Intraspinal microstimulation and diaphragm activation after cervical spinal cord injury

Abstract

Intraspinal microstimulation (ISMS) using implanted electrodes can evoke locomotor movements after spinal cord injury (SCI) but has not been explored in the context of respiratory motor output. An advantage over epidural and direct muscle stimulation is the potential of ISMS to selectively stimulate components of the spinal respiratory network. The present study tested the hypothesis that medullary respiratory activity could be used to trigger midcervical ISMS and diaphragm motor unit activation in rats with cervical SCI. Studies were conducted after acute (hours) and subacute (5-21 days) C hemisection (C2Hx) injury in adult rats. Inspiratory bursting in the genioglossus (tongue) muscle was used to trigger a 250-ms train stimulus (100 Hz, 100-200 μA) to the ventral C spinal cord, targeting the phrenic motor nucleus. After both acute and subacute injury, genioglossus EMG activity effectively triggered ISMS and activated diaphragm motor units during the inspiratory phase. The ISMS paradigm also evoked short-term potentiation of spontaneous inspiratory activity in the previously paralyzed hemidiaphragm (i.e., bursting persisting beyond the stimulus period) in ∼70% of the C2Hx animals. We conclude that medullary inspiratory output can be used to trigger cervical ISMS and diaphragm activity after SCI. Further refinement of this method may enable "closed-loop-like" ISMS approaches to sustain ventilation after severe SCI. We examined the feasibility of using intraspinal microstimulation (ISMS) of the cervical spinal cord to evoke diaphragm activity ipsilateral to acute and subacute hemisection of the upper cervical spinal cord of the rat. This proof-of-concept study demonstrated the efficacy of diaphragm activation, using an upper airway respiratory EMG signal to trigger ISMS at the level of the ipsilesional phrenic nucleus during acute and advanced postinjury intervals.

Enhancing neural activity to drive respiratory plasticity following cervical spinal cord injury

“…The primary therapeutic goal of neural stimulation post-SCI is to activate otherwise silenced/paralyzed circuitry and muscles. When applied under the right conditions the beneficial effects can also persist after termination of treatment (Mercier et al, 2016; Posluszny et al, 2014). Such therapies, summarized in Figure 3, are designed to stimulate neural activity via electrical stimuli applied to the periphery (functional electrical stimulation (A)), spinal cord (epidural stimulation (B) or intraspinal microstimulation (C), and transcranial magnetic stimulation (D)) or supraspinal regions (transcranial magnetic stimulation and deep brain stimulation), or via physical stimuli (locomotor training (F) and respiratory rehabilitation (E)).…”

“…In recent years, intraspinal microstimulation (see Figure 3C) has been shown to effectively promote some recovery of both lower (Bamford and Mushahwar, 2011; Bamford et al, 2011; Bamford et al, 2010) and upper (Kasten et al, 2013; Moritz et al, 2007; Sunshine et al, 2013) extremities post-SCI. Intraspinal microstimulation has now also been used to activate respiratory circuitry caudal to SCI (Mercier et al, 2016). Stimulating the C4 ventral grey matter via a single tungsten microwire (100Hz), Mercier et al (2016) demonstrated restoration of activity to the paralyzed hemidiaphragm acutely following C2Hx, that persisted even once stimulation ceased.…”

“…Intraspinal microstimulation has now also been used to activate respiratory circuitry caudal to SCI (Mercier et al, 2016). Stimulating the C4 ventral grey matter via a single tungsten microwire (100Hz), Mercier et al (2016) demonstrated restoration of activity to the paralyzed hemidiaphragm acutely following C2Hx, that persisted even once stimulation ceased. The authors also employed a closed-loop paradigm, using recorded genioglossus activity as the trigger for intraspinal microstimulation, enhancing the physiological relevance of this strategy further.…”

Role of Propriospinal Neurons in Control of Respiratory Muscles and Recovery of Breathing Following Injury

“…High-frequency spinal cord stimulation has also successfully been used to restore cough in patients with SCI (DiMarco et al, 2014). Direct intraspinal stimulation has also been used in rats to activate phrenic motor neurons for breathing, likely via propriospinal neurons (Mercier et al, 2017). However, the neural substrates upon which the spinal cord stimulation acts are not currently clear.…”

Restoring ventilatory control using an adaptive bioelectronic system

“…Previous studies have suggested technology that can be used to synchronize artificial ventilation with intrinsic respiratory drive or to replicate its function. These methods include development of a controllable stimulator with an update frequency higher than the stimulation frequency and a real-time processing controller (Castelli et al, 2017), implementation of a bio-inspired spiking neural network model that follows intrinsic respiratory rate (Zbrzeski et al, 2016), predictive algorithms using body temperature and heart rate (Kimura et al, 1992), and breath-triggering through the use of genioglossus muscle activity (Mercier et al, 2017). However, these approaches have not yet been sufficiently developed or investigated.…”