Transcranial magnetic stimulation to the dorsolateral prefrontal cortex modulates single-neuron activity in humans

Transcranial magnetic stimulation (TMS) to the dorsolateral prefrontal cortex (dlPFC) is an established treatment for depression, yet the fundamental question of how cortical stimulation influences single neurons in deep brain circuits critical for mood regulation remains unanswered. Using a rare opportunity to record from intracranial microelectrodes while TMS was delivered in four neurosurgical patients, we evaluated the responses of 185 single neurons. Artifact cleaning enabled single-neuron spikes to be resolved as early as 8 ms after stimulation. We found that single-pulse TMS to the left dlPFC elicited time-locked firing responses in 46% of neurons (26% facilitated only, 19% suppressed only, 1% both). These responses occurred within deep bilateral cortical and subcortical structures, including the putamen and thalamus. Single-pulse TMS tended to facilitate spiking in striato-thalamic putative inhibitory neurons from ~8 ms, peaking at ~80 to 100 ms, and decaying until ~600 ms. In contrast, putative excitatory neurons and limbic areas were suppressed with a slower time course lasting to ~1,000 ms. TMS-evoked potentials recorded from intracranial depth macroelectrodes to quantify network activity revealed that the modulation of responsive neurons was positively correlated with cortico-striato-thalamic network activity and anticorrelated with limbic network activity in one participant with sufficient network and unit sampling. These results suggest that dlPFC TMS recruits a high percentage of neurons spanning cortical and subcortical brain regions bilaterally. The recruitment pattern selectively involves increasing the firing rate of inhibitory neurons in executive control networks while suppressing limbic excitatory drive, providing a candidate cellular mechanism for how cortical stimulation modulates distributed brain networks.