Biomedical subjects

Dominic E Job

Publications and source records attributed to Dominic E Job.

15 recordsLinked to original sources

PubMed2006

Grey matter changes can improve the prediction of schizophrenia in subjects at high risk.

BACKGROUND: We hypothesised that subjects at familial high risk of developing schizophrenia would have a reduction over time in grey matter, particularly in the temporal lobes, and that this reduction may predict schizophrenia better than clinical measurements. METHODS: We analysed magnetic resonance images of 65 high-risk subjects from the Edinburgh High Risk Study sample who had two scans a mean of 1.52 years apart. Eight of these 65 subjects went on to develop schizophrenia an average of 2.3 years after their first scan. RESULTS: Changes over time in the inferior temporal gyrus gave a 60% positive predictive value (likelihood ratio >10) of developing schizophrenia compared to the overall 13% risk in the cohort as a whole. CONCLUSION: Changes in grey matter could be used as part of a predictive test for schizophrenia in people at enhanced risk for familial reasons, particularly for positive predictive power, in combination with other clinical and cognitive predictive measures, several of which are strong negative predictors. However, because of the limited number of subjects, this test requires independent replication to confirm its validity.

Brain↗

PubMed2006

A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms.

NRG1, encoding neuregulin 1, is a susceptibility gene for schizophrenia, but no functional mutation causally related to the disorder has yet been identified. Here we investigate the effects of a variant in the human NRG1 promoter region in subjects at high risk of schizophrenia. We show that this variant is associated with (i) decreased activation of frontal and temporal lobe regions, (ii) increased development of psychotic symptoms and (iii) decreased premorbid IQ.

Adult↗

PubMed2006

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.

Adolescent↗

PubMed2006

Brain-behaviour relationships in people at high genetic risk of schizophrenia.

The brain is known to be structurally abnormal in schizophrenia, with replicated findings between anatomical deficits and some dysfunctions. These structure-function associations have, however, only very rarely been studied in relatives at risk of schizophrenia. We studied the relationships between structure and schizotypal features (assessed using RISC and SIS) and verbal learning and memory (measured using RAVLT) in relatives at high risk of developing schizophrenia and normal controls. Since these behavioural test scores are strong predictors of schizophrenia in the Edinburgh High Risk Study, we hypothesised that these relationships would differ between those high-risk subjects who will develop schizophrenia from those who will not. We performed multiple regressions of the grey matter segments of the subjects and controls, produced using grey matter optimised, voxel-based morphometry, with their RAVLT, SIS and RISC scores in SPM. Where significant relationships were found, we used SPSS to test for subject group by behavioural score interactions. In those high-risk subjects who became ill, grey matter density (GMD) was significantly correlated with RISC in the left superior temporal gyrus. In subjects who remained well, SIS was significantly correlated with GMD in the right pulvinar. Across the whole HR group, GMD in the right medial dorsal thalamic nucleus was significantly correlated with RAVLT. In those subjects who developed symptoms, RAVLT significantly correlated with GMD in right parahippocampal gyrus whereas in those who became ill, significant correlations existed bilaterally in the pulvinar. These results suggest complex and changing patterns of structural-functional relationships in those subjects at high-risk of schizophrenia.

Adolescent↗

PubMed2006

A visual joke fMRI investigation into Theory of Mind and enhanced risk of schizophrenia.

Theory of Mind (ToM) or mentalizing is the ability of individuals to determine the intentions and behavior of others. This ability is known to be compromised in schizophrenia and has been shown to fluctuate with symptom severity. Neuropsychological investigations into relatives of individuals with schizophrenia have shown that some relatives also show a deficit in this area of social cognition. In order to address this state and trait issue, we investigated the performance of high-risk relatives of individuals with schizophrenia to those of a matched control group (n = 13) on a blocked design visual joke fMRI paradigm. The task involved looking at two sets of cartoon jokes, one set which required mentalizing abilities to understand the jokes and another set that did not require such abilities. Relatives were divided into two groups based on the presence (HR+, n = 12) or absence (HR-, n = 12) of positive symptoms. The task provided robust activations across the groups in areas previously associated with mentalizing abilities, such as the PFC, precuneus, and temporal lobes. Significant between-group activations were observed in the PFC (primarily BA6, 8, and 9) with the HR- activating significantly greater than the HR+ in these regions. Both a secondary state-specific analysis and a third post hoc analysis further investigating state effects showed significant PFC between-group differences. This study is the first time relatives of individuals with schizophrenia have been imaged using a ToM paradigm, and the results provide evidence of both a state and state-mediated trait effect.

Adult↗

PubMed2006

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.

Frontal Lobe↗

PubMed2006

Genetic liability to schizophrenia or bipolar disorder and its relationship to brain structure.

Bipolar disorder and schizophrenia are highly heritable conditions that are associated with structural brain abnormalities. Although brain abnormalities are found in the well relatives of people with schizophrenia, the extent to which genetic liability relates to brain structure in either disorder is still unclear. This study sought to ascertain the effects of genetic liability to schizophrenia and bipolar disorder on white and grey matter volume in patients with these diagnoses and their well relatives. Seventy-one patients and 72 unaffected relatives were recruited for the study. Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Samples of unaffected relatives of each patient group were also recruited. Subjects underwent an MRI scan of the brain, which was analysed using optimised voxel-based morphometry (VBM). Grey and white matter volume was then related to a continuous measure of genetic liability based on a threshold-liability model. Genetic liability to schizophrenia was associated with decreased grey matter volume in dorso- (DLPFC) and ventrolateral prefrontal (VLPFC) cortices. The relationship remained after diagnostic status had been taken into account. Complementary white matter changes were also demonstrated. No relationship was demonstrated between a genetic liability to bipolar disorder and either white or grey matter volume. Genes that raise the likelihood of developing schizophrenia may exert their effects by diminishing grey matter volume in the DLPFC and VLPFC and their associated white matter connections. Genes for bipolar illness might have subtle effects on brain structure, which may need particularly large samples to detect.

Algorithms↗

PubMed2005

Empirical comparison of maximal voxel and non-isotropic adjusted cluster extent results in a voxel-based morphometry study of comorbid learning disability with schizophrenia.

We present an empirical comparison of cluster extent and maximal voxel results in a voxel-based morphometry (VBM) study of brain structure. The cluster extents are adjusted for underlying deviation from uniform smoothness. We implement this comparison on a four-group cohort that has previously shown evidence of a neuro-developmental component in schizophrenia (Moorhead, T.W.J., Job, D.E., Whalley, H.C., Sanderson, T.L., Johnstone, E.C. and Lawrie, S.M. 2004. Voxel-based morphometry of comorbid schizophrenia and learning disability: analyses in normalized and native spaces using parametric and nonparametric statistical methods. NeuroImage 22: 188-202.). We find that adjusted cluster extent results provide information on the nature of deficits that occur in the schizophrenia affected groups, and these important structural differences are not all shown in maximal voxel results. The maximal voxel and cluster extent results are corrected for multiple comparisons using Random Fields (RF) methods. In order to apply the cluster extent measures, we propose a post-hoc method for determining the primary threshold in the analysis. Unadjusted cluster extent results are reported, for these, no allowance is made for non-isotropic smoothness, and comparison with the adjusted extent results shows that the unadjusted results can be either conservative or anti-conservative depending upon the underlying tissue distributions.

Cluster Analysis↗

PubMed2005

White matter density in patients with schizophrenia, bipolar disorder and their unaffected relatives.

BACKGROUND: This study sought to assess white matter density in patients and relatives with histories of bipolar disorder and/or schizophrenia. METHODS: Subjects included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives of the three patient groups were also recruited. Subjects underwent an MRI brain scan which was analyzed using a white-matter optimized technique. RESULTS: Subjects with schizophrenia and bipolar disorder showed reduced white matter density in the anterior limb of the internal capsule which was not found in unaffected relatives. Reductions were found in frontal subgyral white matter density in affected subjects with a family history of schizophrenia only. CONCLUSIONS: Abnormal anterior internal capsule white matter may provide a structural substrate for both disorders.

Adult↗

PubMed2005

Grey matter changes over time in high risk subjects developing schizophrenia.

Schizophrenia affects approximately 1% of the population and is associated with reductions in brain volume, but when these are first evident is unknown. Magnetic resonance imaging (MRI) has demonstrated abnormalities of brain structure, particularly of the temporal lobes, in schizophrenia. A study of brain structure in individuals destined to develop schizophrenia, before they do so, is crucial to understanding the illness. We used Voxel Based Morphometry (VBM) to map changes in Grey Matter Density (GMD) in 65 young adults at high risk of schizophrenia, for familial reasons, and 19 healthy young adults, over a period of approximately 2 years. All subjects were anti-psychotic naive at both scans. No increases in GMD were found in any of the groups. Within the high-risk group significant declines in GMD were found in the temporal lobes, the right frontal lobe and right parietal lobe. In the control group a decline was found in the right gyrus rectus. No significant differences over time were found between any of the groups. Those individuals at high risk who had transient or isolated psychotic symptoms showed a different spatial pattern of reductions in GMD than those who did not in within group comparisons. In addition, those individuals at high risk who later developed schizophrenia also showed a different spatial pattern of reductions in GMD in the left temporal lobe and right cerebellum, from 2 to 3 years before they were diagnosed. These particular reductions may therefore be able to predict the later onset of schizophrenia.

Adult↗

PubMed2004

Voxel-based morphometry of patients with schizophrenia or bipolar disorder and their unaffected relatives.

BACKGROUND: Structural brain abnormalities in schizophrenia are well replicated; many emerge before the onset of illness and are present in relatives who remain well. Structural changes in bipolar disorder are less clearly established. The possibility that structural abnormalities might provide a means by which the disorders might be separated is one that has attracted limited research effort. This study sought to examine these issues and clarify the associations of phenotypic expression and genetic liability. METHODS: Forty-nine control subjects, 71 patients, and 72 unaffected relatives were recruited for the study. Patients included those with schizophrenia from families affected by schizophrenia alone, those with bipolar disorder from families affected by bipolar disorder alone, and those with bipolar disorder from families affected by both bipolar disorder and schizophrenia. Unaffected relatives were recruited from the families of the three patient groups. Subjects underwent a magnetic resonance imaging scan of the brain, which was analyzed with a grey-matter-optimized, voxel-based morphometry technique. RESULTS: Compared with control subjects, all patient and relative groups showed evidence of reduced anterior thalamic gray matter. Reductions in middle prefrontal gyrus and dorsomedial thalamus were specific to participants with schizophrenia. CONCLUSIONS: Whereas prefrontal and dorsomedial thalamic gray matter reductions seem to be specific to schizophrenia, anterior thalamic reductions seem to be a marker of liability to psychosis in general. These results are discussed in the context of their functional role and in terms of their connections with other cortical and subcortical structures.

Adult↗

PubMed2004

Voxel-based morphometry of comorbid schizophrenia and learning disability: analyses in normalized and native spaces using parametric and nonparametric statistical methods.

We employed voxel-based morphometry (VBM) to compare the distributions of grey matter found in structural magnetic resonance imaging (MRI) brain scans of patients with comorbid learning disability with schizophrenia, schizophrenia alone, learning disability alone, and normal controls. Our primary aim was to replicate a previous region of interest (ROI) finding that comorbids and schizophrenics belong to the same population. Nonparametric analysis in normalized space showed no significant differences in grey matter distribution between the comorbid and schizophrenia groups. Furthermore, this analysis showed significant grey matter reductions in the comorbid and schizophrenia groups when compared to the learning-disabled or the normal controls. Parametric analysis localized the significant grey matter reductions between the normal controls and the comorbid and schizophrenia groups to the prefrontal and temporal lobes. It also identified an area of increased grey matter, on the inferior aspect of the postcentral gyrus, in the learning-disabled alone compared to the other groups. Native space parametric and nonparametric analyses, based on modulation of the normalized scans, confirmed the similarity in grey matter distribution of the comorbid and schizophrenia groups. Results confirm the ROI finding that in native space the learning-disabled group possesses the least and normal controls the most grey matter for the cohort. An increase in the basal ganglia of patients with schizophrenia vs. the learning-disabled, probably attributable to antipsychotic medication, was identified in the native space analysis. The native space results did not however register statistically significant temporal lobe reductions found under normalized analysis between schizophrenics and normal controls. This may be attributable to minor physical anomalies (MPA) in the schizophrenic cranium. Overall, these VBM results replicate previous ROI findings and are compatible with the view that comorbid learning disability with schizophrenia is a severe form of schizophrenia, rather than a consequence of learning disability. VBM has the facility to compare grey matter distributions in this structurally diverse cohort.

Adult↗

PubMed2003

Voxel-based morphometry of grey matter densities in subjects at high risk of schizophrenia.

The grey matter (GM) segments from T1 structural magnetic resonance (MR) images of the brain in subjects at high risk of schizophrenia (n=146) were compared with normal control subjects (n=36) and first episode schizophrenic subjects (n=34) using automated voxel-based morphometry (VBM). The subjects were recruited for the Edinburgh High Risk Study (EHRS) and regional brain volumes had previously been measured using a semi-automated volumetric region of interest (ROI) method of analysis. For the current report, the images were processed using a study specific template and statistically analysed using the SPM99 program. The small volume correction tool in SPM was also used to restrict the analyses to specific voxels. Reductions in the probability of grey matter (GM) density were seen bilaterally in the anterior cingulate, and as a trend in the left parahippocampal gyrus for the high-risk vs. control subjects. In contrast, first episode schizophrenia subjects had less GM than high-risk subjects in several frontal and temporal regions. These results are compatible with the findings of our previous volumetric ROI analysis.

Acute Disease↗

PubMed2003

Structural and functional abnormalities of the amygdala in schizophrenia.

Schizophrenia is characterized by delusions and hallucinations, which tend to respond to treatment with dopamine receptor blockers, and a loss of motivation and affect, which do not. Structural magnetic resonance imaging (sMRI) has convincingly demonstrated reduced volumes of the amygdala-hippocampal complex (AHC) and other limbic and paralimbic structures, on both manual tracing and automated analyses. The Edinburgh High-Risk Study (EHRS) of initially healthy adolescents with at least two affected relatives has found that AHC volumes are reduced pre-morbidly but not to schizophrenic levels, suggesting that further volume reductions may be associated with the onset of schizophrenia. AHC volumes appear to be genetically mediated in families with a dominant pattern of transmission, whereas prefrontal lobe and basal ganglia volumes are related to genetic liability to schizophrenia in the generality of high-risk subjects. Temporal lobe volumes may fall as psychotic symptoms develop, in the context of drug abuse and stress. Neuropsychological testing has also demonstrated pre-morbid impairments and symptom-related deterioration. More detailed analyses of the temporal lobe changes on sMRI and fronto-temporal dysconnectivity on fMRI are in progress. These findings are discussed with reference to other indications of pre-morbid developmental disturbance in our high-risk subjects, animal models of schizophrenia, and reliable findings from neuropathological, neuropsychological, and functional imaging studies of patients with schizophrenia.

Amygdala↗

PubMed2002

Structural gray matter differences between first-episode schizophrenics and normal controls using voxel-based morphometry.

The aim of this study was to compare the gray matter segments from T1 structural MR images of the brain in first-episode schizophrenic subjects (n = 34) and normal control subjects (n = 36) using automated voxel-based morphometry (VBM). This study is novel in that few studies have examined subjects in their first episode of schizophrenia. The subjects were recruited for the Edinburgh High Risk project and regional brain volumes were previously measured using a semi-automated volumetric region of interest (ROI) method of analysis. The primary interest was to compare the results from the compatible parts of the ROI study and the primary VBM approach. Our secondary interest was to compare the results of a study-specific template that was constructed from the control group to those using the generic T1 template (152 Montreal Neurological Institute brains) supplied with SPM99 (statistical parametric mapping). The images were processed and statistically analyzed using the SPM99 program. VBM analysis identified significant decreases in gray matter in the schizophrenics relative to the normal control group at the corrected voxel level (P < 0.05) in the right anterior cingulate, right medial frontal lobe, left middle temporal gyrus, left postcentral gyrus, and the left limbic lobe. There were no increases in gray matter in the schizophrenics relative to the control group. The construction of a customized template appeared to improve the detection of structural abnormalities. The analyses were subsequently restricted to voxels within the amygdala-hippocampal complex using the SPM small-volume correction. This identified gray matter decreases in the schizophrenics, at the corrected voxel level (P < 0.05), in the left and right uncus and parahippocampal gyri and the right amygdala. These results are compatible with and extend the relevant findings of the previous volumetric ROI analysis, when allowing for the differences between the methods and interpretation of their results.

Adult↗