Increased entrainment and decreased excitability predict efficacious treatment of closed-loop phase-locked rTMS for treatment-resistant depression

Abstract

Transcranial magnetic stimulation (TMS) is an FDA-approved therapy for major depressive disorder (MDD), specifically for patients who have treatment-resistant depression (TRD). However, TMS produces response or remission in about 50% of patients but is ineffective for the other 50%. Limits on efficacy may be due to individual patient variability, but to date, there are no good biomarkers or measures of target engagement. In addition, TMS efficacy is typically not assessed until a six-week treatment ends, precluding the evaluation of intermediate improvements during the treatment duration. Here, we report on results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient’s individual electroencephalographic (EEG) prefrontal alpha oscillation informed by functional magnetic resonance imaging (fMRI). We find that, in responders, synchronized delivery of rTMS produces two systematic changes in brain dynamics. The first change is a decrease in global cortical excitability, and the second is an increase in the phase entrainment of cortical dynamics. These two effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly tracking of these biomarkers allows for efficacy prediction and potential of dynamic adjustments through a treatment course, improving the overall response rates.

Circular Clustering With Polar Coordinate Reconstruction

“…In a previous clinical study, we measured the inter-trial phase coherence (ITPC) of the quasi-alpha oscillation (6-13Hz) from participants' EEG signals [9,22,38]. In this study, we hypothesized that stronger and more precise intertrial coherence would be a biomarker of the efficacy of a neurostimulation therapeutic.…”

“…Although there are some circular clustering tools, they either only emphasize a polar angle difference (ignore the amplitude) or are designed with loss of generality -i.e., they are designed to work on datasets that obey specific assumptions [2,3,14]. Due to the absence of suitable tools, certain studies may resort to sub-optimal approaches [20] or concentrate exclusively on the angle difference, disregarding the radius aspect [21,22].…”