¹Semel Institute for Neuroscience and Human Behavior at UCLA, Neuromodulation Divison, Los Angeles, United States, ²Semel Institute for Neuroscience and Human Behavior at UCLA, Neuromodulation Division, Los Angeles, United States

Background: Accelerated Transcranial Magnetic Stimulation (a-TMS) provides relief of symptoms in patients with Major Depressive Disorder (MDD) as rapidly as one week. A number of individuals, however, have incomplete response to a-TMS treatment, and more than half of those who initially respond may suffer relapse within 12 weeks. This limited and/or transient benefit is believed to arise from a failure of treatment to adequately engage brain networks and induce durable changes in connectivity. It is critical to identify methods to better engage brain networks and obtain more reliable and longer-lasting antidepressant benefit.

Aims & Objectives: We aimed to examine whether brain stimulation delivered at multiple frequencies in a single treatment session (mixed frequency TMS, or mf-TMS) could lead to rapid relief of depressive symptoms, with five treatment sessions delivered in a single day. We utilized electroencephalogram data collected during TMS (TMS-EEG) to examine changes in brain functional connectivity during mixed- vs. single-frequency treatment to examine engagement of brain networks during treatment.

Method: We developed a unique mf-TMS treatment protocol in which frequencies from 3 – 20 Hz were administered in random order to patients with MDD within a single session. Subjects received an accelerated course of treatment with five sessions in a single day (amf-TMS) in an open-label study. TMS-EEG data were obtained during the stimulation procedure and changes in network connectivity following administration of mixed frequencies were compared to those recorded during stimulation at a single frequency in order to compare the effects on functional connectivity of amf-TMS and conventional a-TMS.

Results: Subjects received amf-TMS in an open-label treatment protocol. They had average improvement of 54% after one day of treatment and half entered remission. Average time to peak improvement was 11 days post treatment with benefit sustained for 24 days on average. Supplemental single days of “booster treatment” 5x1 amf-TMS, given after 14 and 28 days further enhanced and sustained antidepressant benefit over time. amf-TMS was associated with greater changes in brain function and connectivity than stimulation at a single fixed frequency of stimulation as indicated by TMS-EEG.

Discussion & Conclusions: These findings suggest that amf-TMS can lead to reduction and remission of depressive symptoms in patients with MDD after a single day of treatment. While treatment benefit was immediate for more than half of subjects, peak improvement commonly occurred 1-2 weeks after conclusion of the one-day treatment course. TMS-EEG analyses showed broader functional changes with amf-TMS than with single fixed frequency approaches, suggesting differential brain network engagement. The positive findings support the importance of controlled trials to examine efficacy of amf-TMS for treatment of MDD.