2025 Theses Doctoral

Using Brain Rhythms for Guiding Closed-Loop Non-invasive Neurostimulation in the Treatment of Depression

Sun, Xiaoxiao

Major depressive disorder (MDD) remains a leading cause of disability worldwide, with many patients showing inadequate response to conventional repetitive transcranial magnetic stimulation (rTMS). Since the U.S. Food and Drug Administration (FDA) approved TMS in 2008 as a noninvasive neurostimulation therapy for depression, substantial efforts have focused on improving response rates, increasing durability, and reducing the number of sessions and stimulation dose required. However, the heterogeneity of brain organization and individual differences among patients continue to pose significant challenges. To date, the precise mechanisms underlying rTMS, the optimal combination of stimulation parameters, and reliable biomarkers of target engagement remain elusive. Therefore, personalizing stimulation protocols to account for neuroanatomical and neurophysiological variability is essential to improving treatment efficacy.

This thesis develops and validates a multimodal, closed-loop EEG-synchronized rTMS framework that integrates fMRI-informed spatial targeting with real-time phase estimation of prefrontal alpha oscillations to optimize stimulation timing. Using simultaneous fMRI-EEG-TMS (fET) recordings, we demonstrate that TMS delivery synchronized to individual alpha phase modulates activity in the anterior cingulate cortex (ACC) and networks supporting cognitive control and emotion regulation.

In a randomized, double-blind, active comparator-controlled clinical trial, we show that personalized, phase-synchronized rTMS produces more predictable clinical outcomes in treatment-resistant depression compared to unsynchronized stimulation. We identify two EEG-derived neurophysiological biomarkers -- cortical excitability (Global Mean Field Power) and phase entrainment (weighted Inter-Trial Phase Coherence) -- that differentiate synchronized from unsynchronized stimulation and predict clinical improvement, with responders exhibiting progressive decreases in excitability and increases in entrainment over treatment. These biomarkers inform a personalized stimulation framework that would be used to adaptively optimizes parameters in real time.

Finally, in an accelerated protocol combining EEG-synchronized rTMS with cognitive behavioral therapy in patients with treatment-resistant depression and recent suicide attempts, all participants achieved clinical response and remission, sustained at one month. Biomarker tracking confirmed consistent trajectories toward increased entrainment and decreased excitability, and the preferred stimulation phase for the cognitive flexibility and emotion regulation networks closely aligned with that of the ACC, reinforcing the robustness of our targeting approach.

This work provides mechanistic and translational evidence that brain-state-informed, closed-loop rTMS can bridge superficial stimulation sites with deeper therapeutic targets, enabling precision neuromodulation for depression and potentially other neuropsychiatric disorders.