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1.  Oligodendrocyte Genes, White Matter Tract Integrity, and Cognition in Schizophrenia 
Cerebral Cortex (New York, NY)  2012;23(9):2044-2057.
Oligodendrocyte genes and white matter tracts have been implicated in the pathophysiology of schizophrenia and may play an important etiopathogenic role in cognitive dysfunction in schizophrenia. The objective of the present study in 60 chronic schizophrenia patients individually matched to 60 healthy controls was to determine whether 1) white matter tract integrity influences cognitive performance, 2) oligodendrocyte gene variants influence white matter tract integrity and cognitive performance, and 3) effects of oligodendrocyte gene variants on cognitive performance are mediated via white matter tract integrity. We used the partial least-squares multivariate approach to ascertain relationships among oligodendrocyte gene variants, integrity of cortico-cortical and subcortico-cortical white matter tracts, and cognitive performance. Robust relationships among oligodendrocyte gene variants, white matter tract integrity, and cognitive performance were found in both patients and controls. We also showed that effects of gene variants on cognitive performance were mediated by the integrity of white matter tracts. Our results were strengthened by bioinformatic analyses of gene variant function. To our knowledge, this is the first study that has brought together these lines of investigation in the same population and highlights the importance of the oligodendrocyte/white matter pathway in schizophrenia, particularly as it pertains to cognitive function.
doi:10.1093/cercor/bhs188
PMCID: PMC3729194  PMID: 22772651
cognition; DTI; genetics; oligodendrocytes; white matter
2.  A review of structural neuroimaging in schizophrenia: from connectivity to connectomics 
In patients with schizophrenia neuroimaging studies have revealed global differences with some brain regions showing focal abnormalities. Examining neurocircuitry, diffusion-weighted imaging studies have identified altered structural integrity of white matter in frontal and temporal brain regions and tracts such as the cingulum bundles, uncinate fasciculi, internal capsules and corpus callosum associated with the illness. Furthermore, structural co-variance analyses have revealed altered structural relationships among regional morphology in the thalamus, frontal, temporal and parietal cortices in schizophrenia patients. The distributed nature of these abnormalities in schizophrenia suggests that multiple brain circuits are impaired, a neural feature that may be better addressed with network level analyses. However, even with the advent of these newer analyses, a large amount of variability in findings remains, likely partially due to the considerable heterogeneity present in this disorder.
doi:10.3389/fnhum.2014.00653
PMCID: PMC4142355  PMID: 25202257
magnetic resonance imaging; diffusion tensor imaging; schizophrenia; connectomics; connectivity; white matter
3.  Brain White Matter Development Is Associated with a Human-Specific Haplotype Increasing the Synthesis of Long Chain Fatty Acids 
The Journal of Neuroscience  2014;34(18):6367-6376.
The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with ω-3 and ω-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9–86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age × genotype interactions, pcorrected < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin-related disorders of neurodevelopmental origin.
doi:10.1523/JNEUROSCI.2818-13.2014
PMCID: PMC4004819  PMID: 24790207
brain development; diffusion tensor imaging; fatty acid desaturase genes; myelin; polyunsaturated fatty acids; white matter
4.  Alterations of Superficial White Matter in Schizophrenia and Relationship to Cognitive Performance 
Neuropsychopharmacology  2013;38(10):1954-1962.
Post-mortem studies have demonstrated alterations in superficial white matter (SWM) in schizophrenia patients. Diffusion tensor imaging (DTI) can be used to assess SWM in vivo, and compare SWM fractional anisotropy (FA) in schizophrenia patients vs healthy controls. The assessment of SWM in vivo also provides an opportunity to identify novel neural correlates of cognitive performance, and potential cognitive impairment in schizophrenia patients. Forty-four patients with schizophrenia and 44 matched healthy controls underwent neuroimaging and cognitive protocols. Using an SWM mask and tract-based spatial statistics, differences in SWM-FA were examined between groups. SWM-FA clusters different between groups were then used to predict cognitive performance with multiple linear regression. The relative contribution of SWM fiber subtypes (deep white matter extensions vs U-fibers and intraregional fibers) from significantly different clusters was examined. Compared to controls, patients with schizophrenia had reduced FA in five SWM clusters: the largest a left posterior parieto-occipital cluster, followed by four clusters in the left frontal lobe. SWM-FA in the frontal lobe clusters predicted attention, working memory, and processing speed performance in healthy controls, but not in patients with schizophrenia. The majority of streamlines tracked from these clusters were restricted to U-fibers and intraregional fibers, rather than deep white matter extensions. Our analyses revealed prominent SWM disruption in patients with schizophrenia compared to controls. SWM–cognition relationships shown in healthy individuals were disrupted in patients with schizophrenia. SWM may be an important neurobiological substrate of cognitive performance and a novel cortical treatment target for cognitive deficits in schizophrenia patients.
doi:10.1038/npp.2013.93
PMCID: PMC3746702  PMID: 23591167
cognition; cognitive impairment; diffusion tensor imaging; Imaging; Clinical or Preclinical; neuroanatomy; schizophrenia; schizophrenia/antipsychotics; superficial white matter; u-fibers; schizophrenia; diffusion tensor imaging; superficial white matter; cognitive impairment; U-fibers; tract-based spatial statistics
5.  Cognitive performance of individuals with schizophrenia across seven decades: A study using the MATRICS Consensus Cognitive Battery 
Objectives
The objectives of this study are to determine the effect of aging, schizophrenia, and their interaction on cognitive function.
Design
Cross-sectional controlled study.
Setting
Community-living.
Participants
235 subjects with schizophrenia aged 19-79 and 333 comparison subjects aged 20-81.
Measurements
The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB).
Results
Older age was associated with poorer performance on 9 of 10 MCCB tests in both subjects with schizophrenia and comparison subjects. Subjects with schizophrenia were impaired relative to comparison subjects on each of the 10 tests. However, there was no interaction between aging and schizophrenia on any test. Essentially the same results were observed when analyzing performance on the seven MCCB cognitive domains and MCCB global composite score.
Conclusions
Consistent with other reports, schizophrenia appears to be a disorder marked by generalized cognitive dysfunction. However, the rate of cognitive decline appears to be similar to that observed in healthy comparison subjects. They do not experience acceleration in cognitive aging which supports the hypothesis that schizophrenia is a syndrome of premature aging. Longitudinal studies including very old patients are needed to confirm and extend these findings.
doi:10.1016/j.jagp.2012.10.011
PMCID: PMC3548068  PMID: 23343484
accelerated aging; cognition; life span; MATRICS; neuropsychology; old age; premature aging; schizophrenia
6.  White Matter Deficits in Psychopathic Offenders and Correlation with Factor Structure 
PLoS ONE  2013;8(8):e72375.
Psychopathic offenders show a persistent pattern of emotional unresponsivity to the often horrendous crimes they perpetrate. Recent studies have related psychopathy to alterations in white matter. Therefore, diffusion tensor imaging followed by tract-based spatial statistics (TBSS) analysis in 11 psychopathic offenders matched to 11 healthy controls was completed. Fractional anisotropy was calculated within each voxel and comparisons were made between groups using a permutation test. Any clusters of white matter voxels different between groups were submitted to probabilistic tractography. Significant differences in fractional anisotropy were found between psychopathic offenders and healthy controls in three main white matter clusters. These three clusters represented two major networks: an amygdalo-prefrontal network, and a striato-thalamo-frontal network. The interpersonal/affective component of the PCL-R correlated with white matter deficits in the orbitofrontal cortex and frontal pole whereas the antisocial component correlated with deficits in the striato-thalamo-frontal network. In addition to replicating earlier work concerning disruption of an amygdala-prefrontal network, we show for the first time that white matter integrity in a striato-thalamo-frontal network is disrupted in psychopathic offenders. The novelty of our findings lies in the two dissociable white matter networks that map directly onto the two major factors of psychopathy.
doi:10.1371/journal.pone.0072375
PMCID: PMC3748110  PMID: 23977291
7.  The ZNF804A Gene: Characterization of a Novel Neural Risk Mechanism for the Major Psychoses 
Neuropsychopharmacology  2011;36(9):1871-1878.
Schizophrenia and bipolar disorder share genetic risk, brain vulnerability, and clinical symptoms. The ZNF804A risk variant, rs1344706, confers susceptibility for both disorders. This study aimed to identify neural mechanisms common to both schizophrenia and bipolar disorder through this variant's potential effects on cortical thickness, white matter tract integrity, and cognitive function. Imaging, genetics, and cognitive measures were ascertained in 62 healthy adults aged between 18 and 59 years. High-resolution multimodal MRI/DTI imaging was used to measure cortical thickness and major frontotemporal and interhemispheric white matter tracts. The general linear model was used to examine the influence of the ZNF804A rs1344706 risk variant on cortical thickness, white matter tract integrity, and cognitive measures. Individuals homozygous for the risk variant (‘A' allele) demonstrated reduced cortical gray matter thickness in the superior temporal gyrus, and in the anterior and posterior cingulate cortices compared with C-allele carriers. No effect of the risk variant on microstructural integrity of white matter tracts was found. Reduced attention control was found in risk allele homozygotes, aligning with findings in the anterior cingulate cortex. Our data provide a novel, genetically based neural risk mechanism for the major psychoses by effects of the ZNF804A risk variant on neural structures and cognitive function susceptible in both disorders. Our findings link genetic, imaging, and cognitive susceptibility relevant to both schizophrenia and bipolar disorder.
doi:10.1038/npp.2011.72
PMCID: PMC3154105  PMID: 21525856
ZNF804A; cortical thickness; DTI; white matter; schizophrenia; bipolar disorder; schizophrenia/antipsychotics; depression; unipolar/bipolar; imaging; clinical or preclinical; neurogenetics; MRI; genetics; DTI; cortical thickness
8.  DISC1 and Striatal Volume: A Potential Risk Phenotype For mental Illness 
Disrupted-in-schizophrenia 1 was originally discovered in a large Scottish family with abnormally high rates of severe mental illness, including schizophrenia, bipolar disorder, and depression. An accumulating body of evidence from genetic, postmortem, and animal data supports a role for DISC1 in different forms of mental illness. DISC1 may play an important role in determining structure and function of several brain regions. One brain region of particular importance for several mental disorders is the striatum, and DISC1 mutant mice have demonstrated an increase in dopamine (D2) receptors in this structure. However, association between DISC1 functional polymorphisms and striatal structure have not been examined in humans. We, therefore hypothesized that there would be a relationship between human striatal volume and DISC1 genotype, specifically in the Leu607Phe (rs6675281) and Ser704Cys (rs821618) single nucleotide polymorphisms. We tested our hypothesis by automatically identifying the striatum in 54 healthy volunteers recruited for this study. We also performed an exploratory analysis of cortical thickness, cortical surface area, and structure volume. Our results demonstrate that Phe allele carriers have larger striatal volume bilaterally (left striatum: p = 0.017; right striatum: p = 0.016). From the exploratory analyses we found that the Phe carriers also had larger left hemisphere volumes (p = 0.0074) and right occipital lobe surface area (p = 0.014) compared to LeuLeu homozygotes. However, these exploratory findings do not survive a conservative correction for multiple comparisons. Our findings demonstrate that a functional DISC1 variant influences striatal volumes. Taken together with animal data that this gene influences D2 receptor levels in striatum, a key risk pathway for mental illnesses such as schizophrenia and bipolar disorder may be conferred via DISC1’s effects on the striatum.
doi:10.3389/fpsyt.2012.00057
PMCID: PMC3378182  PMID: 22723785
DISC1; striatum; striatal volume; mental illness; schizophrenia; bipolar disorder; depression
9.  Myelin-Associated Glycoprotein Gene and Brain Morphometry in Schizophrenia 
Myelin and oligodendrocyte disruption may be a core feature of schizophrenia pathophysiology. The purpose of the present study was to localize the effects of previously identified risk variants in the myelin-associated glycoprotein (MAG) gene on brain morphometry in schizophrenia patients and healthy controls. Forty-five schizophrenia patients and 47 matched healthy controls underwent clinical, structural magnetic resonance imaging, and genetics procedures. Gray and white matter cortical lobe volumes along with hippocampal volumes were calculated from T1-weighted MRI scans. Each subject was also genotyped for the two disease-associated MAG single nucleotide polymorphisms (rs720308 and rs720309). Repeated measures general linear model (GLM) analysis found significant region by genotype and region by genotype by diagnosis interactions for the effects of MAG risk variants on lobar gray matter volumes. No significant associations were found with lobar white matter volumes or hippocampal volumes. Follow-up univariate GLMs found the AA genotype of rs720308 predisposed schizophrenia patients to left temporal and parietal gray matter volume deficits. These results suggest that the effects of the MAG gene on cortical gray matter volume in schizophrenia patients can be localized to temporal and parietal cortices. Our results support a role for MAG gene variation in brain morphometry in schizophrenia, align with other lines of evidence implicating MAG in schizophrenia, and provide genetically based insight into the heterogeneity of brain imaging findings in this disorder.
doi:10.3389/fpsyt.2012.00040
PMCID: PMC3342517  PMID: 22563322
schizophrenia; myelin-associated glycoprotein; imaging–genetics; temporal lobe; parietal lobe; gray matter volume
10.  Age-related decline in white matter tract integrity and cognitive performance: A DTI tractography and structural equation modeling study 
Neurobiology of aging  2010;33(1):21-34.
Age-related decline in microstructural integrity of certain white matter tracts may explain cognitive decline associated with normal aging. Whole brain tractography and a clustering segmentation in 48 healthy individuals across the adult lifespan were used to examine: interhemispheric (corpus callosum), intrahemispheric association (cingulum, uncinate, arcuate, inferior longitudinal, inferior occipitofrontal), and projection (corticospinal) fibers. Principal components analysis reduced cognitive tests into 6 meaningful factors: (1) memory and executive function; (2) visuomotor dexterity; (3) motor speed; (4) attention and working memory; (5) set-shifting/flexibility; and (6) visuospatial construction. Using theory-based structural equation modeling, relationships among age, white matter tract integrity, and cognitive performance were investigated. Parsimonious model fit demonstrated relationships where decline in white matter integrity may explain age-related decline in cognitive performance: inferior longitudinal fasciculus (ILF) with visuomotor dexterity; the inferior occipitofrontal fasciculus with visuospatial construction; and posterior fibers (i.e., splenium) of the corpus callosum with memory and executive function. Our findings suggest that decline in the microstructural integrity of white matter fibers can account for cognitive decline in normal aging.
doi:10.1016/j.neurobiolaging.2010.02.009
PMCID: PMC2945445  PMID: 20363050
Aging; Anisotropy; Cognition; Diffusion tensor imaging; White matter
11.  Impaired Structural Connectivity of Socio-Emotional Circuits in Autism Spectrum Disorders: A Diffusion Tensor Imaging Study 
PLoS ONE  2011;6(11):e28044.
Background
Abnormal white matter development may disrupt integration within neural circuits, causing particular impairments in higher-order behaviours. In autism spectrum disorders (ASDs), white matter alterations may contribute to characteristic deficits in complex socio-emotional and communication domains. Here, we used diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS) to evaluate white matter microstructure in ASD.
Methods/Principal Findings
DTI scans were acquired for 19 children and adolescents with ASD (∼8–18 years; mean 12.4±3.1) and 16 age and IQ matched controls (∼8–18 years; mean 12.3±3.6) on a 3T MRI system. DTI values for fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity, were measured. Age by group interactions for global and voxel-wise white matter indices were examined. Voxel-wise analyses comparing ASD with controls in: (i) the full cohort (ii), children only (≤12 yrs.), and (iii) adolescents only (>12 yrs.) were performed, followed by tract-specific comparisons. Significant age-by-group interactions on global DTI indices were found for all three diffusivity measures, but not for fractional anisotropy. Voxel-wise analyses revealed prominent diffusion measure differences in ASD children but not adolescents, when compared to healthy controls. Widespread increases in mean and radial diffusivity in ASD children were prominent in frontal white matter voxels. Follow-up tract-specific analyses highlighted disruption to pathways integrating frontal, temporal, and occipital structures involved in socio-emotional processing.
Conclusions/Significance
Our findings highlight disruption of neural circuitry in ASD, particularly in those white matter tracts that integrate the complex socio-emotional processing that is impaired in this disorder.
doi:10.1371/journal.pone.0028044
PMCID: PMC3223195  PMID: 22132206
12.  Neurexin-1 and Frontal Lobe White Matter: An Overlapping Intermediate Phenotype for Schizophrenia and Autism Spectrum Disorders 
PLoS ONE  2011;6(6):e20982.
Background
Structural variation in the neurexin-1 (NRXN1) gene increases risk for both autism spectrum disorders (ASD) and schizophrenia. However, the manner in which NRXN1 gene variation may be related to brain morphology to confer risk for ASD or schizophrenia is unknown.
Method/Principal Findings
53 healthy individuals between 18–59 years of age were genotyped at 11 single nucleotide polymorphisms of the NRXN1 gene. All subjects received structural MRI scans, which were processed to determine cortical gray and white matter lobar volumes, and volumes of striatal and thalamic structures. Each subject's sensorimotor function was also assessed. The general linear model was used to calculate the influence of genetic variation on neural and cognitive phenotypes. Finally, in silico analysis was conducted to assess potential functional relevance of any polymorphisms associated with brain measures. A polymorphism located in the 3′ untranslated region of NRXN1 significantly influenced white matter volumes in whole brain and frontal lobes after correcting for total brain volume, age and multiple comparisons. Follow-up in silico analysis revealed that this SNP is a putative microRNA binding site that may be of functional significance in regulating NRXN1 expression. This variant also influenced sensorimotor performance, a neurocognitive function impaired in both ASD and schizophrenia.
Conclusions
Our findings demonstrate that the NRXN1 gene, a vulnerability gene for SCZ and ASD, influences brain structure and cognitive function susceptible in both disorders. In conjunction with our in silico results, our findings provide evidence for a neural and cognitive susceptibility mechanism by which the NRXN1 gene confers risk for both schizophrenia and ASD.
doi:10.1371/journal.pone.0020982
PMCID: PMC3110800  PMID: 21687627
13.  Diffusion tensor tractography findings in schizophrenia across the adult lifespan 
Brain  2010;133(5):1494-1504.
In healthy adult individuals, late life is a dynamic time of change with respect to the microstructural integrity of white matter tracts. Yet, elderly individuals are generally excluded from diffusion tensor imaging studies in schizophrenia. Therefore, we examined microstructural integrity of frontotemporal and interhemispheric white matter tracts in schizophrenia across the adult lifespan. Diffusion tensor imaging data from 25 younger schizophrenic patients (≤55 years), 25 younger controls, 25 older schizophrenic patients (≥56 years) and 25 older controls were analysed. Patients with schizophrenia in each group were individually matched to controls. Whole-brain tractography and clustering segmentation were employed to isolate white matter tracts. Groups were compared using repeated measures analysis of variance with 12 within-group measures of fractional anisotropy: (left and right) uncinate fasciculus, arcuate fasciculus, inferior longitudinal fasciculus, inferior occipito-frontal fasciculus, cingulum bundle, and genu and splenium of the corpus callosum. For each white matter tract, fractional anisotropy was then regressed against age in patients and controls, and correlation coefficients compared. The main effect of group (F3,92 = 12.2, P < 0.001), and group by tract interactions (F26,832 = 1.68, P = 0.018) were evident for fractional anisotropy values. Younger patients had significantly lower fractional anisotropy than younger controls (Bonferonni-corrected alpha = 0.0042) in the left uncinate fasciculus (t48 = 3.7, P = 0.001) and right cingulum bundle (t48 = 3.6, P = 0.001), with considerable effect size, but the older groups did not differ. Schizophrenic patients did not demonstrate accelerated age-related decline compared with healthy controls in any white matter tract. To our knowledge, this is the first study to examine the microstructural integrity of frontotemporal white matter tracts across the adult lifespan in schizophrenia. The left uncinate fasciculus and right cingulum bundle are disrupted in younger chronic patients with schizophrenia compared with matched controls, suggesting that these white matter tracts are related to frontotemporal disconnectivity. The absence of accelerated age-related decline, or differences between older community-dwelling patients and controls, suggests that these patients may possess resilience to white matter disruption.
doi:10.1093/brain/awq040
PMCID: PMC2859148  PMID: 20237131
schizophrenia; diffusion tensor; ageing; white matter fibre pathways
14.  Personality Goes a Long a Way: An Interhemispheric Connectivity Study 
Throughout the development of psychology the delineation of personality has played a central role. Together with the NEO-PI-R, a questionnaire derived from the Five Factor Model of Personality, and recent advances in research technology it is now possible to investigate the relationship between personality features and neurophysiological brain processes. The NEO-FFI, the short version of the NEO-PI-R, reliably measures five main personality traits: Neuroticism, Extraversion, Openness to experience, Agreeableness, and Conscientiousness. As behavior and some psychiatric disorders have been related to interhemispheric connectivity, the present study used the combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to measure frontal interhemispheric connectivity and its association with personality as indexed by the NEO-FFI. Results demonstrated that prefrontal interhemispheric connectivity between the left and right dorsolateral prefrontal cortex correlates with Agreeableness in healthy subjects. This is the first study to relate personality features to interhemispheric connectivity through TMS–EEG and suggests that Agreeableness relates to the effectiveness of prefrontal communication between hemispheres.
doi:10.3389/fpsyt.2010.00140
PMCID: PMC3059614  PMID: 21423449
transcranial magnetic stimulation; electroencephalography; interhemispheric connectivity; NEO-PI-R; agreeableness
15.  Quantitative Examination of a Novel Clustering Method using Magnetic Resonance Diffusion Tensor Tractography 
NeuroImage  2008;45(2):370-376.
MR diffusion tensor imaging (DTI) can measure and visualize organization of white matter fibre tracts in vivo. DTI is a relatively new imaging technique, and new tools developed for quantifying fibre tracts require evaluation. The purpose of this study was to compare the reliability of a novel clustering approach with a multiple region of interest (MROI) approach in both healthy and disease (schizophrenia) populations. DTI images were acquired in 20 participants (n=10 patients with schizophrenia: 56 ± 15 years; n=10 controls: 51 ± 20 years) (1.5 Tesla GE system) with diffusion gradients applied in 23 non-collinear directions, repeated three times. Whole brain seeding and creation of fibre tracts were then performed. Interrater reliability of the clustering approach, and the MROI approach, were each evaluated and the methods compared. There was high spatial (voxel-based) agreement within and between the clustering and MROI methods. Fractional anisotropy, trace, and radial and axial diffusivity values showed high intraclass correlation (p<0.001 for all tracts) for each approach. Differences in scalar indices of diffusion between the clustering and MROI approach were minimal. The excellent interrater reliability of the clustering method and high agreement with the MROI method, quantitatively and spatially, indicates that the clustering method can be used with confidence. The clustering method avoids biases of ROI drawing and placement, and, not limited by a priori predictions, may be a more robust and efficient way to identify and measure white matter tracts of interest.
doi:10.1016/j.neuroimage.2008.12.028
PMCID: PMC2646811  PMID: 19159690
diffusion tensor imaging; tractography; streamline; clustering; region of interest; schizophrenia

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