AbstractSubstance use disorder and mental illness are the leading cause of years of life lived with disability worldwide; depressive and anxiety disorders account for about half of total disability-adjusted life years and alcohol and illicit drug (including opioid) use disorder account for about ten percent each. However, it is generally recognised that clinical practice in psychiatry has not fundamentally changed in over half a century. Better understanding of illness mechanisms is required. Consequently, the primary aim of the work described in this thesis was to investigate brain mechanisms of harmful use of alcohol (binge drinking) and opioid dependency.
This work comprised: i) a meta-analysis of functional magnetic resonance imaging (fMRI) studies on substance use disorder and ii) an instrumental learning task with fMRI and spectroscopy which was used to study habitual binge alcohol drinkers using a Research Domain Criteria (RDoC) framework testing allostasis theory hypotheses. In
addition, two neuropsychological and structural MRI studies of opioid dependent patients were done, focusing on behavioural measures of iii) impulsivity (Cambridge Gambling Task; CGT) and iv) compulsivity (Intra/Extra-Dimensional Task; IED).
Compared with healthy controls the meta-analysis concluded that substance users showed blunted dopamine-linked reward prediction error signals in various regions including the bilateral striatum. As hypothesised, binge drinkers showed abnormally decreased striatal dopamine-linked brain activation and blunted reward value encoding in the amygdala-hippocampal complex. Higher alcohol use was associated with increased blunting of the reward value signal, and with aversive events, binge drinkers showed abnormal amygdala-hippocampal complex activation. Opioid dependent subjects showed increased impulsivity and impaired strategic planning and had widespread grey matter reductions in the orbitomedial prefrontal cortex and striatum. Compulsivity was inversely correlated with impulsivity and a higher compulsivity/impulsivity ratio was associated with significantly decreased white matter probability in regions adjacent to the striatum in the abstinent group, compared to the other opioid dependent groups.
In conclusion, the meta-analysis findings help delineate the pathophysiological underpinnings of maladaptive decision-making in substance use. Predictions of functional brain abnormalities in binge alcohol drinkers supported hypotheses generated from Koob’s allostasis theory derived from extensive studies on animals. The study on impulsivity in patients receiving methadone maintenance therapy suggests a benefit in reduction of methadone dose, and the finding of a negative correlation between impulsivity and compulsivity measures supports Holander and Wong’s impulsive-compulsive diathesis model. Further work to integrate invasive studies on animals with non-invasive studies on humans (e.g. using fMRI) may facilitate understanding of psychiatric illness mechanisms.
|Date of Award
|Indivior & Anonymous Trust
|Douglas Steele (Supervisor) & Alex Baldacchino (Supervisor)