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White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging Bipolar disorder (BD) is strongly associated with white matter abnormalities. Postmortem studies have revealed a reduction in glial cells in the subgenual prefrontal cortex (1) and there is evidence from T 2 -weighted magnetic resonance imaging (MRI) that patients with BD have an increase in white matter hyperintensities compared to healthy controls (2, 3). T 1 -weighted MRI has also revealed white matter reductions using both region of interest (ROI) (4, 5) and voxel-based morphometry (VBM) approaches (6).Conventional T 1 -weighted MRI is, however, limited in its ability to identify abnormalities of white matter, since the signal is largely dependent upon water content and is potentially confounded by non-neuronal tissue components. Diffusion tensor imaging (DTI) is a more recent technique that measures the diffusivity of water molecules within tissues in vivo. Yet there have been few DTI studies in BD and all of these have had relatively small sample sizes. Their findings have included 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.

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 (T 1 -weighted MRI) and integrity (DTI) was ascertained. Subjects with the riskassociated 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.

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 to matched neutral stimuli (such as neutral faces). Here we have 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 when compared to 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. 2. The relevance of the findings to symptoms that characterize the disorder would strengthen the paper (i.e., relate the findings to symptoms in individuals with schizophrenia in the context of theories in the literature on amygdala function). Otherwise, the findings seem overly data driven.Response: We have sought to relate the current data to two of the main theories of the pathogenesis of schizophrenia in the discussion (2, 3). The former of these theories (2) argues for inappropriate amygdala activation in schizophrenia, a view which is directly supported by our data. The second hypothesis (3) argues that individual with schizophrenia attribute increased affective salience to otherwise neutral events, providing the setting for the formation of symptoms such as delusional beliefs. We believe that the present finding of increased amygdala activation to neutral faces in schizophrenia provides a potential biological basis for such a liability to psychosis. We have attempted to re-word part of the discussion to make these links more explicit, although fuller coverage is precluded by the word limit. Fear of faces in schizophreniaHall et al looked at the response of the amygdala, a brain region mediating fear, to faces in control subjects and participants with schizophrenia. They found that control subjects show amygdala activation to fearful faces, but not neutral faces. However patients with schizophrenia activated the amygdala fear system to both neutral and fearful faces. These results suggest that people with schizophrenia may perceive neutral faces as fearful, potentially contributing to the development of psychotic symptoms. IN THIS ISSUE StatementHall J et al AbstractBackground The amygdala plays a central role in detecting and responding to fear

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Brain activations during the Hayling task differentiated patients with bipolar disorder from comparison subjects and patients with schizophrenia. Patients with bipolar disorder showed abnormalities in frontostriatal systems associated with performance on a set shifting task. This finding suggests that bipolar disorder patients engaged emotional brain areas more than comparison subjects while performing the Hayling task.