The functional impact of CACNA1C and ANK3 risk genes for bipolar disorder on brain regional activation during emotional and cognitive tasks in healthy individuals, BD patients and their unaffected first-degree relatives

摘要

Bipolar Disorder (BD) is associated with increased familial risk and alterations in the function of large neural networks. There have been several studies that have examined the neural underpinnings of BD. Of particular relevance to this thesis are functional magnetic resonance imaging (fMRI) studies that have examined the neural correlates of affect and working memory processing in BD.The first aim of my thesis was to examine the consistency and relative specificity of affectrelated networks in BD. Using quantitative meta-analytic techniques I examined the neural correlates of facial affect processing in BD compared to healthy individuals and patients with Major Depressive Disorder (MDD) and schizophrenia (SZ). Emotional facial stimuli elicited increased activation in BD patients within the parahippocampus/amygdala, anterior cingulate cortex (ACC) and thalamus compared to all other groups. Decreased activation of the lateral ventral prefrontal cortex (VPFC) was found only when BD patients wherecompared to healthy individuals. Compared to BD patients, those with MDD showed greater activation in the dorsal ACC while those with SZ showed hyperactivation in posterior associative visual cortices.The second aim of this thesis was to define the influence of key risk conferring singlenucleotide polymorphisms (SNPs) on the neural underpinnings of BD. To this purpose I focused on the CACNA1C (rs1006737) and ANK3 (rs10994336, rs9804190) which have the best supported genome-wide association evidence in BD. I analysed fMRI data from 41 BD patients, 25 unaffected first-degree relatives (RELs) and 46 healthy unrelated individuals (HI) while they were performing working memory (N-back) and facial emotion labelling tasks.In the N-back task, HI carriers of the ANK3 rs10994336 risk-allele showed reduced activation in temporal regions while carriers of the ANK3 rs9804190-risk-allele showed inefficient overactivation in prefrontal regions. In BD patients and RELs, risk-alleles at either loci were associated with hyperactivation in the ventral ACC. Additionally, rs9804190 risk-allele carriers with BD evidenced hyperactivation within the posterior cingulate cortex.In the facial emotion labelling task, for the ANK3 rs9804190 a significant group by genotype interaction was noted in the VPFC. The presence of the rs9804190 risk-allele was associated with reduced VPFC activation in BD patients and decreased activation in the RELs and HI. The ANK3 rs10994336 and CACNA1C rs1006737 risk-alleles were associated with increased activation in the inferior occipital and fusiform gyrus and the amygdala in all participants, regardless of group. A significant group by genotype interaction was again noted in the VPFC. The presence of the risk-alleles was associated with inefficient VPFC overactivation in HI and RELs but VPFC hypoactivation in BD patients.