Intermittent theta burst stimulation with synchronised transcranial alternating current stimulation leads to enhanced frontal theta oscillations and a positive shift in emotional bias.

Repetitive transcranial magnetic stimulation (rTMS), delivered to left dorsolateral prefrontal cortex, is an FDA-approved, and NICE-recommended, neuromodulation therapy for major depressive disorder (MDD). However, there is considerable inter-individual variability in rate and extent of clinical response, leading to a focus on approaches for optimising its effectiveness. We present findings from a non-patient study evaluating an approach that combines an efficient type of rTMS-"intermittent theta burst stimulation" (iTBS)-with a second neuromodulation technique-"transcranial alternating current stimulation" (tACS). tACS is delivered in synchrony with the iTBS with the intent of optimising the brain state during stimulation. In four separate sessions, we delivered 3 minutes of iTBS+tACS, iTBS+sham, sham+tACS, or double sham. We measured changes from pre- to post-stimulation in brain theta (4-8 Hz) oscillatory activity using electroencephalography, and we measured emotional bias post-stimulation using a well-studied emotion identification task. Theta activity has previously shown relationships with response to rTMS, and emotional bias has been proposed as a marker of potential antidepressant efficacy. We found that frontal theta power was enhanced following the dual therapy, building up over the 15-minute post-stimulation period to exceed that following either stimulation technique alone or double sham. Emotional bias, measured 20 minutes post-stimulation, was also significantly more positive following dual therapy. These findings indicate that tACS-synchronised iTBS (tsiTBS) holds promise as an augmentation approach for rTMS, which awaits validation in multi-session patient studies.