J.E. Sussmann

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.

Hippocampal function in schizophrenia and bipolar disorder

BACKGROUNDnThe hippocampus plays a central role in memory formation. There is considerable evidence of abnormalities in hippocampal structure and function in schizophrenia, which may differentiate it from bipolar disorder. However, no previous studies have compared hippocampal activation in schizophrenia and bipolar disorder directly.nnnMETHODnFifteen patients with schizophrenia, 14 patients with bipolar disorder and 14 healthy comparison subjects took part in the study. Subjects performed a face-name pair memory task during functional magnetic resonance imaging (fMRI). Differences in blood oxygen level-dependent (BOLD) activity were determined during encoding and retrieval of the face-name pairs.nnnRESULTSnThe patient groups showed significant differences in hippocampal and prefrontal cortex (PFC) activation during face-name pair learning. During encoding, patients with schizophrenia showed decreased anterior hippocampal activation relative to subjects with bipolar disorder, whereas patients with bipolar disorder showed decreased dorsal PFC activation relative to patients with schizophrenia. During retrieval, patients with schizophrenia showed greater activation of the dorsal PFC than patients with bipolar disorder. Patients with schizophrenia also differed from healthy control subjects in the activation of several brain regions, showing impaired superior temporal cortex activation during encoding and greater dorsal PFC activation during retrieval. These effects were evident despite matched task performance.nnnCONCLUSIONSnPatients with schizophrenia showed deficits in hippocampal activation during a memory task relative to patients with bipolar disorder. The disorders were further distinguished by differences in PFC activation. The results demonstrate that these disorders can distinguished at a group level using non-invasive neuroimaging.

Prefrontal gyral folding and its cognitive correlates in bipolar disorder and schizophrenia

Objective:u2002 We sought to address whether dorsal or ventral prefrontal gyrification is abnormal in bipolar disorder and to determine its diagnostic specificity and cognitive associations.

Association of white matter integrity with genetic variation in an exonic DISC1 SNP

The Disrupted-in-Schizophrenia-1 (DISC1) gene was first identified at the breakpoint of a translocation between chromosomes 1 and 11 that co-segregated with a broad psychiatric phenotype in a large Scottish family,1, 2 and subsequent association studies have shown that common genetic variants in DISC1 convey susceptibility to schizophrenia, bipolar disorder and other psychiatric disorders.3 DISC1 is involved in several neurodevelopmental processes, including the development of white matter,4, 5, 6 and white matter abnormalities are well-established in schizophrenia and bipolar disorder7 and have a high genetic correlation with susceptibility to both disorders.8, 9 Here, we report an association between a common missense variant in DISC1, rs821616 (Ser704Cys), previously associated with schizophrenia,3 and white matter integrity as measured by diffusion tensor-magnetic resonance imaging.

Cortical Thickness in Individuals at High Familial Risk of Mood Disorders as They Develop Major Depressive Disorder

BACKGROUNDnFrontal and temporal cortical thickness abnormalities have been observed in mood disorders. However, it is unknown whether cortical thickness abnormalities reflect early adverse effects of genetic and environmental risk factors predisposing to mood disorders or emerge at illness onset.nnnMETHODSnMagnetic resonance imaging was conducted at baseline and after a 2-year follow-up interval in 111 initially unaffected young adults at high familial risk of mood disorders and 93 healthy control subjects (HC). During the follow-up period, 20 high-risk subjects developed major depressive disorder (HR-MDD), with the remainder remaining well (HR-well). Cortical surface reconstruction was applied to measure cortical thickness of frontal and temporal regions of interest. Mixed-effects models were used to investigate differences and longitudinal changes in cortical thickness.nnnRESULTSnReduced cortical thickness in the right parahippocampal and fusiform gyrus across both time points was found in both high-risk groups. HR-MDD also had thinner parahippocampi than HR-well individuals. Over time, HR-well and HC individuals had progressive thickness reductions in the left inferior frontal and precentral gyrus, which were greater in HR-well subjects. HR-MDD showed left inferior frontal gyrus thickening relative to HR-well subjects and left precentral gyrus thickening relative to HR-well and HC individuals.nnnCONCLUSIONSnReduced right parahippocampal and fusiform gyrus thickness are familial trait markers for vulnerability to mood disorders. Increased risk for mood disorders is associated with progressive cortical thinning in the left inferior frontal and precentral gyri in subjects who remain well. In contrast, onset of depression is associated with increasing left inferior frontal and precentral thickness.