Imaging genetic risk and episodic memory in psychosis
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Redpath2016.docx (6.167Mb)
Date
29/11/2016Author
Redpath, Holly Lee
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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.
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