Limbic and paralimbic respiratory modulation: From inhibition to enhancement

Objective Increased understanding of the role of cortical structures in respiratory control may help the understanding of seizure-induced respiratory dysfunction that leads to sudden unexpected death in epilepsy (SUDEP). The aim of this study was to characterize respiratory responses to electrical stimulation (ES), including inhibition and enhancement of respiration. Methods We prospectively recruited 19 consecutive patients with intractable epilepsy undergoing stereotactic electroencephalography (EEG) evaluation from June 2015 to June 2018. Inclusion criteria were patients >= 18 years in whom ES was indicated for clinical mapping of ictal onset or eloquent cortex as part of the presurgical evaluation. ES was carried out at 50 Hz, 0.2 msec, and 1-10 mA current intensity. Common brain regions sampled across all patients were amygdala (AMY), hippocampus (HG), anterior cingulate gyrus (CING), orbitofrontal cortex (OrbF), temporal neocortex (TNC), temporal pole (TP), and entorhinal cortex (ERC). Seven hundred fifty-five stimulations were conducted. Quantitative analysis of breathing signal, that is, changes in breathing rate (BR), depth (TV), and minute ventilation (MV), was carried out during ES using the BreathMetrics breathing waveform analysis toolbox. Electrocardiography, arterial oxygen saturation, end-tidal and transcutaneous carbon dioxide, nasal airflow, and abdominal and thoracic plethysmography were monitored continuously during stimulations. Results Electrical stimulation of TP and CING (at lower current strengths <3 mA) increased TV and MV. At >7-10 mA, CING decreased TV and MV. On the other hand, decreased TV and MV occurred with stimulation of mesial temporal structures such as AMY and HG. Breathing changes were dependent on stimulation intensity. Lateral temporal, entorhinal, and orbitofrontal cortices did not affect breathing either way. Significance These findings suggest that breathing responses other than apnea can be induced by ES. Identification of two regions-the temporal pole and anterior cingulate gyrus-for enhancement of breathing may be important in paving the way to future development of strategies for prevention of SUDEP.