Diffusion imaging is a relatively new and powerful method to measure the three-dimensional profile of water diffusion at each point in the brain. These images can be used to reconstruct fiber directions and pathways in the living brain, providing detailed maps of fiber integrity and connectivity. HARDI data is a powerful new extension of diffusion imaging, which goes beyond the diffusion tensor imaging (DTI) model: mathematically, intensity data is given at every voxel and at any direction on the sphere. Unfortunately, HARDI data is usually highly contaminated with noise, depending on the b-value which is a tuning parameter pre-selected to collect the data. Larger b-values help to collect more accurate information in terms of measuring diffusivity, but more noise is generated by many factors as well. So large b-values are preferred, if we can satisfactorily reduce the noise without losing the data structure. Here we propose two variational methods to denoise HARDI data. The first one directly denoises the collected data S, while the second one denoises the so-called sADC (spherical Apparent Diffusion Coefficient), a field of radial functions derived from the data. These two quantities are related by an equation of the form S = S(S)exp (-b . sADC) (in the noise-free case). By applying these two different models, we will be able to determine which quantity will most accurately preserve data structure after denoising. The theoretical analysis of the proposed models is presented, together with experimental results and comparisons for denoising synthetic and real HARDI data.

Dipolar Second-Order Nonlinear Optical Chromophores Containing Ferrocene, Octamethylferrocene, and Ruthenocene Donors and Strong pi-Acceptors: Crystal Structures and Comparison of pi-Donor Strengths.

Authors: Kinnibrugh TL, Salman S, Getmanenko YA, Coropceanu V, Porter WW, Timofeeva TV, Matzger AJ, Brédas JL, Marder SR, Barlow S.

Crystal structures have been determined for six dipolar polyene chromophores with metallocenyl - ferrocenyl (Fc), octamethylferrocenyl (Fc''), or ruthenocenyl (Rc) - donors and strong heterocyclic acceptors based on 1,3-diethyl-2-thiobarbituric acid or 3-dicyanomethylidene-2,3-dihydrobenzothiophene-1,1-dioxide. In each case, crystals were found to belong to centrosymmetric space groups. For one example, polymer-induced heteronucleation revealed the existence of two additional polymorphs, which were inactive in second-harmonic generation, suggesting that they were also centrosymmetric. The bond-length alternations between the formally double and single bonds of the polyene bridges are reduced compared to simple polyenes, indicating significant contribution from charge-separated resonance structures, although the metallocenes are not significantly distorted towards the [(eta(6)-fulvene)(eta(5)-cyclopentadienyl)metal(II)](+) extreme. DFT geometries are in excellent agreement with those determined crystallographically; while the pi-donor strengths of the three metallocenyl groups are insufficiently different to result in detectable differences in the crystallographic bond-length alternations, the DFT geometries, as well as DFT-calculations of partial charges for atoms, suggest that pi-donor strength decreases in the order Fc'' >> Fc > Rc. NMR, IR and electrochemical evidence also suggests that octamethylferrocenyl is the stronger pi-donor, exhibiting similar pi-donor strength to a p-(dialkylamino)phenyl group, while ferrocenyl and ruthenocenyl show very similar pi-donor strengths to one another in chromophores of this type.

The Brief Negative Symptom Scale: Psychometric Properties.

Authors: Kirkpatrick B, Strauss G, Nguyen L, Fischer BA, Daniel DG, Cienfuegos A, Marder SR.

The participants in the NIMH-MATRICS Consensus Development Conference on Negative Symptoms recommended that an instrument be developed that measured blunted affect, alogia, asociality, anhedonia, and avolition. The Brief Negative Symptom Scale (BNSS) is a 13-item instrument designed for clinical trials and other studies that measures these 5 domains. The interrater, test-retest, and internal consistency of the instrument were strong, with respective intraclass correlation coefficients of 0.93 for the BNSS total score and values of 0.89-0.95 for individual subscales. Comparisons with positive symptoms and other negative symptom instruments supported the discriminant and concurrent validity of the instrument.

Genetics of primary cerebral gyrification: Heritability of length, depth and area of primary sulci in an extended pedigree of Papio baboons.

Authors: Kochunov P, Glahn DC, Fox PT, Lancaster JL, Saleem K, Shelledy W, Zilles K, Thompson PM, Coulon O, Mangin JF, Blangero J, Rogers J.

Genetic control over morphological variability of primary sulci and gyri is of great interest in the evolutionary, developmental and clinical neurosciences. Primary structures emerge early in development and their morphology is thought to be related to neuronal differentiation, development of functional connections and cortical lateralization. We measured the proportional contributions of genetics and environment to regional variability, testing two theories regarding regional modulation of genetic influences by ontogenic and phenotypic factors. Our measures were surface area, and average length and depth of eleven primary cortical sulci from high-resolution MR images in 180 pedigreed baboons. Average heritability values for sulcal area, depth and length (h(2)(Area)=.38+/-.22;h(2)(Depth)=.42+/-.23;h(2)(Length)=.34+/-.22) indicated that regional cortical anatomy is under genetic control. The regional pattern of genetic contributions was complex and, contrary to previously proposed theories, did not depend upon sulcal depth, or upon the sequence in which structures appear during development. Our results imply that heritability of sulcal phenotypes may be regionally modulated by arcuate U-fiber systems. However, further research is necessary to unravel the complexity of genetic contributions to cortical morphology.

Genetics of microstructure of cerebral white matter using diffusion tensor imaging.

Authors: Kochunov P, Glahn DC, Lancaster JL, Winkler AM, Smith S, Thompson PM, Almasy L, Duggirala R, Fox PT, Blangero J.

We analyzed the degree of genetic control over intersubject variability in the microstructure of cerebral white matter (WM) using diffusion tensor imaging (DTI). We performed heritability, genetic correlation and quantitative trait loci (QTL) analyses for the whole-brain and 10 major cerebral WM tracts. Average measurements for fractional anisotropy (FA), radial (L perpendicular) and axial (L(||)) diffusivities served as quantitative traits. These analyses were done in 467 healthy individuals (182 males/285 females; average age 47.9+/-13.5 years; age range:19-85 years), recruited from randomly-ascertained pedigrees of extended families. Significant heritability was observed for FA (h(2)=.52+/-.11; p=10(-7)) and L perpendicular (h(2)=.37+/-.14; p=0.001), while L(||) measurements were not significantly heritable (h(2)=.09+/-.12; p=.20). Genetic correlation analysis indicated that the FA and L perpendicular shared 46% of the genetic variance. Tract-wise analysis revealed a regionally diverse pattern of genetic control, which was unrelated to ontogenic factors, such as tract-wise age-of-peak FA values and rates of age-related change in FA. QTL analysis indicated linkages for whole-brain average FA (LOD=2.36) at the marker D15S816 on chromosome 15q25, and for L perpendicular (LOD=2.24) near the marker D3S1754 on the chromosome 3q27. These sites have been reported to have significant co-inheritance with two psychiatric disorders (major depression and obsessive-compulsive disorder) in which patients show characteristic alterations in cerebral WM. Our findings suggest that the microstructure of cerebral white matter is under a strong genetic control and further studies in healthy as well as patients with brain-related illnesses are imperative to identify the genes that may influence cerebral white matter.

Boosting power for clinical trials using classifiers based on multiple biomarkers.

Authors: Kohannim O, Hua X, Hibar DP, Lee S, Chou YY, Toga AW, Jack CR Jr, Weiner MW, Thompson PM; The Alzheimer's Disease Neuroimaging Initiative.

Machine learning methods pool diverse information to perform computer-assisted diagnosis and predict future clinical decline. We introduce a machine learning method to boost power in clinical trials. We created a Support Vector Machine algorithm that combines brain imaging and other biomarkers to classify 737 Alzheimer's disease Neuroimaging initiative (ADNI) subjects as having Alzheimer's disease (AD), mild cognitive impairment (MCI), or normal controls. We trained our classifiers based on example data including: MRI measures of hippocampal, ventricular, and temporal lobe volumes, a PET-FDG numerical summary, CSF biomarkers (t-tau, p-tau, and Abeta(42)), ApoE genotype, age, sex, and body mass index. MRI measures contributed most to Alzheimer's disease (AD) classification; PET-FDG and CSF biomarkers, particularly Abeta(42), contributed more to MCI classification. Using all biomarkers jointly, we used our classifier to select the one-third of the subjects most likely to decline. In this subsample, fewer than 40 AD and MCI subjects would be needed to detect a 25% slowing in temporal lobe atrophy rates with 80% power-a substantial boosting of power relative to standard imaging measures. Copyright © 2010 Elsevier Inc. All rights reserved.

Everything you never wanted to know about circular analysis, but were afraid to ask.

Authors: Kriegeskorte N, Lindquist MA, Nichols TE, Poldrack RA, Vul E.

Over the past year, a heated discussion about 'circular' or 'nonindependent' analysis in brain imaging has emerged in the literature. An analysis is circular (or nonindependent) if it is based on data that were selected for showing the effect of interest or a related effect. The authors of this paper are researchers who have contributed to the discussion and span a range of viewpoints. To clarify points of agreement and disagreement in the community, we collaboratively assembled a series of questions on circularity herein, to which we provide our individual current answers in

The Content of Substance Abuse and Mental Health Counseling Reported by Patients in a National Survey.

Authors: Landry C, Klap R, Tang L, Liao D, Miranda J, Wells KB.

This study examined counseling content reported by a national sample of persons receiving care for alcohol, drug or mental health (ADM) problems in a year. The sample included 2,722 individuals over 18 who reported past year mental health or substance abuse care or assessments in a nationally representative survey conducted in 2000-2001. Counseling domains approximating commonly practiced or evidence-based approaches for depression, anxiety, or substance abuse were assessed. Patient self-report may be one useful way of tracking whether components of standard therapies are implemented in practice.

On Genome-wide Association Studies for Fami ly-Based Designs: An Integrative Analysis Approach Combining Ascertained Family Samples with Unselected Controls.

Authors: Lasky-Su J, Won S, Mick E, Anney RJ, Franke B, Neale B, Biederman J, Smalley SL, Loo SK, Todorov A, Faraone SV, Weiss ST, Lange C.

Large numbers of control individuals with genome-wide genotype data are now available through various databases. These controls are regularly used in case-control genome-wide association studies (GWAS) to increase the statistical power. Controls are often "unselected" for the disease of interest and are not matched to cases in terms of confounding factors, making the studies more vulnerable to confounding as a result of population stratification. In this communication, we demonstrate that family-based designs can integrate unselected controls from other studies into the analysis without compromising the robustness of family-based designs against genetic confounding. The result is a hybrid case-control family-based analysis that achieves higher power levels than population-based studies with the same number of cases and controls. This strategy is widely applicable and works ideally for all situations in which both family and case-control data are available. The approach consists of three steps. First, we perform a standard family-based association test that does not utilize the between-family component. Second, we use the between-family information in conjunction with the genotypes from unselected controls in a Cochran-Armitage trend test. The p values from this step are then calculated by rank ordering the individual Cochran-Armitage trend test statistics for the genotype markers. Third, we generate a combined p value with the association p values from the first two steps. Simulation studies are used to assess the achievable power levels of this method compared to standard analysis approaches. We illustrate the approach by an application to a GWAS of attention deficit hyperactivity disorder parent-offspring trios and publicly available controls. Copyright © 2010 The American Society of Human Genetics.

Striatal Dopamine D2/D3 Receptor Availability Is Reduced in Methamphetamine Dependence and Is Linked to Impulsivity.

Authors: Lee B, London ED, Poldrack RA, Farahi J, Nacca A, Monterosso JR, Mumford JA, Bokarius AV, Dahlbom M, Mukherjee J, Bilder RM, Brody AL, Mandelkern MA.

While methamphetamine addiction has been associated with both impulsivity and striatal dopamine D(2)/D(3) receptor deficits, human studies have not directly linked the latter two entities. We therefore compared methamphetamine-dependent and healthy control subjects using the Barratt Impulsiveness Scale (version 11, BIS-11) and positron emission tomography with [(18)F]fallypride to measure striatal dopamine D(2)/D(3) receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. They had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales (p < 0.001). Volume-of-interest analysis found lower striatal D(2)/D(3) receptor availability in methamphetamine-dependent than in healthy control subjects (p < 0.01) and a negative relationship between impulsiveness and striatal D(2)/D(3) receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D(2)/D(3) receptor availability in left caudate nucleus and right lateral putamen/claustrum (p < 0.05, determined by threshold-free cluster enhancement). In separate group analyses, correlations involving the head and body of the caudate and the putamen of methamphetamine-dependent subjects and the lateral putamen/claustrum of control subjects were observed at a weaker threshold (p < 0.12 corrected). The findings suggest that low striatal D(2)/D(3) receptor availability may mediate impulsive temperament and thereby influence addiction.

A Schizophrenia Risk Gene, ZNF804A, Influences Neuroanatomical and Neurocognitive Phenotypes.

Authors: Lencz T, Szeszko PR, Derosse P, Burdick KE, Bromet EJ, Bilder RM, Malhotra AK.

ZNF804A is one of the strongest candidate genes for schizophrenia (SZ), yet its function and role in disease pathophysiology are largely unknown. The only in vivo endophenotype study of the SZ-associated SNP (rs1344706) pointed towards effects on brain functional connectivity. We examined the relationship of this SNP to neuroanatomical and neurocognitive phenotypes that were assessed in healthy individuals. Volunteers with no history of psychiatric illness were assessed with structural magnetic resonance imaging (1.5T GE scanner, standard gradient-echo acquisition). Carriers of the minor allele were compared with homozygotes for the T (SZ-associated) allele on measures of total volume of the white matter (WM), gray matter (GM), and cerebrospinal fluid compartments, as well as on voxel-wise measurements of regional brain volumes. After examining the correlation between genotype-associated regions of interest and neurocognitive performance measures, the effects of rs1344706 genotype on a measure of visuomotor performance speed (trails A) were examined in an independent cohort of volunteers. Among healthy subjects, risk allele homozygotes showed larger total WM volumes than carriers of the other allele. Controlling for WM volumes, these same subjects showed reduced GM volumes in several regions comprising the 'default mode network,' including angular gyrus, parahippocampal gyrus, posterior cingulate, and medial orbitofrontal gyrus/gyrus rectus (FDR-corrected p<0.05). The risk allele dosage also predicted impairments on a timed visuomotor performance task (trails A). Results support a role of ZNF804A in phenotypes reflecting altered neural connectivity.Neuropsychopharmacology advance online publication, 21 July 2010; doi:10.1038/npp.2010.102.

Comparison of clinical features among youth with tic disorders, obsessive-compulsive disorder (OCD), and both conditions.

Authors: Lewin AB, Chang S, McCracken J, McQueen M, Piacentini J.

The comorbidity of tic disorders (TD) and obsessive-compulsive disorder (OCD) has long been recognized in the clinical literature and appears to be bidirectional, affecting 20-60% of individuals with each disorder. Coffey et al. (1998) found that adults with TD+OCD had a more severe comorbidity profile than adults with OCD or TD alone. This exploratory study in children attempts to evaluate whether heightened diagnostic severity, increased comorbidity load, and lower functioning is more commonplace in youth with TD+OCD in comparison to either syndrome alone. Participants were 306 children (seeking clinical evaluation) with TD, OCD, or TD+OCD. Assessment consisted of a diagnostic battery (including structured diagnostic interviews and standardized parent-report inventories) to evaluate diagnostic severity, comorbid psychopathology, behavioral and emotional correlates, and general psychosocial functioning. Data from this study sample were not supportive of the premise that youth with both a tic disorder and OCD present with elevated diagnostic severity, higher risk-for or intensity-of comorbidity, increased likelihood of externalizing/internalizing symptomatology, or lower broad-based adaptive functioning. The OCD group had elevated rates of comorbid anxiety disorders and attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) were more prevalent among youth in the TD group. The three groups also differed on key demographic variables. Our findings suggest that, in contrast to adults, TD+OCD in children and adolescents does not represent a more severe condition than either disorder alone on the basis of diagnostic comorbidity, symptom severity, or functional impairment.

Correlates of insight among youth with obsessive-compulsive disorder.

Authors: Lewin AB, Lindsey Bergman R, Peris TS, Chang S, McCracken JT, Piacentini J.

Individuals with Obsessive-Compulsive Disorder (OCD) may lack insight into the irrational nature of their symptoms. Among adults with OCD, poor insight has been linked to greater symptom severity, increased likelihood of comorbid symptoms, lower adaptive functioning, and worse treatment outcomes. Parallel work regarding insight among children and adolescents, with OCD, is lacking. The aim of this research was to examine links between insight and demographic, cognitive, and clinical factors among youth with OCD. Methods: Seventy-one youths with OCD (mean age = 11.7; 63% = male) were assessed as part of a larger treatment trial. Insight was measured via clinician interview. Results: Youth with low insight had poorer intellectual functioning and reported decreased perception of control over their environment. Additionally, youth with low insight were more likely to be younger, to report higher levels of depressive symptoms, and to report lower levels of adaptive functioning. Conclusion: This set of cognitive, developmental and clinical factors that may predispose youth with OCD to have diminished insight. Data provide initial empirical support for diagnostic differences between youth and adults with regard to requiring intact insight. Implications for treatment are discussed.

The relationship between psychotic-like symptoms and neurocognitive performance in a g eneral adolescent psychiatric sample.

Authors: Lindgren M, Manninen M, Laajasalo T, Mustonen U, Kalska H, Suvisaari J, Moilanen K, Cannon TD, Huttunen M, Therman S.

INTRODUCTION: The current criteria for detecting a Clinical High-Risk (CHR) state for psychosis do not address cognitive impairment. A first step for identifying cognitive markers of psychosis risk would be to determine which aspects of neurocognitive performance are related with more severe psychotic-like symptoms. This study assessed cognitive impairment associated with prodromal symptoms in adolescents receiving public psychiatric treatment. METHODS: 189 adolescents were recruited from consecutive new patients aged 15-18 attending mainly outpatient adolescent psychiatric units in Helsinki. They had been screened for prodromal symptoms using the Prodromal Questionnaire, and all screen-positives as well as a random sample of screen-negatives were interviewed using the Structured Interview for Prodromal Symptoms (SIPS) and underwent testing using a large, standardized neurocognitive test battery. The sample included 62 adolescents who met the CHR criteria (CHR) and 112 who did not (non-CHR). A healthy control sample (n=72) was also included to provide age- and gender-matched norms. RESULTS: The CHR group performed worse on visuospatial tasks than the non-CHR group. Among CHR adolescents, negative symptoms were associated with slower processing speed and poorer performance on verbal tasks. Among non-CHR adolescents, positive symptoms were associated with poorer performance on visuospatial tasks, and negative symptoms with poorer performance on verbal tasks. CONCLUSION: Clinical high-risk status is associated with impaired visuospatial task performance. However, both positive, psychotic-like symptoms and negative symptoms are associated with lower levels of neurocognitive functioning among adolescents in psychiatric treatment regardless of whether CHR criteria are met. Thus, even mild positive and negative symptoms may have clinical relevance in adolescents in psychiatric care. Adolescents with both psychotic-like symptoms and neurocognitive deficits constitute a group requiring special attention.

Comparison of the 1988 and 2002 phocine distemper epizootics in British harbour s eal Phoca vitulina populations.

Authors: Lonergan M, Hall A, Thompson H, Thompson PM, Pomeroy P, Harwood J.

In 1988 and 2002 dramatic and well-documented phocine distemper epizootics occurred in Europe. While their progression and impact were remarkably similar and consistent over much of Europe, mortality in the UK varied greatly between and within the 2 epizootics. We use antibody levels in blood samples to show that 51% (Bayesian 95% CI: 41 to 61%) of the individuals alive in 5 UK harbour seal populations at the end of the 1988 epizootic had been exposed to the virus, and that the equivalent figure after the 2002 outbreak was 22% (95% CI: 16 to 30%). Antibody prevalence was significantly higher in females than males after the 2002 epizootic. Combining these estimates with information on reductions in the numbers of animals observed hauled out during surveys of the Wash, Moray Firth, and Orkney populations and a simple epidemiological model, suggests that the differences between the 2 epizootics were primarily due to a 27% (95% CI: 8 to 43%) fall in R0, the basic reproductive rate of the virus. The large geographic variation in population effects observed within the UK during each epizootic appears to have been mainly due to differences in case mortality, with R0 being remarkably similar in all the populations investigated.

Familial Clustering and DRD4 Effects on Electroencephalogram Measures in Multiplex Families With Attention Deficit/Hyperactivity Disorder.

Authors: Loo SK, Hale ST, Hanada G, Macion J, Shrestha A, McGough JJ, McCracken JT, Nelson S, Smalley SL.

The current study tests electroencephalogram (EEG) measures as a potential endophenotype for attention deficit/hyperactivity disorder (ADHD) by examining sibling and parent-offspring similarity, familial clustering with the disorder, and association with the dopamine receptor D4 (DRD4) candidate gene. METHOD:: The sample consists of 531 participants (191 parents and 340 children) from 132 multiplex families with ADHD who participated in a larger genetics study. All members of the families underwent extensive assessment including semi-structured diagnostic interviews and EEG recording. RESULTS:: Strong sibling similarity and parent-offspring correlations in EEG power emerged, suggesting high trait heritability. Increased theta power was observed among children with ADHD when compared with unaffected children, and there were no differences according to ADHD subtype. Within the parent sample, ADHD diagnostic status and ADHD subtype group differences emerged in the theta, alpha, and beta frequency bands. DRD4 effects for both parents and children were apparent in the beta frequency band and for children only in the theta frequency band. CONCLUSIONS:: This study suggests that EEG measures are a promising avenue of study in the search for putative endophenotypes for ADHD, and that variability at the DRD4 gene may contribute to this endophenotype.

When more is less: Associations between corpus callosum size and handedness lateralization.

Authors: Luders E, Cherbuin N, Thompson PM, Gutman B, Anstey KJ, Sachdev P, Toga AW.

Although not consistently replicated, a substantial number of studies suggest that left-handers have larger callosal regions than right-handers. We challenge this notion and propose that callosal size is not linked to left-handedness or right-handedness per se but to the degree of handedness lateralization. To test this hypothesis, we investigated the thickness of the corpus callosum in a large data set (n=361). We analyzed the correlations between callosal thickness and the degree of handedness lateralization in 324 right-handers and 37 left-handers at 100 equidistant points across the corpus callosum. We revealed significant negative correlations within the anterior and posterior midbody suggesting that larger callosal dimensions in these regions are associated with a weaker handedness lateralization. Significant positive correlations were completely absent. In addition, we compared callosal thickness between moderately lateralized left-handers (n=37) and three equally sized groups (n=37) of right-handers (strongly, moderately, and weakly lateralized). The outcomes of these group analyses confirmed the negative association between callosal size and handedness lateralization, although callosal differences between right- and left-handers did not reach statistical significance. This suggests that callosal differences are rather small, if examined as a dichotomy between two handedness groups. Future studies will expand this line of research by increasing the number of left-handers to boost statistical power, and by combining macro- and micro-structural, as well as functional and behavioral measurements to identify the biological mechanisms linking callosal morphology and handedness lateralization. Copyright © 2010. Published by Elsevier Inc.

Mapping the Relationship between Cortical Convolution and Intelligence: Effects of Gender.

Authors: Luders E, Narr KL, Bilder RM, Szeszko PR, Gurbani MN, Hamilton L, Toga AW, Gaser C.

The pronounced convolution of the human cortex may be a morphological substrate that supports some of our species' most distinctive cognitive abilities. Therefore, individual intelligence within humans might be modulated by the degree of folding in certain cortical regions. We applied advanced methods to analyze cortical convolution at high spatial resolution and correlated those measurements with intelligence quotients. Within a large sample of healthy adult subjects (n = 65), we detected the most prominent correlations in the left medial hemisphere. More specifically, intelligence scores were positively associated with the degree of folding in the temporo-occipital lobe, particularly in the outermost section of the posterior cingulate gyrus (retrosplenial areas). Thus, this region might be an important contributor toward individual intelligence, either via modulating pathways to (pre)frontal regions or by serving as a location for the convergence of information. Prominent gender differences within the right frontal cortex were observed; females showed uncorrected significant positive correlations and males showed a nonsignificant trend toward negative correlations. It is possible that formerly described gender differences in regional convolution are associated with differences in the underlying architecture. This might lead to the development of sexually dimorphic information processing strategies and affect the relationship between intelligence and cortical convolution.

Neuroanatomical Correlates of Intelligence.

Authors: Luders E, Narr KL, Thompson PM, Toga AW.

With the advancement of image acquisition and analysis methods in recent decades, unique opportunities have emerged to study the neuroanatomical correlates of intelligence. Traditional approaches examining global measures have been complemented by insights from more regional analyses based on pre-defined areas. Newer state-of-the-art approaches have further enhanced our ability to localize the presence of correlations between cerebral characteristics and intelligence with high anatomic precision. These in vivo assessments have confirmed mainly positive correlations, suggesting that optimally increased brain regions are associated with better cognitive performance. Findings further suggest that the models proposed to explain the anatomical substrates of intelligence should address contributions from not only (pre)frontal regions, but also widely distributed networks throughout the whole brain.

The development of the corpus callosum in the healthy human brain.

Authors: Luders E, Thompson PM, Toga AW.

The corpus callosum changes structurally throughout life, but most dramatically during childhood and adolescence. Even so, existing studies of callosal development tend to use parcellation schemes that may not capture the complex spatial profile of anatomical changes. Thus, more detailed mapping of callosal growth processes is desirable to create a normative reference. This will help to relate and interpret other structural, functional, and behavioral measurements, both from healthy subjects and pediatric patients. We applied computational surface-based mesh-modeling methods to analyze callosal morphology at extremely high spatial resolution. We mapped callosal development and explored sex differences in a large and well matched sample of healthy children and adolescents (n = 190) aged 5-18 years. Except for the rostrum in females, callosal thickness increased across the whole surface, with sex- and region-specific rates of growth, and at times shrinkage. The temporally distinct changes in callosal thickness are likely to be a consequence of varying degrees of axonal myelination, redirection, and pruning. Alternating phases of callosal growth and shrinkage may reflect a permanent adjustment and fine-tuning of fibers connecting homologous cortical areas during childhood and adolescence. Our findings emphasize the importance of taking into account sex differences in future studies, as existing developmental effects might remain disguised (or biased toward the effect of the dominant sex in unbalanced statistical designs) when pooling male and female samples.

Hippocampal volume reduction in congenital central hypoventilation syndrome.

Authors: Macey PM, Richard CA, Kumar R, Woo MA, Ogren JA, Avedissian C, Thompson PM, Harper RM.

Children with congenital central hypoventilation syndrome (CCHS), a genetic disorder characterized by diminished drive to breathe during sleep and impaired CO(2) sensitivity, show brain structural and functional changes on magnetic resonance imaging (MRI) scans, with impaired responses in specific hippocampal regions, suggesting localized injury.We assessed total volume and regional variation in hippocampal surface morphology to identify areas affected in the syndrome. We studied 18 CCHS (mean age+/-std: 15.1+/-2.2 years; 8 female) and 32 healthy control (age 15.2+/-2.4 years; 14 female) children, and traced hippocampi on 1 mm(3) resolution T1-weighted scans, collected with a 3.0 Tesla MRI scanner. Regional hippocampal volume variations, adjusted for cranial volume, were compared between groups based on t-tests of surface distances to the structure midline, with correction for multiple comparisons. Significant tissue losses emerged in CCHS patients on the left side, with a trend for loss on the right; however, most areas affected on the left also showed equivalent right-sided volume reductions. Reduced regional volumes appeared in the left rostral hippocampus, bilateral areas in mid and mid-to-caudal regions, and a dorsal-caudal region, adjacent to the fimbria.The volume losses may result from hypoxic exposure following hypoventilation during sleep-disordered breathing, or from developmental or vascular consequences of genetic mutations in the syndrome. The sites of change overlap regions of abnormal functional responses to respiratory and autonomic challenges. Affected hippocampal areas have roles associated with memory, mood, and indirectly, autonomic regulation; impairments in these behavioral and physiological functions appear in CCHS

3D maps localize caudate nucleus atrophy in 400 Alzheimer's dis ease, mild cognitive impairment, and healthy elderly subjects.

Authors: Madsen SK, Ho AJ, Hua X, Saharan PS, Toga AW, Jack CR Jr, Weiner MW, Thompson PM; The Alzheimer's Disease Neuroimaging Initiative.

MRI research examining structural brain atrophy in Alzheimer's disease (AD) generally focuses on medial temporal and cortical structures, but amyloid and tau deposits also accumulate in the caudate. Here we mapped the 3D profile of caudate atrophy using a surface mapping approach in subjects with AD and mild cognitive impairment (MCI) to identify potential clinical and pathological correlates. 3D surface models of the caudate were automatically extracted from 400 baseline MRI scans (100 AD, 200 MCI, 100 healthy elderly). Compared to controls, caudate volumes were lower in MCI (2.64% left, 4.43% right) and AD (4.74% left, 8.47% right). Caudate atrophy was associated with age, sum-of-boxes and global Clinical Dementia Ratings, Delayed Logical Memory scores, MMSE decline 1 year later, and body mass index. Reduced right (but not left) volume was associated with MCI-to-AD conversion and CSF tau levels. Normal caudate asymmetry (with the right 3.9% larger than left) was lost in AD, suggesting preferential right caudate atrophy. Automated caudate maps may complement other MRI-derived measures of disease burden in AD.

Excited-state dynamics and dye-dye interactions in dye-coated gold nanoparticles with varying alkyl spacer lengths.

Authors: Malicki M, Hales JM, Rumi M, Barlow S, McClary L, Marder SR, Perry JW.

Gold nanoparticles (ca. 3 nm in diameter) coated with bis(diarylamino)biphenyl-based thiols with two different alkyl spacers (propyl and dodecyl) between the chromophore and the surface-anchoring thiol group have been prepared and characterized with a variety of techniques. The excited-state dynamics of the dyes in close proximity to the nanoparticle surface were studied using the time-correlated single-photon counting technique and near-IR fs transient absorption spectroscopy. The excited states of the dyes in the hybrid metal/organic systems exhibit an ultrafast (<5 ps) deactivation as evidenced by the fs transient absorption measurements. The length of the alkyl spacer between the dye and the thiol group has a profound effect on the ultrafast dynamics of the photoexcited systems. An ultrafast formation (ca. 0.5 ps) of a cation-like species has been recorded for the system incorporating the propyl spacer but not for the dodecyl-linker system. The formation of the cation-like species has been shown to be less efficient in a mixed-ligand system in which the bis(diarylamino)biphenyl-based thiol was diluted on the surface with dodecanethiol. Additionally, the ultrafast formation (ca. 1 ps) of a cation-like species with a similar spectroscopic signature has been observed in the solid state of the dye. A combination of the ultrafast dynamics and (1)H NMR spectroscopic data has been used to discuss the observed behavior in terms of dye-dye interactions in the nanoparticle systems. Due to the surface curvature of the nanoparticle, the propyl spacer imposes a closer dye-dye distance than the dodecyl spacer, thus facilitating dye-dye interactions that lead to the formation of a charge-transfer species involving two or more dye molecules.

2010 Wayne Fenton Award for Exceptional Clinical Care: The Wayne Fenton Award for Exceptional Clinical Care was established in 2007 to recognize clinical providers who exemplify Dr. Fenton's commitment to improving the daily lives of individuals with schizophrenia.

Authors: Marder SR

Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation.

Authors: Marder SR, Sorsaburu S, Dunayevich E, Karagianis JL, Dawe IC, Falk DM, Dellva MA, Carlson JL, Cavazzoni PA, Baker RW.

Agitation is a medical emergency with increased risk for poor outcome. Successful treatment often requires intramuscular (IM) psychotropics. Safety data from the first 21 months of olanzapine IM, approved in the United States for the treatment of agitation associated with schizophrenia and bipolar disorder, are presented. METHOD: A Lilly-maintained safety database was searched for all spontaneous adverse events (AEs) reported in temporal association with olanzapine IM treatment. RESULTS: The estimated worldwide patient exposure to olanzapine IM from January 1, 2004, through September 30, 2005, was 539,000; 160 cases containing AEs were reported from patients with schizophrenia (30%), bipolar disorder (21%), unspecified psychosis (10%), dementia (8%), and depression (5%). Many reported concomitant treatment with benzodiazepines (39%) or other antipsychotics (54%). The most frequently reported events involved the following organ systems: central nervous (21%), cardiac (12%), respiratory (6%), vascular (6%), and psychiatric (5%). Eighty-three cases were considered serious, including 29 fatalities. In these fatalities, concomitant benzodiazepines or other antipsychotics were reported in 66% and 76% of cases, respectively. The most frequently reported events in the fatal cases involved the following organ systems: cardiovascular (41%), respiratory (21%), general (17%), and central nervous (10%). The majority of fatal cases (76%) included comorbid conditions and potentially clinically significant risk factors for AEs. CONCLUSIONS: Clinicians should use care when treating agitated patients, especially when they present with concurrent medical conditions and are treated with multiple medications, which may increase the risk of poor or even fatal outcomes. Clinicians should use caution when using olanzapine IM and parenteral benzodiazepines simultaneously.

Using End Groups to Tune the Linear and Nonlinear Optical Properties of Bis(dioxaborine)-Terminated Polymethine Dyes.

Authors: Matichak JD, Hales JM, Ohira S, Barlow S, Jang SH, Jen AK, Brédas JL, Perry JW, Marder SR.

Six anionic pentamethine dyes with different 2,2-difluoro-4-aryl-1,3,2(2 H)-dioxaborin-6-yl termini were synthesized and isolated as tetra-n-octylammonium salts with a variety of aryl groups appended to increase conjugation beyond the dioxaborine termini. The increased conjugation was expected to decrease the energy of the lowest-lying excited state, and increase the transition dipole moment linking this state to the ground state, which would be anticipated to result in an increase in the real part of the third-order polarizability, Re(gamma). UV/Vis-NIR absorption spectroscopy indicates that the absorption maxima in DMSO vary from 691 to 761 nm, with the longest wavelength transitions observed for a derivative where the aryl group is 4-nitrophenyl. Closed-aperture Z-scan measurements at 1.3 mum in DMSO indicate that Re(gamma) varies from -2.9x10(-33) to -5.4x10(-33) esu in these systems. The largest magnitude of Re(gamma) was observed for a dye with E-4-styrylphenyl aryl groups. This result can be rationalized using a two-state expression which relates Re(gamma) to the energy and transition dipole moment of the transition from the ground state to the lowest-lying excited state. A nonamethine analogue of this compound was also synthesized and exhibits a slightly larger Re(gamma) with respect to a previously reported bis(dioxaborine)-terminated nonamethine. The extension of conjugation beyond the dioxaborine termini seems to result in an overall increase in Re(gamma). However, the effects are smaller than those found by increasing conjugation in the polymethine bridge due to reduced participation of terminal groups in the HOMO.

Possible Influence of Variant of the P-Glycoprotein Gene (MDR1/ABCB1) on Clinical Response to Guanfacine in Children with Pervasive Developmental Disorders and Hyperactivity.

Authors: McCracken JT, Aman MG, McDougle CJ, Tierney E, Shiraga S, Whelan F, Arnold LE, Posey D, Ritz L, Vitiello B, Scahill L.

From the Research Units on Pediatric Psychopharmacology Autism Network. University of California at Los Angeles : Principal Investigator James T. McCracken, M.D., Co-investigators Bhavik Shah, M.D., Pegeen Cronin, Ph.D., Lisa Sea-Yun Lee, B.A.; Ohio State University : Principal Investigator Michael G. Aman, Ph.D., Co-Investigators L. Eugene Arnold, M.Ed., M.D., Yaser Ramadan, M.D., Andrea Witwer, B.S., Ronald Lindsay, M.D.; Indiana University : Principal Investigator Christopher J. McDougle, M.D., Co-Investigators David J. Posey, M.D., Naomi Swiezy, Ph.D., Arlene Kohn, B.A.; Yale University : Principal Investigator, Lawrence Scahill, M.S.N., Ph.D., Co-Investigators Andres Martin, M.D., Kathleen Koenig, M.S.N., Deirdre Carroll, M.S.N., Christopher Young, M.D., Allison Lancor, B.A.; Kennedy Krieger Institute : Principal Investigator Elaine Tierney, M.D., Co-Investigators Jaswinder Ghuman, M.D., Nilda M. Gonzalez, M.D., Marco Grados, M.D.; National Institute of Mental Health : Principal Investigator Benedetto Vitiello, M.D., Co-Investigator Louise Ritz, M.B.A.; Columbia University (statistical analysis): Shirley Chuang, M.S., Mark Davies, M.P.H.; Nathan Kline Institute (data management): James Robinson, M.E.D., Don McMahon, M.S. Abstract Objective: Guanfacine has been shown to reduce hyperactive behaviors in children with attention-deficit/hyperactivity disorder (ADHD) and possibly in children with pervasive developmental disorder (PDD) and hyperactivity. The aim of this exploratory study was to examine whether gene variants encoding the multidrug resistance protein (MDR1 or ABCB1) , a drug transporter at the blood-brain barrier, are associated with variability in the efficacy of guanfacine in children with PDD and hyperactivity. Methods: Children with PDD who participated in an 8-week open-label trial of guanfacine were genotyped for the C3435T single-nucleotide polymorphism (SNP) variant of the MDR1 gene, a variant reported to alter function of the transporter. The decrease from baseline to 8 weeks in parent-rated Aberrant Behavior Checklist (ABC) hyperactivity and Swanson, Nolan, and Pelham (SNAP) scores were analyzed by MDR1 genotype. Response was compared between subjects homozygous for the minor allele T of the C34535T MDR1 variant (T/T) versus other genotypes (C/T and C/C). Results: Disruptive behavior decreased during guanfacine treatment as assessed by several end points in the 25 enrolled children (23 boys and 2 girls). Genotype data were available from 22 children. Subjects with either C/T or C/C (n = 16) genotypes showed a three-fold greater improvement than T/T MDR1 C3435T genotype (n = 6) (mean decrease of 15.1 +/- 12.6, or 50.7% from baseline, versus 4.5 +/- 5.1, or 15.6% from baseline) in parent-rated ABC Hyperactivity scores over 8 weeks (p = 0.03). Parent-rated ADHD SNAP scores also differed by genotype (p = 0.05). Conclusions: Gene variants in MDR1 may influence guanfacine response on hyperactive-impulsive behaviors via altered membrane transport. If replicated in larger samples, additional studies would be important to clarify the mechanisms underlying this effect and to determine its clinical significance.

3. J Affect Disord. 2010 Jul 29. [Epub ahead of print] Prevalence and correlates of eating disorders in 875 patients with bipolar disorder.

Authors: McElroy SL, Frye MA, Hellemann G, Altshuler L, Leverich GS, Suppes T, Keck PE, Nolen WA, Kupka R, Post RM.

Relatively little is known about the co-occurrence of bipolar and eating disorders. We therefore assessed the prevalence and clinical correlates of eating disorders in 875 patients with bipolar disorder. METHOD: 875 outpatients with DSM-IV bipolar I or II disorder were evaluated with structured diagnostic interviews and clinician- and self-administered questionnaires to determine bipolar and eating disorder diagnoses, other comorbid Axis I disorder diagnoses, and demographic and historical illness characteristics. RESULTS: 125 (14.3%) patients met DSM-IV criteria for at least one comorbid lifetime Axis I eating disorder, with binge eating disorder (N=77) being more common than bulimia nervosa (n=42) and anorexia nervosa (N=27). There were no significant eating disorder comorbidity differences between bipolar I and bipolar II patients. Presence of a lifetime comorbid eating disorder was associated with female gender, younger age, earlier age of onset of mood symptoms and of bipolar disorder, presentation in a mixed episode, greater number of prior mood episodes, history of rapid cycling and suicide attempts, greater mean BMI, obesity and severe obesity, and family history of depression, bipolar disorder, alcoholism, and drug abuse. When the three eating disorder groups were compared, lifetime anorexia nervosa was associated with normal weight and a lifetime anxiety disorder, lifetime bulimia nervosa was associated with overweight, and lifetime binge eating disorder was associated with obesity and severe obesity. CONCLUSIONS: Patients with bipolar disorder, especially women, not infrequently have comorbid eating disorders, and this comorbidity is associated with an earlier age of onset and more severe course of bipolar illness. Copyright © 2010. Published by Elsevier B.V.

Estimating the size of treatment effects: moving beyond p values.

Authors: McGough JJ, Faraone SV.

Objective: To increase understanding of effect size calculations among clinicians who over-rely on interpretations of P values in their assessment of the medical literature.Design: We review five methods of calculating effect sizes: Cohen's d (also known as the standardized mean difference)-used in studies that report efficacy in terms of a continuous measurement and calculated from two mean values and their standard deviations; relative risk-the ratio of patients responding to treatment divided by the ratio of patients responding to a different treatment (or placebo), which is particularly useful in prospective clinical trials to assess differences between treatments; odds ratio- used to interpret results of retrospective case-control studies and provide estimates of the risk of side effects by comparing the probability (odds) of an outcome occurring in the presence or absence of a specified condition; number needed to treat-the number of subjects one would expect to treat with agent A to have one more success (or one less failure) than if the same number were treated with agent B; and area under the curve (also known as the drug-placebo response curve)-a six-step process that can be used to assess the effects of medication on both worsening and improvement and the probability that a medication-treated subject will have a better outcome than a placebo-treated subject.Conclusion: Effect size statistics provide a better estimate of treatment effects than P values alone.

A Candi date Gene Analysis of Methylphenidate Response in Attention-Deficit/Hyperactivity Disorder.

Authors: McGough JJ, McCracken JT, Loo SK, Manganiello M, Leung MC, Tietjens JR, Trinh T, Baweja S, Suddath R, Smalley SL, Hellemann G, Sugar CA.

This study examines the potential role of candidate genes in moderating treatment effects of methylphenidate (MPH) in attention-deficit/hyperactivity disorder (ADHD). METHOD:: Eighty-two subjects with ADHD aged 6 to 17 years participated in a prospective, double-blind, placebo-controlled, multiple-dose, crossover titration trial of immediate release MPH three times daily. The subjects were assessed on a variety of parent and clinician ratings and a laboratory math test. Data reduction based on principal components analysis identified statistically derived efficacy and side effect outcomes. RESULTS:: Attention-deficit/hyperactivity disorder symptom response was predicted by polymorphisms at the serotonin transporter (SLC6A4) intron 2 VNTR (p =.01), with a suggested trend for catechol-O-methyltransferase (COMT) (p =.04). Gene x dose interactions were noted on math test outcomes for the dopamine D4 receptor (DRD4) promoter (p =.008), DRD4 exon 3 VNTR (p =.006), and SLC6A4 promoter insertion/deletion polymorphism (5HTTLPR) (p =.02). Irritability was predicted by COMT (p =.02). Vegetative symptoms were predicted by 5HTTLPR (p =.003). No significant effects were noted for the dopamine transporter (SLC6A3) or synaptosomal-associated protein 25 (SNAP25). CONCLUSIONS:: This article confirms and expands previous studies suggesting that genes moderate ADHD treatment response. The ADHD outcomes are not unitary but reflect both behavioral and learning domains that are likely influenced by different genes. Future research should emphasize candidate gene and genome-wide association studies in larger samples, symptom reduction as well as side effects outcomes, and responses over full therapeutic dose ranges to assess differences in both gene and gene x dose interactive effects.

Family-Based Genome-Wide Association Scan of Attention -Deficit/Hyperactivity Disorder.

Authors: Mick E, Todorov A, Smalley S, Hu X, Loo S, Todd RD, Biederman J, Byrne D, Dechairo B, Guiney A, McCracken J, McGough J, Nelson SF, Reiersen AM, Wilens TE, Wozniak J, Neale BM, Faraone SV.

OBJECTIVE: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of DSM-IV-TR ADHD. METHOD: Families were ascertained at Massachusetts General Hospital (MGH; N = 309 trios), Washington University at St. Louis (WASH-U; N = 272 trios), and University of California at Los Angeles (UCLA; N = 156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. RESULTS: Our smallest p value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08), but one of the 20 most significant associations was located in a candidate gene of interest for ADHD (SLC9A9, rs9810857, p = 6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. CONCLUSIONS: We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders.

Callosal tissue loss in multiple system atrophy-A one-year follow-up study.

Authors: Minnerop M, Lüders E, Specht K, Ruhlmann J, Schimke N, Thompson PM, Chou YY, Toga AW, Abele M, Wüllner U, Klockgether T.

Multiple system atrophy (MSA) is a neurodegenerative disease not only affecting the basal ganglia, brainstem, cerebellum, and intermediolateral cell columns of the spinal cord but also the cerebral cortex. Clinically, cerebellar (MSA-C) and parkinsonian variants of MSA (MSA-P) are distinguished. We investigated 14 MSA patients (10 MSA-C, 4 MSA-P, men: 7, women: 7; age: 61.1 +/- 3.3 years) and 14 matched controls (men: 7, women: 7; age: 58.6 +/- 5.1 years) with voxel-based morphometry (VBM) to analyze gray and white matter differences both at baseline and at follow-up, 1 year later. Baseline comparisons between patients and controls confirmed significantly less gray matter in MSA in the cerebellum and cerebral cortex, and significantly less white matter in the cerebellar peduncles and brainstem. Comparisons of tissue-loss profiles (i.e., baseline versus follow-up) between patients and controls, revealed white matter reduction in MSA along the middle cerebellar peduncles, reflecting degeneration of the ponto-cerebellar tract as a particularly prominent and progressive morphological alteration in MSA. Comparisons between baseline and follow-up, separately performed in patients and controls, revealed additional white matter reduction in MSA along the corpus callosum at follow-up. This was replicated through additional shape-based analyses indicating a reduced callosal thickness in the anterior and posterior midbody, extending posteriorly into the isthmus. Callosal atrophy may possibly reflect a disease-specific pattern of neurodegeneration and cortical atrophy, fitting well with the predominant impairment of motor functions in the MSA patients. (c) 2010 Movement Disorder Society.

Assessment of Evidence-Based Psychotherapy Practices in Usual Care: Challenges, Promising Approaches, and Future Directions.

Authors: Miranda J, Azocar F, Burnam MA.

Development of a Patient-Report Measure of Psychotherapy for Depression.

Authors: Miranda J, Hepner KA, Azocar F, Greenwood G, Ngo V, Burnam MA.

Despite clear indications of need to improve depression treatment, practical tools that efficiently measure psychotherapy are not available. We developed a patient-report measure of psychotherapy for depression that assesses Cognitive Behavioral (CBT), Interpersonal (IPT), and Psychodynamic therapies. 420 patients with depression from a large managed behavioral health care organization completed the measure. The three subscales measuring CBT, IPT, and Psychodynamic Therapy showed good internal consistency, appropriate item-total correlations, and were supported by a 3-factor structure. Our results suggest that a patient questionnaire is a promising approach for assessing psychotherapy in quality improvement interventions

Striatal volumes and dyskinetic movements in youth at high-risk for psychosis.

Authors: Mittal VA, Daley M, Shiode MF, Bearden CE, O'Neill J, Cannon TD.

Although dyskinesias may be one of the first behavioral indicators of progressive striatal dysfunction, a mechanism critically implicated in the pathogenesis of psychotic disorders, little is known about the association between striatal structures and abnormal movements in high-risk populations. Thirty participants with a prodromal syndrome were rated for dyskinetic movements and underwent structural magnetic resonance imaging (MRI). Volumes of striatal brain structures were delineated. Elevated hyperkinetic movements were found to be associated with smaller putamen and results were replicated in the antipsychotic naïve portion of the sample. Participants who converted over a 2-year follow-up period showed significantly smaller striatal volumes and a trend towards elevated dyskinetic movements, relative to those who did not convert. Movement abnormalities may reflect a striatal pathology that is present before formal psychosis onset, and potentially reflective of a heightened vulnerability for conversion.

Identification and treatment of a pineal region tumor in an adol escent with prodromal psychotic symptoms.

Authors: Mittal VA, Karlsgodt K, Zinberg J, Cannon TD, Bearden CE.

An adolescent male patient originally presented to a prodromal clinical research program with severe obsessive-compulsive behaviors and subthreshold symptoms of psychosis, which eventually developed into first-rank psychotic symptoms. The patient was followed over a 2-year period. His symptoms did not respond to psychotherapy or pharmacotherapy. However, when a pineal region tumor was discovered and treated with chemotherapy and autologous stem cell rescue, both psychotic symptoms and psychosocial functioning reverted toward baseline. Although subcortical brain structures have been implicated in the pathophysiology of idiopathic psychosis, reports of psychiatric sequelae of treatment of subcortical tumors are rare. Etiological pathways that may have played a role in symptom development are of particular interest, as understanding these mechanisms may shed light on the pathophysiology of psychotic disorders more generally.

Detecting network mod ules in fMRI time series: A weighted network analysis approach.

Authors: Mumford JA, Horvath S, Oldham MC, Langfelder P, Geschwind DH, Poldrack RA.

Many network analyses of fMRI data begin by defining a set of regions, extracting the mean signal from each region and then analyzing the correlations between regions. One essential question that has not been addressed in the literature is how to best define the network neighborhoods over which a signal is combined for network analyses. Here we present a novel unsupervised method for the identification of tightly interconnected voxels, or modules, from fMRI data. This approach, weighted voxel coactivation network analysis (WVCNA) is based on a method that was originally developed to find modules of genes in gene networks. This approach differs from many of the standard network approaches in fMRI in that connections between voxels are described by a continuous measure, whereas typically voxels are considered to be either connected or not connected depending on whether the correlation between the two voxels survives a hard threshold value. Additionally, instead of simply using pairwise correlations to describe the connection between two voxels, WVCNA relies on a measure of topological overlap, which not only compares how correlated two voxels are, but also the degree to which the pair of voxels is highly correlated with the same other voxels. We demonstrate the use of WVCNA to parcellate the brain into a set of modules that are reliably detected across data within the same subject and across subjects. In addition we compare WVCNA to ICA and show that the WVCNA modules have some of the same structure as the ICA components, but tend to be more spatially focused. We also demonstrate the use of some of the WVCNA network metrics for assessing a voxel's membership to a module and also how that voxel relates to other modules. Last, we illustrate how WVCNA modules can be used in a network analysis to find connections between regions of the brain and show that it produces reasonable results. Copyright © 2010 Elsevier Inc. All rights reserved.

Widespread Cortical Thinning Is a Robust Anatomical Marker for Attention-Deficit/Hyperactivity Disorder.

Authors: Narr KL, Woods RP, Lin J, Kim J, Phillips OR, Del'homme M, Caplan R, Toga AW, McCracken JT, Levitt JG.

This cross-sectional study sought to confirm the presence and regional profile of previously reported changes in laminar cortical thickness in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) compared with typically developing control subjects. METHOD:: High-resolution magnetic resonance images were obtained from 22 (19 male and 3 female subjects; mean age 11.7 years) children and adolescents with ADHD and 22 age- and sex-matched control subjects (mean age 11.7 years). Brain tissue volumes were estimated for each subject. Cortical pattern matching methods were used to sample measures of laminar thickness at high spatial frequency across homologous regions of the cortex. Volume and thickness measures were compared across diagnostic groups with and without controlling for general intelligence. False discovery rate correction confirmed regional results. RESULTS:: The subjects with ADHD exhibited significant reductions in overall brain volume, gray matter volume, and mean cortical thickness compared with the controls, whereas white matter volumes were significantly increased in ADHD. Highly significant cortical thinning (false discovery rate-corrected p <.0006) was observed over large areas of the frontal, temporal, parietal, and occipital association cortices and aspects of motor cortex but not within the primary sensory regions. CONCLUSIONS:: Cortical thickness reductions present a robust neuroanatomical marker for child and adolescent ADHD. Observations of widespread cortical thinning expand on earlier cross-sectional findings and provide further evidence to support that the neurobiological underpinnings of ADHD extend beyond prefrontal and subcortical circuits.

Meta-Analysis of Genome-Wide Association Studies of Attent ion-Deficit/Hyperactivity Disorder.

Authors: Neale BM, Medland SE, Ripke S, Asherson P, Franke B, Lesch KP, Faraone SV, Nguyen TT, Schäfer H, Holmans P, Daly M, Steinhausen HC, Freitag C, Reif A, Renner TJ, Romanos M, Romanos J, Walitza S, Warnke A, Meyer J, Palmason H, Buitelaar J, Vasquez AA, Lambregts-Rommelse N, Gill M, Anney RJ, Langely K, O'Donovan M, Williams N, Owen M, Thapar A, Kent L, Sergeant J, Roeyers H, Mick E, Biederman J, Doyle A, Smalley S, Loo S, Hakonarson H, Elia J, Todorov A, Miranda A, Mulas F, Ebstein RP, Rothenberger A, Banaschewski T, Oades RD, Sonuga-Barke E, McGough J, Nisenbaum L, Middleton F, Hu X, Nelson S; Psychiatric GWAS Consortium: ADHD Subgroup.

OBJECTIVE: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. METHOD: We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. RESULTS: No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. CONCLUSIONS: Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.

Outcomes for youths from racial-ethnic minority groups in a quality improvement intervention for depression treatment

Authors: Ngo VK, Asarnow JR, Lange J, Jaycox LH, Rea MM, Landon C, Tang L, Miranda J.

This study examined racial-ethnic differences in the impact of the Youth Partners in Care quality improvement intervention. The intervention was designed to improve access to evidence-based depression care, primarily cognitive-behavioral therapy and medication, through primary care. Previous analyses have shown that the quality improvement intervention was associated with improved depression and quality-of-life outcomes at the end of the six-month intervention period. METHODS: A randomized controlled trial comparing quality improvement and usual care for youths from diverse racial-ethnic groups from five health care organizations, including managed care, the public sector, and academic center clinics, was conducted. Depressed youths (N=325), who self-identified as black (N=59), Latino (N=224), and white (N=42), aged 13-21 years, were included in these analyses. To evaluate intervention effects within racial-ethnic groups, regression models were constructed, which adjusted for baseline and study site variation in depression symptoms, mental health status, satisfaction with mental health care, and mental health service utilization. RESULTS: Differential intervention effects were found across racial-ethnic groups. Black youths in the intervention group experienced significant reductions in depression symptoms and had higher rates of use of specialty mental health care at the six-month follow-up. Among Latino youths, the intervention was associated with significantly greater satisfaction with care. Intervention effects were weak among white youths. CONCLUSIONS: Quality improvement interventions may help to reduce disparities in mental health care for youths from racial-ethnic minority groups.

CD34-based enrichment of genetically engineered human T cells for clinical use results in dramatically enhanced tumor targeting.

Authors: Norell H, Zhang Y, McCracken J, Martins da Palma T, Lesher A, Liu Y, Roszkowski JJ, Temple A, Callender GG, Clay T, Orentas R, Guevara-Patiño J, Nishimura MI.

Objective clinical responses can be achieved in melanoma patients by infusion of T cell receptor (TCR) gene transduced T cells. Although promising, the therapy is still largely ineffective, as most patients did not benefit from treatment. That only a minority of the infused T cells were genetically modified and that these were extensively expanded ex vivo may have prevented their efficacy. We developed novel and generally applicable retroviral vectors that allow rapid and efficient selection of T cells transduced with human TCRs. These vectors encode two TCR chains and a truncated CD34 molecule (CD34t) in a single mRNA transcript. Transduced T cells were characterized and the effects of CD34-based enrichment of redirected T cells were evaluated. Both CD8(+) and CD4(+) T cells could be transduced and efficiently co-expressed all introduced transgenes on their surface. Importantly, more than fivefold enrichment of both the frequency of transduced cells and the specific anti-tumor reactivity of the effector population could be achieved by magnetic beads-based enrichment procedures readily available for clinical grade hematopoietic stem cell isolation. This CD34-based enrichment technology will improve the feasibility of adoptive transfer of clinically relevant effectors. In addition to their enhanced tumor recognition, the enriched redirected T cells may also show superior reactivity and persistence in vivo due to the high purity of transduced cells and the shortened ex vivo culture

Photophysical properties of an alkyne-bridged bis(zinc porphyrin)-perylene bis(dicarboximide) derivative.

Authors: Odom SA, Kelley RF, Ohira S, Ensley TR, Huang C, Padilha LA, Webster S, Coropceanu V, Barlow S, Hagan DJ, Van Stryland EW, Brédas JL, Anderson HL, Wasielewski MR, Marder SR.

We report the synthesis, electrochemistry, and photophysical properties of a new donor-acceptor-donor molecule in which the meso carbon atoms of two zinc porphyrin (POR) units are linked through ethynylene bridges to the 1,7-positions of a central perylene-3,4:9,10-bis(dicarboximide) (PDI). In contrast to previously studied systems incorporating POR and PDI groups, this alkyne-based derivative shows evidence of through-bond electronic coupling in the ground state; the new chromophore exhibits absorption features similar to those of its constituent parts as well as lower energy features (at wavelengths up to ca. 1000 nm), presumably arising from donor-acceptor interactions. Transient absorption measurements show that excitation at several visible and near-IR wavelengths results in the formation of an excited-state species with a lifetime of 290 ps in 1% (v/v) pyridine in toluene. The absorption spectrum of this species resembles the sum of the spectra for the chemically generated radical cation and radical anion of the chromophore. The chromophore shows moderate two-photon absorption cross sections (2000-7000 GM) at photon wavelengths close to the onset of its low-energy one-photon absorption feature.

Cognitive Effects of Topiramate in Migraine Patients Aged 12 Through 17 Years.

Authors: Pandina GJ, Ness S, Polverejan E, Yuen E, Eerdekens M, Bilder RM, Ford L.

Neuropsychologic data are presented from a randomized, double-blind, placebo-controlled, multicenter study with placebo, topiramate 50 mg/day, and topiramate 100 mg/day. The Cambridge Neuropsychological Test Automated Battery (CANTAB) and cognitive adverse events were used to evaluate neurocognitive effects of topiramate. Topiramate 100 mg/day vs placebo was associated with slight statistically significant score increases, indicating slowing, from baseline vs placebo in three CANTAB measures: five-choice reaction time (P = 0.028), pattern recognition memory mean correct latency (P = 0.027), and rapid visual information processing mean latency (P = 0.040). No other patterns related to topiramate treatment were observed in measurements of learning, memory, and visual information processing, except for potential improvement with topiramate 100 mg/day vs placebo in spatial span total errors (accuracy test) (P = 0.040). The most common cognitive and neuropsychiatric adverse events with a higher incidence in the topiramate 50 and 100 mg/day groups vs placebo were anorexia (9% and 11% vs 3%), insomnia (9% and 3% vs 3%), fatigue (6% and 9% vs 6%), and dizziness (6% and 9% vs 0%). Thus, topiramate 100 mg/day was associated with modest increases in psychomotor reaction times. Learning, memory, and executive function were unchanged. The tolerability profile, including cognitive adverse events, appeared to be acceptable.

Applying health care reform principles to mental health and substance abuse services

Authors: Patel K, Wells K.

LONI MiND: Metadata in NIfTI for DWI.

Authors: Patel V, Dinov ID, Van Horn JD, Thompson PM, Toga AW.

A wide range of computational methods have been developed for reconstructing white matter geometry from a set of diffusion-weighted images (DWIs), and many clinical studies rely on publicly-available implementations of these methods for analyzing DWI data sets. Unfortunately, the poor interoperability between DWI analysis tools often effectively restricts users to the algorithms provided by a single software suite, which may be suboptimal relative to those in other packages, or outdated given recent developments in the field. A major barrier to data portability and the interoperability between DWI analysis tools is the lack of a standard format for representing and communicating essential DWI-related metadata at various stages of post-processing. In this report, we address this issue by developing a framework for storing Metadata in NIfTI for DWI (MiND). We utilize the standard NIfTI format extension mechanism to store essential DWI metadata in an extended header for multiple commonly-encountered DWI data structures. We demonstrate the utility of this approach by implementing a full suite of tools for DWI analysis workows which communicate solely through the MiND mechanism. We also show that the MiND framework allows for simple, direct DWI data visualization, and we illustrate its effectiveness by constructing a group atlas for 330 subjects using solely MiND-centric tools for DWI processing. Our results indicate that the MiND framework provides a practical solution to the problem of interoperability between DWI analysis tools, and it effectively expands the analysis options available to end users.

Mesh-Based Spherical Deconvolution: A Flexible Approach to Reconstruction of Non-Negative Fiber Orientati on Distributions.

Authors: Patel V, Shi Y, Thompson PM, Toga AW.

Diffusion-weighted MRI has enabled the imaging of white matter architecture in vivo. Fiber orientations have classically been assumed to lie along the major eigenvector of the diffusion tensor, but this approach has well-characterized short-comings in voxels containing multiple fiber populations. Recently proposed methods for recovery of fiber orientation via spherical deconvolution utilize a spherical harmonics framework and are susceptible to noise, yielding physically-invalid results even when additional measures are taken to minimize such artifacts. In this work, we reformulate the spherical deconvolution problem onto a discrete spherical mesh. We demonstrate how this formulation enables the estimation of fiber orientation distributions which strictly satisfy the physical constraints of realness, symmetry, and non-negativity. Moreover, we analyze the inuence of the exible regularization parameters included in our formulation for tuning the smoothness of the resultant fiber orientation distribution (FOD). We show that the method is robust and reliable by reconstructing known crossing fiber anatomy in multiple subjects. Finally, we provide a software tool for computing the FOD using our new formulation in hopes of simplifying and encouraging the adoption of spherical deconvolution techniques.

Clinical and cognitive correlates of depressive symptoms among youth with obsessive compulsive disorder.

Authors: Peris TS, Bergman RL, Asarnow JR, Langley A, McCracken JT, Piacentini J.

Depression is the most common comorbidity among adults with obsessive compulsive disorder (OCD), yet little is known about depressive symptoms in childhood OCD. This study examined clinical and cognitive variables associated with depressive symptomatology in 71 youths (62% male, M age = 12.7 years) with primary OCD. Youths presented with a range of depressive symptoms, with 21% scoring at or above the clinical cutoff on the self-report measure of depression. Higher levels of depressive symptoms were associated with higher levels of cognitive distortions assessed on measures of insight, perceived control, competence, and contingencies. Depressive symptoms were also linked to older age and more severe OCD. Low perceived control and self-competence and high OCD severity independently predicted depression scores.

Decoding the Large-Scale Structure of Brain Function by Classifying Mental States Across Individuals.

Authors: Poldrack RA, Halchenko YO, Hanson SJ.

Brain-imaging research has largely focused on localizing patterns of activity related to specific mental processes, but recent work has shown that mental states can be identified from neuroimaging data using statistical classifiers. We investigated whether this approach could be extended to predict the mental state of an individual using a statistical classifier trained on other individuals, and whether the information gained in doing so could provide new insights into how mental processes are organized in the brain. Using a variety of classifier techniques, we achieved cross-validated classification accuracy of 80% across individuals (chance = 13%). Using a neural network classifier, we recovered a low-dimensional representation common to all the cognitive-perceptual tasks in our data set, and we used an ontology of cognitive processes to determine the cognitive concepts most related to each dimension. These results revealed a small organized set of large-scale networks that map cognitive processes across a highly diverse set of mental tasks, suggesting a novel way to characterize the neural basis of cognition.

Interpreting developmental changes in neuroimaging signals.

Authors: Poldrack RA.

The imaging of developmental changes in brain function is challenging, but great strides have been made in addressing many of the conceptual issues that this work raises. I highlight a set of issues that remain to be addressed in this literature. First, I argue that the appeal to developmental neurobiology is often misplaced, as it focuses on neurodevelopmental processes that are mostly completed by the age at which neuroimaging studies can be performed. Second, I argue that the concept of "normative" development needs to be reexamined, as it reflects fundamental value judgments about brain development that seem inappropriate for scientific investigation. Third, I examine the ways in which developmental changes are often interpreted, arguing that common interpretations, including the concepts of "efficiency" and "focalization" may be less useful than commonly supposed. To put developmental neuroimaging on stronger footing, we need to develop stronger connections between computational and neurobiological accounts of developmental changes.

Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood.

Authors: Post RM, Leverich GS, Kupka RW, Keck PE Jr, McElroy SL, Altshuler LL, Frye MA, Luckenbaugh DA, Rowe M, Grunze H, Suppes T, Nolen WA.

We examined the influence of age at onset of illness and the delay in time to first treatment on morbidity in adulthood. METHOD: 529 adult outpatients with a mean age of 42 years, who entered our research network from 1996 through 2001 and who were diagnosed with bipolar disorder according to DSM-IV criteria, were rated prospectively on a daily basis with the National Institute of Mental Health-Life Chart Method during naturalistic treatment for up to 4 years. RESULTS: Fifty percent of patients had illness onset in childhood (<13 years of age) or adolescence (13-18 years of age). In year 1 of follow-up, these patients, compared to those with adult onset, showed significantly (P<.05) greater severity of depression and mania, greater number of episodes, more days depressed, more days of ultradian cycling, and fewer days euthymic. After 4 years, the mean severity and duration of depression remained greater and the number of days euthymic fewer in those with childhood compared to adult onset (P<.05). The delays to first treatment correlated inversely with age at onset of illness. Independently, delay to first treatment was associated with more time depressed, greater severity of depression, greater number of episodes, more days of ultradian cycling, and fewer days euthymic (all P<.05). CONCLUSIONS: These data converge with other evidence that onset of bipolar disorder in childhood is common and often associated with extraordinarily long delays to first pharmacologic treatment. Both childhood onset and treatment delay were associated with a persistently more adverse course of illness rated prospectively in adults. These data should help foster efforts to ensure earlier and more effective treatment of bipolar illness in children and adolescents. It is hoped that appropriate early intervention would result in a more benign illness and a better prognosis in adulthood. © Copyright 2010 Physicians Postgraduate Press, Inc.

FDDNP binding using MR derived cortical surface maps

Authors: Protas HD, Huang SC, Kepe V, Hayashi K, Klunder A, Braskie MN, Ercoli L, Bookheimer S, Thompson PM, Small GW, Barrio JR.

To assess quantitatively the cortical pattern profile of regional FDDNP binding to beta-amyloid and neurofibrillary tangles on MR derived cortical maps, FDDNP PET images were corrected for movement and partial volume (PV), and optimized for kernel size. METHODS: FDDNP DVR PET images from 23 subjects (7 with Alzheimer's disease (AD), 6 with mild cognitive impairment and 10 controls) were obtained from Logan analysis using cerebellum as reference. A hemispheric cortical surface model for each subject was extracted from the MRI. The same transformations were applied to the FDDNP DVR PET images to map them into the same space. The cortical map with PV correction was calculated as the ratio of the DVR cortical surface and that of the simulated map, created from the mask derived from MRI and smoothed to the PET resolution. Discriminant analysis was used to order the FDDNP DVR cortical surfaces based on subjects' disease state. Linear regression was used to assess the rate of change of DVR vs. MMSE for each hemispheric cortical surface point. RESULTS: The FDDNP DVR cortical surface corrected for movement and PV had less hemispheric asymmetry. Optimal kernel size was determined to be 9 mm. The corrected cortical surface map of FDDNP DVR showed clear spatial pattern that was consistent with the known pathological progression of AD. CONCLUSION: Correcting for movement, PV as well as optimizing kernel size provide sensitive statistical analysis of FDDNP distribution which confirms in the living brain known pathology patterns earlier observed with cognitive decline with brain specimens.

Use of a high electron-affinity molybdenum dithiolene complex to p-dope hole-transport layers.

Authors: Qi Y, Sajoto T, Barlow S, Kim EG, Brédas JL, Marder SR, Kahn A.

Experimental and theoretical results are presented on the electronic structure of molybdenum tris[1,2-bis(trifluoromethyl) ethane-1,2-dithiolene] (Mo(tfd)(3)), a high electron-affinity organometallic complex that constitutes a promising candidate as a p-dopant for organic molecular semiconductors. The electron affinity of the compound, determined via inverse photoemission spectroscopy, is 5.6 eV, which is 0.4 eV larger than that of the commonly used p-dopant F(4)-TCNQ. The LUMO level of Mo(tfd)(3) is calculated to be delocalized over the whole molecule, which is expected to lead to low pinning potential. Efficient p-doping of a standard hole transport material (alpha-NPD) is demonstrated via measurements of Fermi level shifts and enhanced conductivity in alpha-NPD:1% Mo(tfd)(3). Rutherford backscattering measurements show good stability of the three-dimensional Mo(tfd)(3) molecule in the host matrix with respect to diffusion.

Brain structure and obesity

Authors: Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, Hua X, Leow AD, Toga AW, Thompson PM.

Obesity is associated with increased risk for cardiovascular health problems including diabetes, hypertension, and stroke. These cardiovascular afflictions increase risk for cognitive decline and dementia, but it is unknown whether these factors, specifically obesity and Type II diabetes, are associated with specific patterns of brain atrophy. We used tensor-based morphometry (TBM) to examine gray matter (GM) and white matter (WM) volume differences in 94 elderly subjects who remained cognitively normal for at least 5 years after their scan. Bivariate analyses with corrections for multiple comparisons strongly linked body mass index (BMI), fasting plasma insulin (FPI) levels, and Type II Diabetes Mellitus (DM2) with atrophy in frontal, temporal, and subcortical brain regions. A multiple regression model, also correcting for multiple comparisons, revealed that BMI was still negatively correlated with brain atrophy (FDR <5%), while DM2 and FPI were no longer associated with any volume differences. In an Analysis of Covariance (ANCOVA) model controlling for age, gender, and race, obese subjects with a high BMI (BMI > 30) showed atrophy in the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus compared with individuals with a normal BMI (18.5-25). Overweight subjects (BMI: 25-30) had atrophy in the basal ganglia and corona radiata of the WM. Overall brain volume did not differ between overweight and obese persons. Higher BMI was associated with lower brain volumes in overweight and obese elderly subjects. Obesity is therefore associated with detectable brain volume deficits in cognitively normal elderly subjects. Hum Brain Mapp, 2009. (c) 2009 Wiley-Liss, Inc

Six problems for causal inference from fMRI.

Authors: Ramsey JD, Hanson SJ, Hanson C, Halchenko YO, Poldrack RA, Glymour C.

Neuroimaging (e.g. fMRI) data are increasingly used to attempt to identify not only brain regions of interest (ROIs) that are especially active during perception, cognition, and action, but also the qualitative causal relations among activity in these regions (known as effective connectivity; Friston, 1994). Previous investigations and anatomical and physiological knowledge may somewhat constrain the possible hypotheses, but there often remains a vast space of possible causal structures. To find actual effective connectivity relations, search methods must accommodate indirect measurements of nonlinear time series dependencies, feedback, multiple subjects possibly varying in identified regions of interest, and unknown possible location-dependent variations in BOLD response delays. We describe combinations of procedures that under these conditions find feed-forward sub-structure characteristic of a group of subjects. The method is illustrated with an empirical data set and confirmed with simulations of time series of non-linear, randomly generated, effective connectivities, with feedback, subject to random differences of BOLD delays, with regions of interest missing at random for some subjects, measured with noise approximating the signal to noise ratio of the empirical data

Cerebellar grey matter deficits in first-episode schizophrenia mapped using cortical pattern matching.

Authors: Rasser PE, Schall U, Peck G, Cohen M, Johnston P, Khoo K, Carr VJ, Ward PB, Thompson PM.

Cerebellar dysfunction has been proposed to lead to "cognitive dysmetria" in schizophrenia via the cortico-cerebellar-thalamic-cortical circuit, contributing to a range of cognitive and clinical symptoms of the disorder. Here we investigated total cerebellar grey and white matter volumes and cerebellar regional grey matter abnormalities in 13 remitted first-episode schizophrenia patients with less than two years' duration of illness. Patient data were compared to 13 pair-wise age, gender, and handedness-matched healthy volunteers using cortical pattern averaging on high-resolution magnetic resonance images. Total cerebellar volume and total grey matter volumes in first-episode schizophrenia patients did not differ from healthy control subjects, but total cerebellar white matter was increased and total grey to white matter ratios were reduced in patients. Four clusters of cerebellar grey matter reduction were identified: (i) in superior vermis; (ii) in the left lobuli VI; (iii) in right-inferior lobule IX, extending into left lobule IX; (iv) bilaterally in the areas of lobuli III, peduncle and left flocculus. Grey matter deficits were particularly prominent in right lobuli III and IX, left flocculus and bilateral pedunculi. These cerebellar areas have been implicated in attention control, emotional regulation, social functioning, initiation of smooth pursuit eye movements, eye-blink conditioning, language processing, verbal memory, executive function and the processing of spatial and emotional information. Consistent with common clinical, cognitive, and pathophysiological signs of established illness, our findings demonstrate cerebellar pathology as early as in first episode schizophrenia. Copyright © 2010. Published by Elsevier Inc.

Schizophrenia: Genome, Interrupted

Authors: Rita M. Cantor1,2,* and Daniel H. Geschwind1,2,3,*

Structural chromosomal variation is increasingly recognized as an important contributor to human diseases, particularly those of neurodevelopment, such as autism. A current paper makes a significant advance to schizophrenia genetics by establishing an association with rare copy number variants (CNV), which are over-represented in neurodevelopmental genes.

Evaluating imaging biomarkers for neurodegeneration in presymptomatic Huntington's Disease using machine learning techniques.

Authors: Rizk-Jackson A, Stoffers D, Sheldon S, Kuperman J, Dale A, Goldstein J, Corey-Bloom J, Poldrack RA, Aron AR.

The development of MRI measures as biomarkers for neurodegenerative disease could prove extremely valuable for the assessment of neuroprotective therapies. Much current research is aimed at developing such biomarkers for use in people who are gene-positive for Huntingtons disease yet exhibit few or no clinical symptoms of the disease (pre-HD). We acquired structural (T1), diffusion weighted and functional MRI (fMRI) data from 39 pre-HD volunteers and 25 age-matched controls. To determine whether it was possible to decode information about disease state from neuroimaging data, we applied multivariate pattern analysis techniques to several derived voxel-based and segmented region-based datasets. We found that different measures of structural, diffusion weighted, and functional MRI could successfully classify pre-HD and controls using support vector machines (SVM) and linear discriminant analysis (LDA) with up to 76% accuracy. The model producing the highest classification accuracy used LDA with a set of six volume measures from the basal ganglia. Furthermore, using support vector regression (SVR) and linear regression models, we were able to generate quantitative measures of disease progression that were significantly correlated with established measures of disease progression (estimated years to clinical onset, derived from age and genetic information) from several different neuroimaging measures. The best performing regression models used SVR with neuroimaging data from regions within the grey matter (caudate), white matter (corticospinal tract), and fMRI (insular cortex). These results highlight the utility of machine learning analyses in addition to conventional ones. We have shown that several neuroimaging measures contain multivariate patterns of information that are useful for the development of disease-state biomarkers for HD.

Mixed-Handedness Is Linked to Mental Health Problems in Children and Adolescents.

Authors: Rodriguez A, Kaakinen M, Moilanen I, Taanila A, McGough JJ, Loo S, Järvelin MR.

Problems with language and symptoms of attention-deficit/hyperactivity disorder (ADHD) in childhood and adolescence are often strongly linked to low scholastic performance. Early recognition of children who are at increased risk is necessary. Our objective was to determine whether mixed-handedness, which is associated with atypical cerebral laterality, is associated with language, scholastic, and ADHD symptoms in childhood and adolescence. Methods: Prospective data come from the Northern Finland Birth Cohort 1986, a longitudinal, population-based birth cohort with assessments when children were 7 to 8 and 16 years of age (N = 7871). Teacher, parent, and/or adolescent reports were used to assess language difficulties, scholastic performance, and mental health, including ADHD symptoms. Results: Mixed-handed children, relative to right-handed, had approximately a twofold increase in odds of having difficulties with language and scholastic performance at the age of 8 years. Eight years later, as 16-year-olds, adolescents had twofold increase in odds concerning difficulties in school with language and with ADHD symptoms. Mixed-handed children were more likely to have scores indicating probable psychiatric disturbance, including ADHD symptoms. As adolescents, mixed-handed children with previous behavioral problems were at considerably higher risk for scoring within the range of probable ADHD-inattention or ADHD-combined case. Mixed-handedness was associated with greater symptom severity in children and adolescents (P = .01) concerning psychiatric disturbance and ADHD inattention but not ADHD hyperactivity. Conclusions: The results indicate that mixed-handed children have a greater likelihood of having language, scholastic, and mental health problems in childhood and that these persist into adolescence. Thus, these results suggest that mixed-handedness, particularly in the presence of difficulties, could aid in the recognition of children who are at risk for stable problems. Additional research is needed to understand the connections between neural substrates related to atypical cerebral asymmetry, mixed-handedness, and mental health problems including ADHD symptoms.

Association of IRF5 polymorphisms with activation of the Interferon-alpha pathway.

Authors: Rullo OJ, Woo JM, Wu H, Hoftman AD, Maranian P, Brahn BA, McCurdy D, Cantor R, Tsao B.

Genetic association of Interferon Regulatory Factor 5 (IRF5) with SLE susceptibility has been convincingly established. To gain understanding of the effect of IRF5 variation in individuals without SLE, we examined whether such genetic variation predisposes to activation of the Interferon-alpha) (IFN-alpha) pathway. METHODS: In this in silico approach, 14 SNPs and haplotypes of IRF5 were tested for association with mRNA expression levels of IRF5, IFN--alpha), and interferon-inducible genes and chemokines in lymphoblastoid cell lines (LCLs) from individuals of European (CEU), Han Chinese (CHB), Japanese (JPT) and Yoruba Nigerian (YRI) backgrounds. Interferon-inducible gene expression was assessed in LCLs from pediatric SLE patients in the presence and absence of IFN-alpha) stimulation. RESULTS: The major alleles of IRF5 rs13242262 and rs2280714 were associated with increased IRF5 mRNA expression levels in the CEU, CHB+JPT, and YRI samples. The minor allele of IRF5 rs10488631 was associated with increased IRF5, IFN-alpha) and interferon-inducible chemokine expression in CEU (pc = 0.0005, 0.01 and 0.04, respectively). A haplotype containing these risk alleles of rs13242262, rs10488631 and rs2280714 was associated with increased IRF5, IFN-alpha) and interferon-inducible chemokine expression in CEU LCLs. In vitro studies showed specific activation of interferon-inducible genes in LCLs by IFN-alpha). CONCLUSIONS: SNPs of IRF5 in healthy individuals of multiple ethnic groups were associated with increased mRNA expression of IRF5. In European-derived individuals, an IRF5 haplotype was associated with increased IRF5, IFN-alpha) and interferon-inducible chemokine expression. Identifying individuals genetically predisposed to increased interferon-inducible gene and chemokine expression may allow early detection of risk for SLE.

Language network dysfunction as a predictor of outcome in youth at clinical high risk for psychosis.

Authors: Sabb FW, van Erp TG, Hardt ME, Dapretto M, Caplan R, Cannon TD, Bearden CE.

Language processing abnormalities are a hallmark feature of schizophrenia. Yet, no study to date has investigated underlying neural networks associated with discourse processing in adolescents at clinical high risk (CHR) for developing psychosis. METHODS: Forty CHR youth and 24 demographically comparable healthy controls underwent functional magnetic resonance imaging while performing a naturalistic discourse processing paradigm. We assessed differences in blood oxygenation level-dependent (BOLD) activity between task conditions (Topic Maintenance vs. Reasoning) and between groups. Furthermore, we examined the association of regional brain activity with symptom severity and social outcome at follow-up, 6 to 24months after the scan. RESULTS: Relative to controls, CHR participants showed increased neural activity in a network of language-associated brain regions, including the medial prefrontal cortex bilaterally, left inferior frontal (LIFG; BA44/45, 47) and middle temporal gyri, and the anterior cingulate (BA24 and 32). Further, increased activity in the superior temporal gyrus (STG), caudate, and LIFG distinguished those who subsequently developed psychosis. Within the CHR sample, severity of positive formal thought disorder at follow-up was positively correlated with signal change in the LIFG, superior frontal gyrus, and inferior/middle temporal gyri, whereas social outcome was inversely correlated with signal change in the LIFG and anterior cingulate. CONCLUSIONS: These findings are consistent with a neural inefficiency hypothesis in those at greatest risk for psychosis, and additionally suggest that baseline activation differences may predict symptomatic and functional outcome. These results highlight the need to further investigate the neural systems involved in conversion to psychosis, and how language disruption changes over time in at-risk adolescents.

Symptomatic and functional correlates of regional brain physiology during working memory processing in patients with recent onset schizophrenia.

Authors: Sanz JH, Karlsgodt KH, Bearden CE, van Erp TG, Nandy RR, Ventura J, Nuechterlein K, Cannon TD.

Patients with schizophrenia show altered patterns of functional activation during working memory processing; specifically, high-performing patients appear to hyper-activate and low-performing patients appear to hypo-activate when compared with controls. It remains unclear how these individual differences in neurophysiological activation relate to the clinical presentation of the syndrome. In this functional magnetic resonance imaging (fMRI) study, the relationship is examined using partial least squares (PLS), a multivariate statistical technique that selects underlying latent variables based on the covariance between two sets of variables, in this case, clinical variables and regional fMRI activations during a verbal working memory task. The PLS analysis extracted two latent variables, and the significance of these associations was confirmed through permutation. Lower levels of activation during task performance across frontal and parietal regions of interest in the left hemisphere were found to covary with poorer role functioning and greater severity of negative and disorganized symptoms, while lower activation in right frontal and subcortical regions of interest was found to covary with better social functioning and fewer positive symptoms. These results suggest that appropriately lateralized patterns of functional activation during working memory processing are related to the severity of negative and disorganized symptoms and to the level of role and social functioning in schizophrenia.

Alzheimer's Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans.

Authors: Saykin AJ, Shen L, Foroud TM, Potkin SG, Swaminathan S, Kim S, Risacher SL, Nho K, Huentelman MJ, Craig DW, Thompson PM, Stein JL, Moore JH, Farrer LA, Green RC, Bertram L, Jack CR Jr, Weiner MW; Alzheimer's Disease Neuroimaging Initiative.

The role of the Alzheimer's Disease Neuroimaging Initiative Genetics Core is to facilitate the investigation of genetic influences on disease onset and trajectory as reflected in structural, functional, and molecular imaging changes; fluid biomarkers; and cognitive status. Major goals include (1) blood sample processing, genotyping, and dissemination, (2) genome-wide association studies (GWAS) of longitudinal phenotypic data, and (3) providing a central resource, point of contact and planning group for genetics within the Alzheimer's Disease Neuroimaging Initiative. Genome-wide array data have been publicly released and updated, and several neuroimaging GWAS have recently been reported examining baseline magnetic resonance imaging measures as quantitative phenotypes. Other preliminary investigations include copy number variation in mild cognitive impairment and Alzheimer's disease and GWAS of baseline cerebrospinal fluid biomarkers and longitudinal changes on magnetic resonance imaging. Blood collection for RNA studies is a new direction. Genetic studies of longitudinal phenotypes hold promise for elucidating disease mechanisms and risk, development of therapeutic strategies, and refining selection criteria for clinical trials.

Hippocampal morphometry in population-based i ncident Alzheimer's disease and vascular dementia: the HAAS.

Authors: Scher AI, Xu Y, Korf ES, Hartley SW, Witter MP, Scheltens P, White LR, Thompson PM, Toga AW, Valentino DJ, Launer LJ.

Background Hippocampal changes may be a useful biomarker for Alzheimer's disease if they are specific to dementia sub-type. We compare hippocampal volume and shape in population-based incident cases of Alzheimer's disease and vascular dementia (VaD). Methods Participants are Japanese-American men from the Honolulu Asia Aging Study. The following analysis is based on a sub-group of men with mild incident Alzheimer's disease (n=24: age=82.5±4.6) or incident VaD (n=14: age=80.5±4.5). To estimate hippocampal volume, one reader, blinded to dementia diagnosis, manually outlined the left and right formation of the hippocampus using published criteria. We used 3-D mapping methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal width between dementia groups. Results Hippocampal volume was about 5% smaller in the Alzheimer's disease group compared to the VaD group, but the difference was not significant. Hippocampal shape differed between the two case groups for the left (p<0.04) but not right (p<0.21) hippocampus. The specific region of the hippocampus that most consistently differed between the Alzheimer's disease and VaD cases was in the lateral portion of the left hippocampus. Our interpretation of this region is that it intersects the CA1 sub-region to a great extent but also includes the dentate gyrus (and hilar region) and subiculum. Conclusion As indicated by shape analysis, there are some differences in atrophy localisation between the Alzheimer's disease and VaD cases, despite the finding that volume of the hippocampi did not differ. These findings suggest hippocampal atrophy in Alzheimer's disease may be more focal than in VaD.

Predicting the longitudinal effects of the family environment on prodromal symptoms and functioning in patients at-risk for psychosis.

Authors: Schlosser DA, Zinberg JL, Loewy RL, Casey-Cannon S, O'Brien MP, Bearden CE, Vinogradov S, Cannon TD.

The current study examined the relationship between the family environment and symptoms and functioning over time in a group of adolescents and young adults at clinical high risk for psychosis (N=63). The current study compared the ability of interview-based versus self-report ratings of the family environment to predict the severity of prodromal symptoms and functioning over time. The family environmental factors were measured by interviewer ratings of the Camberwell Family Interview (CFI), self-report questionnaires surveying the patient's perceptions of criticism and warmth, and parent reported perceptions of their own level of criticism and warmth. Patients living in a critical family environment, as measured by the CFI at baseline, exhibited significantly worse positive symptoms at a 6-month follow-up, relative to patients living in a low-key family environment. In terms of protective effects, warmth and an optimal level of family involvement interacted such that the two jointly predicted improved functioning at the 6-month follow-up. Overall, both interview-based and self-report ratings of the family environment were predictive of symptoms and functioning at follow-up; however patient's self-report ratings of criticism had stronger predictive power. These results suggest that the family environment should be a specific target of treatment for individuals at risk for psychosis.

Promoting mental health recovery after hurricanes Katrina and Rita: what can be done at what cost.

Authors: Schoenbaum M, Butler B, Kataoka S, Norquist G, Springgate B, Sullivan G, Duan N, Kessler RC, Wells K.

Concerns about mental health recovery persist after the 2005 Gulf storms. We propose a recovery model and estimate costs and outcomes. OBJECTIVE: To estimate the costs and outcomes of enhanced mental health response to large-scale disasters using the 2005 Gulf storms as a case study. DESIGN: Decision analysis using state-transition Markov models for 6-month periods from 7 to 30 months after disasters. Simulated movements between health states were based on probabilities drawn from the clinical literature and expert input. SETTING: A total of 117 counties/parishes across Louisiana, Mississippi, Alabama, and Texas that the Federal Emergency Management Agency designated as eligible for individual relief following hurricanes Katrina and Rita. PARTICIPANTS: Hypothetical cohort, based on the size and characteristics of the population affected by the Gulf storms. Intervention Enhanced mental health care consisting of evidence-based screening, assessment, treatment, and care coordination. MAIN OUTCOME MEASURES: Morbidity in 6-month episodes of mild/moderate or severe mental health problems through 30 months after the disasters; units of service (eg, office visits, prescriptions, hospital nights); intervention costs; and use of human resources. RESULTS: Full implementation would cost $1133 per capita, or more than $12.5 billion for the affected population, and yield 94.8% to 96.1% recovered by 30 months, but exceed available provider capacity. Partial implementation would lower costs and recovery proportionately. CONCLUSIONS: Evidence-based mental health response is feasible, but requires targeted resources, increased provider capacity, and advanced planning.

Amygdala volumes in childhood absence epilepsy.

Authors: Schreibman Cohen A, Daley M, Siddarth P, Levitt J, Loesch IK, Altshuler L, Ly R, Shields WD, Gurbani S, Caplan R.

Abnormal amygdala volumes in pediatric mood-anxiety disorders and attention deficit hyperactivity disorder (ADHD), as well as high rates of these diagnoses in childhood absence epilepsy (CAE), prompted this study of amygdala volume in CAE. Twenty-six children with CAE and 23 normal children, aged 6.6-15.8years, underwent MRI at 1.5T. The tissue imaged with MRI was segmented, and amygdala volumes were obtained by manual tracings. There were no significant amygdala volume differences between the CAE and normal groups. Within the CAE group, however, the children with ADHD had significantly smaller amygdala volumes than the subjects with CAE with no psychopathology and those with mood/anxiety diagnoses. There was also a significant relationship between higher seizure frequency and greater amygdala asymmetry in the epilepsy group. Given ongoing development of the amygdala during late childhood and adolescence, despite the lack of significant group differences in amygdala volumes, the association of amygdala volume abnormalities with ADHD and seizure frequency implies a possible impact of the disorder on amygdala development and CAE-associated comorbidities, such as ADHD.

Reward processing in autism.

Authors: Scott-Van Zeeland AA, Dapretto M, Ghahremani DG, Poldrack RA, Bookheimer SY.

The social motivation hypothesis of autism posits that infants with autism do not experience social stimuli as rewarding, thereby leading to a cascade of potentially negative consequences for later development. While possible downstream effects of this hypothesis such as altered face and voice processing have been examined, there has not been a direct investigation of social reward processing in autism. Here we use functional magnetic resonance imaging to examine social and monetary rewarded implicit learning in children with and without autism spectrum disorders (ASD). Sixteen males with ASD and sixteen age- and IQ-matched typically developing (TD) males were scanned while performing two versions of a rewarded implicit learning task. In addition to examining responses to reward, we investigated the neural circuitry supporting rewarded learning and the relationship between these factors and social development. We found diminished neural responses to both social and monetary rewards in ASD, with a pronounced reduction in response to social rewards (SR). Children with ASD also demonstrated a further deficit in frontostriatal response during social, but not monetary, rewarded learning. Moreover, we show a relationship between ventral striatum activity and social reciprocity in TD children. Together, these data support the hypothesis that children with ASD have diminished neural responses to SR, and that this deficit relates to social learning impairments.

Neuropsychology of the prodrome to psychosis in the NAPLS consortium: relationship to family history and conversion to psychosis.

Authors: Seidman LJ, Giuliano AJ, Meyer EC, Addington J, Cadenhead KS, Cannon TD, McGlashan TH, Perkins DO, Tsuang MT, Walker EF, Woods SW, Bearden CE, Christensen BK, Hawkins K, Heaton R, Keefe RS, Heinssen R, Cornblatt BA; North American Prodrome Longitudinal Study (NAPLS) Group.

Early detection and prospective evaluation of clinical high-risk (CHR) individuals who may develop schizophrenia or other psychotic disorders is critical for predicting psychosis onset and for testing preventive interventions. OBJECTIVES: To elucidate the neuropsychology of the CHR syndrome, to determine the association of neuropsychological function with conversion to psychosis and family history of psychosis, and to examine whether baseline neuropsychological functioning predicts subsequent psychosis. DESIGN: Longitudinal study with 2(1/2) years of follow-up. SETTING: Eight centers participating in the North American Prodrome Longitudinal Study. PARTICIPANTS: Three hundred four prospectively identified CHR individuals meeting Structured Interview for Prodromal Syndromes criteria, 52 non-CHR persons with a family history of psychosis in first- or second-degree relatives (family high-risk group), and 193 normal controls with neither a family history of psychosis nor a CHR syndrome, all of whom underwent baseline neuropsychological evaluations. MAIN OUTCOME MEASURES: A neurocognitive composite score, 8 individual neuropsychological measures, an IQ estimate, and high-risk status. RESULTS: Global ("composite") neuropsychological functioning was comparably impaired in the CHR and family high-risk groups compared with controls, but profiles differed significantly between groups. Neuropsychological functioning in the CHR group was significantly lower in persons who progressed to psychosis than in those who did not and was worst in the subgroup with a family history of psychosis. Tests of processing speed and verbal learning and memory were most sensitive in discriminating CHR individuals from controls, although reductions were less severe than in established schizophrenia. Neuropsychological functioning did not contribute uniquely to the prediction of psychosis beyond clinical criteria, but worse verbal memory predicted more rapid conversion. CONCLUSIONS: These findings document that CHR individuals have significant neuropsychological difficulties, particularly those who later develop psychosis. This dysfunction is generally of moderate severity but less than in first-episode schizophrenia, suggesting that further decline may occur after baseline CHR assessment.

Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus.

Authors: Shen N, Fu Q, Deng Y, Qian X, Zhao J, Kaufman KM, Wu YL, Yu CY, Tang Y, Chen JY, Yang W, Wong M, Kawasaki A, Tsuchiya N, Sumida T, Kawaguchi Y, Howe HS, Mok MY, Bang SY, Liu FL, Chang DM, Takasaki Y, Hashimoto H, Harley JB, Guthridge JM, Grossman JM, Cantor RM, Song YW, Bae SC, Chen S, Hahn BH, Lau YL, Tsao BP.

Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that predominantly affects women. Previous findings that duplicated Toll-like receptor 7 (Tlr7) promotes lupus-like disease in male BXSB mice prompted us to evaluate TLR7 in human SLE. By using a candidate gene approach, we identified and replicated association of a TLR7 3'UTR SNP, rs3853839 (G/C), with SLE in 9,274 Eastern Asians (P(combined) = 6.5 x 10(-10)), with a stronger effect in male than female subjects [odds ratio, male vs. female = 2.33 (95% CI = 1.64-3.30) vs. 1.24 (95% CI = 1.14-1.34); P = 4.1 x 10(-4)]. G-allele carriers had increased TLR7 transcripts and more pronounced IFN signature than C-allele carriers; heterozygotes had 2.7-fold higher transcripts of G-allele than C-allele. These data established a functional polymorphism in type I IFN pathway gene TLR7 predisposing to SLE, especially in Chinese and Japanese male subjects.

Inverse-consistent surface mapping with Laplace-Beltrami eigen-features.

Authors: Shi Y, Morra JH, Thompson PM, Toga AW.

We propose in this work a novel variational method for computing maps between surfaces by combining informative geometric features and regularizing forces including inverse consistency and harmonic energy. To tackle the ambiguity in defining homologous points on smooth surfaces, we design feature functions in the data term based on the Reeb graph of the Laplace-Beltrami eigenfunctions to quantitatively describe the global geometry of elongated anatomical structures. For inverse consistency and robustness, our method computes simultaneously the forward and backward map by iteratively solving partial differential equations (PDEs) on the surfaces. In our experiments, we successfully mapped 890 hippocampal surfaces and report statistically significant maps of atrophy rates between normal controls and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD).

Neurofibromin regulates corticostriatal inhibitory networks during working memory performance.

Authors: Shilyansky C, Karlsgodt KH, Cummings DM, Sidiropoulou K, Hardt M, James AS, Ehninger D, Bearden CE, Poirazi P, Jentsch JD, Cannon TD, Levine MS, Silva AJ.

Neurofibromatosis type I (NF1) is one of the most common single-gene causes of learning disabilities. Here, we use behavioral working memory probes and electrophysiological studies in a mouse model of NF1 (Nf1 heterozygous null mutants; Nf1(+/-) ) to demonstrate that (i) Neurofibromin regulates prefrontal and striatal inhibitory networks, specifically activity-dependent GABA release and (ii) is required for working memory performance, with inhibition-dependent working memory deficits seen in Nf1(+/-) mice. We find that increased inhibition in medial prefrontal cortex (mPFC) is sufficient to alter persistent activity in a biophysical model of an mPFC microcircuit, suggesting a possible mechanism for Nf1(+/-) working memory deficits. Accordingly, working memory assays applied during functional MRI (fMRI) studies in human subjects with NF1 reveal hypoactivation of corticostriatal networks, which is associated with impaired working memory performance. Collectively, these integrative mouse and human studies reveal molecular and cellular mechanisms contributing to working memory deficits in NF1.

Charge photogeneration in polythiophene-perylene diimide blend films.

Authors: Shoaee S, An Z, Zhang X, Barlow S, Marder SR, Duffy W, Heeney M, McCulloch I, Durrant JR.

Transient absorption spectroscopy is employed to monitor charge photogeneration in polythiophene-perylene diimide blend films; in contrast to polythiophene-PCBM blends, efficient charge photogeneration is observed even for small energetic driving forces.

Acceptor Energy Level Control of Charge Photogeneration in Organic Donor/Acceptor Blends.

Authors: Shoaee S, Clarke TM, Huang C, Barlow S, Marder SR, Heeney M, McCulloch I, Durrant JR.

In this paper we focus upon the role of interfacial energetics in influencing the separation of charge transfer states into dissociated charge carriers in organic donor/acceptor blend films. In particular, we undertake transient optical studies of films comprising regioregular poly(3-hexylthiophene) (P3HT) blended with a series of perylene-3,4:9,10-tetracarboxydiimide (PDI) electron acceptors. For this film series, we observe a close correlation between the PDI electron affinity and the efficiency of charge separation. This correlation is discussed in the context of studies of charge photogeneration for other organic donor/acceptor blend films, including other polymers, blend compositions, and the widely used electron acceptor 3'-phenyl-3'H-cyclopropa[1,9](C(60)-I(h))[5,6]fullerene-3'-butanoic acid methyl ester (PCBM).

Optimization of arylindenopyrimidines as potent adenosine A(2A)/A(1) antagonists.

Authors: Shook BC, Rassnick S, Chakravarty D, Wallace N, Ault M, Crooke J, Barbay JK, Wang A, Leonard K, Powell MT, Alford V, Hall D, Rupert KC, Heintzelman GR, Hansen K, Bullington JL, Scannevin RH, Carroll K, Lampron L, Westover L, Russell R, Branum S, Wells K, Damon S, Youells S, Beauchamp D, Li X, Rhodes K, Jackson PF.

Two reactive metabolites were identified in vivo for the dual A(2A)/A(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity

Methylene amine substituted arylindenopyrimidi nes as potent adenosine A(2A)/A(1) antagonists.

Authors: Shook BC, Rassnick S, Hall D, Rupert KC, Heintzelman GR, Hansen K, Chakravarty D, Bullington JL, Scannevin RH, Magliaro B, Westover L, Carroll K, Lampron L, Russell R, Branum S, Wells K, Damon S, Youells S, Li X, Osbourne M, Demarest K, Tang Y, Rhodes K, Jackson PF.

A novel series of arylindenopyrimidines were identified as A(2A) and A(1) receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson's disease when dosed orally

Missing Data in Longitudinal Trials - Part B, Analytic Issues.

Authors: Siddique J, Brown CH, Hedeker D, Duan N, Gibbons RD, Miranda J, Lavori PW.

Longitudinal designs in psychiatric research have many benefits, including the ability to measure the course of a disease over time. However, measuring participants repeatedly over time also leads to repeated opportunities for missing data, either through failure to answer certain items, missed assessments, or permanent withdrawal from the study. To avoid bias and loss of information, one should take missing values into account in the analysis. Several popular ways that are now being used to handle missing data, such as the last observation carried forward (LOCF), often lead to incorrect analyses. We discuss a number of these popular but unprincipled methods and describe modern approaches to classifying and analyzing data with missing values. We illustrate these approaches using data from the WECare study, a longitudinal randomized treatment study of low income women with depression.

ADHD familial loading and abnormal EEG alpha asymmetry in children with ADHD.

Authors: Sigi Hale T, Smalley SL, Dang J, Hanada G, Macion J, Loo SK.

OBJECTIVE: Abnormal brain laterality (ABL) is indicated in ADHD. ADHD and brain laterality are heritable. Genetic factors contributing to lateralization of brain function may contribute to ADHD. If so, increased ADHD family loading should be associated with greater ABL. Previous studies have shown increased rightward alpha asymmetry in ADHD. We tested whether this was more pronounced in ADHD children with increased ADHD family loading. METHODS: We compared EEG alpha asymmetry at rest and during the Conner's Continuous Performance Test (CPT) in ADHD children with and without ADHD affected parents, and replicated our findings in a second larger sample. The replication study additionally stratified the parent-affected sample by parental persistent versus non-persistent ADHD status, increased spatial resolution of EEG measures, and assessed low versus high-alpha. RESULTS: Study-1: the parent-affected group showed increased rightward asymmetry across frontal and central regions and reduced rightward parietal asymmetry during an eyes closed (EC) condition, as well as increasing rightward parietal asymmetry with advancing age during the CPT. Study-2 replicated these findings and further delineated influences of low versus high-alpha, recording site, and effects of parental persistent versus non-persistent ADHD status. CONCLUSION: Increased ADHD familial loading was associated with increased rightward frontal asymmetry. In contrast, increased rightward parietal asymmetry was associated with reduced ADHD family loading. Frontal results are consistent with an ADHD endophenotype. Parietal results suggest an ADHD adaptive trait prevalent with less ADHD family loading. Age effects indicate a unique developmental course among ADHD children whose parents have non-persistent ADHD.

Mindfulness and attention deficit hyperactivity disorder

Authors: Smalley SL, Loo SK, Hale TS, Shrestha A, McGough J, Flook L, Reise S.

Attention deficit hyperactivity disorder (ADHD) is a disorder characterized by attentional difficulties. Mindfulness is a receptive attention to present experience. Both ADHD and mindfulness are associated with attention and personality. This study tests whether individuals with ADHD have lower mindfulness scores than controls and, if true, whether personality contributes to these differences. One hundred and five adults (half with ADHD) were assessed for mindfulness, using the Kentucky Inventory of Mindfulness Skills, and personality, using the Tridimensional Character Inventory. Individuals with ADHD report themselves as less mindful than non-ADHD controls and more novelty-seeking, less self-directed, and more self-transcendent. Mindfulness is negatively associated with ADHD and positively associated with self-directedness and self-transcendence. Analyses of subscales of mindfulness suggest that ADHD is associated most with the "Acting in Awareness" dimension, perhaps because of shared items reflecting attentional variability. The current findings support that a large portion of variability in trait mindfulness can be explained by ADHD status and personality traits of self-directedness and self-transcendence. It further suggests that interventions that increase mindfulness might improve symptoms of ADHD and increase self-directedness and/or self-transcendence.

History of prostate cancer treatment

Authors: Sriprasad S, Feneley MR, Thompson PM.

The last two decades have seen great advancements in our understanding of the prostate anatomy and approach including laparoscopic and robotic techniques. One should not however, forget that the techniques evolved with time. The history of developments in prostate cancer surgery, radiotherapy and hormonal therapy is fascinating and urologists through the ages had the quest to find an ideal treatment for prostate cancer in spite of their limitations of resources and understanding. Surgeons have now practiced radical prostatectomy for prostate cancer for over 100 years. Initially feared because of its complications and difficulty, the operation can now be carried out safely owing principally to advances in our knowledge of the surgical anatomy. Refinements in surgical technique based on anatomical understanding have enabled morbidity to be progressively reduced to a widely acceptable level. Within the past 10 years, the same principles have been applied successfully in laparoscopic and robotic techniques of prostatectomy. There are constant improvements in the field of radiotherapy, evolution of cryotherapy and changes in the role of hormones. To the future, the matching of patients to the treatment modality most appropriate to their tumour, and quality of life outcomes are likely to become increasingly important in determining future practice. It is worth while to look at the evolution to plan for the future.

Voxelwise Genome-Wide Association Study (vGWAS).

Authors: Stein JL, Hua X, Lee S, Ho AJ, Leow AD, Toga AW, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Dechairo BM, Potkin SG, Weiner MW, Thompson PM; the Alzheimer’s Disease Neuroimaging Initiative.

The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each of 31,622 voxels of the entire brain across 740 elderly subjects (mean age +/- s.d.: 75.52 +/- 6.82 years; 438 male) including subjects with Alzheimer's disease, Mild Cognitive Impairment, and healthy elderly controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used tensor-based morphometry to measure individual differences in brain structure at the voxel level relative to a study-specific template based on healthy elderly subjects. We then conducted a genome-wide association at each voxel to identify genetic variants of interest. By studying only the most associated variant at each voxel, we developed a novel method to address the multiple comparisons problem and computational burden associated with the unprecedented amount of data. No variant survived the strict significance criterion, but several genes worthy of further exploration were identified, including CSMD2 and CADPS2. These genes have high relevance to brain structure. This is the first voxelwise genome wide association study to our knowledge, and offers a novel method to discover genetic influences on brain structure.

Genome-wide analysis reveals novel genes influe ncing temporal lobe structure with relevance to neurodegeneration in Alzheimer's disease.

Authors: Stein JL, Hua X, Morra JH, Lee S, Hibar DP, Ho AJ, Leow AD, Toga AW, Sul JH, Kang HM, Eskin E, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Stephan DA, Webster J, Dechairo BM, Potkin SG, Jack CR Jr, Weiner MW, Thompson PM; the Alzheimer's Disease Neuroimaging Initiative.

In a genome-wide association study of structural brain degeneration, we mapped the 3D profile of temporal lobe volume differences in 742 brain MRI scans of Alzheimer's disease patients, mildly impaired, and healthy elderly subjects. After searching 546,314 genomic markers, 2 single nucleotide polymorphisms (SNPs) were associated with bilateral temporal lobe volume (P<5x10(-7)). One SNP, rs10845840, is located in the GRIN2B gene which encodes the N-Methyl-D-Aspartate (NMDA) glutamate receptor NR2B subunit. This protein - involved in learning and memory, and excitotoxic cell death - has age-dependent prevalence in the synapse and is already a therapeutic target in Alzheimer's disease. Risk alleles for lower temporal lobe volume at this SNP were significantly over-represented in AD and MCI subjects versus controls (odds ratio=1.273; P=0.039) and were associated with the mini-mental state exam (MMSE; t=-2.114; P=0.035) demonstrating a negative effect on global cognitive function. Voxelwise maps of genetic association of this SNP with regional brain volumes, revealed intense temporal lobe effects (FDR correction at q=0.05; critical P=0.0257). This study uses large-scale brain mapping for gene discovery with implications for Alzheimer's disease.

Expanding the range of ZNF804A variants conferring risk of psychosis.

Authors: Steinberg S, Mors O, Børglum AD, Gustafsson O, Werge T, Mortensen PB, Andreassen OA, Sigurdsson E, Thorgeirsson TE, Böttcher Y, Olason P, Ophoff RA, Cichon S, Gudjonsdottir IH, Pietiläinen OP, Nyegaard M, Tuulio-Henriksson A, Ingason A, Hansen T, Athanasiu L, Suvisaari J, Lonnqvist J, Paunio T, Hartmann A, Jürgens G, Nordentoft M, Hougaard D, Norgaard-Pedersen B, Breuer R, Möller HJ, Giegling I, Glenthøj B, Rasmussen HB, Mattheisen M, Bitter I, Réthelyi JM, Sigmundsson T, Fossdal R, Thorsteinsdottir U, Ruggeri M, Tosato S, Strengman E; GROUP, Kiemeney LA, Melle I, Djurovic S, Abramova L, Kaleda V, Walshe M, Bramon E, Vassos E, Li T, Fraser G, Walker N, Toulopoulou T, Yoon J, Freimer NB, Cantor RM, Murray R, Kong A, Golimbet V, Jönsson EG, Terenius L, Agartz I, Petursson H, Nöthen MM, Rietschel M, Peltonen L, Rujescu D, Collier DA, Stefansson H, St Clair D, Stefansson K.

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 x 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 x 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 x 10(-8). In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR=1.08, P=0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N=609, OR=1.09, P=0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P=0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P=0.0016 for association with the larger set of psychiatric disorders).Molecular Psychiatry advance online publication.

Elucidating a Magnetic Resonance Imaging-Based Neuroanatomic Biomarker for Psychosis: Classification Analysis Using Probabilistic Brain Atlas and Machine Learning Algorithms.

Authors: Sun D, van Erp TG, Thompson PM, Bearden CE, Daley M, Kushan L, Hardt ME, Nuechterlein KH, Toga AW, Cannon TD.

No objective diagnostic biomarkers or laboratory tests have yet been developed for psychotic illness. Magnetic resonance imaging (MRI) studies consistently find significant abnormalities in multiple brain structures in psychotic patients relative to healthy control subjects, but these abnormalities show substantial overlap with anatomic variation that is in the normal range and therefore nondiagnostic. Recently, efforts have been made to discriminate psychotic patients from healthy individuals using machine-learning-based pattern classification methods on MRI data. METHODS: Three-dimensional cortical gray matter density (GMD) maps were generated for 36 patients with recent-onset psychosis and 36 sex- and age-matched control subjects using a cortical pattern matching method. Between-group differences in GMD were evaluated. Second, the sparse multinomial logistic regression classifier included in the Multivariate Pattern Analysis in Python machine-learning package was applied to the cortical GMD maps to discriminate psychotic patients from control subjects. RESULTS: Patients showed significantly lower GMD, particularly in prefrontal, cingulate, and lateral temporal brain regions. Pattern classification analysis achieved 86.1% accuracy in discriminating patients from controls using leave-one-out cross-validation. CONCLUSIONS: These results suggest that even at the early stage of illness, psychotic patients present distinct patterns of regional cortical gray matter changes that can be discriminated from the normal pattern. These findings indicate that we can detect complex patterns of brain abnormality in early stages of psychotic illness, which has critical implications for early identification and intervention in individuals at ultra-high risk for developing psychosis/schizophrenia.

No decision is without risk.

Authors: Suri R, Altshuler LL.

Lack of association between neuropsychological performance and level of psychosis-proneness in an adolescent psychiatric sample

Authors: Therman S, Suvisaari JM, Kalska H, Huttunen MO, Manninen M, Cannon TD.

Studies of the prodromal stage of schizophrenia show that the late prepsychotic phase is associated with mild neuropsychological deficits that parallel those of schizophrenia. However, it is still unclear whether this association is present across the whole range of symptoms of psychosis-proneness, or specific to the extreme groups. In this study, the linear associations between dimensions of psychosis-proneness (as measured by the 92-item Prodromal Questionnaire) and performance on 20 neuropsychological measures were assessed in a group of 71 nonpsychotic adolescent psychiatric patients. A structure of positive, negative and disorganized prodromal symptom dimensions was found, replicating earlier findings. No symptom dimension was significantly associated with neuropsychological performance, even when corrected for nonspecific psychological distress. These findings suggest that the association between symptoms and neuropsychological performance is specific to high levels of symptoms or to the truly prodromal subpopulation. The results also highlight the importance of simultaneous assessment of affective state.

Assessing the responses of coastal cetaceans to the construction of offshore wind turbines.

Authors: Thompson PM, Lusseau D, Barton T, Simmons D, Rusin J, Bailey H.

The expansion of offshore renewables has raised concerns over potential disturbance to coastal cetaceans. In this study, we used passive acoustic monitoring to assess whether cetaceans responded to pile-driving noise during the installation of two 5MW offshore wind turbines off NE Scotland in 2006. Monitoring was carried out at both the turbine site and a control site in 2005, 2006 and 2007. Harbour porpoises occurred regularly around the turbine site in all years, but there was some evidence that porpoises did respond to disturbance from installation activities. We use these findings to highlight how uncertainty over cetacean distribution and the scale of disturbance effects constrains opportunities for B-A-C-I studies. We explore alternative approaches to assessing the impact of offshore wind farm upon cetaceans, and make recommendations for the research and monitoring that will be required to underpin future developments. Copyright © 2010. Published by Elsevier Ltd.

Imaging genomics.

Authors: Thompson PM, Martin NG, Wright MJ.

Imaging genomics is an emerging field that is rapidly identifying genes that influence the brain, cognition, and risk for disease. Worldwide, thousands of individuals are being scanned with high-throughput genotyping (genome-wide scans), and new imaging techniques [high angular resolution diffusion imaging and resting state functional magnetic resonance imaging (MRI)] that provide fine-grained measures of the brain's structural and functional connectivity. Along with clinical diagnosis and cognitive testing, brain imaging offers highly reproducible measures that can be subjected to genetic analysis. RECENT FINDINGS: Recent studies of twin, pedigree, and population-based datasets have discovered several candidate genes that consistently show small to moderate effects on brain measures. Many studies measure single phenotypes from the images, such as hippocampal volume, but voxel-wise genomic methods can plot the profile of genetic association at each 3D point in the brain. This exploits the full arsenal of imaging statistics to discover and replicate gene effects. SUMMARY: Imaging genomics efforts worldwide are now working together to discover and replicate many promising leads. By studying brain phenotypes closer to causative gene action, larger gene effects are detectable with realistic sample sizes obtainable from meta-analysis of smaller studies. Imaging genomics has broad applications to dementia, mental illness, and public health.

Paternal age as a risk factor for schizophrenia: How important is it?

Authors: Torrey EF, Buka S, Cannon TD, Goldstein JM, Seidman LJ, Liu T, Hadley T, Rosso IM, Bearden C, Yolken RH.

Advanced paternal age has been widely cited as a risk factor for schizophrenia among offspring and even claimed to account for one-quarter of all cases. We carried out a new study on 25,025 offspring from the Collaborative Perinatal Project (CPP), including 168 diagnosed with psychosis and 88 with narrowly defined schizophrenia. We also conducted a meta-analysis of this and nine other studies for which comparable age-cohort data were available. The mean paternal age for the CPP cases was slightly, but not significantly, higher than the matched controls (p=0.28). Meta-analyses including these new results were conducted to determine the relative risk associated with alternative definitions of advanced paternal age (35, 45 or 55years and older). These yielded pooled odds ratios and 95% confidence intervals of 1.28 (1.10, 1.48), 1.38 (0.95, 2.01) and 2.22 (1.46, 3.37), respectively. Thus, increased paternal age appears to be a risk factor for schizophrenia primarily among offspring of fathers ages 55 and over. In these 10 studies, such fathers accounted for only 0.6% of all births. Compared with other known risk factors for schizophrenia, advanced paternal age appears to be intermediate in magnitude. Advanced paternal age is also known to be a risk factor for some chromosomal and neoplastic diseases in the offspring where the cause is thought to be chromosomal aberrations and mutations of the aging germline. Similar mechanisms may account for the relationship between advanced paternal age and schizophrenia risk.

fMRI activation in the a mygdala and the orbitofrontal cortex in unmedicated subjects with major depressive disorder.

Authors: Townsend JD, Eberhart NK, Bookheimer SY, Eisenberger NI, Foland-Ross LC, Cook IA, Sugar CA, Altshuler LL.

Although amygdala and frontal lobe functional abnormalities have been reported in patients with mood disorders, the literature regarding major depressive disorder (MDD) is inconsistent. Likely confounds include heterogeneity of patient samples, medication status, and analytic approach. This study evaluated the amygdala and frontal lobe activation in unmedicated MDD patients. Fifteen MDD patients and 15 matched healthy controls were scanned using fMRI during the performance of an emotional face task known to robustly activate the amygdala and prefrontal cortex (PFC). Whole-brain and region of interest analyses were performed, and correlations between clinical features and activation were examined. Significant amygdala and lateral PFC activation were seen within patient and control groups. In a between-group comparison, patients showed significantly reduced activation in the insula, temporal and occipital cortices. In MDD, the presence of anxiety symptoms was associated with decreased orbitofrontal activation. We found robust activation in both the MDD and control groups in fronto-limbic regions with no significant between-group differences using either analytic approach. The current study replicates previous research on unmedicated subjects showing no significant differences in amygdala function in depressed vs. control subjects with respect to simple tasks involving emotion observation.

Individual Variability in Brain Activity: A Nuisance or an Opportunity?

Authors: Van Horn JD, Grafton ST, Miller MB.

Functional imaging research has been heavily influenced by results based on population-level inference. However, group average results may belie the unique patterns of activity present in the individual that ordinarily are considered random noise. Recent advances in the evolution of MRI hardware have led to significant improvements in the stability and reproducibility of blood oxygen level dependent (BOLD) measurements. These enhancements provide a unique opportunity for closer examination of individual patterns of brain activity. Three objectives can be accomplished by considering brain scans at the individual level; (1) Mapping functional anatomy at a fine grained analysis; (2) Determining if an individual scan is normative with respect to a reference population; and (3) Understanding the sources of intersubject variability in brain activity. In this review, we detail these objectives, briefly discuss their histories and present recent trends in the analyses of individual variability. Finally, we emphasize the unique opportunities and challenges for understanding individual differences through international collaboration among Pacific Rim investigators.

The Cognitive Assessment Interview (CAI) : Development and validation of an empirically derived, brief interview-based measure of cognition.

Authors: Ventura J, Reise SP, Keefe RS, Baade LE, Gold JM, Green MF, Kern RS, Mesholam-Gately R, Nuechterlein KH, Seidman LJ, Bilder RM.

Practical, reliable "real world" measures of cognition are needed to supplement neurocognitive performance data to evaluate possible efficacy of new drugs targeting cognitive deficits associated with schizophrenia. Because interview-based measures of cognition offer one possible approach, data from the MATRICS initiative (n=176) were used to examine the psychometric properties of the Schizophrenia Cognition Rating Scale (SCoRS) and the Clinical Global Impression of Cognition in Schizophrenia (CGI-CogS). METHOD: We used classical test theory methods and item response theory to derive the 10-item Cognitive Assessment Interview (CAI) from the SCoRS and CGI-CogS ("parent instruments"). Sources of information for CAI ratings included the patient and an informant. Validity analyses examined the relationship between the CAI and objective measures of cognitive functioning, intermediate measures of cognition, and functional outcome. RESULTS: The rater's score from the newly derived CAI (10 items) correlate highly (r=.87) with those from the combined set of the SCoRS and CGI-CogS (41 items). Both the patient (r=.82) and the informant (r=.95) data were highly correlated with the rater's score. The CAI was modestly correlated with objectively measured neurocognition (r=-.32), functional capacity (r=-.44), and functional outcome (r=-.32), which was comparable to the parent instruments. CONCLUSIONS: The CAI allows for expert judgment in evaluating a patient's cognitive functioning and was modestly correlated with neurocognitive functioning, functional capacity, and functional outcome. The CAI is a brief, repeatable, and potentially valuable tool for rating cognition in schizophrenia patients who are participating in clinical trials. Copyright © 2010 Elsevier B.V. All rights reserved.

Disorganization and reality distortion in schizophrenia: A meta-analysis of the relationship between positive symptoms and neurocognitive deficits.

Authors: Ventura J, Thames AD, Wood RC, Guzik LH, Hellemann GS.

Factor analytic studies have shown that in schizophrenia patients, disorganization (e.g., conceptual disorganization and bizarre behavior) is a separate dimension from other types of positive symptoms such as reality distortion (delusions and hallucinations). Although some studies have found that disorganization is more strongly linked to neurocognitive deficits and poor functional outcomes than reality distortion, the findings are not always consistent. METHODS: A meta-analysis of 104 studies (combined n=8015) was conducted to determine the magnitude of the relationship between neurocognition and disorganization as compared to reality distortion. Additional analyses were conducted to determine whether the strength of these relationships differed depending on the neurocognitive domain under investigation. RESULTS: The relationship between reality distortion and neurocognition was weak (r=-.04; p=.03) as compared to the moderate association between disorganization and neurocognition (r=-.23; p<.01). In each of the six neurocognitive domains that were examined, disorganization was more strongly related to neurocognition (r's range from -.20 to -.26) than to reality distortion (r's range from .01 to -.12). CONCLUSIONS: The effect size of the relationship between neurocognition and disorganization was significantly larger than the effect size of the relationship between neurocognition and reality distortion. These results hold across several neurocognitive domains. These findings support a dimensional view of positive symptoms distinguishing disorganization from reality distortion. Copyright © 2010 Elsevier B.V. All rights reserved.

Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study

Authors: Voyiaziakis E, Evgrafov O, Li D, Yoon HJ, Tabares P, Samuels J, Wang Y, Riddle MA, Grados MA, Bienvenu OJ, Shugart YY, Liang KY, Greenberg BD, Rasmussen SA, Murphy DL, Wendland JR, McCracken JT, Piacentini J, Rauch SL, Pauls DL, Nestadt G, Fyer AJ, Knowles JA.

Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P=0.0089) and Int7 (P=0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj)=0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk=1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.Molecular Psychiatry advance online publication, 6 October 2009; doi:10.1038/mp.2009.100.

The relation of antipsychotic and antidepressant medication with baseline symptoms and symptom progression: A naturalistic study of the North American Prodrome Longitudinal Sample.

Authors: Walker EF, Cornblatt BA, Addington J, Cadenhead KS, Cannon TD, McGlashan TH, Perkins DO, Seidman LJ, Tsuang MT, Woods SW, Heinssen R.

A substantial number of patients who meet criteria for a prodromal syndrome for first psychosis are treated with antipsychotic and/or antidepressant medications. There is suggestive evidence that both classes of medication may reduce prodromal symptoms. This longitudinal study examined the relation of antipsychotic and antidepressant medication with prodromal symptom severity at baseline and 6-month follow-up. Participants met Structured Interview for Prodromal Syndromes (SIPS) criteria for the prodrome, and were evaluated at eight centers as part of the North American Prodrome Longitudinal Study (NAPLS). Symptom ratings (positive, negative, disorganized and general) and data on antipsychotics, SSRIs, and other antidepressant medications were obtained at baseline and 6-month follow-up. Analyses revealed that all symptom dimensions declined in severity over time, but there were differences in the magnitude of the decline as a function of antipsychotic medication. Those never on antipsychotics showed less reduction in positive and disorganized symptoms over time. SSRIs and other antidepressants were not linked with declines in symptom severity. Consistent with findings from small-sample, clinical trials, the present results suggest that atypical antipsychotics may be effective in reducing the severity of attenuated positive symptoms associated with the prodrome to psychotic disorders. Limitations of the present study are noted, including the fact that it is not a randomized trial, and data on duration and dosage of medication and 2-year follow-up were not available for most participants. The results are discussed in light of the relative risks and benefits of preventive interventions, both medication and cognitive therapies, and the importance of future clinical trials.

Executive Function in Pediatric Bipolar Disorder and Attention-Deficit Hyperactivity Disorder: In Search of Distinct Phenotypic Profiles.

Authors: Walshaw PD, Alloy LB, Sabb FW.

Often, there is diagnostic confusion between bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) in youth due to similar behavioral presentations. Both disorders have been implicated as having abnormal functioning in the prefrontal cortex; however, there may be subtle differences in the manner in which the prefrontal cortex functions in each disorder that could assist in their differentiation. Executive function is a construct thought to be a behavioral analogy to prefrontal cortex functioning. We provide a qualitative review of the literature on performance on executive function tasks for BD and ADHD in order to determine differences in task performance and neurocognitive profile. Our review found primary differences in executive function in the areas of interference control, working memory, planning, cognitive flexibility, and fluency. These differences may begin to establish a pediatric BD profile that provides a more objective means of differential diagnosis between BD and ADHD when they are not reliably distinguished by clinical diagnostic methods.

Multivariate Tensor-based Morphometry on Surfaces: Application to Mapping Ventricular Abnormalities in HIV/AIDS.

Authors: Wang Y, Zhang J, Gutman B, Chan TF, Becker JT, Aizenstein HJ, Lopez OL, Tamburo RJ, Toga AW, Thompson PM.

Here we developed a new method, called multivariate tensor-based surface morphometry (TBM), and applied it to study lateral ventricular surface dif- ferences associated with HIV/AIDS. Using concepts from differential geome- try and the theory of differential forms, we created mathematical structures known as holomorphic one-forms, to obtain an efficient and accurate confor- mal parameterization of the lateral ventricular surfaces in the brain. The new meshing approach also provides a natural way to register anatomical surfaces across subjects, and improves on prior methods as it handles sur- faces that branch and join at complex 3D junctions. To analyze anatomical differences, we computed new statistics from the Riemannian surface met- rics - these retain multivariate information on local surface geometry. We applied this framework to analyze lateral ventricular surface morphometry in 3D MRI data from 11 subjects with HIV/AIDS and 8 healthy controls. Our method detected a 3D profile of surface abnormalities even in this small sample. Multivariate statistics on the local tensors gave better effect sizes for detecting group differences, relative to other TBM-based methods including analysis of the Jacobian determinant, the largest and smallest eigenvalues of the surface metric, and the pair of eigenvalues of the Jacobian matrix. The resulting analysis pipeline may improve the power of surface-based morphometry studies of the brain.

Linear and Nonlinear Spectroscopy of a Porphyrin-Squaraine-Porphyrin Conjugated System.

Authors: Webster S, Odom SA, Padilha LA, Przhonska OV, Peceli D, Hu H, Nootz G, Kachkovski AD, Matichak J, Barlow S, Anderson HL, Marder SR, Hagan DJ, Van Stryland EW.

The linear and nonlinear absorption properties of a squaraine-bridged porphyrin dimer (POR-SQU-POR) are investigated using femto-, pico-, and nanosecond pulses to understand intramolecular processes, obtain molecular optical parameters, and perform modeling of the excited-state dynamics. The optical behavior of POR-SQU-POR is compared with its separate porphyrin and squaraine constituent moieties. Linear spectroscopic studies include absorption, fluorescence, excitation and emission anisotropy, and quantum yield measurements. Nonlinear spectroscopic studies are performed across a wide range ( approximately 150 fs, approximately 25 ps, and approximately 5 ns) of pulsewidths and include two-photon absorption (2PA), single and double pump-probe, and Z-scan measurements with detailed analysis of excited-state absorption induced by both one- and two-photon absorption processes. The 2PA from the constituent moieties shows relatively small 2PA cross sections; below 10 GM (1 GM = 1 x 10(-50) cm(4) s/photon) for the porphyrin constituent and below 100 GM for the squaraine constituent except near their one-photon resonances. In stark contrast, the composite POR-SQU-POR molecule shows 2PA cross sections greater than 10(3) GM over most of the spectral range from 850 to 1600 nm (the minimum value being 780 GM at 1600 nm). The maximum value is approximately 11 000 GM near the Nd:YAG laser wavelength of 1064 nm. This broad spectral range of large 2PA cross sections is unprecedented in any other molecular system and can be explained by intramolecular charge transfer. A theoretical quantum-chemical analysis in combination with different experimental techniques allows insight into the energy-level structure and origin of the nonlinear absorption behavior of POR-SQU-POR.

Nanoscale tunable reduction of graphene oxide for graphene electronics.

Authors: Wei Z, Wang D, Kim S, Kim SY, Hu Y, Yakes MK, Laracuente AR, Dai Z, Marder SR, Berger C, King WP, de Heer WA, Sheehan PE, Riedo E.

The reduced form of graphene oxide (GO) is an attractive alternative to graphene for producing large-scale flexible conductors and for creating devices that require an electronic gap. We report on a means to tune the topographical and electrical properties of reduced GO (rGO) with nanoscopic resolution by local thermal reduction of GO with a heated atomic force microscope tip. The rGO regions are up to four orders of magnitude more conductive than pristine GO. No sign of tip wear or sample tearing was observed. Variably conductive nanoribbons with dimensions down to 12 nanometers could be produced in oxidized epitaxial graphene films in a single step that is clean, rapid, and reliable.

Investigation of variants identified in caucasian genome-wide association studies for plasma high-density lipoprotein cholesterol and triglycerides levels in mexican dyslipidemic study samples.

Authors: Weissglas-Volkov D, Aguilar-Salinas CA, Sinsheimer JS, Riba L, Huertas-Vazquez A, Ordoñez-Sánchez ML, Rodriguez-Guillen R, Cantor RM, Tusie-Luna T, Pajukanta P.

Although epidemiological studies have demonstrated an increased predisposition to low high-density lipoprotein cholesterol and high triglyceride levels in the Mexican population, Mexicans have not been included in any of the previously reported genome-wide association studies for lipids. METHODS AND RESULTS: We investigated 6 single-nucleotide polymorphisms associated with triglycerides, 7 with high-density lipoprotein cholesterol, and 1 with both triglycerides and high-density lipoprotein cholesterol in recent Caucasian genome-wide association studies in Mexican familial combined hyperlipidemia families and hypertriglyceridemia case-control study samples. These variants were within or near the genes ABCA1, ANGPTL3, APOA5, APOB, CETP, GALNT2, GCKR, LCAT, LIPC, LPL (2), MMAB-MVK, TRIB1, and XKR6-AMAC1L2. We performed a combined analysis of the family-based and case-control studies (n=2298) using the Z method to combine statistics. Ten of the single-nucleotide polymorphisms were nominally significant and 5 were significant after Bonferroni correction (P=2.20x10(-3) to 2.6x10(-11)) for the number of tests performed (APOA5, CETP, GCKR, and GALNT2). Interestingly, our strongest signal was obtained for triglycerides with the minor allele of rs964184 (P=2.6x10(-11)) in the APOA1/C3/A4/A5 gene cluster region that is significantly more common in Mexicans (27%) than in whites (12%). CONCLUSIONS: It is important to confirm whether known loci have a consistent effect across ethnic groups. We show replication of 5 Caucasian genome-wide association studies lipid associations in Mexicans. The remaining loci will require a comprehensive investigation to exclude or verify their significance in Mexicans. We also demonstrate that rs964184 has a large effect (odds ratio, 1.74) and is more frequent in the Mexican population, and thus it may contribute to the high predisposition to dyslipidemias in Mexicans.

Work through the valley: evaluate.

Authors: Wells K, Koegel P, Jones L, Meade B.

While all stages of a community-partnered participatory research (CPPR) initiative involve evaluation, the main focus is the evaluation of the action plans, which often involves the most rigorous evaluation activities of the project, from both a community-engagement and scientific perspective. This article reviews evaluation principles for a community-based project, and describes the goals and functions of the Council's research and evaluation committee. It outlines 10 steps to partnered evaluation, and concludes by emphasizing the importance of asset-based evaluation that builds capacity for the community and the partnership.

Mixture Model Clustering of Phenotype Features Reveals Evidence for Association of DTNBP1 to a Specific Subtype of Schizophrenia.

Authors: Wessman J, Paunio T, Tuulio-Henriksson A, Koivisto M, Partonen T, Suvisaari J, Turunen JA, Wedenoja J, Hennah W, Pietiläinen OP, Lönnqvist J, Mannila H, Peltonen L.

While DTNBP1, DISC1, and NRG1 have been extensively studied as candidate genes of schizophrenia, results remain inconclusive. Possible explanations for this are that the genes might be relevant only to certain subtypes of the disease and/or only in certain populations. METHODS: We performed unsupervised clustering of individuals from Finnish schizophrenia families, based on extensive clinical and neuropsychological data, including Structured Clinical Interview for DSM-IV (SCID) information. Families with at least one affected member with DSM-IV diagnosis of a schizophrenia spectrum psychosis were included in a register-based ascertainment. Final sample consisted of 904 individuals from 288 families. We then used the cluster phenotypes in a genetic association study of candidate genes. RESULTS: A robust three-class clustering of individuals emerged: 1) psychotic disorder with mood symptoms (n = 172), 2) core schizophrenia (n = 223), and 3) absence of psychotic disorder (n = 509). One third of the individuals diagnosed with schizophrenia were assigned to cluster 1. These individuals had fewer negative and positive psychotic symptoms and cognitive deficits but more depressive symptoms than individuals in cluster 2. There was a significant association of cluster 2 cases with the DTNBP1 gene, while the DISC1 gene indicated a significant association with schizophrenia spectrum disorders based on the DSM-IV criteria. CONCLUSIONS: In the Finnish population, DTNBP1 gene is associated with a schizophrenia phenotype characterized by prominent negative symptoms, generalized cognitive impairment, and few mood symptoms. Identification of genes and pathways related to schizophrenia necessitates novel definitions of disease phenotypes associated more directly with underlying biology.

Structural and Functional Reorganization of the Corpus Callosum between the Age of 6 and 8 Years.

Authors: Westerhausen R, Luders E, Specht K, Ofte SH, Toga AW, Thompson PM, Helland T, Hugdahl K.

The establishment of an efficient exchange of information between the cerebral hemispheres is of crucial importance in the developing functionally lateralized brain. The corpus callosum, the major connection between the cerebral hemispheres, grows constantly throughout childhood and adolescence. However, behavioral studies suggest the existence of a critical time period for callosal functional development starting around the age of 6 years. In the present longitudinal study, examining a cohort of 20 children at the age of 6 and 8 years, we assessed the relationship between structural and functional callosal development during this time period. The structural development was quantified by calculating the increase in callosal thickness using a shape-based computational analysis of the mid-sagittal corpus callosum as obtained with magnetic resonance imaging. The functional development was assessed with a speech discrimination task based on the dichotic presentation of consonant-vowel syllables. The statistical analysis revealed that children whose callosal isthmus increased in thickness over the course of 2 years showed a decrease in interhemispheric information transfer. However, children exhibiting a decrease in isthmus thickness revealed an increase in information transfer. These results might indicate a refinement process of the callosal connections to optimize the neuronal communication between the developing cerebral hemispheres.

Assessing the Reliability to Detect Cerebral Hypometabolism in Probable Alzheimer's Disease and Amnestic Mild Cognitive Impai rment.

Authors: Wu X, Chen K, Yao L, Ayutyanont N, Langbaum JB, Fleisher A, Reschke C, Lee W, Liu X, Alexander GE, Bandy D, Foster NL, Thompson PM, Harvey DJ, Weiner MW, Koeppe RA, Jagust WJ, Reiman EM.

Fluorodeoxyglucose positron emission tomography (FDG-PET) studies report characteristic patterns of cerebral hypometabolism in probable Alzheimer's disease (pAD) and amnestic mild cognitive impairment (aMCI). This study aims to characterize the consistency of regional hypometabolism in pAD and aMCI patients enrolled in the AD Neuroimaging Initiative (ADNI) using statistical parametric mapping (SPM) and bootstrap resampling, and to compare bootstrap based reliability index to the commonly used type-I error approach with or without correction for multiple comparisons. Batched SPM5 was run for each of 1,000 bootstrap iterations to compare FDG-PET images from 74 pAD and 142 aMCI patients, respectively, to 82 normal controls. Maps of the hypometabolic voxels detected for at least a specific percentage of times over the 1000 runs were examined and compared to an overlap of the hypometabolic maps obtained from 3 randomly partitioned independent sub-datasets. The results from the bootstrap derived reliability of regional hypometabolism in the overall data set were similar to that observed in each of the three non-overlapping sub-sets using family-wise error. Strong but non-linear association was found between the bootstrap based reliability index and the type-I error. For threshold p=0.0005, pAD was associated with extensive hypometabolic voxels in the posterior cingulate/precuneus and parietotemporal regions with reliability between 90% and 100%. Bootstrap analysis provides an alternative to the parametric family-wise error approach used to examine consistency of hypometabolic brain voxels in pAD and aMCI patients. These results provide a foundation for the use of bootstrap analysis characterize statistical ROIs or search regions in both cross-sectional and longitudinal FDG PET studies. This approach offers promise in the early detection and tracking of AD, the evaluation of AD-modifying treatments, and other biologically or clinical important measurements using brain images and voxel-based data analysis techniques. Copyright © 2010. Published by Elsevier B.V.

Mismatch Negativity, Social Cognition, and Functioning in Schizophrenia Patients.

Authors: Wynn JK, Sugar C, Horan WP, Kern R, Green MF.

Cognition and social cognition have been found to influence functional outcome in schizophrenia patients. However, little is known about the underlying neural substrates that are associated with social cognition or daily functioning. Prior studies found associations between mismatch negativity (MMN), an event-related potential response indexing early auditory processing, and functioning in schizophrenia patients. METHODS: In this study, we examined MMN, social cognition (social perception and theory of mind), and four domains of functioning (work, independent living, social networks, and family networks) in 33 schizophrenia patients and 42 demographically comparable healthy control subjects. RESULTS: Schizophrenia patients exhibited reduced MMN activity at frontocentral electrode sites compared with healthy control subjects. Within the schizophrenia sample, greater MMN activity at frontocentral sites correlated with better work and independent living (but not social or family networks) and with better social perception. CONCLUSIONS: These results suggest that MMN activity is more closely tied to some outcome domains (work and independent living) than others. Mismatch negativity has been previously shown to be associated with basic cognition and functional outcome in schizophrenia, but these findings are the first, to our knowledge, to show MMN associations with social cognition. These results are consistent with cascade models of information processing in which deficits in early perceptual processing have a downstream impact on higher order social cognition and community functioning. Published by Elsevier Inc.

Greater Neural Pattern Similarity Across Repetitions Is Associated with Better Memory.

Authors: Xue G, Dong Q, Chen C, Lu Z, Mumford JA, Poldrack RA.

Repeated study improves memory, but the underlying neural mechanisms of this improvement are not well understood. Using functional magnetic resonance imaging and representational similarity analysis of brain activity, we found that, compared with forgotten items, subsequently remembered faces and words showed greater similarity in neural activation across multiple study in many brain regions, including (but not limited to) the regions whose mean activities were correlated with subsequent memory. This result addresses a longstanding debate in the study of memory by showing that successful episodic memory encoding occurs when the same neural representations are more precisely reactivated across study episodes, rather than when patterns of activation are more variable across time.

Spaced Learning Enhances Subsequent Recognition Memory by Reducing Neural Repetition Suppression.

Authors: Xue G, Mei L, Chen C, Lu ZL, Poldrack R, Dong Q.

Spaced learning usually leads to better recognition memory as compared with massed learning, yet the underlying neural mechanisms remain elusive. One open question is whether the spacing effect is achieved by reducing neural repetition suppression. In this fMRI study, participants were scanned while intentionally memorizing 120 novel faces, half under the massed learning condition (i.e., four consecutive repetitions with jittered interstimulus interval) and the other half under the spaced learning condition (i.e., the four repetitions were interleaved). Recognition memory tests afterward revealed a significant spacing effect: Participants recognized more items learnt under the spaced learning condition than under the massed learning condition. Successful face memory encoding was associated with stronger activation in the bilateral fusiform gyrus, which showed a significant repetition suppression effect modulated by subsequent memory status and spaced learning. Specifically, remembered faces showed smaller repetition suppression than forgotten faces under both learning conditions, and spaced learning significantly reduced repetition suppression. These results suggest that spaced learning enhances recognition memory by reducing neural repetition suppression.

The International Society for Bipolar Disorders-Battery for Assessment of Neurocognition (ISBD-BANC).

Authors: Yatham LN, Torres IJ, Malhi GS, Frangou S, Glahn DC, Bearden CE, Burdick KE, Martínez-Arán A, Dittmann S, Goldberg JF, Ozerdem A, Aydemir O, Chengappa KN.

Although cognitive impairment is recognized as an important clinical feature of bipolar disorder, there is no standard cognitive battery that has been developed for use in bipolar disorder research. The aims of this paper were to identify the cognitive measures from the literature that show the greatest magnitude of impairment in bipolar disorder, to use this information to determine whether the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB), developed for use in schizophrenia, might be suitable for bipolar disorder research, and to propose a preliminary battery of cognitive tests for use in bipolar disorder research. METHODS: The project was conducted under the auspices of the International Society for Bipolar Disorders and involved a committee that comprised researchers with international expertise in the cognitive aspects of bipolar disorder. In order to identify cognitive tasks that show the largest magnitude of impairment in bipolar disorder, we reviewed the literature on studies assessing cognitive functioning (including social cognition) in bipolar disorder. We further provided a brief review of the cognitive overlap between schizophrenia and bipolar disorder and evaluated the degree to which tasks included in the MCCB (or other identified tasks) might be suitable for use in bipolar disorder. RESULTS: Based on evidence that cognitive deficits in bipolar disorder are similar in pattern but less severe than in schizophrenia, it was judged that most subtests comprising the MCCB appear appropriate for use in bipolar disorder. In addition to MCCB tests, other specific measures of more complex verbal learning (e.g., the California Verbal Learning Test) or executive function (Stroop Test, Trail Making Test-part B, Wisconsin Card Sorting Test) also show substantial impairment in bipolar disorder. CONCLUSIONS: Our analysis reveals that the MCCB represents a good starting point for assessing cognitive deficits in research studies of bipolar disorder, but that other tasks including more complex verbal learning measures and tests of executive function should also be considered in assessing cognitive compromise in bipolar disorder. Several promising cognitive tasks that require further study in bipolar disorder are also presented.

Integrity of emotional and motivational states during the prodromal, first-episode, and chronic phases of schizophrenia.

Authors: Yee CM, Mathis KI, Sun JC, Sholty GL, Lang PJ, Bachman P, Williams TJ, Bearden CE, Cannon TD, Green MF, Subotnik KL, Ventura J, Nuechterlein KH.

Emotional and motivational dysfunction is fundamental to schizophrenia, and yet, the nature and scope of associated deficits are not well understood. This study assessed the integrity of emotional responding from the perspective of its underlying motivational systems during different phases of schizophrenia. Evaluative, somatic, and autonomic responses were measured during viewing of pictures categorized by emotional content, including threat, mutilation, contamination, illness, pollution, mild erotica, families, food, and nature. Participants were 13 patients at ultra high risk or prodromal for psychosis, 40 first-episode schizophrenia patients, 37 chronic schizophrenia patients, and 74 healthy comparison subjects. Irrespective of phase of illness, schizophrenia patients showed a robust and normal pattern of response across multiple systems, with differential engagement of the defensive and appetitive systems as a function of the motivational significance assigned to specific emotional contexts. Although the integrity of core motivational states also appeared to be intact in prodromal patients, a less consistent pattern of response was observed. As continuing efforts are made to identify emotional and motivational abnormalities in schizophrenia, identified deficits will likely be independent of a fundamental dysfunction in basic emotion and motivation response systems and involve integration with higher order processes.

Topological correction of brain surface meshes using spherical harmonics.

Authors: Yotter RA, Dahnke R, Thompson PM, Gaser C.

Surface reconstruction methods allow advanced analysis of structural and functional brain data beyond what can be achieved using volumetric images alone. Automated generation of cortical surface meshes from 3D brain MRI often leads to topological defects and geometrical artifacts that must be corrected to permit subsequent analysis. Here, we propose a novel method to repair topological defects using a surface reconstruction that relies on spherical harmonics. First, during reparameterization of the surface using a tiled platonic solid, the original MRI intensity values are used as a basis to select either a "fill" or "cut" operation for each topological defect. We modify the spherical map of the uncorrected brain surface mesh, such that certain triangles are favored while searching for the bounding triangle during reparameterization. Then, a low-pass filtered alternative reconstruction based on spherical harmonics is patched into the reconstructed surface in areas that previously contained defects. Self-intersections are repaired using a local smoothing algorithm that limits the number of affected points to less than 0.1% of the total, and as a last step, all modified points are adjusted based on the T1 intensity. We found that the corrected reconstructions have reduced distance error metrics compared with a "gold standard" surface created by averaging 12 scans of the same brain. Ninety-three percent of the topological defects in a set of 10 scans of control subjects were accurately corrected. The entire process takes 6-8 min of computation time. Further improvements are discussed, especially regarding the use of the T1-weighted image to make corrections. Hum Brain Mapp, 2010. (c) 2010 Wiley-Liss, Inc.

Algorithms to Improve the Reparameterization of Spherical Mappings of Brain Surface Meshes.

Authors: Yotter RA, Thompson PM, Gaser C.

A spherical map of a cortical surface is often used for improved brain registration, for advanced morphometric analysis (eg, of brain shape), and for surface-based analysis of functional signals recorded from the cortex. Furthermore, for intersubject analysis, it is usually necessary to reparameterize the surface mesh into a common coordinate system. An isometric map conserves all angle and area information in the original cortical mesh; however, in practice, spherical maps contain some distortion. Here, we propose fast new algorithms to reduce the distortion of initial spherical mappings generated using one of three common spherical mapping methods. The algorithms iteratively solve a nonlinear optimization problem to reduce distortion. Our results demonstrate that our correction process is computationally inexpensive and the resulting spherical maps have improved distortion metrics. We show that our corrected spherical maps improve reparameterization of the cortical surface mesh, such that the distance error measures between the original and reparameterized surface are significantly decreased.

Routine Outcomes Monitoring to Support Improving Care for Schizophrenia: Report from the VA Mental He alth QUERI.

Authors: Young AS, Niv N, Chinman M, Dixon L, Eisen SV, Fischer EP, Smith J, Valenstein M, Marder SR, Owen RR.

In schizophrenia, treatments that improve outcomes have not been reliably disseminated. A major barrier to improving care has been a lack of routinely collected outcomes data that identify patients who are failing to improve or not receiving effective treatments. To support high quality care, the VA Mental Health QUERI used literature review, expert interviews, and a national panel process to increase consensus regarding outcomes monitoring instruments and strategies that support quality improvement. There was very good consensus in the domains of psychotic symptoms, side-effects, drugs and alcohol, depression, caregivers, vocational functioning, and community tenure. There are validated instruments and assessment strategies that are feasible for quality improvement in routine practice.

How does angular resolution affect diffusion imaging measures?

Authors: Zhan L, Leow AD, Jahanshad N, Chiang MC, Barysheva M, Lee AD, Toga AW, McMahon KL, de Zubicaray GI, Wright MJ, Thompson PM.

A key question in diffusion imaging is how many diffusion-weighted images suffice to provide adequate signal-to-noise ratio (SNR) for studies of fiber integrity. Motion, physiological effects, and scan duration all affect the achievable SNR in real brain images, making theoretical studies and simulations only partially useful. We therefore scanned 50 healthy adults with 105-gradient high-angular resolution diffusion imaging (HARDI) at 4 Tesla. From gradient image subsets of varying size (6

2. Addiction. 2010 Oct;105(10):1809-18. doi: 10.1111/j.1360-0443.2010.03066.x. Withdrawal symptoms in abstinent methamphetamine-dependent subjects.

Authors: Zorick T, Nestor L, Miotto K, Sugar C, Hellemann G, Scanlon G, Rawson R, London ED.

Aims  Withdrawal symptoms have been linked to a propensity for relapse to drug abuse. Inasmuch as this association applies to methamphetamine (MA) abuse, an understanding of the course of MA withdrawal symptoms may help to direct treatment for MA dependence. Previous studies of symptoms manifested during abstinence from MA have been limited in size and scope. We asked (i) whether debilitating psychological and/or physical symptoms appear during the first several weeks of MA abstinence, (ii) how craving for MA evolves and (iii) whether psychiatric symptoms (e.g. depression, psychosis) persist beyond a month of abstinence. Design  A study of MA-dependent participants, who initiated and maintained abstinence from the drug for up to 5 weeks, compared to a matched healthy comparison group. Setting  In-patient research hospital ward (MA-dependent subjects) and out-patient (comparison subjects). Participants  Fifty-six MA-dependent and eighty-nine comparison subjects. Measurements  Rater-assessed MA withdrawal questionnaire and self-report assessment of craving (MA-dependent subjects) and self-report assessment of psychiatric symptoms (both groups). Findings  At study entry, MA-dependent subjects exhibited a wide range in severity of depressive symptoms, with the average score at a mild-moderate level of severity. Symptoms of psychosis were also prevalent. While depressive and psychotic symptoms largely resolved within a week of abstinence, craving did not decrease significantly from the time of initiating abstinence until the second week, and then continued at a reduced level to the fifth week. Conclusions  Depressive and psychotic symptoms accompany acute withdrawal from methamphetamine but resolve within 1 week. Craving is also present and lasts at least 5 weeks.