Balanced translocation linked to psychiatric disorder, glutamate, and cortical structure/function.

Rare genetic variants of large effect can help elucidate the pathophysiology of brain disorders. Here we expand the clinical and genetic analyses of a family with a (1;11)(q42;q14.3) translocation multiply affected by major psychiatric illness and test the effect of the translocation on the structure and function of prefrontal, and temporal brain regions. The translocation showed significant linkage (LOD score 6.1) with a clinical phenotype that included schizophrenia, schizoaffective disorder, bipolar disorder, and recurrent major depressive disorder. Translocation carriers showed reduced cortical thickness in the left temporal lobe, which correlated with general psychopathology and positive psychotic symptom severity. They showed reduced gyrification in prefrontal cortex, which correlated with general psychopathology severity. Translocation carriers also showed significantly increased activation in the caudate nucleus on increasing verbal working memory load, as well as statistically significant reductions in the right dorsolateral prefrontal cortex glutamate concentrations. These findings confirm that the t(1;11) translocation is associated with a significantly increased risk of major psychiatric disorder and suggest a general vulnerability to psychopathology through altered cortical structure and function, and decreased glutamate levels.

Cortical thickness in first-episode schizophrenia patients and individuals at high familial risk: a cross-sectional comparison.

BACKGROUND: Schizophrenia is associated with cortical thickness reductions in the brain, but it is unclear whether these are present before illness onset, and to what extent they are driven by genetic factors. METHODS: In the Edinburgh High Risk Study, structural MRI scans of 150 young individuals at high familial risk for schizophrenia, 34 patients with first-episode schizophrenia and 36 matched controls were acquired, and clinical information was collected for the following 10 years for the high-risk and control group. During this time, 17 high-risk individuals developed schizophrenia, on average 2.5 years after the scan, and 57 experienced isolated or sub-clinical psychotic symptoms. We applied surface-based analysis of the cerebral cortex to this cohort, and extracted cortical thickness in automatically parcellated regions. RESULTS: Analysis of variance revealed widespread thinning of the cerebral cortex in first-episode patients, most pronounced in superior frontal, medial parietal, and lateral occipital regions (corrected p<10(-4)). In contrast, cortical thickness reductions were only found in high-risk individuals in the left middle temporal gyrus (corrected p<0.05). There were no significant differences between those at high risk who later developed schizophrenia and those who remained well. CONCLUSIONS: These findings confirm cortical thickness reductions in schizophrenia patients. Increased familial risk for schizophrenia is associated with thinning in the left middle temporal lobe, irrespective of subsequent disease onset. The absence of widespread cortical thinning before disease onset implies that the cortical thinning is unlikely to simply reflect genetic liability to schizophrenia but is predominantly driven by disease-associated factors.

Longitudinal gray matter change in young people who are at enhanced risk of schizophrenia due to intellectual impairment.

BACKGROUND: Existing studies of brain structural changes before the onset of schizophrenia have considered individuals with either familial risk factors or prodromal symptomatology. We aimed to determine whether findings from these studies are also applicable to those at enhanced risk of developing schizophrenia for another reason-intellectual impairment. METHODS: Participants with intellectual impairment (mean IQ: 78.2) received magnetic resonance imaging of the brain at baseline (mean age: 16 years old) and again 6 years later. The Positive and Negative Syndrome Scale was used to assess psychotic symptoms. Participants were dichotomized using their Positive and Negative Syndrome Scale scores at follow-up and gray matter changes were compared between the groups using tensor based morphometry and semiautomated region of interest analysis. RESULTS: Forty-six individuals had scans of sufficient quality to be included in the study. The tensor based morphometry analyses revealed that those with psychotic symptoms at follow-up showed significantly greater gray matter reductions over 6 years in the medial temporal lobes bilaterally. Region of interest analyses revealed that those individuals with psychotic symptoms at follow-up showed a reduced right hippocampal volume at age 16 and reduced bilateral hippocampal volumes at follow-up. CONCLUSIONS: This unique study of individuals vulnerable to schizophrenia due to intellectual impairment highlights aberrant development in the medial temporal lobe associated with the occurrence of psychotic symptoms. These developmental changes are also evident in populations at enhanced risk of schizophrenia for familial and symptomatic reasons, suggesting they are central to the development of the disorder regardless of the nature of the vulnerability state.

White matter integrity in individuals at high genetic risk of bipolar disorder.

BACKGROUND: Bipolar disorder is a familial psychiatric disorder associated with reduced white matter integrity, but it is not clear whether such abnormalities are present in young unaffected relatives and, if so, whether they have behavioral correlates. We investigated with whole brain diffusion tensor imaging whether increased genetic risk for bipolar disorder is associated with reductions in white matter integrity and whether these reductions are associated with cyclothymic temperament. METHODS: Diffusion tensor imaging data of 117 healthy unaffected relatives of patients with bipolar disorder and 79 control subjects were acquired. Cyclothymic temperament was measured with the cyclothymia scale of the Temperament Evaluation of Memphis, Pisa and San Diego auto-questionnaire. Voxel-wise between-group comparisons of fractional anisotropy (FA) and regression of cyclothymic temperament were performed with tract-based spatial statistics. RESULTS: Compared to the control group, unaffected relatives had reduced FA in one large widespread cluster. Cyclothymic temperament was inversely related to FA in the internal capsules bilaterally and in left temporal white matter, regions also found to be reduced in high-risk subjects. CONCLUSIONS: These results show that widespread white matter integrity reductions are present in unaffected relatives of bipolar patients and that more localized reductions might underpin cyclothymic temperament. These findings suggest that white matter integrity is an endophenotype for bipolar disorder with important behavioral associations previously linked to the etiology of the condition.

Genetic variants in the ErbB4 gene are associated with white matter integrity.

Variations in the signalling NRG1-ErbB4 pathway have been associated with genetic susceptibility for both bipolar disorder and schizophrenia, although the underlying neural mechanisms are still uncertain. Reduced integrity of the anterior limb of the internal capsule (ALIC) has been found in association with risk-associated genetic variation in the 5' region of the NRG1 gene. We hypothesised that variation in the gene encoding the NRG1 receptor, ErbB4, would also be associated with reduced ALIC integrity and with cognitive impairments characteristic of individuals with bipolar disorder and schizophrenia. Using diffusion tensor imaging (DTI), we examined the white matter integrity associations of the ErbB4 polymorphism rs4673628, which resides within intron 12 of the gene encoding ErbB4, in 36 healthy individuals. We also sought to clarify the cognitive effects of any findings. We found that genetic variation at the rs4673628 locus in the ErbB4 gene was significantly associated with ALIC white matter integrity which was also significantly and positively associated with mnemonic function. These findings provide further evidence to support a key role of NRG1-ErbB4 signalling in the pathophysiology of major mental disorders.

Functional Magnetic Resonance Imaging (fMRI) reproducibility and variance components across visits and scanning sites with a finger tapping task.

Multicentre MRI studies offer great potential to increase study power and flexibility, but it is not yet clear how reproducible the results from multiple centres may be. Here we present results from the multicentre study 'CaliBrain', examining the reproducibility of fMRI data within and between three sites. Fourteen subjects were scanned twice on three 1.5 T GE scanners using an identical scanning protocol. We present data from a motor task with three conditions, sequential and random finger tapping and rest. Similar activation maps were obtained for each site and visit; brain areas consistently activated during the task included the premotor, primary motor and supplementary motor areas, the striatum and cerebellum. Reproducibility was evaluated within and between sites by comparing the extent and spatial agreement of activation maps at both the subject and group levels. The results were within the range previously reported for similar tasks on single scanners and both measures were found to be comparable within and between sites, with between site reproducibility similar to the within site measures. A variance components analysis was used to examine the effects of site, subject and visit. The contributions of site and visit were small and reproducibility was similar between and within sites, whereas the variance between subjects, and unexplained variance was large. These findings suggest that we can have confidence in combined results from multicentre fMRI studies, at least when a consistent protocol is followed on similar machines in all participating scanning sites and care is taken to select homogeneous subject groups.

Genetic variation in the G72 (DAOA) gene affects temporal lobe and amygdala structure in subjects affected by bipolar disorder.

BACKGROUND: Variation in the G72 (DAOA) gene is understood to convey susceptibility for bipolar disorder through an uncertain mechanism. Little is known about the structural brain phenotypes associated with this gene. We hypothesised that reductions in temporal lobe and amygdala gray matter would be associated with variation at two loci in the gene for which evidence of genetic linkage has been repeatedly demonstrated. METHODS: We examined the temporal lobe and amygdala gray matter associations of the risk variants M23 and M24 at the 5' end of the gene encoding G72 in 81 controls and 38 people with bipolar disorder. RESULTS: Genetic variation at both the M23 and M24 loci in G72 were associated with decreased gray matter density within the left temporal pole in people with bipolar disorder. M23 was also associated with reductions in right amygdala gray matter density. The genetic imaging associations were found only in patients with bipolar disorder. CONCLUSIONS: Genetic variation at single nucleotide polymorphisms in the G72 gene previously associated with bipolar disorder is related to reductions in temporal pole and amygdala gray matter structure in people with bipolar disorder.

Prospective multi-centre Voxel Based Morphometry study employing scanner specific segmentations: procedure development using CaliBrain structural MRI data.

BACKGROUND: Structural Magnetic Resonance Imaging (sMRI) of the brain is employed in the assessment of a wide range of neuropsychiatric disorders. In order to improve statistical power in such studies it is desirable to pool scanning resources from multiple centres. The CaliBrain project was designed to provide for an assessment of scanner differences at three centres in Scotland, and to assess the practicality of pooling scans from multiple-centres. METHODS: We scanned healthy subjects twice on each of the 3 scanners in the CaliBrain project with T1-weighted sequences. The tissue classifier supplied within the Statistical Parametric Mapping (SPM5) application was used to map the grey and white tissue for each scan. We were thus able to assess within scanner variability and between scanner differences. We have sought to correct for between scanner differences by adjusting the probability mappings of tissue occupancy (tissue priors) used in SPM5 for tissue classification. The adjustment procedure resulted in separate sets of tissue priors being developed for each scanner and we refer to these as scanner specific priors. RESULTS: Voxel Based Morphometry (VBM) analyses and metric tests indicated that the use of scanner specific priors reduced tissue classification differences between scanners. However, the metric results also demonstrated that the between scanner differences were not reduced to the level of within scanner variability, the ideal for scanner harmonisation. CONCLUSION: Our results indicate the development of scanner specific priors for SPM can assist in pooling of scan resources from different research centres. This can facilitate improvements in the statistical power of quantitative brain imaging studies.

Structural abnormalities of ventrolateral and orbitofrontal cortex in patients with familial bipolar disorder.

OBJECTIVES: Abnormalities of ventral prefrontal function have been widely reported in bipolar disorder, but reports of structural abnormalities in the same region are less consistent. We examined the presence and location of ventral prefrontal abnormalities in a large sample of individuals with bipolar disorder and their relationship to gender, psychotic symptoms, and age. METHODS: Structural magnetic resonance imaging brain scans were carried out on 66 individuals with bipolar disorder, type I, and 66 controls. Voxel-based morphometry was used to examine differences in grey and white matter density between the groups and their relationship with a lifetime occurrence of psychotic symptoms and age. RESULTS: Reductions in grey matter density were seen in the left and right lateral orbital gyri and the right inferior frontal gyrus, while white matter density reductions were seen in the corona radiata and the left temporal stem. In contrast, hallucinations and positive symptoms were associated with grey matter reduction in the left middle temporal gyrus. Age was more strongly associated with the right inferior frontal gyrus grey matter reductions in the bipolar group than in the controls, but not with any other finding. CONCLUSION: Abnormalities of the ventral prefrontal cortex are likely to be involved in the aetiopathology of bipolar disorder, while hallucinations appear to be more closely associated with temporal lobe abnormality, extending earlier work in schizophrenia. Further prospective studies are required to comprehensively address the trajectory of these findings.

Changes in gyrification over 4 years in bipolar disorder and their association with the brain-derived neurotrophic factor valine(66) methionine variant.

BACKGROUND: Evidence suggests that structural brain changes occur over time in bipolar disorder but few studies have examined this longitudinally. Additional work implicates brain-derived neurotrophic factor (BDNF) valine (val)(66)methionine (met) variant in these changes. The present study examined longitudinal trends in prefrontal gyrification index (GI) in bipolar disorder and the effect of BDNF genotype. METHODS: Eighteen patients with bipolar I disorder and 18 control subjects underwent magnetic resonance imaging at study entry and after 4 years. Prefrontal GI was computed as the ratio of folded inner contour to exposed outer contour. RESULTS: Ventral and dorsal GI decreased significantly with time in both cohorts; the rate did not differ for bipolar patients. Within the bipolar cohort, individuals with one or more BDNF met alleles showed greater losses in GI, an effect that correlated with gray matter loss in the left hemisphere. CONCLUSIONS: Gyrification index may be sensitive to atrophy, as well as being a neurodevelopmental measure. While the loss of prefrontal gyrification over time is not accelerated in bipolar disorder, a greater rate of loss is associated with the possession of one or more BDNF met alleles.

White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging.

OBJECTIVES: Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders. METHODS: DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis. RESULTS: Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication. CONCLUSIONS: Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.

Genetic variation in the DAOA (G72) gene modulates hippocampal function in subjects at high risk of schizophrenia.

BACKGROUND: Strong evidence exists for an association between genetic variation in the gene DAOA (D-amino acid oxidase activator, also known as G72) and risk for schizophrenia. Preliminary evidence in healthy control subjects has implicated genetic variation in the DAOA gene in the modulation of hippocampal complex and prefrontal cortex activation. METHODS: Assessment was performed on 61 subjects at high genetic risk of schizophrenia for familial reasons. All subjects were genotyped for two closely linked single nucleotide polymorphisms in the DAOA gene complex, M23 (rs3918342) and M24 (rs1421292), that have previously shown association with schizophrenia. The effect of genotype on brain activation was assessed with functional magnetic resonance imaging data gathered during performance of the verbal initiation section of the Hayling Sentence Completion Task. RESULTS: Differences between DAOA genotype groups were seen in the activation of the left hippocampus and parahippocampus in the contrast of sentence completion versus rest. In addition the DAOA genotype groups differed in their recruitment of right inferior prefrontal cortex in relation to increasing task difficulty. The effects of genotype on brain activation could not be explained in terms of differences in grey matter density. CONCLUSIONS: These results support the view that genetic variation in the DAOA gene influences hippocampal complex and prefrontal cortex function, an effect that might be particularly prominent in the context of enhanced genetic risk for schizophrenia.

Low birthweight and preterm birth in young people with special educational needs: a magnetic resonance imaging analysis.

BACKGROUND: Although neuroanatomical and cognitive sequelae of low birthweight and preterm birth have been investigated, little is understood as to the likely prevalence of a history of low birthweight or preterm birth, or neuroanatomical correlates of such a history, within the special educational needs population. Our aim was to address these issues in a sample of young people receiving additional learning support. METHODS: One hundred and thirty-seven participants aged 13-22 years, receiving additional learning support, were recruited via their schools or colleges and underwent structural magnetic resonance imaging (MRI). Obstetric records, available in 98 cases, included birthweight and gestational data in 90 and 95 cases, respectively. Both qualitative and quantitative voxel-based analyses of MRI data were conducted. RESULTS: A history of low birthweight and preterm birth was present in 13.3% and 13.7% of cases, respectively. Low birthweight and preterm birth were associated with specific qualitative anomalies, including enlargement of subarachnoid cisterns and thinning of the corpus callosum. Low birthweight was associated with reduced grey matter density (GMD) in the superior temporal gyrus (STG) bilaterally, left inferior temporal gyrus and left insula. Prematurity of birth was associated with reduced GMD in the STG bilaterally, right inferior frontal gyrus and left cerebellar hemisphere. Comparison of subjects with no history of low birthweight or preterm birth with a previously defined control sample of cognitively unimpaired adolescents (n = 72) demonstrated significantly greater scores for several anomalies, including thinning of the corpus callosum, loss of white matter and abnormalities of shape of the lateral ventricles. CONCLUSION: Although a two-fold increased prevalence of a history of low birthweight and preterm birth exists within the special educational needs population, other aetiological factors must be considered for the overwhelming majority of cases. Neuroanatomical findings within this sample include qualitative anomalies of brain structure and grey matter deficits within temporal lobe structures and the cerebellum that persist into adolescence. These findings suggest a neurodevelopmental mechanism for the cognitive difficulties associated with these obstetric risk factors.

Increased right prefrontal cortical folding in adolescents at risk of schizophrenia for cognitive reasons.

BACKGROUND: Two of the strongest predictors of later schizophrenia in the Edinburgh High Risk Study (EHRS) were the presence of schizotypal features and increased right prefrontal lobe cortical folding. We examined the association between these measures in adolescents at enhanced risk of developing schizophrenia due to cognitive impairment. METHODS: One hundred forty-three adolescents receiving special education were divided into two groups using the cut-off on the Structured Interview for Schizotypy (SIS) which optimally predicted later schizophrenia in the EHRS. Each participant received a structural magnetic resonance imaging scan. Prefrontal tissue volumes and a standard measure of cortical folding, the gyrification index (GI), were determined automatically using automated (A)-GI methodology. RESULTS: Those who scored above the SIS cut-off had a significantly higher right prefrontal lobe GI compared to those below the cut-off (F = 4.72, p = .03). GI correlated strongly with prefrontal tissue volumes, although when prefrontal volume was added as a covariate to the GI analysis a trend towards a group difference remained evident. CONCLUSIONS: The level of schizotypal cognitions among adolescents with cognitive impairment identifies a group with the same pattern of cortical folding seen in those with familial risk factors who later develop the disorder. Increased right prefrontal GI may reflect disordered connectivity in individuals with the greatest risk of developing schizophrenia.

Progressive gray matter loss in patients with bipolar disorder.

BACKGROUND: Structural brain abnormalities of the medial temporal lobe have been found in people with bipolar disorder (BPD). It is not known whether these abnormalities progress over the course of the illness or how they relate to neuropsychologic functioning. We sought to address these uncertainties in a prospective cohort study of people with bipolar I disorder. METHODS: Twenty patients with bipolar I disorder and 21 control subjects were recruited from the community. Participants were group matched for age, sex, and premorbid IQ. Longitudinal change in gray matter density was assessed using magnetic resonance imaging and evaluated using the technique of tensor-based morphometry with SPM2 software. Changes in gray and white matter density were estimated and compared with changes in cognitive function and clinical outcome. RESULTS: Patients with BPD showed a larger decline in hippocampal, fusiform, and cerebellar gray matter density over 4 years than control subjects. No significant changes in white matter density were found. Reductions in temporal lobe gray matter correlated with decline in intellectual function and with the number of intervening mood episodes over the follow-up period. CONCLUSIONS: Patients with BPD lose hippocampal, fusiform and cerebellar gray matter at an accelerated rate compared with healthy control subjects. This tissue loss is associated with deterioration in cognitive function and illness course.

Increased prefrontal gyrification in a large high-risk cohort characterizes those who develop schizophrenia and reflects abnormal prefrontal development.

BACKGROUND: In our cohort considered at high risk (HR) of developing schizophrenia, we previously found a significant difference in extent of right prefrontal cortical folding between those who subsequently developed schizophrenia and a matched group who remained well. This study aimed to determine if this preexisting difference distinguished 17 individuals who developed schizophrenia from the 128 HR individuals in the cohort who remained well and to explore possible underlying differences in cortical composition. METHODS: Prefrontal cortical folding was measured by an automated version of the Gyrification Index (A-GI), a ratio reflecting extent of folding. Multivariate logistic regression assessed the probability that prefrontal A-GI predicts diagnostic outcome and subsequently assessed the effect on A-GI of regional cerebrospinal fluid and gray and white matter. RESULTS: High-risk individuals who subsequently developed schizophrenia were distinguished from the remaining cohort by increased right prefrontal cortex (PFC) A-GI. Mean right PFC gray matter volume also differed between groups, but white matter volume did not. Correlations of age with gray and white matter further distinguished groups and a linear regression analysis showed a significant interaction between age and diagnosis on mean volume of right PFC white matter. CONCLUSIONS: Increased A-GI appears to indicate abnormal right prefrontal development in those who develop schizophrenia.

Grey matter correlates of early psychotic symptoms in adolescents at enhanced risk of psychosis: a voxel-based study.

A three-fold enhanced risk of schizophrenia is conferred by learning disability. Here we use voxel-based morphometry (VBM) to investigate grey matter correlates of early psychotic and related symptoms in 137 adolescents at enhanced risk of this disorder because of intellectual disability. Anxiety, hallucinations, incoherence of speech and delusions were assessed at clinical interview, and VBM was used to examine linear associations between symptom severity and grey matter density (GMD). We found significant correlations between anxiety and GMD in the right dorsomedial thalamic nucleus, left parahippocampal gyrus and left hippocampus. Incoherence of speech was associated with GMD in the left cerebellar hemisphere. Gender-separate analysis demonstrated correlations between anxiety and GMD in the right dorsomedial thalamic nucleus of males and the right pulvinar nucleus of females, hallucinations and GMD in the right STG of males, delusions and GMD in the left middle temporal gyrus (MTG) of females, and incoherence of speech and GMD in the right MTG of males and both cerebellar hemispheres and right inferior temporal gyrus of females. Findings are consistent with symptom-structure associates previously reported in populations with schizophrenia or at enhanced genetic risk, and suggest an anatomical basis for the psychopathology found in this young nonclinical population.

Relationship of catechol-O-methyltransferase variants to brain structure and function in a population at high risk of psychosis.

BACKGROUND: There is growing evidence that the gene catechol-O-methyltransferase (COMT) is involved in the etiopathogenesis of schizophrenia. This study sought to clarify the effects of the COMT Val158Met polymorphism on brain structure, function, and risk of developing schizophrenia in a well-characterized cohort of individuals at high risk of schizophrenia for familial reasons. METHODS: In a sample of 78 people at high genetic risk of schizophrenia, the risk of progression to schizophrenia associated with the COMT Val allele was estimated. The relationship of the Val allele to brain structure and function was investigated using structural magnetic resonance imaging (sMRI) and functional magnetic resonance imaging (fMRI) data collected on the high-risk subjects before their disease outcome was known. RESULTS: The COMT Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with the COMT Val allele had reduced gray matter density in anterior cingulate cortex. In addition, there was evidence of increased activation in lateral prefrontal cortex and anterior and posterior cingulated, with increasing sentence difficulty in those with the COMT Val allele despite a similar level of performance. CONCLUSIONS: The COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk, in whom it has demonstrable effects on prefrontal brain structure and function. These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples.

Structural correlates of intellectual impairment and autistic features in adolescents.

Intellectual disability, a common but under-researched condition, is strongly associated with autism spectrum disorders (ASD). Although studies have investigated the neural correlates of intelligence quotient (IQ) and ASD in intellectually unimpaired subjects, these issues have not been addressed in intellectually impaired subjects. We studied 63 intellectually disabled adolescents receiving additional learning support and 72 controls using whole brain tissue volumes extracted from native space and voxel-based morphometry (VBM) in normalised space. We applied a qualitative and quantitative review of VBM preprocessing and modified the optimised method to establish optimum co-registration of the brains in normalised space. We report tissue density differences at cluster level with adjustment for underlying smoothness. Individuals with intellectual disability had smaller total white matter and total brain tissue volumes than controls, as well as reduced grey matter density in the right cerebellar hemisphere and left temporo-parietal cortex, and reduced white matter density in the posterior corpus callosum. Intellectually disabled subjects were additionally subgrouped according to their degree of reported autistic features. Reduced grey matter density was detected in the thalamus of subjects with autistic features scoring within the pervasive developmental disorder range as compared to subjects below the threshold for ASD, and increased white matter density was detected in the left superior temporal gyrus of subjects scoring above the threshold for autism as compared to subjects below the threshold for ASD.

Automated computation of the Gyrification Index in prefrontal lobes: methods and comparison with manual implementation.

In this paper, we introduce an automated method of calculating Gyrification Index (GI), a measure of cortical folding. Automated GI (A-GI) is an in vivo GI implementation applied to MRI T1 weighted scans and is designed as an extension to the SPM analysis package. The A-GI tool is unbiased in its application, and is unlimited in the size of test cohort to which it can be applied. In comparison to manual methods, A-GI substantially reduces the time costs and improves repeatability. The current A-GI implementation is limited to analysis of prefrontal lobes, but an extension to provide whole brain A-GI is under consideration. In determination of the GI inner contour, A-GI traces high spatial frequencies typically missed in manual tracing, and thus, A-GI reports a high GI value. We examine the operation of this tool in two scan cohorts. We establish that the tool has good repeatability through its application to a cohort where 5 well individuals were scanned 5 times over a period of 6 months. This indicates that A-GI has low susceptibility to scanner noise and is not affected by the variability in brain representation given by repeat scans. We demonstrate replication of hand tracing results by comparisons with a manual GI study that has shown differences between high risk subjects who go on to develop schizophrenia and those who are at high risk but remain well. Direct scan by scan comparisons are carried out between manual and A-GI methods. In respect of scan orientation and coronal sampling, the methods differ, and these considerations contribute to a between methods right prefrontal ICC of 0.67 and left prefrontal ICC of 0.63. The replication results demonstrate that A-GI has discriminatory power equivalent to manual methods. A-GI is therefore a reliable measure of cortical folding that could be usefully applied to a number of MRI data sets of the brain in health and disease.