A pharmacological investigation of cholinergic modulation of emotion-related brain connectivity and cognition in bipolar disorder

Introduction: In bipolar disorder (BD), alterations in functional and effective connectivity and involvement of an impaired muscarinic-cholinergic system contribute to substantial emotional and cognitive disturbances which significantly negatively impact quality of life. Compared with controls, functional neural network connectivity alterations are correlated with compromised executive function, social cognition, and memory ability in BD, while effective connectivity alterations between prefrontal and limbic regions may underlie emotion processing deficits in the disorder. Based upon emotion-related task-based fMRI and muscarinic-cholinergic positron emission tomography research, the muscarinic-cholinergic system is also implicated in emotional and cognitive processing, is altered in BD, and may further impact the emotional and cognitive disturbances experienced across BD states. However, there is little research concerning how intrinsic, resting-state network and prefrontal cingulate effective connectivity alterations, together with underlying muscarinic- cholinergic dysfunction, underpins the poorer cognitive and emotional processing experienced in BD. Yet, this information will elucidate both the intrinsic, neuroanatomical composition and mechanistic neurochemical basis of these widespread symptoms, which may inform novel, more efficient treatment options for those with BD. Therefore, in the current thesis, we aim to use resting-state functional magnetic resonance imaging methods, effective connectivity techniques, and muscarinic-cholinergic drug challenges to investigate how connectivity differences and modulated muscarinic-cholinergic transmission may underlie the persistent emotional and cognitive deficits in BD. Methods: The manuscripts herein comprise data from individuals with euthymic or depressed BD and psychiatrically healthy controls (HC). In the first manuscript (Chapter 3), subjects with euthymic BD and HC underwent structural and resting-state fMRI scans and cognitive testing. Independent component analysis of resting-state timeseries extracted signal components organized into the following intrinsic networks: occipital, pericentral, midcingulo-insular, and dorsal, lateral, and medial frontoparietal networks. Intra- and inter- network connectivity and related relationships with cognitive performance was assessed between groups through the use of a generalized linear model. In the second manuscript (Chapter 4), individuals who are euthymic and have a diagnosis of BD or are HC underwent fMRI scanning during an emotion inhibition task at baseline and during intravenous physostigmine or placebo challenge. Effective connectivity between the anterior cingulate, posterior cingulate, and middle frontal gyrus was investigated at baseline and during the drug-challenge using bilinear dynamic causal modeling and Bayesian statistics to elucidate the optimal model which explains the observed neuroimaging data during emotion inhibition of the negative valence and underlying involvement of the muscarinic cholinergic system in BD compared with HC. In manuscript three (Chapter 5), muscarinic-cholinergic antagonism (through scopolamine, which has an opposing mechanism of action to physostigmine) and related cognitive impairments in depressed BD were investigated using the administration of intravenous scopolamine or placebo and the Cambridge Neuropsychological Test Automated Battery (CANTAB) to measure cognition. Cognitive testing for emotion recognition, executive function, memory, and attention was conducted three times: first at baseline following placebo run-in, then at an acute timepoint 40-50 minutes following scopolamine or placebo (between 2 and 7 days following baseline), and thirdly, approximately one week following the third of three doses to assess the long-term effects of scopolamine on cognition. Acute and long-term effects of scopolamine on cognitive accuracy and latency were examined using linear regression, accounting for baseline performance. Results: In manuscript one (Chapter 3), we observed altered resting-state functional connectivity within the lateral frontoparietal network, related to executive functioning, altered pericentral, lateral and dorsal frontoparietal, and occipital network connectivity, correlated with social cognition, and altered midcingulo-insular, lateral and dorsal frontoparietal, and occipital network features related with memory performance in BD compared with HC. In manuscript two (Chapter 4), in effective connectivity, we also observed that a modulation on the connection from the posterior cingulate to the middle frontal gyrus best explained the emotion inhibition of negatively valenced stimuli. After the administration of physostigmine, analyses revealed an increase in modulatory connection strength, at this connection, in HC that was absent in BD. Furthermore, positive and negative connection strength values indicated increased and decreased effective connectivity in HC and BD, respectively. In manuscript three (Chapter 5), there were no significant effects of scopolamine on emotion recognition accuracy during averaged anger and disgust trials at acute or long-term timepoints. Additionally, at acute and long-term timepoints, there were no significant effects of scopolamine on accuracy or latency during emotion recognition (total score and six emotions separately), visual memory, sustained attention, or executive function. Discussion: The findings in manuscript one (Chapter 3) suggest that intrinsic, network connectivity disruptions contribute to persistent cognitive features in BD. Cognitive impairment may be further underpinned by altered effective connectivity between prefrontal and cingulate cortex regions, and the results of manuscript two (Chapter 4) suggest a compromised muscarinic-cholinergic system in BD, with diminished influence of the posterior cingulate cortex on the middle frontal gyrus during emotion inhibition of the negative valence. In the BOLD fMRI study which formed the basis for the effective connectivity analyses (Chapter 4), physostigmine, an agent that increases cholinergic transmission, improved accuracy in BD on emotion inhibition task performance (Nabulsi et al., 2022). However, a novel cholinergic drug, scopolamine (used in Chapter 5), acts in the opposite direction to physostigmine, and has been proposed to provide antidepressant relief in BD depression. Therefore, as a muscarinic acetylcholine receptor antagonist which decreases cholinergic transmission, it was crucial to investigate whether scopolamine may impair cognition in a depressed BD sample, where cognitive deficits already exist. However, our results in manuscript three (Chapter 5) suggest that, at the hypothesized therapeutic dose of intravenous scopolamine (4 μg/kg), emotion recognition, memory, attention and executive function are not further impaired at acute or long-term timepoints. If intravenous scopolamine is utilized as an antidepressant in the future, it may not exacerbate the cognitive deficits associated with bipolar depression. Overall, cognitive impairment is a core feature of BD across states, is sustained during clinical remission, and greatly impacts quality of life of impacted individuals. This is depicted through alterations in resting-state functional connectivity in intrinsic, cognitive-related networks and differential, cholinergic-based effective connectivity patterns between prefrontal and cingulate regions. Current treatments for BD depression remain suboptimal; taken together, the three manuscripts observe how functional and effective connectivity differences and related muscarinic-cholinergic alterations underpin cognitive impairment in BD, which may inform the development of targeted, effective treatments (such as scopolamine) which preserve or enhance cognitive function with the aim of improving the quality of life of individuals with bipolar disorder.

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University of Galway

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University of Galway Theses (PhD Theses)