- Publications

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.

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.

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

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

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.

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

Authors: Bilder RM

The Neuropsychology of Schizophrenia Circa 2009

Authors: Bilder RM

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

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 (http://Pipeline.loni.ucla.edu

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).

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.

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.

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.

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

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

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.

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.

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.

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

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.

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.

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

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.

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.

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.

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

Authors: Patel K, Wells K.

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.

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

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.

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.

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.

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

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

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 biol

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