Adaptation in the spinal cord after stroke: Implications for restoring cortical control over the final common pathway.

Control of voluntary movement is predicated on integration between circuits in the brain and spinal cord. Although damage is often restricted to supraspinal or spinal circuits in cases of neurological injury, both spinal motor neurons and axons linking these cells to the cortical origins of descending motor commands begin showing changes soon after the brain is injured by stroke. The concept of 'transneuronal degeneration' is not new and has been documented in histological, imaging and electrophysiological studies dating back over a century. Taken together, evidence from these studies agrees more with a system attempting to survive rather than one passively surrendering to degeneration. There tends to be at least some preservation of fibres at the brainstem origin and along the spinal course of the descending white matter tracts, even in severe cases. Myelin-associated proteins are observed in the spinal cord years after stroke onset. Spinal motor neurons remain morphometrically unaltered. Skeletal muscle fibres once innervated by neurons that lose their source of trophic input receive collaterals from adjacent neurons, causing spinal motor units to consolidate and increase in size. Although some level of excitability within the distributed brain network mediating voluntary movement is needed to facilitate recovery, minimal structural connectivity between cortical and spinal motor neurons can support meaningful distal limb function. Restoring access to the final common pathway via the descending input that remains in the spinal cord therefore represents a viable target for directed plasticity, particularly in light of recent advances in rehabilitation medicine.

Corticospinal recruitment of spinal motor neurons in human stroke survivors.

KEY POINTS: Muscle weakness after stroke results from damage to corticospinal fibres that structurally and functionally connect cerebral cortex to the spinal cord. Here, we show an asymmetry in corticospinal recruitment of spinal motor neurons that is linked to maximal voluntary output of hand muscles weakened by stroke. Spike timing-dependent plasticity of synapses between corticospinal and spinal motor neurons transiently reversed recruitment failures in some survivors. These modulatory effects were strongly associated with recruitment asymmetry and hand impairment. Our findings highlight the functional relevance of spinal motor neuron recruitment by corticospinal inputs and the viability of corticospinal motor neuronal synapses for restoring activation of lower motor neurons after stroke. ABSTRACT: Corticospinal input to spinal motor neurons is structurally and functionally altered by hemiparetic stroke. The pattern and extent to which corticospinal recruitment of spinal motor neurons is reorganized and whether such changes are linked to the severity of motor impairments is not well understood. Here, we performed experiments using the triple stimulation technique to quantify corticospinal recruitment of spinal motor neurons serving paretic and non-paretic intrinsic hand muscles of humans with longstanding motor impairment secondary to stroke (n = 13). We also examined whether recruitment failures could be transiently reversed by strengthening corticospinal-motoneuronal synaptic connectivity via targeted, temporally controlled non-invasive stimulation to elicit spike timing-dependent plasticity (STDP). Asymmetries were detected in corticospinal recruitment of spinal motor neurons, central conduction time and motor-evoked potential (MEP) latency. However, only recruitment asymmetry correlated with maximal voluntary motor output from the paretic hand. STDP-like effects were observed as an increase in spinal motor neuron recruitment. Control experiments to isolate the locus of plasticity demonstrated a modulation in MEPs elicited by electrical stimulation of primary motor cortex but not F-wave size or persistence, suggesting that plasticity was mediated through enhanced efficacy of residual corticospinal-motor neuronal synapses. The modulation in recruitment was strongly associated with baseline recruitment asymmetry and impairment severity. Our findings demonstrate that asymmetry in corticospinal recruitment of spinal motor neurons is directly related to impairments experienced by stroke survivors. These recruitment deficits may be partially and transiently reversed by spike timing-dependent plasticity of synapses between upper and lower motor neurons in the spinal cord, downstream of supraspinal circuits damaged by stroke.

Effects of noninvasive neuromodulation targeting the spinal cord on early learning of force control by the digits.

AIMS: Control of finger forces underlies our capacity for skilled hand movements acquired during development and reacquired after neurological injury. Learning force control by the digits, therefore, predicates our functional independence. Noninvasive neuromodulation targeting synapses that link corticospinal neurons onto the final common pathway via spike-timing-dependent mechanisms can alter distal limb motor output on a transient basis, yet these effects appear subject to individual differences. Here, we investigated how this form of noninvasive neuromodulation interacts with task repetition to influence early learning of force control during precision grip. METHODS: The unique effects of neuromodulation, task repetition, and neuromodulation coinciding with task repetition were tested in three separate conditions using a within-subject, cross-over design (n = 23). RESULTS: We found that synchronizing depolarization events within milliseconds of stabilizing precision grip accelerated learning but only after accounting for individual differences through inclusion of subjects who showed upregulated corticospinal excitability at 2 of 3 time points following conditioning stimulation (n = 19). CONCLUSIONS: Our findings provide insights into how the state of the corticospinal system can be leveraged to drive early motor skill learning, further emphasizing individual differences in the response to noninvasive neuromodulation. We interpret these findings in the context of biological mechanisms underlying the observed effects and implications for emerging therapeutic applications.

Force oscillations underlying precision grip in humans with lesioned corticospinal tracts.

Stability of precision grip depends on the ability to regulate forces applied by the digits. Increased frequency composition and temporal irregularity of oscillations in the force signal are associated with enhanced force stability, which is thought to result from increased voluntary drive along the corticospinal tract (CST). There is limited knowledge of how these oscillations in force output are regulated in the context of dexterous hand movements like precision grip, which are often impaired by CST damage due to stroke. The extent of residual CST volume descending from primary motor cortex may help explain the ability to modulate force oscillations at higher frequencies. Here, stroke survivors with longstanding hand impairment (n = 17) and neurologically-intact controls (n = 14) performed a precision grip task requiring dynamic and isometric muscle contractions to scale and stabilize forces exerted on a sensor by the index finger and thumb. Diffusion spectrum imaging was used to quantify total white matter volume within the residual and intact CSTs of stroke survivors (n = 12) and CSTs of controls (n = 14). White matter volumes within the infarct region and an analogous portion of overlap with the CST, mirrored onto the intact side, were also quantified in stroke survivors. We found reduced ability to stabilize force and more restricted frequency ranges in force oscillations of stroke survivors relative to controls; though, more broadband, irregular output was strongly related to force-stabilizing ability in both groups. The frequency composition and temporal irregularity of force oscillations observed in stroke survivors did not correlate with maximal precision grip force, suggesting that it is not directly related to impaired force-generating capacity. The ratio of residual to intact CST volumes contained within infarct and mirrored compartments was associated with more broadband, irregular force oscillations in stroke survivors. Our findings provide insight into granular aspects of dexterity altered by corticospinal damage and supply preliminary evidence to support that the ability to modulate force oscillations at higher frequencies is explained, at least in part, by residual CST volume in stroke survivors.

Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans.

BACKGROUND: Transcutaneous stimulation of the external ear is thought to recruit afferents of the auricular vagus nerve, providing a means to activate noradrenergic pathways in the central nervous system. Findings from human studies examining the effects of auricular stimulation on noradrenergic biomarkers have been mixed, possibly relating to the limited and variable parameter space explored to date. OBJECTIVE: We tested the extent to which brief pulse trains applied to locations of auricular innervation (canal and concha) elicit acute pupillary responses (PRs) compared to a sham location (lobe). Pulse amplitude and frequency were varied systematically to examine effects on PR features. METHODS: Participants (n = 19) underwent testing in three separate experiments, each with stimulation applied to a different external ear location. Perceptual threshold (PT) was measured at the beginning of each experiment. Pulse trains (∼600 ms) consisting of different amplitude (0.0xPT, 0.8xPT, 1.0xPT, 1.5xPT, 2.0xPT) and frequency (25 Hz, 300 Hz) combinations were administered during eye tracking procedures. RESULTS: Stimulation to all locations elicited PRs which began approximately halfway through the pulse train and peaked shortly after the final pulse (≤1 s). PR size and incidence increased with pulse amplitude and tended to be greatest with canal stimulation. Higher pulse frequency shortened the latency of PR onset and peak dilation. Changes in pupil diameter elicited by pulse trains were weakly associated with baseline pupil diameter. CONCLUSION: (s): Auricular stimulation elicits acute PRs, providing a basis to synchronize neuromodulator release with task-related neural spiking which preclinical studies show is a critical determinant of therapeutic effects. Further work is needed to dissociate contributions from vagal and non-vagal afferents mediating activation of the biomarker.