Neural population dynamics reveals disruption of spinal circuits' responses to proprioceptive input during electrical stimulation of sensory afferents.

While neurostimulation technologies are rapidly approaching clinical applications for sensorimotor disorders, the impact of electrical stimulation on network dynamics is still unknown. Given the high degree of shared processing in neural structures, it is critical to understand if neurostimulation affects functions that are related to, but not targeted by, the intervention. Here, we approach this question by studying the effects of electrical stimulation of cutaneous afferents on unrelated processing of proprioceptive inputs. We recorded intraspinal neural activity in four monkeys while generating proprioceptive inputs from the radial nerve. We then applied continuous stimulation to the radial nerve cutaneous branch and quantified the impact of the stimulation on spinal processing of proprioceptive inputs via neural population dynamics. Proprioceptive pulses consistently produce neural trajectories that are disrupted by concurrent cutaneous stimulation. This disruption propagates to the somatosensory cortex, suggesting that electrical stimulation can perturb natural information processing across the neural axis.

Supraspinal control of motoneurons after paralysis enabled by spinal cord stimulation.

Spinal cord stimulation (SCS) restores motor control after spinal cord injury (SCI) and stroke. This evidence led to the hypothesis that SCS facilitates residual supraspinal inputs to spinal motoneurons. Instead, here we show that SCS does not facilitate residual supraspinal inputs but directly triggers motoneurons action potentials. However, supraspinal inputs can shape SCS-mediated activity, mimicking volitional control of motoneuron firing. Specifically, by combining simulations, intraspinal electrophysiology in monkeys and single motor unit recordings in humans with motor paralysis, we found that residual supraspinal inputs transform subthreshold SCS-induced excitatory postsynaptic potentials into suprathreshold events. We then demonstrated that only a restricted set of stimulation parameters enables volitional control of motoneuron firing and that lesion severity further restricts the set of effective parameters. Our results explain the facilitation of voluntary motor control during SCS while predicting the limitations of this neurotechnology in cases of severe loss of supraspinal axons.

SUPRASPINAL CONTROL OF MOTONEURONS AFTER PARALYSIS ENABLED BY SPINAL CORD STIMULATION.

Spinal cord stimulation (SCS) restores motor control after spinal cord injury (SCI) and stroke. This evidence led to the hypothesis that SCS facilitates residual supraspinal inputs to spinal motoneurons. Instead, here we show that SCS does not facilitate residual supraspinal inputs but directly triggers motoneurons action potentials. However, supraspinal inputs can shape SCS-mediated activity, mimicking volitional control of motoneuron firing. Specifically, by combining simulations, intraspinal electrophysiology in monkeys and single motor unit recordings in humans with motor paralysis, we found that residual supraspinal inputs transform subthreshold SCS-induced excitatory postsynaptic potentials into suprathreshold events. We then demonstrated that only a restricted set of stimulation parameters enables volitional control of motoneuron firing and that lesion severity further restricts the set of effective parameters. Our results explain the facilitation of voluntary motor control during SCS while predicting the limitations of this neurotechnology in cases of severe loss of supraspinal axons.

POTENTIATION OF CORTICO-SPINAL OUTPUT VIA TARGETED ELECTRICAL STIMULATION OF THE MOTOR THALAMUS.

Cerebral white matter lesions prevent cortico-spinal descending inputs from effectively activating spinal motoneurons, leading to loss of motor control. However, in most cases, the damage to cortico-spinal axons is incomplete offering a potential target for new therapies aimed at improving volitional muscle activation. Here we hypothesized that, by engaging direct excitatory connections to cortico-spinal motoneurons, stimulation of the motor thalamus could facilitate activation of surviving cortico-spinal fibers thereby potentiating motor output. To test this hypothesis, we identified optimal thalamic targets and stimulation parameters that enhanced upper-limb motor evoked potentials and grip forces in anesthetized monkeys. This potentiation persisted after white matter lesions. We replicated these results in humans during intra-operative testing. We then designed a stimulation protocol that immediately improved voluntary grip force control in a patient with a chronic white matter lesion. Our results show that electrical stimulation targeting surviving neural pathways can improve motor control after white matter lesions.

GABA Increases Sensory Transmission In Monkeys.

Sensory input flow is central to voluntary movements. For almost a century, GABA was believed to modulate this flow by inhibiting sensory axons in the spinal cord to sculpt neural inputs into skilled motor output. Instead, here we show that GABA can also facilitate sensory transmission in monkeys and consequently increase spinal and cortical neural responses to sensory inputs challenging our understanding of generation and perception of movement.

Robot Assisted Neurosurgery for High-Accuracy, Minimally-Invasive Deep Brain Electrophysiology in Monkeys.

Traditional methods to access subcortical structures involve the use of anatomical atlases and high precision stereotaxic frames but suffer from significant variations in implantation accuracy. Here, we leveraged the use of the ROSA One(R) Robot Assistance Platform in non-human primates to study electrophysiological interactions of the corticospinal tract with spinal cord circuits. We were able to target and stimulate the corticospinal tract within the internal capsule with high accuracy and efficiency while recording spinal local field potentials and multi-unit spikes. Our method can be extended to any subcortical structure and allows implantation of multiple deep brain stimulation probes at the same time. Clinical Relevance- Our method will allow us to elucidate further roles of the corticospinal tract and its interactions with other processing centers in intact animals and in motor syndromes in the future.

Poststroke arm and hand paresis: should we target the cervical spinal cord?

Despite advances in understanding of corticospinal motor control and stroke pathophysiology, current rehabilitation therapies for poststroke upper limb paresis have limited efficacy at the level of impairment. To address this problem, we make the conceptual case for a new treatment approach. We first summarize current understanding of motor control deficits in the arm and hand after stroke and their shared physiological mechanisms with spinal cord injury (SCI). We then review studies of spinal cord stimulation (SCS) for recovery of locomotion after SCI, which provide convincing evidence for enhancement of residual corticospinal function. By extrapolation, we argue for using cervical SCS to restore upper limb motor control after stroke.

Defining drug and target protein distributions after stent-based drug release: Durable versus deployable coatings.

BACKGROUND: Innovations in drug eluting stent designs make it increasingly important to develop models for differentiating performance through spatial definition of drug, receptor binding and cell state. METHODS: Two designs of sirolimus analog eluting stents were implanted into porcine coronary arteries for 28, 60 or 90 days (n = 9/time point), durable coating (Xience) and deployable absorbable coating (MiStent). Explanted arteries were evaluated for drug content (n = 3/time point) by LC-MS/MS and for drug and target protein (mTOR) distributions by immunofluorescence (IF, n = 6/time point). A computational model was developed to predict drug release and arterial distribution maps. RESULTS: Both stents released the majority of drug load by 28 days, with different tissue retention efficiencies (91.4 ±â€¯4.9% MiStent versus 21.5 ±â€¯1.9% Xience, P < 0.001). Computational modeling of MiStent coating deployment and microcrystal dissolution recapitulated in vivo drug release and net tissue content and predicted that >98.5% of deployed drug remains crystalline through 90 days. Immunofluorescence and computational modeling showed peristrut drug localization for both stents, with similar peaks, but high interstrut levels only at sites of coating deployment from the absorbable coating. Co-localization of mTOR-IF with drug-IF for both devices showed persistent drug effects, though with differential drug-receptor pharmacokinetics. CONCLUSIONS: Immunofluorescence and computational modeling provide insights into drug distribution and binding status that can help differentiate drug delivery technologies. Herein we found that tissue deployment of slow dissolving crystalline drug particles results in temporally and spatially more uniform drug delivery to interstrut zones that might otherwise be under-dosed without excess peristrut drug.