The Neurocognitive Dynamics Underlying Loss of Control in Alcohol Misuse and Addiction

“That’s the problem with drinking, I thought, as I poured myself a drink. If something bad happens you drink in an attempt to forget; if something good happens you drink in order to celebrate; and if nothing happens you drink to make something happen.” Charles Bukowski, Women Diverse motivations may underlie our alcohol consumption, yet what are the driving factors that sustain drinking behaviour even when confronted with unfavourable repercussions? Furthermore, how do we discern the boundary between moderate and problematic drinking, and why is this distinction often unnoticed until unhealthy patterns emerge? Alcohol consumption which detrimentally impacts one’s health, interpersonal dynamics, or ability to work- termed alcohol misuse- can, in its extremity, evolve into an addiction. This advanced stage is characterised by an overwhelming urge to seek and consume alcohol, a diminished ability to regulate intake, and persistent drinking despite recognition of the associated adverse consequences. Repeated, yet unsuccessful, attempts to abstain can lead to significant and potentially catastrophic functional impairment (United States Office of the Surgeon General, 2016). Alcohol misuse and addiction present as complex pathologies, broadly conceptualised as dynamic dysregulation of neural circuitry, subject to modulation by socio-environmental and genetic determinants (Koob & Volkow, 2016). Given the ubiquity of alcohol use and societal impact, a paramount task in cognitive neuroscience is the elucidation of the neuroadaptive variations distinguishing controlled and uncontrolled alcohol consumption, with the aim to discern clinical biomarkers pertinent to risk prediction and therapeutic prognosis (Heilig et al., 2010). This investigation gains urgency in light of the observed surge in alcohol consumption and associated morbidity and mortality during the COVID-19 pandemic and the concomitant isolation period (Office for National Statistics, 2020)- a trend which, alarmingly, has persisted post-pandemic (Angus et al., 2022). The prevailing adherence to traditional nosologies, which classify disorders based on the description and enumeration of heterogenous symptoms within arbitrary clinical boundaries- often overlapping with other disorders, is notably devoid of a biological basis (Morris & Cuthbert, 2012). While clinically invaluable, this approach has obfuscated a mechanistic understanding of aetiopathogenesis of addiction. Alternatively, emergent dimensional psychiatric frameworks underscore the conceptual application of endophenotypes (Gottesman & Gould, 2003)- or “intermediate phenotypes” that express tractable and causally relevant neurocognitive signatures (Kendler & Neale, 2010)- transcending traditional psychiatric categorisation, which may elucidate the aetiology and risk factors intrinsic not only to alcohol-related disorders but to a broader spectrum of psychopathologies (Robbins et al., 2012). Ultimately, these endophenotypes may present potential targets for neuromodulation interventions, via pharmacological or neurostimulation methods (Yee et al., 2015). Central to this thesis is a detailed examination of two intimately connected endophenotypes emblematic of the “loss of control” inherent to the addiction cycle (Robbins et al., 2012): impulsivity (i.e., “actions which are poorly conceived, prematurely expressed, unduly risky or inappropriate to the situation and that often result in undesirable consequences” [Daruna & Barnes, 1993]) and compulsivity (i.e., “actions which persist inappropriate to the situation, have no obvious relationship to the overall goal and which often result in undesirable consequences” [Dalley et al., 2011]). These constructs are delineated by unique motoric, cognitive, and neurobiological profiles (Voon & Dalley, 2016), and are theorised to play cardinal roles at different stages in the evolution of addiction (Koob & Le Moal, 1997). While incipient stages are typified by impulsivity, in which alcohol use is driven by immediate gratification, later stages are dominated by compulsivity, facilitated by neuroadaptations from escalated alcohol intake and ensuing psycho-emotional and physiological dependency (Koob & Le Moal, 2008; Everitt & Robbins, 2005). Neuro-functionally, this cycle reflects a shift from systems involved in reward anticipation to those involved in habit formation and stress (Koob & Volkow, 2010)- anchored by perturbations of fronto-striatal brain circuitry (Goldstein & Volkow, 2002)- culminating in observable impairments in incentive salience, negative emotionality, and executive function domains (Kwako et al., 2016; Voon et al., 2020). Critically, these neurocognitive deficits extend beyond alcohol addiction, indicating a shared pathophysiological basis integral to a range of disorders, including various substance and behavioural addictions (Grant & Chamberlain, 2014), and other disorder types, such as obsessive-compulsive disorder (OCD) (Voon et al., 2015), irrespective of their apparent phenotypic differences. Despite the extensive corpus of existing neuropsychiatric research delving into these areas, this thesis uniquely prioritises the pivotal transitional phase from impulsive to compulsive alcohol use and its associated biomarkers across both clinical and non-clinical cohorts (Everitt & Robbins, 2005). Accordingly, this thesis acknowledges the multifaceted natures of impulsivity (e.g., motor, decisional, trait) and compulsivity (e.g., attentional set-shifting vs. habitual learning) endophenotypes (Voon & Dalley, 2016), drawing from foundational research conducted using rodent models (Dalley et al., 2011). This understanding has been extrapolated to human subjects through a series of experiments tied to distinct stages of the addiction trajectory- and its corresponding neurofunctional impairments- leveraging three interrelated methodologies: Cognitive Task Development: <br>Fundamental to this research is the development, optimisation, and validation of novel cognitive paradigms designed to quantify cognitive control in relation to impulsivity and compulsivity dimensions and their respective subtypes. The aim is dual-pronged: to refine neuropsychological evaluation of these constructs in humans, and to elucidate their interactions with other cognitive-emotional domains intrinsic to addiction psychopathology. Within the domain of impulsivity, emphasis is placed on waiting impulsivity, a motor impulsivity subtype characterised by a lack of internal restraint toward anticipated reward (Chapter 1). This feature is further operationalised in the context of alcohol cue reactivity, or the measurement of the conditioned response elicited by alcohol-related stimuli (Chapter 2). Concurrently, specific facets of compulsivity are delineated, chiefly habit formation mechanisms that signify an automatic response pattern bypassing deliberative decision-making processes. These mechanisms, tied to both reward/approach- and threat/avoidance-oriented dynamics, were operationalised for online empirical assessment (Chapter 3). The interplay among waiting impulsivity, previous exposure to alcohol, and habit is examined- emphasising a central aim of this thesis. Neurostimulation Intervention: Repetitive Transcranial Magnetic Stimulation (rTMS): <br>Neuromodulatory techniques, such as repetitive transcranial magnetic stimulation (rTMS), are employed in this research to target salient brain regions and networks to identify and validate biomarkers associated with operationalised components of impulsivity and compulsivity, thereby elucidating their mechanistic contributions within the addiction spectrum. Insights from this approach not only augments our understanding of the neural circuitry underpinning alcohol addiction and related disorders, but also may inform neural substrates for therapeutic intervention. Using this methodology, attention is again accorded to motoric subtypes of impulsivity, specifically differentiating neural mechanisms governing the capacity to withhold an action (i.e., waiting impulsivity) versus those dictating the cessation of an already initiated action (i.e., response inhibition). To this end, two distinct rTMS protocols are employed, both tailored to specific neuromodulatory objectives. First, a neural region previously identified by functional magnetic resonance imaging (fMRI) is targeted utilising an inhibitory TMS protocol, termed continuous theta burst stimulation (cTBS), with the objective to discern a causal nexus between the activity of this region and waiting impulsivity, positioning it as a potential neuromodulation target for addiction disorders (Chapter 1). Second, a cortical paired associative stimulation (cPAS) protocol is applied to interrogate cortical excitability within the hyperdirect fronto-striatal response inhibition network in AUD patients to identify a potential neural mechanism giving rise to the observed cognitive deficit in this population, with implications for clinical course and treatment outcomes (Chapter 4). Epidemiological Analysis: <br>Envisioned on a broader scale, this research further aimed to assess global health trends by analysing consumption patterns of alcohol and specific internet-based modalities- namely online gaming and pornography viewing- pre- to intra-COVID-19 to gauge the pandemic’s acute impact on addiction trajectories. This entailed the development and international distribution of an online survey tracking not only changes in quantity and frequency of consumption, but probes deeper into usage severity, highlighting potential amplification of addictive behaviours within the pandemic’s milieu. Furthermore, this instrument assesses the effects of psychiatric symptoms- primarily within the spheres of impulsivity and negative emotionality- and specific contextual stressors- such as occupational displacement and isolation- on these behavioural patterns (Chapter 5).

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Sallie, Samantha

Advisor dc:contributor.advisor

• Voon, Valerie

• Alcohol Misuse and Addiction
• Compulsivity
• Habit
• Impulsivity
• Transcranial Magnetic Stimulation

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9a5914b2-e9c2-4bfd-88d7-c9735686c321/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0003-0161-3995

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/368499