Cognitive impairment and frontostriatal dysfunction in major depression and alcohol dependence.

A critical feature of human cognition is the ability to flexibly adapt one's thoughts and behaviours towards a current goal. The capability to select and process those mental representations which are contextually appropriate, while simultaneously suppressing responses to prepotent, yet inappropriate representations (i.e. cognitive inhibition), is fundamental to the control of basic behaviours and thoughts. Recent studies have suggested that deficits of cognitive inhibition may underlie key symptoms of a number of psychiatric disorders. This association is further supported by brain imaging studies; whereby, cognitive inhibitory processes involve the activation of frontostriatal circuitry, the same brain circuitry implicated across a number of psychiatric disorders. However, to date, the specific nature of these frontally-mediated cognitive inhibitory deficits within various psychiatric disorders is poorly understood. This thesis explores the presence of these neurocognitive inhibitory deficits across two highly prevalent and devastating psychiatric disorders: Major Depressive Disorder (MDD) and Alcohol Dependence (AD). Despite significantly different clinical symptomatology, the cognitive inhibitory processes, and the involvement of frontostriatal circuitry, are nevertheless remarkably similar across both disorders. Therefore, the current thesis aimed to (i) examine the presence of cognitive inhibitory deficits across both psychiatric populations, (ii) utilize newly developed brain stimulation techniques to assess the involvement of the disrupted frontostriatal circuitry, and (iii) discuss the potential clinical ramifications of these frontally-mediated cognitive inhibitory deficits. To examine regulatory deficits across the two disorders, three cognitive inhibitory tasks were administered: The Sustained Attention to Response Task, Emotional Stroop, and the Random Number Generation Task. Each of these tasks characterizes a distinct aspect of cognitive inhibitory function and provides a frontally-mediated measure of cognitive inhibition within depressive and alcohol dependent patients. To assess the involvement of the frontostriatal circuitry, two newly-developed transcranial magnetic stimulation (TMS) techniques were delivered across both patient groups. Deep TMS was administered to the MDD patients to explore whether stimulation of the frontal cortex and deeper cortical structures could attenuate cognitive inhibitory impairment within a MDD sample. The combined TMS and electroencephalography (TMS-EEG) technique was administered to the AD group to provide the first direct measure of altered cortical excitability within the frontal cortex of an alcohol dependent sample. The major research aims were achieved. In terms of MDD, significant cognitive inhibitory deficits were observed within the depressive population, and the frontostriatal circuitry was found to play a critical role in cognitive symptoms of depression. With regards to AD, enduring cognitive inhibitory deficits were revealed within the alcohol dependent post detoxification population, and a direct index of altered cortical inhibition within the frontal cortex of alcohol dependent patients was demonstrated for the first time. When combined, these studies provide empirical evidence of the presence of cognitive inhibitory deficits, and the involvement of the frontostriatal circuitry, across both depressive and alcohol dependent disorders. Further insight into these frontally-mediated cognitive inhibitory deficits may advance our understanding of the cognitive features of these disorders, and expand the current pathophysiological models of depression and alcohol dependence.