Cell-type specific responses to single-pulse electrical stimulation of the human brain

Neuromodulation techniques, such as deep brain stimulation, intraoperative brain mapping, and responsive neurostimulation, use electricity to alter brain activity. Despite daily clinical use in thousands of patients, it remains fundamentally unknown how human neurons respond to intracranial stimulation. We address this question at a basic level by characterizing neuronal cell-type specific firing rate responses to single pulses of electrical stimulation of the human brain. We carried out broadly distributed stimulation in 30 patients undergoing neuromonitoring for epilepsy while recording from isolated neurons on microwires implanted into the medial temporal and frontal lobes. Out of a total of 228 recorded units, 16.2% (N = 191) were classified as interneurons and 83.8% (N = 37) were classified as principal cells, using a threshold clustering method, based on intrinsic waveshape characteristics. To see how stimulation affected neuronal activation for each cell type, we calculated firing rate change between a pre-stimulation and post-stimulation window and observed that 174 units were significantly modulated with the vast majority (91%) showing firing rate suppression. We then characterized stimulation-evoked changes in firing rate to gain insight into cell type-specific responses. Additionally, in a subset of the units, we observed that firing rate responses were modulated by stimulation distance, where local stimulation (within approximately 40 mm) could evoke instantaneous firing, whereas distant stimulation reliably suppressed firing in the same units. Finally, we analyzed a subset of units within the seizure onset zone, which exhibited unique waveform features and responses to stimulation. This study bridges a gap in the neuromodulation field by examining the single-unit firing rate response to direct electrical stimulation of the human brain and analyzing cell-type specific firing rate responses. We show that low frequency, single-pulse stimulation broadly elicits firing rate suppression, but parameters, such as distance from the unit, can have diverse effects on firing rate responses. This work informs the neuronal basis of CCEP generation and therefore has implications for clinical mapping and informs novel active probing strategies for precision diagnosis and neuromodulation of seizure pathophysiology in surgical cases. Moreover, this research has general implications for understanding neuromodulation via direct brain stimulation. Highlights- Putative principal cell waveform shapes are characterized by longer trough-to-peak and full-width half max durations (s) compared to interneurons. - Monopolar stimulation @ 3 mA generally has a widespread suppressive effect on neuronal firing, lasting approximately 1.5 s. - Principal cells show greater suppression amplitude and longer suppression durations than interneurons. - Stimulation within [~] 40 mm is capable of evoking instantaneous firing, despite general suppression from stimulation at greater distances.