Imaging genetic risk and episodic memory in psychosis

Abstract

A key feature of many psychiatric disorders, including schizophrenia and bipolar disorder, are pervasive deficits in several domains of cognition. Episodic memory is one of the most consistently observed cognitive deficits exhibited by patients with schizophrenia, and can be a predictor of overall functional outcome. Several neuroimaging studies have assessed episodic memory in psychosis, however the neural mechanisms underlying this deficit remain somewhat unclear. Studying the impact of rare genetic variants of large effect can offer a powerful method to further our understanding of the pathophysiology of psychiatric disorders. One such gene, DISC1 (Disrupted in Schizophrenia 1) is a putative susceptibility gene for a spectrum of major psychiatric disorders such as schizophrenia, bipolar disorder and major depression. DISC1 was originally identified in a large Scottish pedigree, in which it is disrupted by a balanced translocation between chromosomes 1 and 11, and this translocation confers a dramatically increased risk of major psychiatric disorder. However, the impact of this translocation on brain imaging measures is largely unknown. The rarity of this variation results in small group numbers for analysis, however rare variants are likely to have large neural effects. This thesis offers a unique investigation into the effects of the t(1;11) translocation, by examining fMRI of members of the original Scottish pedigree. Four groups of participants; 19 family members (8 with the translocation, 11 without), 30 patients with schizophrenia, 11 patients with bipolar disorder and 40 healthy controls underwent a functional MRI episodic memory encoding and recognition paradigm. Data processing and statistical analyses were performed using the standard approach in SPM8. The primary aim of this work was to investigate functional activation during episodic memory in individuals with and without the translocation, to examine the impact of the t(1;11) translocation. Analyses were also performed to examine differences between controls and patients with schizophrenia and bipolar disorder, to compare the effects of the translocation to the effects of a having a psychotic illness. During encoding of neutral scenes, translocation carriers showed greater activation of the left posterior cingulate, right fusiform gyrus and right superior frontal gyrus compared to non-carriers. During recognition, carriers showed greater activation in the right fusiform gyrus, left posterior cerebellum, right superior temporal gyrus, left anterior cingulate, right ventrolateral prefrontal cortex (VLPFC) and right dorsolateral prefrontal cortex (DLPFC). For both contrasts, no regions were found to be more active in family members without the translocation when compared to carriers. There were no significant differences between the groups in terms of their performance or reaction time on encoding and recognition conditions. Compared to healthy controls, patients with schizophrenia demonstrated increased activation during encoding in the inferior parietal lobe bilaterally, and decreased activation during recognition in a region encompassing the caudate nucleus and anterior cingulate cortex. Patients with bipolar disorder showed no difference in activation compared to controls during encoding, and increased activation during recognition in a region encompassing the caudate and anterior cingulate, extending to the inferior frontal lobe and insula. There was also a significant difference between patients with schizophrenia and bipolar disorder during recognition, with patients with bipolar disorder again showing increased activation in the caudate extending to the anterior cingulate cortex. These findings support previous research suggesting overactivation of fronto-limbic and striatal structures including the anterior cingulate and caudate in bipolar disorder, with a relative underactivation in schizophrenia. This thesis presents the first evidence of functional alterations during episodic memory in association with the translocation, primarily in fronto-temporal regions. Brain regions that were over activated in translocation carriers have been shown to be involved in memory encoding and recognition, and are known to be affected in patients with major psychiatric disorders and unaffected relatives. Family members with the translocation demonstrated a more similar pattern of activation during recognition to patients with bipolar disorder compared to schizophrenia, perhaps due to the fact that most diagnoses in the carriers were of an affective disorder rather than a schizophrenia-related psychosis. Based on these findings it can be argued that the translocation has an influence on brain activations in areas associated with episodic memory processes. These findings begin to provide a better understanding of the neural effects of the t(1;11) translocation, and highlight the significance of rare but biologically informative genetic variants in understanding psychosis.