Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury

Abstract

Recovery from serious neurological injury requires substantial rewiring of neural circuits. Precisely-timed electrical stimulation could be used to restore corrective feedback mechanisms and promote adaptive plasticity after neurological insult, such as spinal cord injury (SCI) or stroke. This study provides the first evidence that closed-loop vagus nerve stimulation (CLV) based on the synaptic eligibility trace leads to dramatic recovery from the most common forms of SCI. The addition of CLV to rehabilitation promoted substantially more recovery of forelimb function compared to rehabilitation alone following chronic unilateral or bilateral cervical SCI in a rat model. Triggering stimulation on the most successful movements is critical to maximize recovery. CLV enhances recovery by strengthening synaptic connectivity from remaining motor networks to the grasping muscles in the forelimb. The benefits of CLV persist long after the end of stimulation because connectivity in critical neural circuits has been restored.

Vagus nerve stimulation as a tool for enhancing extinction in exposure-based therapies

“…Repeated pairing of VNS with a sensory stimulus or specific motor movement remodels cortical maps (Engineer et al 2011; Porter et al 2012; Shetake et al 2012). Furthermore, VNS facilitates plasticity-driven rehabilitation following stroke (Khodaparast et al 2013; Hays et al 2014; Khodaparast et al 2016; Meyers et al 2018), spinal cord injury (Ganzer et al 2018), and traumatic brain injury (Pruitt et al 2016). VNS also modulates neural plasticity in the hippocampus.…”

“…A growing body of evidence suggests that VNS paired with sensory and motor events reorganizes cortical maps and restores impaired function (Engineer et al 2011; Porter et al 2012; Khodaparast et al 2013; Hays et al 2014; Pruitt et al 2016; Ganzer et al 2018; Meyers et al 2018). However, one important difference between these studies and the ones describing evidence that VNS facilitates memory extinction is that the duration of pairings is generally 0.5 second in the cortical plasticity studies, in contrast with the 30-second stimulation used in the extinction studies (Clark et al 1995; Clark et al 1998; Pena et al 2013; Pena et al 2014; Noble et al 2017a).…”

“…However, one important difference between these studies and the ones describing evidence that VNS facilitates memory extinction is that the duration of pairings is generally 0.5 second in the cortical plasticity studies, in contrast with the 30-second stimulation used in the extinction studies (Clark et al 1995; Clark et al 1998; Pena et al 2013; Pena et al 2014; Noble et al 2017a). In addition to the inverted-U function for stimulation intensity, recent evidence indicates that the timing of VNS administration is critical for maximizing plasticity and recovery following spinal cord injury (Ganzer et al 2018). This suggests that rather than increasing training duration or stimulation intensity, precisely timed VNS-paired extinction may be critical for optimizing therapeutic outcome.…”

“…It has been safely used in tens of thousands of patients and it is well-tolerated (Englot et al 2011; Englot et al 2012). Current pharmacological tools cannot provide the temporal control that VNS offers, and trains of stimulation as short as 0.5 second can drive pairing-specific plasticity in rats (Engineer et al 2011; Khodaparast et al 2013; Borland et al 2016; Ganzer et al 2018; Meyers et al 2018). Pharmacological tools that both augment the effects of exposure therapy and reduce anxiety are lacking.…”

Neurorestorative interventions involving bioelectronic implants after spinal cord injury

“…VNS is thought to lead to the release of monoamines within the cerebral cortex, which may promote plasticity of neural circuits and enhance motor learning (Hulsey et al 2016). Based on these encouraging results, this strategy was tested in rodent models of unilateral cervical contusion (C6) (Ganzer et al 2018). Rats were trained to retrieve food reward with their forepaw.…”