EEG phase-amplitude coupling during adolescent development: a neurobiological marker for cognition, psychological distress, and mental wellbeing

Dashiell Sacks

doi:10.25907/00758

The aim of this thesis was to investigate resting-state phase-amplitude coupling (PAC), a type of cross-frequency coupling between the phase of slower oscillatory activity and the amplitude of faster oscillatory activity in the brain, as a neurobiological marker (biomarker) for mental health and cognition during adolescence. Adolescence is recognised as a critical period for mental health in which young people undergo rapid biological, psychological, social, and emotional development. As a result, adolescents are at an increased risk of developing discrete mental health disorders and frequently present with subthreshold, non-specific symptoms that can be associated with significant, ongoing socio-occupational impairment. Delineating biomarkers of developing psychopathology is crucial to improving early identification and treatment – a key strategy for reducing the burden of mental ill-health. PAC is considered a fundamental neurological process that facilitates synchronisation between local and global networks in the brain, as well as connecting and integrating activity in different frequency bands. The amplitude of high frequency activity is believed to reflect activity in local neuron populations, while the phase of low-frequency oscillations regulates the excitability of neuron ensembles. Thus, low frequency neural activity regulates information exchange between brain regions by modulating the amplitude of high frequency oscillations. PAC occurs hierarchically throughout the cortex, between any slower phase-generating frequency and any faster amplitude-generating frequency. The relationship between interregional, resting-state PAC measured using EEG and measures of cognition, psychological distress, and wellbeing during adolescence is investigated in this thesis using data from the Longitudinal Adolescent Brain Study (LABS) at the Thompson Institute, UniSC. The LABS is an ongoing five-year multimodal, community-based, longitudinal cohort study acquiring neuroimaging data in conjunction with cognitive and psychological factors known to influence or reflect mental health. This thesis begins with a literature review in which current evidence for the potential utility of PAC as a biomarker for mental health is discussed. This first paper (Paper 1) provides a summary of early research that established PAC as an underlying mechanism in various cognitive processes, including working and long-term memory, attention, language, and fluid intelligence. From here, recent literature that suggests abnormalities in PAC may be associated with mental disorder and that PAC may have utility in treatment as it can be directly targeted with neurostimulation, is discussed. Crucially, evidence that PAC likely has both measurable, state-based and stable components, despite early research focusing on cognitive, task-based research, and thus the importance of investigating resting-state PAC as a biomarker is highlighted. The first study (Paper 2) in this thesis investigated associations between interregional (posterior-anterior cortex), resting-state PAC and cognition and psychological distress in N = 77 12-year-old LABS participants cross-sectionally. Firstly, while left theta-beta PAC showed a moderate positive correlation (r = .529, p<.01), right theta-gamma PAC showed a weak positive correlation (r = .283, p<.05) with psychological distress. In terms of cognition, moderate correlations were observed between: (i) increased left theta-beta PAC and increased psychomotor speed (r = -.367, p<.05); (ii) increased left alpha-beta PAC and decreased attention (r = .355, p<.01); and (iii) increased left alpha-beta PAC and decreased verbal learning and memory (r = -.352, p<.01). Whereas weak associations were observed for: (i) increased left alpha-beta PAC and decreased executive functioning scores (r = .284, p<.05); and (ii) increased left alpha-gamma PAC and increased attention (r = -.272, p<.05). The second study (Paper 3) builds on Paper 2 with a follow up investigation between theta-beta PAC and mental health. This study used generalised estimating equations (GEE) to investigate longitudinal associations between interregional (posterior-anterior cortex), resting-state theta-beta PAC and psychological distress, as well as psychological wellbeing in N=99 LABS participants (aged 12-15-years). Wellbeing was included in this study as an important, distinct facet of mental health. Whereas traditionally, research has focussed on psychopathology, assuming prevention and early intervention will lead to improved mental health and wellbeing, only around a quarter of the genetic, environmental, and biological factors that define psychopathology and wellbeing are shared. In the right hemisphere there was a significant relationship, whereby increased psychological distress was associated with decreased theta-beta PAC and psychological distress increased with increased age. In the left hemisphere there was a significant relationship whereby decreased wellbeing was associated with decreased theta-beta PAC and wellbeing scores decreased with increased age. The third and final study (Paper 4) builds on Papers 2 and 3 by investigating the relationship between interregional, resting-state theta-beta PAC and cognition longitudinally in N = 79 12-15-year-old LABS participants using GEE. Consistent with Paper 2, theta-beta PAC was associated with faster psychomotor speed in the longitudinal analysis. Increased theta-beta PAC MI was also associated with improved attention and working memory (1-back) scores, longitudinally. In the right hemisphere, there was a relationship between increased theta-beta PAC and increased attention and executive functioning scores. For working memory, verbal learning and memory, psychomotor speed, and attention and working memory there were further associations involving the phase-providing and amplitude-providing frequency for PAC and performance. This thesis provides novel evidence for PAC as a potential biomarker for adolescent mental health. Together, the studies in this thesis demonstrate that resting-state, interregional phase-amplitude coupling is associated with facets of cognition, psychological distress, and wellbeing during early adolescence. This is important as cognition and mental health are closely intertwined; consistent cognitive deficits are present across mental disorders in youth and relate directly to functioning and illness trajectory. Despite this, these patterns were observed at a population level (general population of early adolescents) with some variations in hemispheric asymmetry and directionality across studies. This trend is consistent with other neurobiological literature, in which effects across populations are observed, but results often vary between studies and biomarkers with utility at the individual level are elusive. Furthermore, there are some limitations with current PAC measures susceptible to the recording of spurious PAC. In spite of this, PAC is a promising biomarker that can be measured accessibly with EEG and has direct treatment applications using neurostimulation. This thesis highlights the potential for PAC as a biomarker for adolescent mental health and cognition and the importance of further PAC research in the future.

EEG phase-amplitude coupling during adolescent development: a neurobiological marker for cognition, psychological distress, and mental wellbeing

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