Prefrontal Inefficiency Is Associated With Polygenic Risk for Schizophrenia

Considering the diverse clinical presentation and likely polygenic etiology of schizophrenia, this investigation examined the effect of polygenic risk on a well-established intermediate phenotype for schizophrenia. We hypothesized that a measure of cumulative genetic risk based on additive effects of many genetic susceptibility loci for schizophrenia would predict prefrontal cortical inefficiency during working memory, a brain-based biomarker for the disorder. The present study combined imaging, genetic and behavioral data obtained by the Mind Clinical Imaging Consortium study of schizophrenia (n = 255). For each participant, we derived a polygenic risk score (PGRS), which was based on over 600 nominally significant single nucleotide polymorphisms, associated with schizophrenia in a separate discovery sample comprising 3322 schizophrenia patients and 3587 control participants. Increased polygenic risk for schizophrenia was associated with neural inefficiency in the left dorsolateral prefrontal cortex after covarying for the effects of acquisition site, diagnosis, and population stratification. We also provide additional supporting evidence for our original findings using scores based on results from the Psychiatric Genomics Consortium study. Gene ontology analysis of the PGRS highlighted genetic loci involved in brain development and several other processes possibly contributing to disease etiology. Our study permits new insights into the additive effect of hundreds of genetic susceptibility loci on a brain-based intermediate phenotype for schizophrenia. The combined impact of many common genetic variants of small effect are likely to better reveal etiologic mechanisms of the disorder than the study of single common genetic variants.Key words: schizophrenia, DLPFC, working memory, intermediate phenotype, fMRI, genetic risk score     

Phase-specific brain change of spatial working memory processing in genetic and ultra-high risk groups of schizophrenia

Spatial working memory (WM) processing has 3 distinct phases: encoding, maintenance, and retrieval and its dysfunction is a core feature in schizophrenia. We examined phase-specific brain activations associated with spatial WM in first-degree relatives of schizophrenia (genetic high risk, GHR), ultra-high risk (UHR) subjects, patients with schizophrenia, and healthy controls. We used an event-related functional magnetic resonance imaging in 17 GHR subjects, 21 UHR subjects, 15 clinically stable patients with schizophrenia and 16 healthy controls, while subjects were performing a spatial delayed-response task. During the encoding phase, the GHR group showed increased activation in the fronto-parietal regions, whereas the UHR and schizophrenia groups showed significantly less activation in these regions than did the healthy control group. Especially, frontal activation was strongest in GHR subjects, followed by healthy controls, and occurred to a lesser degree in the UHR group, with the least activation occurring in the schizophrenia group. During the maintenance phase, the thalamus showed a differential activation, similar to frontal activation pattern during the encoding phase. During the retrieval phase, no prominent differential activations were found. Increased activations were observed in the superior temporal gyrus during the encoding and maintenance phases in the GHR, UHR, and schizophrenia groups relative to healthy controls. Our findings suggest that functional deficits associated with spatial WM processing emerge in the UHR before the onset of schizophrenia and compensatory neural processes exist in the GHR with genetic liability to schizophrenia.     

Influence of ZNF804a on Brain Structure Volumes and Symptom Severity in Individuals With Schizophrenia

CONTEXT The single-nucleotide polymorphism rs1344706 in the gene ZNF804a has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia. OBJECTIVE To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia. DESIGN Case-control analysis of covariance. SETTING University-based research hospital. PARTICIPANTS Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers. MAIN OUTCOME MEASURES Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized. RESULTS The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F =?3.98, P?=?.02; F =?4.95, P?=?.007; and F =?3.08, P?=?.05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F =?3.93, P?=?.02) and frontal WM volumes (F =?7.16, P?<?.001) and on psychotic symptom severity (F =?6.07, P?=?.003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F =?4.61, P?=?.03), replicating a previously reported association. CONCLUSIONS A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia.     

Neural Changes Associated With Relational Learning in Schizophrenia

Relational learning, which is learning the relationship among items, is impaired in schizophrenia but can be improved with training. This study investigated neural changes with functional magnetic resonance imaging before and after training on a relational learning task in schizophrenia and healthy control subjects. Despite their acquiring similar relational learning performance, the groups exhibited different neural activation patterns before and following training. Controls engaged regions within the relational learning network that included frontal, parietal, and medial temporal lobe, before and following training. Controls also exhibited activation reductions in region and spatial extent with relational learning proficiency, a commonly observed phenomenon in successful learning. In contrast, subjects with schizophrenia displayed no positive activations compared with the control condition before training. After training, subjects with schizophrenia displayed bilateral inferior parietal region activation as predicted. Contrary to hypothesis, hippocampal activation was not observed following training in schizophrenia. These findings suggest that the parietal lobe may be receptive to cognitive training interventions and that successful relational learning may be achieved in schizophrenia through the use of alternative extrahippocampal brain regions.     

Impact of schizophrenia‐risk gene dysbindin 1 on brain activation in bilateral middle frontal gyrus during a working memory task in healthy individuals

Working memory (WM) dysfunction is a hallmark feature of schizophrenia. Functional imaging studies using WM tasks have documented both prefrontal hypo‐ and hyperactivation in schizophrenia. Schizophrenia is highly heritable, and it is unclear which susceptibility genes modulate WM and its neural correlates. A strong linkage between genetic variants in the dysbindin 1 gene and schizophrenia has been demonstrated. The aim of this study was to investigate the influence of the DTNBP1 schizophrenia susceptibility gene on WM and its neural correlates in healthy individuals. Fifty‐seven right‐handed, healthy male volunteers genotyped for DTNBP1 SNP rs1018381 status were divided in heterozygous risk‐allele carriers (T/C) and homozygous noncarriers (C/C). WM was assessed by a 2‐back vs. 0‐back version of the Continuous Performance Test (CPT), while brain activation was measured with fMRI. DTNBP1 SNP rs1018381 carrier status was determined and correlated with WM performance and brain activation. Despite any differences in behavioral performance, risk‐allele carriers exhibited significantly increased activation of the bilateral middle frontal gyrus (BA 9), a part of the dorsolateral prefrontal cortex (DLPFC), compared to noncarriers. This difference did not correlate with WM performance. The fMRI data provide evidence for an influence of genetic variation in DTNBP1 gene region tagged by SNP rs1018381 on bilateral middle frontal gyrus activation during a WM task. The increased activation in these brain areas may be a consequence of “inefficient” or compensatory DLPFC cognitive control functions. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

White matter abnormalities in adults with 22q11 deletion syndrome with and without schizophrenia

Dysfunction of cerebral white matter (WM) is a potential factor underlying the neurobiology of schizophrenia. People with 22q11 deletion syndrome have altered brain morphology and increased risk for schizophrenia, therefore decreased WM integrity may be related to schizophrenia in 22q11DS. We measured fractional anisotropy (FA) and WM volume in 27 adults with 22q11DS with schizophrenia (n = 12, 22q11DS SCZ+) and without schizophrenia (n = 15, 22q11DS SCZ−), 12 individuals with idiopathic schizophrenia and 31 age-matched healthy controls. We found widespread decreased WM volume in posterior and temporal brain areas and decreased FA in areas of the frontal cortex in the whole 22q11DS group compared to healthy controls. In 22q11DS SCZ+ compromised WM integrity included inferior frontal areas of parietal and occipital lobe. Idiopathic schizophrenia patients showed decreased FA in inferior frontal and insular regions compared to healthy controls. We found no WM alterations in 22q11DS SCZ+ vs. 22q11DS SCZ−. However, there was a negative correlation between FA and PANSS scores (Positive and Negative Symptom Scale) in the whole 22q11DS group in the inferior frontal, cingulate, insular and temporal areas. This is the first study to investigate WM integrity in adults with 22q11DS. Our results suggest that pervasive WM dysfunction is intrinsic to 22q11DS and that psychotic development in adults with 22q11DS involves similar brain areas as seen in schizophrenia in the general population.     

The nature of brain abnormalities in schizophrenia: What do we really know?

The etiopathology of schizophrenia remains unknown in spite of a century of investigations of the brain. Neuro-imaging research has shown involvement of frontal cortex, temporal lobe cortex, and subcortical structures. Enlarged ventricles, reduced volumes of frontal cortex (dorsolateral prefrontal cortex), temporal lobe cortex (superior temporal cortex), and subcortical structures such as hippocampus and amygdala have been consistently reported and imply inadequate functioning of these structures. These brain abnormalities as group differences between patients and matched healthy controls are present at the onset and some even before the onset of psychosis, supporting the neurodevelopmental theory of schizophrenia. Dopamine is still believed to be the major neurotransmitter involved in schizophrenia, although others such as serotonin and glutamate are possibly involved. Schizophrenia is inherited, but genetic research has not yielded a clear answer, possibly due to the complex nature of the genetic involvement. Although a thorough understanding of the brain abnormalities is far from clear, the evidence is constantly accumulating and converging toward a possibly complex illness of a brain network that is affected by a genetically mediated developmental deviance.     

Verbal Working Memory Dysfunction in Schizophrenia: An fMRI Investigation

Impaired processing of working memory information is one of the cognitive deficits seen in patients with schizophrenia. This study aims at corroborating the differences in the brain activities involved in the process of working memory between patients with schizophrenia and the controls. Twelve patients with schizophrenia and 11 controls participated in the study. Functional magnetic resonance imaging (fMRI) was used to assess cortical activities during the performance of a two-back verbal working memory paradigm using the Korean alphabet as mnemonic content. Group analysis revealed that inferior fontal, middle frontal, and superior temporal region showed decreased cortical activities in the patient group compared to those of the controls. This study showed a decreased activation in inferior fontal (BA 47), middle frontal (BA 6), and superior temporal (BA 22/38) neural networks from the patient group and confirmed the earlier findings on the impaired working memory of schizophrenic patients in the fMRI investigation.     

Altered brain activation in dorsolateral prefrontal cortex in adolescents and young adults at genetic risk for schizophrenia: an fMRI study of working memory

OBJECTIVE: Adult first-degree relatives of persons with schizophrenia carry elevated genetic risk for the illness, demonstrate working memory (WM) impairments, and manifest alterations in dorsolateral prefrontal cortical (DLPFC) function during WM. Because substantially less is known about these phenotypes in adolescent subjects we sought to demonstrate that young relatives of persons with schizophrenia manifest impaired WM and altered prefrontal activation. METHODS: Participants were 21 non-psychotic, unmedicated first-degree relatives of persons with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder, depressed type and 24 unmedicated controls, recruited from the community and hospitals in metropolitan Boston (ages 13-28). We compared groups on an auditory WM task with interference prior to scanning and used functional magnetic resonance imaging (fMRI) to compare groups while performing visual 2-back WM and control vigilance tasks. Blood oxygen level dependent signal change was measured using two whole-brain gradient echo EPI pulse acquisitions (21 contiguous, 5mm axial slices), acquired on a Siemens 1.5T MR scanner. Data were analyzed using Statistical Parametric Mapping-99. RESULTS: The high risk subjects were significantly impaired on the auditory WM task, had significantly greater Phobic Anxiety, and marginally greater Psychoticism than controls on the Symptom Checklist-90-Revised, and showed significantly greater task-elicited activation in the right DLPFC (BA 46). Psychopathology, IQ, and in-scanner WM performance did not account for group differences in brain activation. CONCLUSIONS: Data support a physiological difference (an exaggerated fMRI response) in DLPFC in adolescents at genetic risk for schizophrenia, independent of psychosis. Future work can study the relationship of these measures to possible onset of schizophrenia.     

The effect of working memory performance on functional MRI in schizophrenia

INTRODUCTION: Studies of prefrontal cortical (PFC) function in schizophrenia have been inconsistent, with studies showing both increased and decreased PFC activation compared to healthy controls. Discrepant findings may be due to task performance effects or demographic differences between samples. We report functional magnetic resonance imaging (fMRI) data comparing subjects with schizophrenia and healthy controls performing a 2-back working memory (WM) task, addressing the effects of task performance. METHODS: Twenty-two controls and 14 patients with DSM-IV schizophrenia, scanned on a Siemens 1.5 T scanner, performed a visual letter 2-back task and control task (CPT-X) during fMRI. Data were analyzed using Statistical Parametric Mapping (SPM)-99. RESULTS: After statistical adjustment for performance differences, persons with schizophrenia showed significantly greater activation than controls in the right medial frontal gyrus and left inferior parietal lobule/medial temporal gyrus region (BA 39/40), and a trend toward greater activation in the left ventrolateral PFC. This pattern was also observed in demographically matched subgroups of participants. CONCLUSIONS: Data are consistent with findings reported in recent studies showing increased PFC and parietal activation in schizophrenia when the effects of reduced WM task performance in patients with schizophrenia are addressed. Further studies are needed to clarify the pathophysiological basis of WM load sensitivity in schizophrenia and its relationship to genes.     

Neural correlates of working memory performance in adolescents and young adults with dyslexia

Behavioral studies indicate deficits in phonological working memory (WM) and executive functioning in dyslexics. However, little is known about the underlying functional neuroanatomy. In the present study, neural correlates of WM in adolescents and young adults with dyslexia were investigated using event-related functional magnetic resonance imaging (fMRI) and a parametric verbal WM task which required the manipulation of verbal material. Dyslexics were not significantly slower than controls; however, they were less accurate with the highest WM demand. The functional analysis excluded incorrectly performed and omitted trials, thus controlling for potential activation confounds. Compared with control subjects, both increased and decreased activation of the prefrontal cortex were found in the dyslexic group. Dyslexics showed significantly more activation than controls with increasing WM demand in the left superior frontal gyrus (BA 8), as well as in the inferior frontal gyrus including Broca's area (BA 44) and its right homologue. Less activation was found in the middle frontal gyrus (BA 6) and in the superior parietal cortex (BA 7). A positive correlation between activation of prefrontal regions and verbal WM performance (as measured by digit span backwards) was found only in the dyslexic group. Accuracy deficits at the highest cognitive demand during the verbal WM task and the digit span backwards suggest that manipulation rather than maintenance is selectively impaired in dyslexics. The fMRI data provide further evidence for functional differences in cortical regions associated with language processing and executive function in subjects with dyslexia.     

Plasticity of language networks in patients with brain tumors: a positron emission tomography activation study.

We investigated plasticity of language networks exposed to slowly evolving brain damage. Single subject 0-15-water language activation positron emission tomography studies were analyzed in 61 right-handed patients with brain tumors of the left hemisphere, and 12 normal controls. In controls, activations were found in left Brodmann's Area (BA)44 and BA45, superior posterior temporal gyrus bilaterally, and right cerebellum. Patients additionally activated left BA46, BA47, anterior insula, and left cerebellum. Superior temporal activation was less frequent, and activations in areas other than posterior temporal gyrus were found bilaterally. Frontolateral activations within the nondominant hemisphere were only seen in patients (63%) with frontal or posterior temporal lesions. Laterality indices of frontolateral cortex showed reversed language dominance in 18% of patients. Laterality indices of the cerebellum were negatively correlated with language performance. Two compensatory mechanisms in patients with slowly evolving brain lesions are described: An intrahemispheric mechanism with recruitment of left frontolateral regions other than classic language areas; and an interhemispheric compensatory mechanism with frontolateral activation in the nondominant hemisphere. The latter one was only found in patients with frontal or posterior temporal lesions, thus supporting the hypothesis that right frontolateral activations are a disinhibition phenomenon.     

Associations of White Matter Integrity and Cortical Thickness in Patients With Schizophrenia and Healthy Controls

Typical brain development includes coordinated changes in both white matter (WM) integrity and cortical thickness (CT). These processes have been shown to be disrupted in schizophrenia, which is characterized by abnormalities in WM microstructure and by reduced CT. The aim of this study was to identify patterns of association between WM markers and cortex-wide CT in healthy controls (HCs) and patients with schizophrenia (SCZ). Using diffusion tensor imaging and structural magnetic resonance imaging data of the Mind Clinical Imaging Consortium study (130 HC and 111 SCZ), we tested for associations between (a) fractional anisotropy in selected manually labeled WM pathways (corpus callosum, anterior thalamic radiation, and superior longitudinal fasciculus) and CT, and (b) the number of lesion-like WM regions (“potholes”) and CT. In HC, but not SCZ, we found highly significant negative associations between WM integrity and CT in several pathways, including frontal, temporal, and occipital brain regions. Conversely, in SCZ the number of WM potholes correlated with reduced CT in the left lateral temporal gyrus, left fusiform, and left lateral occipital brain area. Taken together, we found differential patterns of association between WM integrity and CT in HC and SCZ. Although the pattern in HC can be explained from a developmental perspective, the reduced gray matter CT in SCZ patients might be the result of focal but spatially heterogeneous disruptions of WM integrity.Key words: cortical thickness, fractional anisotropy, structural MRI, DTI, schizophrenia     

An event-related fMRI study of the neural networks underlying the encoding, maintenance, and retrieval phase in a delayed-match-to-sample task

Memory loads exceeding the limited capacity of working memory (WM) have been shown to expand the prefrontal areas that participate in WM and have revealed substantial individual differences in performance. We used a delayed-match-to-sample (DMS) task in an event-related fMRI study to map the full extent of the expanded regional activations associated with supracapacity loads. A 6-letter study array was compared to arrays of 1 and 3 letters. The task comprised separate encoding, retention, and retrieval fMRI epochs. A brain-wide spatial covariance analysis was applied to the data of all task epochs to identify patterns of correlated regional activations whose expression increased monotonically across 3 memory-load levels on a subject-by-subject basis. Such load-related activation patterns were in all task phases. Of greatest interest is the activation pattern that was obtained during the maintenance phase: increasing activation with memory load was found not only in the lateral PFC (BA 9,44) but also in the parietal lobe (BA 7,40), anterior cingulate (BA 32), and cerebellum. Decreasing activation was found in the occipito-temporal lobe (BA 19,39) as well as the medial prefrontal cortex (BA 9,10). Subject increases in pattern expression from 1 to 6 items were positively correlated with the corresponding reaction time increases (p<0.05) and negatively correlated with NARTIQ (p<0.05), indicating that people who were faster in their responses and had higher NARTIQ had to increase their subject expression of the memory-load-related activation pattern less and were more efficient at the cognitive task. Our method thus not only reproduced findings of other WM studies but also addressed the issue of interactions between lateral PFC and other parts of the brain during the task, for the retention of the to-be-remembered information. The load-related activation patterns from encoding and retrieval phase and their relationship to behavior are also discussed.     

The Impact of Substance Use on Brain Structure in People at High Risk of Developing Schizophrenia

Ventricular enlargement and reduced prefrontal volume are consistent findings in schizophrenia. Both are present in first episode subjects and may be detectable before the onset of clinical disorder. Substance misuse is more common in people with schizophrenia and is associated with similar brain abnormalities. We employ a prospective cohort study with nested case control comparison design to investigate the association between substance misuse, brain abnormality, and subsequent schizophrenia. Substance misuse history, imaging data, and clinical information were collected on 147 subjects at high risk of schizophrenia and 36 controls. Regions exhibiting a significant relationship between level of use of alcohol, cannabis or tobacco, and structure volume were identified. Multivariate regression then elucidated the relationship between level of substance use and structure volumes while accounting for correlations between these variables and correcting for potential confounders. Finally, we established whether substance misuse was associated with later risk of schizophrenia. Increased ventricular volume was associated with alcohol and cannabis use in a dose-dependent manner. Alcohol consumption was associated with reduced frontal lobe volume. Multiple regression analyses found both alcohol and cannabis were significant predictors of these abnormalities when simultaneously entered into the statistical model. Alcohol and cannabis misuse were associated with an increased subsequent risk of schizophrenia. We provide prospective evidence that use of cannabis or alcohol by people at high genetic risk of schizophrenia is associated with brain abnormalities and later risk of psychosis. A family history of schizophrenia may render the brain particularly sensitive to the risk-modifying effects of these substances.     

Spatial Characteristics of White Matter Abnormalities in Schizophrenia

There is considerable evidence implicating brain white matter (WM) abnormalities in the pathophysiology of schizophrenia; however, the spatial localization of WM abnormalities reported in the existing studies is heterogeneous. Thus, the goal of this study was to quantify the spatial characteristics of WM abnormalities in schizophrenia. One hundred and fourteen patients with schizophrenia and 138 matched controls participated in this multisite study involving the Universities of Iowa, Minnesota, and New Mexico, and the Massachusetts General Hospital. We measured fractional anisotropy (FA) in brain WM regions extracted using 3 different image-processing algorithms: regions of interest, tract-based spatial statistics, and the pothole approach. We found that FA was significantly lower in patients using each of the 3 image-processing algorithms. The region-of-interest approach showed multiple regions with lower FA in patients with schizophrenia, with overlap at all 4 sites in the corpus callosum and posterior thalamic radiation. The tract-based spatial statistic approach showed (1) global differences in 3 of the 4 cohorts and (2) lower frontal FA at the Iowa site. Finally, the pothole approach showed a significantly greater number of WM potholes in patients compared to controls at each of the 4 sites. In conclusion, the spatial characteristics of WM abnormalities in schizophrenia reflect a combination of a global low-level decrease in FA, suggesting a diffuse process, coupled with widely dispersed focal reductions in FA that vary spatially among individuals (ie, potholes).Key words: diffusion tensor imaging, fractional anisotropy, pothole, tract-based spatial statistics     

Brain activation deficit in increased-load working memory tasks among adults with ADHD using fMRI

Working memory (WM) is impaired among adults with attention-deficit hyperactivity disorder (ADHD). This study aimed to investigate the brain activation deficit for low-level or increased-load WM among adults with ADHD. A total of 20 adults with ADHD and controls were recruited according to diagnostic interviewing by a psychiatrist. Phonological and visual–spatial 2-back and 3-back tasks were performed under functional magnetic resonance scanning. The results demonstrated that both the adults with ADHD and the controls exhibited activation of the fronto-parietal network for WM, and the intensity was greater in the adult ADHD group. The ADHD group had higher brain activation over the bilateral anterior cingulate, left inferior frontal lobe, hippocampus, and supplementary motor area (SMA) for phonological WM than the control group. When the task loading increased from 2-back to 3-back tasks, the adults with ADHD perceived greater difficulty. The control group exhibited increased brain activation over the frontal–parietal network in response to increased phonological WM load. However, the ADHD group showed decreased brain activation over the left precuneus, insula, and SMA. Further analysis demonstrated that the ADHD group exhibited a greater decrease in brain activation over the left fronto-parietal network, including the precuneus, SMA, insula/inferior frontal lobe, and dorsolateral prefrontal cortex, than the control group. These results suggest that adults with ADHD pay more effort to low demanding phonological WM. On the other hand, brain activation of the left fronto-parietal network is impaired when the demands of WM exceed the capacity of adults with ADHD.     

Picture-naming in patients with left frontal lobe tumor – a functional neuroimaging study

The objective of this study was to investigate behavioral performance as well as cortical activation patterns while picture-naming, in patients with left frontal lobe tumor prior to surgery. Functional magnetic resonance imaging was used to compare behavior and brain activations while 10 patients with a tumor in the left frontal lobe and 9 controls, named aloud simple pictures presented in a block design inside a 3 T Philips Achieva scanner. Evaluations of task performance included naming accuracy and articulation time. Behaviorally, patients took significantly longer to articulate picture names but naming accuracy was preserved. Analysis of brain activations showed differences only in the frontal regions of the cortical network. In particular, while the frontal activations in the control population were focused and localized in the left inferior orbito-frontal gyrus, in patients the frontal network was distributed and included a significantly greater number of clusters that were distributed in homologous or near homologous areas of the (orbito-frontal gyrus) left and/or right hemisphere of the frontal lobe. Our results suggest that in patients with a left frontal lobe tumor the process of naming simple pictures is preserved but the cortical network of activation in the frontal region is altered and is distributed in the frontal regions of both hemispheres.     

Comparing Fractional Anisotropy in Patients With Childhood-Onset Schizophrenia,Their Healthy Siblings,and Normal Volunteers Through DTI

Background:

Diffusion tensor imaging is a neuroimaging method that quantifies white matter (WM) integrity and brain connectivity based on the diffusion of water in the brain. White matter has been hypothesized to be of great importance in the development of schizophrenia as part of the dysconnectivity model. Childhood-onset schizophrenia (COS), is a rare, severe form of the illness that resembles poor outcome adult-onset schizophrenia. We hypothesized that COS would be associated with WM abnormalities relative to a sample of controls.

Methods:

To evaluate WM integrity in this population 39 patients diagnosed with COS, 39 of their healthy (nonpsychotic) siblings, and 50 unrelated healthy volunteers were scanned using a diffusion tensor imaging (DTI) sequence during a 1.5 T MRI acquisition. Each DTI scan was processed via atlas-based analysis using a WM parcellation map, and diffeomorphic mapping that shapes a template atlas to each individual subject space. Fractional anisotropy (FA), a measure of WM integrity was averaged over each of the 46 regions of the atlas. Eleven WM regions were examined based on previous reports of WM growth abnormalities in COS.

Results:

Of those regions, patients with COS, and their healthy siblings had significantly lower mean FA in the left and right cuneus as compared to the healthy volunteers (P < .005). Together, these findings represent the largest DTI study in COS to date, and provide evidence that WM integrity is significantly impaired in COS. Shared deficits in their healthy siblings might result from increased genetic risk.Key words: DTI, COS, siblings, cuneus, FA     

Association of the ZNF804A gene polymorphism rs1344706 with white matter density changes in Chinese schizophrenia

Background

ZNF804A gene polymorphism rs1344706, the first genetic risk variant to achieve genome wide significance for schizophrenia, has been linked to neural functional connectivity. Dysconnectivity of WM may be the primary pathological mechanism of schizophrenia. Association of this variant with regional WM density has not been investigated in schizophrenic patients.

Methods

69 healthy controls and 80 patients with schizophrenia underwent genotyping of rs1344706 SNPs, and were examined for WM density (T1-weighted MRI). The association of rs1344706 with WM changes in schizophrenia patients and healthy controls was analyzed using a full-factorial 2 × 2 analysis of variance.

Results

1. There was an interaction on WM density in the left prefrontal lobe between the rs1344706 genotype and schizophrenic diagnosis, where the risk T allele carriers presented higher WM density in the schizophrenia patients and lower WM density in healthy controls in comparison with the non-risk allele carriers.2. The risk allele was associated with an increased WM density of the bilateral hippocampus in both the patients and the healthy group.

Limitation

The influence of antipsychotics to the white matter in schizophrenic patients was not fully eliminated.

Conclusions

The ZNF804A variant may confer risk for schizophrenia by exerting its effects on the WM in the left prefrontal lobe together with other risk factors for schizophrenia.