Stimulation-induced respiratory enhancement in corticothalamic regions

Objective: We aimed to identify corticothalamic areas and electrical stimulation paradigms that optimally enhance breathing. Methods: Twenty-nine patients with medically intractable epilepsy were prospectively recruited in an epilepsy monitoring unit while undergoing stereoelectroencephalographic evaluation. Direct electrical stimulation in cortical and thalamic regions was carried out using low (<1 Hz) and high (≥10 Hz) frequencies, and low (<5 mA) and high (≥5 mA) current intensities, with pulse width of.1 ms. Electrocardiography, arterial oxygen saturation (SpO₂), end-tidal carbon dioxide (ETCO₂), oronasal airflow, and abdominal and thoracic plethysmography were monitored continuously during stimulations. Airflow signal was used to estimate breathing rate, tidal volume, and minute ventilation (MV) changes during stimulation, compared to baseline. Results: Electrical stimulation increased MV in the amygdala, anterior cingulate, anterior insula, temporal pole, and thalamus, with an average increase in MV of 20.8% ± 28.9% (range = 0.2%–165.6%) in 19 patients. MV changes were associated with SpO₂ and ETCO₂ changes (p <.001). Effects on respiration were parameter and site dependent. Within amygdala, low-frequency stimulation of the medial region produced 78.49% greater MV change (p <.001) compared to high-frequency stimulation. Longer stimulation produced greater MV changes (an increase of 4.47% in MV for every additional 10 s, p =.04). Significance: Stimulation of amygdala, anterior cingulate gyrus, anterior insula, temporal pole, and thalamus, using certain stimulation paradigms, enhances respiration. Among tested paradigms, low-frequency, low-intensity, long-duration stimulation of the medial amygdala is the most effective breathing enhancement stimulation strategy. Such approaches may pave the way for the future development of neuromodulatory techniques that aid rescue from seizure-related apnea, potentially as a targeted sudden unexpected death in epilepsy prevention method.