The neural network basis of cognitive impairment in bipolar disorder
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Background: Despite well-documented cognitive deficits that contribute to poorer quality of life in bipolar disorder (BD) and evidence of altered topology and connectivity within neural networks, little work has been done to assess the potential impact of brain network alterations on cognitive functioning in BD. Neuroimaging investigations have provided evidence of possible neuroanatomical and functional underpinnings of these impairments, however they have generally focused on few cognitive domains and in a localized manner on select brain areas or connections. Measures of network connectivity can uncover disrupted integration between distinct neural systems unlike anatomically focal measurements and therefore may better capture the neuroanatomical basis of emergent functions such as cognitive performance. Within this thesis, I examine the multivariate patterns of network connectivity that underlie cognitive impairment in BD using both anatomical and functional neural network representations. I approach this from the framework of shared and differential cognition-brain network relationships in BD compared to psychiatrically healthy individuals, to provide insights into how network dysconnectivity in BD may manifest to impact the support of complex cognitive processing. Methods: Cognitive performance was measured using the Weschler Adult Intelligence Scale, the Cambridge Automated Neuropsychological Test Battery (CANTAB) and the Reading the Mind in the Eyes test. Two types of neural network representations were constructed; (1) anatomical networks, by mapping constrained spherical deconvolution reconstructed white matter between 86 cortical/subcortical bilateral brain regions delineated in the individual’s own coordinate space (Manuscript 1) and (2) functional networks, by correlating the average resting-state blood oxygen level-dependent time series between every pair of the 86 regions (Manuscript 2 & 3). In the first manuscript using anatomical brain networks, intelligence and executive function were investigated as distributed functions using measures of global, rich-club and interhemispheric connectivity while memory and social cognition were examined in relation to anatomical subnetwork connectivity. In the second manuscript using functional brain networks, intelligence, executive function and episodic memory were investigated in relation to measures of global topology and intelligence in relation to functional subnetwork connectivity, with additional exploratory analyses of variance in connectivity patterns underlying executive function, memory, social cognition and a general factor of response time, all commonly impaired in BD. Finally in the third manuscript, I examined alterations in resting-state modular organization in BD compared to controls and examined whether fronto-parietal dysconnectivity relates to intelligence and executive function, default-mode dysconnectivity to memory and social cognition, and connector hub connectivity to performance across these distinct cognitive tasks in BD. Results: Individuals with BD performed significantly poorer on tests of intelligence, executive function, episodic and short-term memory and social cognition but not spatial recognition memory compared to psychiatrically healthy controls. Lower executive functioning related to higher global clustering coefficient in bipolar participants, and lower IQ performance may present with a differential relationship between global and interhemispheric efficiency in BD relative to controls. Spatial recognition memory accuracy and response times were associated with basal ganglia and thalamus interconnectivity and connectivity within extended anatomical subnetworks in all participants. Across all subjects, anti-synchronous activity between frontal, parietal, temporal, occipital, cingulate, insula and amygdala regions related to improved spatial and episodic memory performance. Faster response times in controls related to synchronous activity between frontal, parietal, cingulate, temporal and occipital regions; similar response times in BD related to anti-synchronous activity between regions of this subnetwork. No anatomical or resting-state subnetworks related to intelligence, executive function, short-term memory or social cognition performance in the overall sample or in a manner that would explain deficits in these facets in BD. Connectivity within commonly observed functional modules and coupling between modules was preserved in BD compared to controls. A direct relationship was found between interconnectivity of the frontal module and executive function errors but not intelligence. Interconnectivity of the default-mode was not associated with memory or social cognitive performance and the distribution of connector hub connectivity across modules did not relate to intelligence, executive function, memory or social cognition. Neither intramodular nor connector hub connectivity explained deficits in these domains in BD relative to the control group. Conclusions: I demonstrate selective influence of anatomical and functional subnetwork patterns of connectivity in underlying cognitive performance generally. This includes a direct link between increased static interconnectivity of frontal and parieto-temporal modules and poorer executive function performance, which may indicate less flexible dynamics between fronto-parietal regions and other systems that are crucial for successful completion of complex executive function tasks. In BD, I observe cognitive impairment across multiple domains and demonstrate that alterations in the global topology of anatomical networks, and not alterations in rich-club connectivity previously reported, contribute to both intelligence and executive function deficits. Disrupted functional connectivity in fronto-limbic, fronto-temporal and default-mode systems appears to specifically impact response timing and not performance or errors on the same tasks. Further, preserved modular structure in BD that may be characteristic of mood symptom remission does not appear to contribute to cognitive deficits extant in BD. Together this work is suggestive of a prominent role of global anatomical network topology in cognitive deficits that rely heavily on global integration, namely intelligence and executive function. This does not localise to specific patterns of rich-club, connector hub or subnetwork connectivity, while more discrete or statistically subtle effects may be more relevant for memory and social cognition impairments, all of which to contribute to poorer quality of life in BD. Future examination of dynamically reconfiguring communication patterns across the brain can be used to build on the present findings and comprehensively describe how cognitive deficits are reflected in and possibly mediated by altered network dynamics in BD.
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