Investigating the neurobiology of repetitive transcranial magnetic stimulation as a treatment for major depressive disorder

Abstract

Clinical depression poses a significant and growing burden on the New Zealand population and is a leading cause of disability. Resistance to currently offered treatments, both pharmacological and psychotherapeutic, is common. Repetitive transcranial magnetic stimulation (rTMS) is a treatment offered internationally demonstrating good efficacy for depression with few reported side effects. The first aim of this thesis was to investigate the effectiveness and acceptability of rTMS for treatment-resistant depression in the setting of New Zealand health care systems. A naturalistic, open-label study was used in which 44 patients with moderate to severe treatment-resistant depression were treated with a course of daily rTMS for four weeks (20 sessions). Daily sessions of rTMS were successfully administered and were effective in reducing depression symptom severity in treatment-resistant depression, with a response rate of 43%. The treatment was accessible and well-tolerated by the majority of the study participants. It was concluded that rTMS should be made available in New Zealand as a treatment option. The secondary aim of this thesis was to establish a more comprehensive understanding of the neurophysiological effects of rTMS. A combination of magnetic resonance spectroscopy (MRS), electroencephalography (EEG), simultaneous TMS and EEG, and functional magnetic resonance imaging (fMRI) were used to investigate cortical excitability and functional connectivity prior to and following a course of rTMS treatment. Clinical response to rTMS was correlated with reduced functional connectivity from baseline to post-rTMS within the salience network (SN), indicating reduced SN connectivity may be mechanistically relevant to how rTMS produces antidepressant effects. Furthermore, rTMS increased cortical levels of the excitatory neurotransmitter glutamate, increased connectivity between the SN and default mode network (DMN), and increased EEG functional connectivity in the delta, theta, alpha, and low beta frequency bands. Baseline neuroimaging characteristics were also correlated with subsequent antidepressant response, with lower functional connectivity within the DMN and EEG theta band associated with better treatment outcome. This thesis demonstrates the effectiveness and feasibility of offering rTMS as a treatment for treatment-resistant depression in New Zealand. Using a variety of neuroimaging methods, this thesis also provides evidence for an effect of rTMS on neural network connectivity which may underlie the antidepressant response to treatment.