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 FDA-cleared treatment for depression, yet how cortical stimulation influences single neurons in deep brain circuits remains unknown. Using intracranial microelectrode recordings in four neurosurgical patients, we resolved single-neuron spikes as early as 8 ms from 185 single neurons after single-pulse left dlPFC TMS. TMS elicited time-locked firing responses in 46% of neurons across deep cortical and subcortical structures bilaterally. TMS facilitated putative interneuron spiking in striato-thalamic regions from [~]8 ms, peaking at [~]80-100 ms, and lasting to [~]1000 ms, while suppressing putative pyramidal cell spiking with a delayed and slower time course. Trial-by-trial single-neuron modulations were positively correlated with cortico-striato-thalamic network activity and anti-correlated with limbic network activity. These findings reveal that dlPFC TMS facilitates inhibitory firing in executive control networks while suppressing limbic excitatory drive, providing a cellular mechanism for how cortical stimulation modulates distributed brain networks.