Transcutaneous cervical vagus nerve stimulation improves sensory performance in humans: a randomized controlled crossover pilot study.

Accurate senses depend on high-fidelity encoding by sensory receptors and error-free processing in the brain. Progress has been made towards restoring damaged sensory receptors. However, methods for on-demand treatment of impaired central sensory processing are scarce. Prior invasive studies demonstrated that continuous vagus nerve stimulation (VNS) in rodents can activate the locus coeruleus-norepinephrine system to rapidly improve central sensory processing. Here, we investigated whether transcutaneous VNS improves sensory performance in humans. We conducted three sham-controlled experiments, each with 12 neurotypical adults, that measured the effects of transcutaneous VNS on metrics of auditory and visual performance, and heart rate variability (HRV). Continuous stimulation was delivered to cervical (tcVNS) or auricular (taVNS) branches of the vagus nerve while participants performed psychophysics tasks or passively viewed a display. Relative to sham stimulation, tcVNS improved auditory performance by 37% (p = 0.00052) and visual performance by 23% (p = 0.038). Participants with lower performance during sham conditions experienced larger tcVNS-evoked improvements (p = 0.0040). Lastly, tcVNS increased HRV during passive viewing, corroborating vagal engagement. No evidence for an effect of taVNS was observed. These findings validate the effectiveness of tcVNS in humans and position it as a method for on-demand interventions of impairments associated with central sensory processing dysfunction.

Clinically Relevant Levels of 4-Aminopyridine Strengthen Physiological Responses in Intact Motor Circuits in Rats, Especially After Pyramidal Tract Injury.

BACKGROUND: 4-Aminopyridine (4-AP) is a Food and Drug Administration-approved drug to improve motor function in people with multiple sclerosis. Preliminary results suggest the drug may act on intact neural circuits and not just on demyelinated ones. OBJECTIVE: To determine if 4-AP at clinically relevant levels alters the excitability of intact motor circuits. METHODS: In anesthetized rats, electrodes were placed over motor cortex and the dorsal cervical spinal cord for electrical stimulation, and electromyogram electrodes were inserted into biceps muscle to measure responses. The motor responses to brain and spinal cord stimulation were measured before and for 5 hours after 4-AP administration both in uninjured rats and rats with a cut lesion of the pyramidal tract. Blood was collected at the same time as electrophysiology to determine drug plasma concentration with a goal of 20 to 100 ng/mL. RESULTS: We first determined that a bolus infusion of 0.32 mg/kg 4-AP was optimal: it produced on average 61.5 ± 1.8 ng/mL over the 5 hours after infusion. This dose of 4-AP increased responses to spinal cord stimulation by 1.3-fold in uninjured rats and 3-fold in rats with pyramidal tract lesion. Responses to cortical stimulation also increased by 2-fold in uninjured rats and up to 4-fold in the injured. CONCLUSION: Clinically relevant levels of 4-AP strongly augment physiological responses in intact circuits, an effect that was more robust after partial injury, demonstrating its broad potential in treating central nervous system injuries.

Improvements in hand function after intensive bimanual training are not associated with corticospinal tract dysgenesis in children with unilateral cerebral palsy.

Unilateral cerebral palsy (CP) results from damage to the developing brain that occurs within the first 2 years of life. Previous studies found associations between asymmetry in the size of the corticospinal tract (CST) from the two hemispheres and severity of hand impairments in children with unilateral CP. The extent to which CST damage affects the capacity for hand function improvement is unknown. This study examines the association between an estimate of CST dysgenesis and (1) hand function and (2) the efficacy of intensive bimanual training in improving hand function. Children with unilateral CP, age 3.6-14.9 years, n = 35, received intensive bimanual training. Children engaged in bimanual functional/play activities (6 h/day, 15 days). Peduncle asymmetry, an estimate of CST dysgenesis, was measured on T1-weighted magnetic resonance imaging scans. Hand function was measured pre- and post-treatment using the assisting hand assessment (AHA) and Jebsen-Taylor test of hand function (JTTHF). AHA and JTTHF improved post-treatment (p < 0.001). Peduncle asymmetry was correlated with baseline AHA and JTTHF (p < 0.001) but not with AHA or JTTHF improvement post-training (R(2) < 0.1, p > 0.2). An estimate of CST dysgenesis is correlated with baseline hand function but is a poor predictor of training efficacy, possibly indicating a flexibility of developing motor systems to mediate recovery.

Electrical stimulation of motor cortex in the uninjured hemisphere after chronic unilateral injury promotes recovery of skilled locomotion through ipsilateral control.

Partial injury to the corticospinal tract (CST) causes sprouting of intact axons at their targets, and this sprouting correlates with functional improvement. Electrical stimulation of motor cortex augments sprouting of intact CST axons and promotes functional recovery when applied soon after injury. We hypothesized that electrical stimulation of motor cortex in the intact hemisphere after chronic lesion of the CST in the other hemisphere would restore function through ipsilateral control. To test motor skill, rats were trained and tested to walk on a horizontal ladder with irregularly spaced rungs. Eight weeks after injury, produced by pyramidal tract transection, half of the rats received forelimb motor cortex stimulation of the intact hemisphere. Rats with injury and stimulation had significantly improved forelimb control compared with rats with injury alone and achieved a level of proficiency similar to uninjured rats. To test whether recovery of forelimb function was attributable to ipsilateral control, we selectively inactivated the stimulated motor cortex using the GABA agonist muscimol. The dose of muscimol we used produces strong contralateral but no ipsilateral impairments in naive rats. In rats with injury and stimulation, but not those with injury alone, inactivation caused worsening of forelimb function; the initial deficit was reinstated. These results demonstrate that electrical stimulation can promote recovery of motor function when applied late after injury and that motor control can be exerted from the ipsilateral motor cortex. These results suggest that the uninjured motor cortex could be targeted for brain stimulation in people with large unilateral CST lesions.

Chronic electrical stimulation of the intact corticospinal system after unilateral injury restores skilled locomotor control and promotes spinal axon outgrowth.

Injury to the brain or spinal cord usually preserves some corticospinal (CS) connections. These residual circuits sprout spontaneously and in response to activity-based treatments. We hypothesized that augmenting activity in spared CS circuits would restore the skilled motor control lost after injury and augment outgrowth of CS terminations in the spinal cord. After selective injury of one half of the CS tract (CST) in the rat, we applied 10 d of electrical stimulation to the forelimb area of motor cortex of the spared half and tested motor performance for 30 d. Rats with injury and CST stimulation showed substantial improvements in skilled paw placement while walking over a horizontal ladder. By the end of the testing period, the walking errors of the previously impaired forelimb in rats with injury and stimulation returned to baseline, while the errors remained elevated in rats with injury only. Whereas the time to perform the task returned to normal in all animals, the pattern of errors returned to normal only in the stimulated group. Electrical stimulation also caused robust outgrowth of CST axon terminations in the ipsilateral spinal cord, the side of impairment, compared with rats with injury only. The outgrowth was directed to the normal gray matter territory of ipsilateral CST axon terminations. Thus, stimulation of spared CS circuits induced substantial axon outgrowth to the largely denervated side of the spinal cord and restored normal motor control in the previously impaired limbs.

Motor cortex bilateral motor representation depends on subcortical and interhemispheric interactions.

The corticospinal tract is a predominantly crossed pathway. Nevertheless, the primary motor cortex (M1) is activated bilaterally during unilateral movements and several animal studies showed that M1 has a bilateral motor representation. A better understanding of the uncrossed corticospinal system is especially important for elucidating its role in recovery of limb control after unilateral injury. We used intracortical microstimulation (ICMS) to determine the representation of contralateral and ipsilateral forelimb joints at single M1 sites in the rat. Most sites representing an ipsilateral joint corepresented the same joint contralaterally. We next determined whether ipsilateral responses evoked in one hemisphere depended on the function of M1 in the opposite hemisphere using reversible inactivation and pyramidal tract lesion. Ipsilateral responses were eliminated when the homotopic forelimb area of M1 in the opposite hemisphere was inactivated or when the pyramidal tract on the nonstimulated side was sectioned. To determine the role of transfer between M1 in each hemisphere we sectioned the corpus callosum, which produced a 33% increase in ipsilateral ICMS thresholds. Neither M1 inactivation nor callosal section changed contralateral response thresholds, indicating the absence of tonic excitatory or inhibitory drive to the opposite M1. Finally, ipsilateral responses following M1 inactivation and pyramidal tract lesion could be evoked after systemic administration of the K(+) channel blocker 4-aminopyridine, suggesting the presence of latent connections. Our findings show important interactions between the corticospinal systems from each side, especially at the spinal level. This has important implications for recruiting the ipsilateral corticospinal system after injury.

Electrical stimulation of spared corticospinal axons augments connections with ipsilateral spinal motor circuits after injury.

Activity-dependent competition shapes corticospinal (CS) axon outgrowth in the spinal cord during development. An important question in neural repair is whether activity can be used to promote outgrowth of CS axons in maturity. After injury, spared CS axons sprout and make new connections, but often not enough to restore function. We propose that electrically stimulating spared axons after injury will enhance sprouting and strengthen connections with spinal motor circuits. To study the effects of activity, we electrically stimulated CS tract axons in the medullary pyramid. To study the effects of injury, one pyramid was lesioned. We studied sparse ipsilateral CS projections of the intact pyramid as a model of the sparse connections preserved after CNS injury. We determined the capacity of CS axons to activate ipsilateral spinal motor circuits and traced their spinal projections. To understand the separate and combined contributions of injury and activity, we examined animals receiving stimulation only, injury only, and injury plus stimulation. Both stimulation and injury alone strengthened CS connectivity and increased outgrowth into the ipsilateral gray matter. Stimulation of spared axons after injury promoted outgrowth that reflected the sum of effects attributable to activity and injury alone. CS terminations were densest within the ventral motor territories of the cord, and connections in these animals were significantly stronger than after injury alone, indicating that activity augments injury-induced plasticity. We demonstrate that activity promotes plasticity in the mature CS system and that the interplay between activity and injury preferentially promotes connections with ventral spinal motor circuits.