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Direct electrical stimulation (DES) has become a standard treatment for a multitude of neurological diseases including Parkinson’s disease and epilepsy. Yet, we only have a rudimentary understanding of the mechanistic effects of DES on single cortical neurons in the human brain. It has been postulated that DES engages excitatory cells followed by engagement of inhibitory neurons. This is supported by in vitro and ex vivo research in different animal models but has not been verified through in vivo investigations in humans.

Using microelectrodes during intraoperative neurosurgical resection, we applied DES to examine single unit activity and local circuit responses in human lateral prefrontal and temporal cortices (N=11). Separately, in the Epilepsy Monitoring Unit, we examined neural responses from microelectrodes implanted semi-chronically (< 29 days) in patients (N=4). We examined excitatory or inhibitory cell-type dynamics from extracellular recordings and the relationship between stimulation intensity, distance, and the E-then-I sequence response.

We found stimulation would induce overall activation of neuronal populations (p<0.001, Wilcoxon rank-sum test; N=9). A subset of neurons had an early activation response that lasted ~ 50 ms (0.034±0.036 sec). This brief response was also found in units recorded from semi-chronic microelectrodes when the stimulus reached 4 mA (n=10 trials). We found other populations of cells which were inhibited for a longer duration (2 sec, n=18 units). Moving the stimulating site induced different subsets of units to respond, with some locations inducing shorter duration (0.024±0.058 sec) above threshold responses while some locations induced longer responses (0.17±0.50 sec). 

These results support a sequential activation of excitatory then inhibitory activity during DES. Through this deeper understanding, we can design more focal, targeted, and informed stimulation approaches targeting specific neuronal cell types. This strategy may lead to more precise and tailored therapeutic applications of electrical stimulation for an array of neurological disorders.