Restoration of breathing after opioid overdose and spinal cord injury using temporal interference stimulation

摘要

a Schematic of wire placement targeting C3 to activate the phrenic motor pool (green column). Stimulation was delivered via a pair of wires on each side of the neck. One wire per side was inserted into the neck musculature with intent to target the ventral and dorsal aspect of the spinal column near C3. The left electrode pair (blue) was stimulated with current-1 (I1) and frequency-1 (f1), and the right pair (pink) was stimulated with current-2 (I2) and frequency-2 (f2). b Stimulation paradigm. f1 = 5000 Hz (blue), f2 = 5001 Hz (pink), produces a TI field with a modulation envelope or beat frequency of 1 Hz (purple), which produced a respiratory rate of 60 breaths per minute. c TI stimulation causes robust diaphragm EMG activation in phase with the TI beat frequency (shown in green). TI-induced stimulation (black triangles) was able to activate the diaphragm well above levels seen during the spontaneously breathing baseline period (white triangles). d Temporal interference (TI) stimulation results in robust phasic activation of the diaphragm in n = 3/3 animals, while control high frequency (HF), and low frequency (LF) waveforms do not activate the diaphragm (Fisher’s exact test, diaphragm: p = 0.0119, intercostal: p = 0.083, bicep: p = 0.083). e Representative data from a single animal showing right hemi-diaphragm activity and respiratory airflow during spontaneous breathing (baseline, left panel), cessation of diaphragm inspiratory EMG activity following opioid overdose (apnea, middle-left panel), restoration of EMG activity and respiratory airflow via TI stimulation (middle-right panel), and resumption of spontaneous EMG activity and respiratory airflow lasting 30 min beyond the TI stimulation period (right panel). Respiratory airflow at baseline occurs in phase with spontaneous diaphragm EMG bursts. Intravenous fentanyl stopped respiratory airflow (remaining oscillations reflect cardiac pressures). TI rescue activated the left diaphragm in phase with the TI beat frequency (illustrated by the green trace). In this example, TI stimulation activated the left diaphragm well above baseline values but did not activate the right diaphragm. Left diaphragm activation was sufficient to sustain life until opioid-induced respiratory depression was no longer present. Scale bar units: stimulation (mA), diaphragm (mV), and respiratory flow (ml/s).