Cortical Inhibition and Working Memory in Schizophrenia: A TMS-EEG Study (2017)

Schizophrenia is a debilitating neuropsychiatric disorder characterised by a diverse range of behavioural, perceptual, mood and cognitive symptoms. The presentation of schizophrenia is heterogeneous across individuals, making it a difficult disorder to treat effectively. Given this clinical heterogeneity the development of treatments which target specific symptomatology would be beneficial, but first requires a comprehensive understanding of the pathophysiology involved. Development of treatments for cognitive symptoms is particularly important, as conventional interventions are only effective in targeting behavioural and perceptual symptoms while cognitive symptoms are largely treatment resistant despite having a detrimental effect on patient outcomes. Working memory (WM) impairment in schizophrenia is particularly pervasive and impactful. WM is crucial for the successful execution of a number of higher-level cognitive processes and therefore deficits have a significant impact on patient outcomes. Dysfunctional or reduced gamma-aminobutyric acid (GABA) inhibitory neurotransmission, or cortical inhibition (CI), in the dorsolateral prefrontal cortex (DLPFC) has been suggested as a potential mechanism through which WM impairment in schizophrenia may manifest. Therefore, the goal of the research presented in this thesis was to better understand the nature of the CI deficits in schizophrenia and their role in WM function.<br> <br> I first investigated the utility of using paired-pulse transcranial magnetic stimulation (ppTMS) in combination with electroencephalography (EEG) to measure various forms of cortical functions, including fast (ion gated receptor mediated) and slow (ligand gated receptor mediated) GABA neurotransmission, in the DLPFC. Paired-pulse TMS involves administering two TMS pulses at various interstimulus intervals. Neuronal activity following ppTMS is then compared to that following a single TMS pulse in order to assess inhibition or facilitation.” These techniques were then used to investigate the nature of CI deficits in the DLPFC in schizophrenia and the impact of such deficits on WM function. Patients with schizophrenia demonstrated abnormal CI in this region. Specifically, my results replicate previous findings of impairments in slow acting inhibitory function. A different pattern of slow acting GABAergic impairments was observed in patients with schizophrenia than those with Major Depressive Disorder (MDD), suggesting elements of CI dysfunction observed in schizophrenia may have a degree of diagnostic specificity. As the aim of thesis focused on WM abnormalities in schizophrenia, WM was assessed in schizophrenia patients and controls only. Slow acting GABAergic function in the DLPFC was associated with WM performance overall and in patients with schizophrenia alone.<br> <br> The findings of this thesis provide a valuable contribution to the understanding of CI in schizophrenia and the importance of this function in WM performance. Our findings indicated that prefrontal inhibition should be considered as both a potential endophenotype for schizophrenia and a treatment target for the WM deficits observed in this disorder. As the paradigm implemented to assess fast-acting GABAergic function did not result in inhibition, this thesis also highlights the need for further research aimed at optimizing TMS-EEG techniques in order to assess these inhibitory processes. It is hoped that this knowledge will lead to the development of treatments that target the underlying pathophysiology of the WM impairments seen in schizophrenia and ultimately improved patient outcomes.