Local and distant cortical responses to single pulse intracranial stimulation in the human brain are differentially modulated by specific stimulation parameters

Background: Electrical neuromodulation via direct electrical stimulation (DES) is an increasingly common therapy for a wide variety of neuropsychiatric diseases. Unfortunately, therapeutic efficacy is inconsistent, likely due to our limited understanding of the relationship between the massive stimulation parameter space and brain tissue responses. Objective: To better understand how different parameters induce varied neural responses, we systematically examined single pulse-induced cortico-cortico evoked potentials (CCEP) as a function of stimulation amplitude, duration, brain region, and whether grey or white matter was stimulated. Methods: We measured voltage peak amplitudes and area under the curve (AUC) of intracranially recorded stimulation responses as a function of distance from the stimulation site, pulse width, current injected, location relative to grey and white matter, and brain region stimulated (N = 52, n = 719 stimulation sites). Results: Increasing stimulation pulse width increased responses near the stimulation location. Increasing stimulation amplitude (current) increased both evoked amplitudes and AUC nonlinearly. Locally (15 mm), white matter stimulation consistently produced larger responses than stimulation in or near grey matter. The stimulation location-response curves followed different trends for cingulate, lateral frontal, and lateral temporal cortical stimulation. Conclusion: These results demonstrate that a stronger local response may require stimulation in the grey-white boundary while stimulation in the white matter could be needed for network activation. Thus, stimulation parameters tailored for a specific anatomical-functional outcome may be key to advancing neuromodulatory therapy.