UC San Diego

Major depressive disorder (MDD) is a heterogeneous and complex disorder with asubstantial proportion of individuals failing to respond to first-line therapies. This treatment resistance can lead to years of ineffective interventions that incur significant personal and societal burden. Due to these high rates of resistance, there has been growing interest in tailoring treatments to individual patient characteristics to improve clinical outcomes. Transcranial magnetic stimulation (TMS) is one therapeutic approach that is rapidly evolving and has the potential to address difficult-to-treat symptoms of depression through personalization. This dissertation investigates the clinical utility and mechanistic underpinnings of personalizing TMS stimulation to patient neurophysiology. In the first study, we conducted a clinical trial comparing frequency individualized TMS to standard TMS and sham with the aim of determining whether tailoring the stimulation frequencies can enhance antidepressant response. While there was an effect over time with patients reporting reductions in symptoms, there was no significant effect of treatment group or interaction between time and treatment, indicating that the three treatments did not differ. However, this trial was slightly underpowered and cannot conclusively rule out the possibility of addressing treatment resistant depression through individualized therapies. To better understand the neural mechanisms associated with treatment response, subsequent chapters used electroencephalography (EEG) to explore neurophysiological predictors and changes following TMS therapy for depression. In Chapter two, using data from the trial described above, we modeled the relationship between changes in clinical outcomes and neurophysiology, identifying potential signatures of neuroplasticity. In the third chapter, an analysis of a large secondary dataset of MDD patients undergoing TMS therapy identified potential markers of treatment response. Finally, the fourth chapter examined whether stratifying clinical scale questions into depression symptom subgroups revealed distinct neurophysiological profiles of pre-treatment clinical severity, offering further insights into how heterogeneity may obscure treatment efficacy. Together, this work highlights both the promise and current limitations of personalizing neuromodulation therapy for depression. While findings from the clinical trial were inconclusive, exploratory analyses suggest that features derived from EEG may inform individualized treatment strategies. These findings underscore the importance of mechanistic and personalized approaches in advancing precision psychiatry.