Over the last three decades, there has been substantial progress in the development of neurocircuitry models of the brain. These developments have paved the way for hypothesis-driven interventional approaches directly targeting specific brain circuits, offering new possibilities for effective interventions and therapeutic strategies. The modification of brain functioning derived from these devices or surgically based neuromodulations, in turn, has refined and deepened our understanding of the neural and cognitive mechanisms central to the pathophysiology of psychiatric illnesses. This thesis aims to employ this circular structure of knowledge to explore the therapeutic outcomes and underlying mechanisms of two clinically well-established approaches to neuromodulation, namely, the invasive anterior capsulotomy procedure and the non-invasive transcranial magnetic stimulation (TMS) for the management of two common psychiatric disorders that can be clinically intractable: obsessive-compulsive disorder (OCD) and major depressive disorder (MDD).

In CHAPTER 1: GENERAL INTRODUCTION, I reviewed the evolution of the understanding regarding the pathophysiology of OCD and MDD, which has led to the emergence and refinement of neurocircuitry models of psychiatric disorders. I included a brief outline of the current therapeutic options available for OCD/MDD, with special highlights on the evolution of modern technologies that have been translated into invasive or non-invasive neuromodulation techniques for managing severe and refractory cases of psychiatric illnesses. This introductory chapter also reviewed how circuit-based disease models can be considered and later examined for both ablative and stimulation-based therapies. It outlined the motivation for the multimodal investigation of therapeutic mechanism underlying the OCD anterior capsulotomy procedure detailed in Chapter 2 and 3, and the MDD TMS protocol detailed in Chapter 4 and 5.

In CHAPTER 2: ANTERIOR CAPSULOTOMY FOR OBSESSIVE-COMPULSIVE DISORDER: A COGNITIVE AND NEUROANATOMICAL STUDY, and CHAPTER 3: NEURAL CORRELATES OF ANTERIOR CAPSULOTOMY FOR OBSESSIVE COMPULSIVE DISORDER: NEGATIVE AFFECT PROCESSING, I asked which prefrontal regions and underlying cognitive processes might be implicated in the effects of capsulotomy. I utilized both functional MRI tasks and cognitive tasks selected from the Cambridge Neuropsychological Automated Test Battery (CANTAB) to assess OCD-relevant cognitive mechanisms known to map across prefrontal regions connected to the tracts targeted by capsulotomy, with specific focus on the functional changes at key nodes or connections within the frontostriatal circuitry. Task results showed lower brain activity during the aversive learning phase (anticipation or feedback of aversive events) and during the extinction phase in the nucleus accumbens (NAc), the rostral anterior cingulate cortex (rACC), and the inferior frontal gyrus (IFG) in the post-capsulotomy patients, with attenuated functional connectivity between seed NAc and rACC during aversive versus neutral anticipation. These findings contribute to the literature on the clinical efficacy of anterior capsulotomy, suggesting a neurosurgical effect in downregulating the functional communication along the frontostriatal pathways to be underlying the symptomatic improvement, and highlighted an overlap in neurocircuit-based optimal targeting between deep brain stimulation (DBS) and capsulotomy in OCD neuromodulation.

In CHAPTER 4: A DUAL-SITE ACCELERATED rTMS PROTOCOL FOR TREATMENT RESISTANT DEPRESSION, and CHAPTER 5: NEUROIMAGING MECHANISM OF RESPONSE TO DUAL-SITE rTMS, I focused on searching for more effective treatment protocols of TMS for the management of MDD. Considering the cost and time it usually takes for conventional neuronavigation-based TMS protocols to take effect in severe suicidal MDD cases, I tested a novel dual-site accelerated TMS protocol using an EEG 10-20 system-guided approach in a double-blind randomized controlled trial of 20 sessions over five consecutive days comparing (1) the dual-site stimulation group (inhibitory continuous theta burst stimulation of right lateral orbitofrontal cortex (OFC) followed sequentially by excitatory 20 Hz rTMS of left dorsolateral prefrontal cortex (dlPFC)); (2) the active single-site comparator group (sham right lateral OFC followed by excitatory left dlPFC) and (3) the sham TMS group (sham for both targets). The results showed more clinical responders (a reduction of at least 50% from baseline in Hamilton Rating Scale of Depression, HRSD-24) by the end of all sessions in the Dual (47.8%) relative to Single (18.2%) and Sham group (4.3%), and a decreased lateral OFC-subcallosal cingulate (SCC) functional connectivity post-treatment in the Dual group. I also found that a greater lateral OFC-thalamic connectivity decrease was associated with better response, with the capacity to predict treatment outcome. Thus, this dual target accelerated TMS protocol showed a rapid onset of antidepressant efficacy, suggesting a non-reward lateral OFC cortico-striatal-thalamic circuit to be implicated in tracking and predicting depression improvement following TMS treatment. This finding also has implications for novel designs of TMS protocols in a real-world clinical setting when neuronavigation is not available.

Taken together, these results provided further evidence that the functional restoration of neurocircuit dysfunctions of psychiatric conditions could be achieved via direct modulation of circuit components with either invasive procedures (CHAPTER 2 and 3: anterior capsulotomy) or non-invasive devices (CHAPTER 4 and 5: TMS). Functional imaging studies pre- and post brain modulation provided further support for the existing hypotheses of OCD/MDD circuit based pathophysiology, with room and potential for refinements in precision targeting. Future investigations in neurocircuitry dysfunctions may have the potential to enhance clinical management with novel OCD/MDD treatment targets or nodes that can account for inter individual variability and cater to a wider range of individuals with varied clinical presentations.