Restoration of Breathing after Opioid Overdose and Spinal Cord Injury Using Temporal Interference Stimulation

Michael D. Sunshine, Antonino M. Cassarà, Esra Neufeld, Nir Grossman, Thomas H. Mareci, Kevin J. Otto, Edward S. Boyden, and David D. Fuller, Communications Biology 2021, Volume 4, Article number 107, online 25 January 2021; doi:

Respiratory insufficiency is a leading cause of death due to drug overdose or neuromuscular disease. We hypothesized that a stimulation paradigm using temporal interference (TI) could restore breathing in such conditions. Following opioid overdose in rats, two high frequency (5000 Hz and 5001 Hz), low amplitude waveforms delivered via intramuscular wires in the neck immediately activated the diaphragm and restored ventilation in phase with waveform offset (1 Hz or 60 breaths/min). Following cervical spinal cord injury (SCI), TI stimulation via dorsally placed epidural electrodes uni- or bilaterally activated the diaphragm depending on current and electrode position. In silico modeling indicated that an interferential signal in the ventral spinal cord predicted the evoked response (left versus right diaphragm) and current-ratio-based steering. We conclude that TI stimulation can activate spinal motor neurons after SCI and prevent fatal apnea during drug overdose by restoring ventilation with minimally invasive electrodes.

The scientific and technical impact of the study can be summarized as:

  • The development of a novel approach based on TI stimulation to effect immediate resumption and control of breathing that could be of high value in emergency medicine is presented
  • In vivo and in silico data indicate that TI stimulation by means of epidurally placed electrodes allows current to be steered within the spinal cord to activate the diaphragm selectively with a high level of control
  • The results suggest a mechanism by which spinal-cord-directed TI stimulation modulates, as a function of the magnitude of the local TI modulation amplitude, the diaphragm response via activation of phrenic motor neurons
  • Computational modeling in Sim4Life can be used to numerically simulate TI stimulation to improve the understanding and optimization of targeted neurostimulation to restore lost motor, sensory, and organ function