Early Feasibility Study of Intracalvarial Prefrontal Cortical Stimulation in Severe Treatment-Resistant Depression

Introduction: Treatment resistant depression (TRD) is chronic and relapses despite multiple therapies. We are trialing safety and feasibility of novel functional MRI-defined targeting of prefrontal cortex neuromodulation with intracalvarial neurostimulation electrodes.

Methods: We obtained Investigational Device Exemption from the USA Food and Drug Administration for off-label use of a neurostimulator (Cirtec, Inc.), approval of the local Institutional Review Board, and registered on clinicaltrials.gov (NCT05393622). Three TRD subjects who responded and relapsed after transcranial magnetic stimulation (one female, two male) were recruited and underwent resting state MRI for localization of personalized left prefrontal targets within the executive control/ventral attention network (Hacker et al., Neuroimage, 2013). Partial-depth craniectomies over functional imaging-defined targets were drilled using neuronavigation, leaving cranial inner tables intact. Electrode arrays were secured against bone and cemented. Tunneled leads were connected to implanted rechargeable neurostimulators secured to pectoralis fascia. Postoperative CT-MRI fusions were used to select contacts for monopolar group stimulation. Current amplitude thresholds for subjective awareness (e.g. scalp paresthesias) were determined, and subsequent therapy was set at tolerable amplitudes. Montgomery-Asberg Depression Rating Scales were collected prospectively.

Results: Subject 1 underwent continuous high-frequency (100 Hz) stimulation for 12 months, exhibited up to 26% unstained improvement in depression, and was explanted after completing the study. Subject 2 self-administered once-to-twice daily 40-minute sessions of low-frequency (10 Hz) stimulation for 12 months, exhibited 83% improvement in depression, remission for >6 months despite multiple personal stressors, and opted to continue therapy indefinitely. Subject 3 self-administered twice daily 40-minute sessions of 10 Hz stimulation up to 30% improvement at early follow-up (2 months). No serious adverse events have been observed in any subject.

Conclusion : In this early feasibility study of intracalvarial prefrontal cortical stimulation in severe TRD, surgery and neurostimulation with either continuous or pulsed therapy were found to be potentially safe and effective in the first three subjects.