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1.  Mechanisms of Dopaminergic and Serotonergic Neurotransmission in Tourette Syndrome: Clues from an in vivo Neurochemistry Study with PET 
Tourette syndrome (TS) is a neuropsychiatric disorder with childhood onset characterized by motor and phonic tics. Obsessive-compulsive disorder (OCD) is often concomitant with TS. Dysfunctional tonic and phasic dopamine (DA) and serotonin (5-HT) metabolism may play a role in the pathophysiology of TS. We simultaneously measured the density, affinity, and brain distribution of dopamine D2 receptors (D2-Rs), dopamine transporter (DAT) binding potential (BP), and amphetamine (AMP)-induced dopamine release (DArel) in 14 adults with TS and 10 normal adult controls. We also measured the brain distribution and BP of serotonin 5-HT2A receptors (5-HT2AR), and serotonin transporter (SERT) BP, in 11 subjects with TS and 10 normal control subjects.
As compared with controls, DArel was significantly increased in the ventral striatum among subjects with TS. Adults with TS+OCD exhibited a significant D2-R increase in left ventral striatum. SERT binding potential in midbrain and caudate/putamen was significantly increased in adults with TS (TS+OCD and TS−OCD). In 3 subjects with TS+OCD, in whom D2-R, 5-HT2AR, and SERT were measured within a 12-month period, there was a weakly significant elevation of DArel and 5-HT2A BP, when compared with TS−OCD subjects and normal controls.
The current study confirms, with a larger sample size and higher resolution PET scanning, our earlier report that elevated DArel is a primary defect in TS (Singer et al, 2002). The finding of decreased SERT BP, and the possible elevation in 5-HT2aR in individuals with TS who had increased DArel, suggest a condition of increased phasic DArel modulated by low 5-HT in concomitant OCD.
PMCID: PMC3696501  PMID: 17987065
2.  Sex Differences in Cognition in Healthy Elderly Individuals 
Sex differences in patterns of cognitive test performance have been attributed to factors, such as sex hormones or sexual dimorphisms in brain structure, that change with normal aging. The current study examined sex differences in patterns of cognitive test performance in healthy elderly individuals. Cognitive test scores of 957 men and women (age 67–89), matched for overall level of cognitive test performance, age, education, and depression scale score, were compared. Men and women were indistinguishable on tests of auditory divided attention, category fluency, and executive functioning. In contrast, women performed better than men on tests of psychomotor speed and verbal learning and memory, whereas men outperformed women on tests of visuoconstruction and visual perception. Our finding that the pattern of sex differences in cognition observed in young adults is observed in old age has implications for future studies of both healthy elderly individuals and of those with cognitive disorders.
PMCID: PMC3518851  PMID: 22670852
Cognitive; sex differences; elderly; organizational effects; sexual dimorphism
3.  Impaired cortico-striatal functional connectivity in prodromal Huntington’s Disease 
Neuroscience Letters  2012;514(2):204-209.
Huntington’s Disease (HD) is a neurodegenerative disease caused by a CAG triplet-repeat expansion-mutation in the Huntingtin gene. Subjects at risk for HD can be identified by genetic testing in the prodromal phase. Structural changes of basal-ganglia nuclei such as the caudate nucleus are well-replicated findings observable early in prodromal-HD subjects and may be preceded by distinct functional alterations of cortico-striatal circuits. This study aims to assess functional integrity of the motor system as a cortico-striatal circuit with particular clinical relevance in HD.
Ten subjects in the prodromal phase of HD and ten matched controls were administered blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) at rest (3 Tesla). Functional connectivity was measured as synchrony of BOLD activity between the caudate nucleus and thirteen cortical brain regions (seeds). Basal-ganglia volumes were assessed as established markers of disease progression in prodromal-HD. Linear regression analysis was performed to test for a relationship between structural changes and group differences in functional connectivity.
Prodromal-HD subjects showed reduced BOLD synchrony between two seeds in the premotor cortex (BA6) and the caudate nucleus. While similar effect sizes could be observed for reduced basal-ganglia volumes and differences in functional connectivity, coefficients of determination indicate a moderate relationship between functional connectivity and striatal atrophy.
Our data show reduced cortico-striatal functional connectivity at rest in prodromal-HD and suggest a relation to early structural brain changes. Additional longitudinal studies are necessary to elucidate the temporal relationship between functional alterations and earliest structural brain changes in prodromal-HD.
PMCID: PMC3331724  PMID: 22425717
4.  Effects of cognitive impairment on substance abuse treatment attendance: predictive validation of a brief cognitive screening measure 
Background and Objectives
Neuropsychological impairment among patients with substance use disorders (SUDs) contributes to poorer treatment processes and outcomes. However, neuropsychological assessment is typically not an aspect of patient evaluation in SUD treatment programs because it is prohibitively time and resource consuming. In a previous study, we examined the concurrent validity, classification accuracy, and clinical utility of a brief screening measure, the Montreal Cognitive Assessment (MoCA), in identifying cognitive impairment among SUD patients. To provide further evidence of criterion-related validity, MoCA classification should optimally predict a clinically relevant behavior or outcome among SUD patients. The purpose of this study was to examine the validity of the MoCA in predicting treatment attendance.
We compared previously-collected clinical assessment data on 60 SUD patients receiving treatment in a program of short duration and high intensity to attendance data obtained via medical chart review.
Though the proportion of therapy sessions attended did not differ between groups, cognitively impaired subjects were significantly less likely than unimpaired subjects to attend all of their group therapy sessions.
These results complement our previous findings by providing further evidence of criterion-related validity of the MoCA in predicting a clinically relevant behavior (i.e., perfect attendance) among SUD patients.
Scientific Significance
The capacity of the MoCA to predict a clinically relevant behavior provides support for its validity as a brief cognitive screening measure.
PMCID: PMC3593077  PMID: 22443860
substance use disorder; addiction; cognitive screening measure; Montreal Cognitive Assessment
5.  Levodopa is Not a Useful Treatment for Lesch-Nyhan Disease 
Lesch-Nyhan disease (LND) is characterized by dystonia, cognitive abnormalities, and self-injurious behavior. No effective therapies are available. LND is associated with a presynaptic dopaminergic deficit, but the reported effects of dopamine replacement therapy are conflicting. The current prospective open-label study assesses the effects of levodopa on both neurological and behavioral features of LND. All 6 study participants discontinued levodopa early, due to lack of effect and sometimes worsening of motor function. The results provide important clues for pathophysiological mechanisms and suggestions for future treatment options.
PMCID: PMC3523804  PMID: 21506156
Lesch-Nyhan disease; treatment; levodopa; dystonia; dyskinesias; self-injurious behavior
6.  A Neuropsychological Study of Personality: Trait Openness in Relation to Intelligence, Fluency, and Executive Functioning 
Openness is a personality trait that has been linked to intelligence and divergent thinking. DeYoung, Peterson, and Higgins (2005) theorized that trait Openness depends on dopamine function, especially in the prefrontal cortex. We tested their theory in 335 healthy adults by hypothesizing that individual differences in Openness would correlate more strongly with performance on tests of executive function than on tests of intelligence and fluency. However, Openness correlated more strongly with verbal/crystallized intelligence (Gc; r=0.44) than with executive functioning (r=0.16) and fluency (r=0.24). Further, the partial correlation between Openness and Gc increased from r=0.26 among young adults to r=0.53 among elderly adults. These findings suggest that Openness is more closely associated with the acquisition of broad verbal intellectual skills and knowledge than with executive abilities localized to a specific brain region or neurotransmitter system.
PMCID: PMC2937090  PMID: 20408002
Openness; crystallized intelligence; fluid intelligence; personality; neuropsychology; prefrontal cortex; executive function
7.  Does the Iowa Gambling Task Measure Executive Function? 
The Iowa Gambling Task (IGT) is assumed to measure executive functioning, but this has not been empirically tested by means of both convergent and discriminant validity. We used structural equation modeling (SEM) to test whether the IGT is an executive function (EF) task (convergent validity) and whether it is not related to other neuropsychological domains (discriminant validity). Healthy community-dwelling participants (N = 214) completed a comprehensive neuropsychological battery. We analyzed the conventional IGT metric and three alternative metrics based on the overall difference of advantageous minus disadvantageous choices made during the last 60 IGT responses and advantageous minus disadvantageous choices based on two specific decks of cards (D minus A). An a priori six-factor hierarchical model of neuropsychological functioning was confirmed with SEM. Attention and processing speed were grouped as “non-associative” factors. Fluency, executive functioning, visual learning/memory, and verbal learning/memory were grouped as higher-level “associative” factors. Of the non-associative factors, attention, but not speed, predicted IGT performance. When each associative factor was entered along with attention, only EF improved the model fit and that was only for metrics based on trials 41–100. SEM indicates metrics based on trails 1–100 are influenced by attention, and metrics based on trails 41–100 are influenced by attention and EF. Its associative strength with attention is twice that of EF. Conceptually, the IGT is a multi-trait task involving novel problem-solving and attentional domains to a greater extent, and executive functioning to a lesser extent.
PMCID: PMC3254153  PMID: 22015855
Iowa Gambling Task; Decision-making; Executive function; Neuropsychological evaluation; Structural equation modeling
8.  Delineation of the motor disorder of Lesch–Nyhan disease 
Brain : a journal of neurology  2006;129(Pt 5):1201-1217.
Lesch–Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.
PMCID: PMC3508431  PMID: 16549399
cerebral palsy; choreoathetosis; dystonia; neurogenetics
9.  Target Optimization in Transcranial Direct Current Stimulation 
Transcranial direct current stimulation (tDCS) is an emerging neuromodulation therapy that has been experimentally determined to affect a wide range of behaviors and diseases ranging from motor, cognitive, and memory processes to depression and pain syndromes. The effects of tDCS may be inhibitory or excitatory, depending on the relative polarities of electrodes and their proximity to different brain structures. This distinction is believed to relate to the interaction of current flow with activation thresholds of different neural complexes. tDCS currents are typically applied via a single pair of large electrodes, with one (the active electrode) sited close to brain structures associated with targeted processes. To efficiently direct current toward the areas presumed related to these effects, we devised a method of steering current toward a selected area by reference to a 19-electrode montage applied to a high-resolution finite element model of the head. We used a non-linear optimization procedure to maximize mean current densities inside the left inferior frontal gyrus (IFG), while simultaneously restricting overall current, and median current densities within the accumbens. We found that a distributed current pattern could be found that would indeed direct current toward the IFG in this way, and compared it to other candidate 2-electrode configurations. Further, we found a combination of four anterior-posterior electrodes could direct current densities to the accumbens. We conclude that a similar method using multiple electrodes may be a useful means of directing current toward or away from specific brain regions and also of reducing tDCS side effects.
PMCID: PMC3474130  PMID: 23087654
tDCS; neuroplasticity; finite element model; optimization
10.  Altering Automatic Verbal Processes with Transcranial Direct Current Stimulation 
Background: Word retrieval during verbal fluency tasks invokes both automatic and controlled cognitive processes. A distinction has been made between the generation of words clusters and switches between such clusters on verbal fluency tasks. Clusters, defined by the reporting of contiguous words that constitute semantic or phonemic subcategories, are thought to reflect relatively automatic processing. In contrast, switching from one subcategory to another is thought to require a more controlled, effortful form of cognitive processing. Objective: In this single-blind, sham-controlled experiment, we investigated whether anodal and cathodal transcranial direct current stimulation (tDCS) can differentially modify controlled or automatic processes that support lexical retrieval, as assessed by clustering and switching on verbal fluency tasks, in 24 healthy right-handed adults. Methods: Participants were randomly assigned to receive 1 mA of either anodal (excitatory) or cathodal (inhibitory) active tDCS over the left dorsolateral prefrontal cortex in addition to sham stimulation over the same region in counterbalanced order. Participants engaged in various cognitive activities during the first 23 min of stimulation. Then, during the final segment of each 30-min session, they completed letter- and category-cued word fluency tasks. Results: Participants reported more words on category-cued word fluency tasks during anodal than sham stimulation (25.9 vs. 23.0 words; p = 0.055). They also showed a net increase in the number of clustered words during anodal stimulation compared to a net decrease during cathodal stimulation (1.3 vs. −1.5 words; p = 0.038). Conclusion: tDCS can selectively alter automatic aspects of speeded lexical retrieval in a polarity-dependent fashion during a category-guided fluency task.
PMCID: PMC3412390  PMID: 22888321
verbal fluency; clustering; switching; transcranial direct current stimulation
11.  Mechanisms for phenotypic variation in Lesch–Nyhan disease and its variants 
Human genetics  2010;129(1):71-78.
Lesch–Nyhan disease is a neurogenetic disorder caused by mutation of the HPRT1 gene on the X chromosome. There is significant variation in the clinical phenotype, with more than 300 different known mutations. There are few studies that have addressed whether similar mutations result in similar phenotypes across different patients because hypoxanthine–guanine phosphoribosyltransferase (HGprt) deficiency is rare, and most mutations are unique or limited to individual families. However, recent studies have revealed multiple unrelated patients with similar mutations, providing an opportunity to examine genotype–phenotype correlations. We found significant variation among the clinical features of 10 patients from 8 unrelated families all carrying a mutation replacing guanine with adenine at base position 143 (c.143G>A) in the HPRT1 gene. This mutation results in replacement of arginine by histidine at amino acid position 48 (p.arg48his) in the HGprt enzyme. Biochemically, the enzyme exhibits reduced thermal integrity, a mechanism that may explain clinical variation. The literature reveals similar clinical variation among other patients with similar mutations, although the variation is relatively minor across the whole population of patients. Identifiable sources of clinical variation include known limitations of clinical ascertainment and mechanisms that affect residual enzyme activity and stability. These results are helpful for understanding genotype–phenotype correlations and discordance and likely are applicable to other neurogenetic disorders where similar variation occurs.
PMCID: PMC3034646  PMID: 20981450
13.  Rapid Cognitive Screening of Patients with Substance Use Disorders 
To date, there has not been a time-efficient and resource-conscious way to identify cognitive impairment in patients with substance use disorders (SUD). The present study assesses the validity, accuracy, and clinical utility of a brief (10 min) screening instrument, the Montreal Cognitive Assessment (MoCA), in identifying cognitive impairment among SUD patients. The Neuropsychological Assessment Battery-Screening Module (NAB-SM), a 45-minute battery with known sensitivity to the mild-to-moderate deficits observed in SUD patients, was used as the reference criterion for determining agreement, rates of correct and incorrect decision classifications, and criterion-related validity for the MoCA. Classification accuracy of the MoCA, based on receiver-operating characteristic (ROC) analysis, was strong, with an area under the ROC curve = 0.86 [95% CI: 0.75-0.97]. The MoCA also showed acceptable sensitivity (83.3%) and specificity (72.9%) for the identification of cognitive impairment. Using a cut-off of 25 on the MoCA, the overall agreement was 75.0%; chance-corrected agreement (kappa) was 41.9%. These findings indicate that the MoCA provides a time-efficient and resource-conscious way to identify SUD patients with neuropsychological impairment, thus addressing a critical need in the addiction treatment research community.
PMCID: PMC3144764  PMID: 19803633
14.  Neuropsychological Functioning in Bipolar Disorder and Schizophrenia 
Biological psychiatry  2006;62(2):179-186.
Some patients with bipolar disorder (BD) demonstrate neuropsychological deficits even when stable. However, it remains unclear whether these differ qualitatively from those seen in schizophrenia (SZ).
We compared the nature and severity of cognitive deficits shown by 106 patients with SZ and 66 patients with BD to 316 healthy adults (NC). All participants completed a cognitive battery with 19 individual measures. After adjusting their test performance for age, sex, race, education, and estimated premorbid IQ, we derived regression-based T-scores for each measure and the six cognitive domains.
Both patient groups performed significantly worse than NCs on most (BD) or all (SZ) cognitive tests and domains. The resulting effect sizes ranged from 0.37 to 1.32 (mean = 0.97) across tests for SZ patients and from 0.23 to 0.87 (mean = 0.59) for BD patients. The Pearson correlation of these effect sizes was 0.71 (p < 0.001).
Patients with bipolar disorder suffer from cognitive deficits that are milder but qualitatively similar to those of patients with schizophrenia. These findings support the notion that schizophrenia and bipolar disorder show greater phenotypic similarity in terms of the nature than severity of their neuropsychological deficits.
PMCID: PMC2041824  PMID: 17161829
bipolar disorder; schizophrenia; cognitive testing; neuropsychology; biomarker
15.  Gray matter in amnestic mild cognitive impairment: voxel-based morphometry 
Neuroreport  2010;21(4):259-263.
Multiple regression voxel-based morphometry analyses were used to examine the relationship between regional gray matter volumes and neurocognitive performance in 10 patients with amnestic mild cognitive impairment and 20 healthy age-matched controls. Cognitive functioning was assessed with seven standardized neuropsychological tests. Patients with amnestic mild cognitive impairment exhibited impaired cognitive performance (on the Mini Mental State Examination, tests of verbal fluency, verbal and spatial learning and memory, and visual-motor abilities) and reduced gray matter volume in the right temporal pole. Across all participants, better performance on several neuropsychological tests was associated with higher regional gray matter volumes. Voxel-based morphometry provides an operator-unbiased means to investigate volumetric differences, which may be related to impaired neuropsychological functioning.
PMCID: PMC3041512  PMID: 20042900
aging; gray matter volume; mild cognitive impairment; neuropsychological assessment; temporal lobe; voxel-based morphometry
16.  Cranial Volume, Mild Cognitive Deficits, and Functional Limitations Associated with Diabetes in a Community Sample 
Diabetes is associated with dementia in older adults, but it remains unclear whether nondemented adults with type 2 diabetes show subtle abnormalities across cognition, neuroanatomy, and everyday functioning. Using the Aging, Brain Imaging, and Cognition study sample of 301 community-dwelling, middle-aged and older adults, we conducted a secondary analysis on 28 participants with and 150 participants without diabetes. We analyzed brain magnetic resonance imaging data, cognitive test performance, and informant ratings of personal and instrumental activities of daily living (PADL/IADL). Relative to controls, participants with diabetes had lower brain-to-intracranial volume ratios (69.3 ± 4.5% vs. 71.7 ± 4.6%; p < .02), and performed more poorly on measures of working memory, processing speed, fluency, and crystallized intelligence (all p <.05). Decrements in working memory and processing speed were associated with IADL limitations (p < .01). Nondemented adults with diabetes exhibit neuroanatomic and cognitive abnormalities. Their cognitive deficits correlate with everyday functional limitations.
PMCID: PMC2809552  PMID: 19942595
Diabetes; Endocrine disorders; Cognition; Neuropsychological testing; MRI; Function; Behavior
17.  Aggression after Traumatic Brain Injury: Prevalence & Correlates 
Aggression after traumatic brain injury (TBI) is common but not well defined. Sixty-seven participants with first-time TBI were seen within three months of injury and evaluated for aggression. The prevalence of aggression was found to be 28.4% and to be predominantly verbal aggression. Post-TBI aggression was associated with new-onset major depression (p=0.02), poorer social functioning (p=0.04), and increased dependency on activities of daily living (p=0.03), but not with a history of substance abuse or adult/childhood behavioral problems. Implications of the study include early screening for aggression, evaluation for depression, and consideration of psychosocial support in aggressive patients.
PMCID: PMC2918269  PMID: 19996251
18.  Predictors of New-Onset Depression after Mild Traumatic Brain Injury 
Mild traumatic brain injury (mTBI) is the most common form of TBI. Most people recover after mTBI but a small percentage continues to have persistent problems, predominantly depression. There is however minimal literature on the risk factors associated with mTBI depression. In a sample of 43 mTBI patients, followed longitudinally for one year the prevalence of new-onset depression was found to be 18%. Older age and presence of frontal subdural hemorrhage were the only two significant findings noted in the depressed group compared to the non-depressed group. Identifying risk factors for mTBI depression can aid in early diagnosis and treatment.
PMCID: PMC2918274  PMID: 20160216
19.  White Matter Abnormalities and Cognition in a Community Sample 
White matter hyperintensities (WMH) can compromise cognition in older adults, but differences in sampling, WMH measurements, and cognitive assessments contribute to discrepant findings across studies. We examined linear and nonlinear effects of WMH volumes on cognition in 253 reasonably healthy adults. After adjusting for demographic characteristics and total brain volumes, WMH burden was not associated with cognition in those aged 20–59. In participants aged 60 and older, models accounted for ≥58% of the variance in performance on tests of working memory, processing speed, fluency, and fluid intelligence, and WMH volumes accounted for variance beyond that explained by age and other demographic characteristics. Larger increases in WMH burden over 5 years also were associated with steeper cognitive declines over the same interval. Results point to both age-related and age-independent effects of WMH on cognition in later life and suggest that the accumulation of WMH might partially explain normal age-related declines in cognition.
PMCID: PMC2765350  PMID: 19617597
White matter hyperintensities; Aging; Cognition; Cardiovascular disease
Neuroscience research  2009;63(4):227-235.
Individuals with epilepsy are at increased risk of having psychotic symptoms that resemble those of schizophrenia. More controversial and less searched is if schizophrenia is a risk factor for epilepsy. Here we review overlapping epidemiological, clinical, neuropathological and neuroimaging features of these two diseases. We discuss the role of temporal and other brain areas in the development of schizophrenia-like psychosis of epilepsy. We underline the importance of ventricular enlargement in both conditions as a phenotypic manifestation of a shared biologic liability that might relate to abnormalities in neurodevelopment. We suggest that genes implicated in neurodevelopment may play a common role in both conditions and speculate that recently identified causative genes for partial complex seizures with auditory features might help explain the pathophysiology of schizophrenia. These particularly include the leucine-rich glioma inactivated (LGI) family gene loci overlap with genes of interest for psychiatric diseases like schizophrenia. Finally, we conclude that LGI genes associated with partial epilepsy with auditory features might also represent genes of interest for schizophrenia, especially among patients with prominent auditory hallucinations and formal thought disorder.
PMCID: PMC2768382  PMID: 19367784
schizophrenia; epilepsy; temporal lobe; susceptibility; neurodevelopment; LGI genes
21.  Attenuated variants of Lesch-Nyhan disease 
Brain  2010;133(3):671-689.
Lesch–Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine–guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch–Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch–Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine–guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch–Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine–guanine phosphoribosyltransferase deficiency.
PMCID: PMC2842514  PMID: 20176575
neurogenetics; genotype–phenotype correlation; metabolic disease; uric acid; dystonia; behaviour; Kelly–Seegmiller syndrome
22.  Source-Based Morphometry: The Use of Independent Component Analysis to Identify Gray Matter Differences With Application to Schizophrenia 
Human brain mapping  2009;30(3):711-724.
We present a multivariate alternative to the voxel-based morphometry (VBM) approach called source-based morphometry (SBM), to study gray matter differences between patients and healthy controls. The SBM approach begins with the same preprocessing procedures as VBM. Next, independent component analysis is used to identify naturally grouping, maximally independent sources. Finally, statistical analyses are used to determine the significant sources and their relationship to other variables. The identified “source networks,” groups of spatially distinct regions with common covariation among subjects, provide information about localization of gray matter changes and their variation among individuals. In this study, we first compared VBM and SBM via a simulation and then applied both methods to real data obtained from 120 chronic schizophrenia patients and 120 healthy controls. SBM identified five gray matter sources as significantly associated with schizophrenia. These included sources in the bilateral temporal lobes, thalamus, basal ganglia, parietal lobe, and frontotemporal regions. None of these showed an effect of sex. Two sources in the bilateral temporal and parietal lobes showed age-related reductions. The most significant source of schizophrenia-related gray matter changes identified by SBM occurred in the bilateral temporal lobe, while the most significant change found by VBM occurred in the thalamus. The SBM approach found changes not identified by VBM in basal ganglia, parietal, and occipital lobe. These findings show that SBM is a multivariate alternative to VBM, with wide applicability to studying changes in brain structure.
PMCID: PMC2751641  PMID: 18266214
schizophrenia; structural MRI; source-based morphometry; independent component analysis; voxel-based morphometry
23.  A Large Scale (N=400) Investigation of Gray Matter Differences in Schizophrenia Using Optimized Voxel-based Morphometry 
Schizophrenia research  2008;101(1-3):95-105.
Many studies have employed voxel-based morphometry (VBM) of MRI images as an automated method of investigating cortical gray matter differences in schizophrenia. However, results from these studies vary widely, likely due to different methodological or statistical approaches.
To use VBM to investigate gray matter differences in schizophrenia in a sample significantly larger than any published to date, and to increase statistical power sufficiently to reveal differences missed in smaller analyses.
Magnetic resonance whole brain images were acquired from four geographic sites, all using the same model 1.5T scanner and software version, and combined to form a sample of 200 patients with both first episode and chronic schizophrenia and 200 healthy controls, matched for age, gender and scanner location. Gray matter concentration was assessed and compared using optimized VBM.
Compared to the healthy controls, schizophrenia patients showed significantly less gray matter concentration in multiple cortical and subcortical regions, some previously unreported. Overall, we found lower concentrations of gray matter in regions identified in prior studies, most of which reported only subsets of the affected areas.
Gray matter differences in schizophrenia are most comprehensively elucidated using a large, diverse and representative sample.
PMCID: PMC2504740  PMID: 18378428
Schizophrenia; Structural MRI; multi-site; voxel based morphometry; gray matter

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