Dominic Job

Principles in the Evolutionary Design of Digital Circuits—Part II

In a previous work it was argued that by studying evolved designs of gradually increasing scale, one might be able to discern new, efficient, and generalisable principles of design. These ideas are tested in the context of designing digital circuits, particularly arithmetic circuits. This process of discovery is seen as a principle extraction loop in which the evolved data is analysed both phenotypically and genotypically by processes of data mining and landscape analysis. The information extracted is then fed back into the evolutionary algorithm to enhance its search capabilities and hence increase the likelihood of identifying new principles which explain how to build systems which are too large to evolve.

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.

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.

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.

The effects of a neuregulin 1 variant on white matter density and integrity.

Theories of abnormal anatomical and functional connectivity in schizophrenia and bipolar disorder are supported by evidence from functional magnetic resonance imaging (MRI), structural MRI and diffusion tensor imaging (DTI). The presence of similar abnormalities in unaffected relatives suggests such disconnectivity is genetically mediated, albeit through unspecified loci. Neuregulin 1 (NRG1) is a psychosis susceptibility gene with effects on neuronal migration, axon guidance and myelination that could potentially explain these findings. In the current study, unaffected subjects were genotyped at the NRG1 single nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) locus, previously associated with increased risk for psychosis, and the effect of genetic variation at this locus on white matter density (T1-weighted MRI) and integrity (DTI) was ascertained. Subjects with the risk-associated TT genotype had reduced white matter density in the anterior limb of the internal capsule and evidence of reduced structural connectivity in the same region using DTI. We therefore provide the first imaging evidence that genetic variation in NRG1 is associated with reduced white matter density and integrity in human subjects. This finding is discussed in the context of NRG1 effects on neuronal migration, axon guidance and myelination.

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.

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.

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.

Overactivation of fear systems to neutral faces in schizophrenia

BACKGROUND The amygdala plays a central role in detecting and responding to fear-related stimuli. A number of recent studies have reported decreased amygdala activation in schizophrenia to emotional stimuli (such as fearful faces) compared with matched neutral stimuli (such as neutral faces). We investigated whether the apparent decrease in amygdala activation in schizophrenia could actually derive from increased amygdala activation to the neutral comparator stimuli. METHODS Nineteen patients with schizophrenia and 24 matched control participants viewed pictures of faces with either fearful or neutral facial expressions, and a baseline condition, during functional magnetic resonance imaging scanning. RESULTS Patients with schizophrenia showed a relative decrease in amygdala activation to fearful faces compared with neutral faces. However, this difference resulted from an increase in amygdala activation to the neutral faces in patients with schizophrenia, not from a decreased response to the fearful faces. CONCLUSIONS Patients with schizophrenia show an increased response of the amygdala to neutral faces. This is sufficient to explain their apparent deficit in amygdala activation to fearful faces compared with neutral faces. The inappropriate activation of neural systems involved in fear to otherwise neutral stimuli may contribute to the development of psychotic symptoms in schizophrenia.

Grey matter differences in bipolar disorder: a meta-analysis of voxel-based morphometry studies

Selvaraj S, Arnone D, Job D, Stanfield A, Farrow TFD, Nugent AC, Scherk H, Gruber O, Chen X, Sachdev PS, Dickstein DP, Malhi GS, Ha TH, Ha K, Phillips ML, McIntosh AM. Grey matter differences in bipolar disorder: a meta‐analysis of voxel‐based morphometry studies. Bipolar Disord 2012: 14: 135–145.