Intraspinal microstimulation of the ventral horn has therapeutically relevant cross-modal effects on nociception.

Electrical stimulation of spinal networks below a spinal cord injury is a promising approach to restore functions compromised by inadequate and/or inappropriate neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared descending motor pathways and spinal motoneurons rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by spinal cord injury. Debilitating spasms, spasticity and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. Whereas spasms and spasticity can often be managed pharmacologically, spinal cord injury-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from aetiologies other than spinal cord injury, and the limited evidence available to date suggests that it holds considerable promise for reducing spinal cord injury-related neuropathic pain, as well. Spinal stimulation for pain amelioration has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for rehabilitation of movement impairments. Thus, we hypothesize that spinal stimulation intended to increase the ability to move voluntarily may simultaneously reduce transmission in spinal pain pathways. To test this hypothesis, we coupled a rat model of incomplete thoracic spinal cord injury, which results in moderate to severe bilateral movement impairments and spinal cord injury-related neuropathic pain, with in vivo electrophysiological measures of neural transmission in networks of spinal neurons integral to the development and persistence of the neuropathic pain state. We find that when intraspinal microstimulation is delivered to the ventral horn with the intent of enhancing voluntary movement, transmission through nociceptive specific and wide dynamic range neurons is significantly depressed in response to pain-related sensory feedback. By comparison, spinal responsiveness to non-pain-related sensory feedback is largely preserved. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with spinal cord injury.

Testing the Validity and Reliability of a Standardized Virtual Examination for Concussion.

Background and Objectives: We determined inter-modality (in-person vs telemedicine examination) and inter-rater agreement for telemedicine assessments (2 different examiners) using the Telemedicine Buffalo Concussion Physical Examination (Tele-BCPE), a standardized concussion examination designed for remote use. Methods: Patients referred for an initial evaluation for concussion were invited to participate. Participants had a brief initial assessment by the treating neurologist. After a patient granted informed consent to participate in the study, the treating neurologist obtained a concussion-related history before leaving the examination room. Using the Tele-BCPE, 2 virtual examinations in no specific sequence were then performed from nearby rooms by the treating neurologist and another neurologist. After the 2 telemedicine examinations, the treating physician returned to the examination room to perform the in-person examination. Intraclass correlation coefficients (ICC) determined inter-modality validity (in-person vs remote examination by the same examiner) and inter-rater reliability (between remote examinations done by 2 examiners) of overall scores of the Tele-BCPE within the comparison datasets. Cohen's kappa, κ, measured levels of agreement of dichotomous ratings (abnormality present vs absent) on individual components of the Tele-BCPE to determine inter-modality and inter-rater agreement. Results: For total scores of the Tele-BCPE, both inter-modality agreement (ICC = 0.95 [95% CI 0.86-0.98, p < 0.001]) and inter-rater agreement (ICC = 0.88 [95% CI 0.71-0.95, p < 0.001]) were reliable (ICC >0.70). There was at least substantial inter-modality agreement (κ ≥ 0.61) for 25 of 29 examination elements. For inter-rater agreement (2 telemedicine examinations), there was at least substantial agreement for 8 of 29 examination elements. Discussion: Our study demonstrates that the Tele-BCPE yielded consistent clinical results, whether conducted in-person or virtually by the same examiner, or when performed virtually by 2 different examiners. The Tele-BCPE is a valid indicator of neurologic examination findings as determined by an in-person concussion assessment. The Tele-BCPE may also be performed with excellent levels of reliability by neurologists with different training and backgrounds in the virtual setting. These findings suggest that a combination of in-person and telemedicine modalities, or involvement of 2 telemedicine examiners for the same patient, can provide consistent concussion assessments across the continuum of care.

Unintentionally intentional: unintended effects of spinal stimulation as a platform for multi-modal neurorehabilitation after spinal cord injury.

Electrical stimulation of spinal neurons has emerged as a valuable tool to enhance rehabilitation after spinal cord injury. In separate parameterizations, it has shown promise for improving voluntary movement, reducing symptoms of autonomic dysreflexia, improving functions mediated by muscles of the pelvic floor (e.g., bowel, bladder, and sexual function), reducing spasms and spasticity, and decreasing neuropathic pain, among others. This diverse set of actions is related both to the density of sensorimotor neural networks in the spinal cord and to the intrinsic ability of electrical stimulation to modulate neural transmission in multiple spinal networks simultaneously. It also suggests that certain spinal stimulation parameterizations may be capable of providing multi-modal therapeutic benefits, which would directly address the complex, multi-faceted rehabilitation goals of people living with spinal cord injury. This review is intended to identify and characterize reports of spinal stimulation-based therapies specifically designed to provide multi-modal benefits and those that report relevant unintended effects of spinal stimulation paradigms parameterized to enhance a single consequence of spinal cord injury.

Temporal expression of brainstem neurotrophic proteins following mild traumatic brain injury.

BDNF, a neurotrophic factor, and its receptors have been implicated in the pathophysiology of mild traumatic brain injury (mTBI). The brainstem houses many vital functions, that are also associated with signs and symptoms of mTBI, but has been understudied in mTBI animal models. We determined the extent to which neurotrophic protein and associated receptor expression is affected within the brainstem of adult rats following mTBI. Their behavioral function was assessed and temporal expression of the 'negative' regulators of neuronal function (p75, t-TrkB, and pro-BDNF) and 'positive' neuroprotective (FL-TrkB and m-BDNF) protein isoforms were determined via western blot and immunohistochemistry at 1, 3, 7, and 14 post-injury days (PID) following mTBI or sham (control) procedure. Within the brainstem, p75 expression increased at PID 1 vs. sham animals. t-TrkB and pro-BDNF expression increased at PID 7 and 14. The 'positive' protein isoforms of FL-TrkB and m-BDNF expression were increased only at PID 7. The ratio of t-TrkB:FL-TrkB (negative:positive) was substantial across groups and time points, suggesting a negative impact of neurotrophic signaling on neuronal function. Additional NeuN experiments revealed cell death occurring within a subset of neurons within the medulla. While behavioral measures improved by PID 7-14, negative neurotrophic biochemical responses persisted. Despite the assertion that mTBI produces "mild" injury, evidence of cell death was observed in the medulla. Ratios of TrkB and BDNF isoforms with conflicting functions suggest that future work should specifically measure each subtype since they induce opposing downstream effects on neuronal function.

An Exploratory Analysis of Physical Examination Subtypes in Pediatric Athletes With Concussion.

OBJECTIVE: Pediatric athletes with concussion present with a variety of impairments on clinical assessment and require individualized treatment. The Buffalo Concussion Physical Examination is a brief, pertinent clinical assessment for individuals with concussion. The purpose of this study was to identify physical examination subtypes in pediatric athletes with concussion within 2 weeks of injury that are relevant to diagnosis and treatment. DESIGN: Secondary analysis of a published cohort study and clinician consensus. SETTING: Three university-affiliated sports medicine centers. PARTICIPANTS: Two hundred seventy children (14.9 ± 1.9 years). INDEPENDENT VARIABLES: Orthostatic intolerance, horizontal and vertical saccades, smooth pursuits, vestibulo-ocular reflex, near-point convergence, complex tandem gait, neck range of motion, neck tenderness, and neck spasm. MAIN OUTCOME MEASURES: Correlations between independent variables were calculated, and network graphs were made. k -means and hierarchical clustering were used to identify clusters of impairments. Optimal number of clusters was assessed. Results were reviewed by experienced clinicians and consensus was reached on proposed subtypes. RESULTS: Physical examination clusters overlapped with each other, and no optimal number of clusters was identified. Clinician consensus suggested 3 possible subtypes: (1) visio-vestibular (horizontal and vertical saccades, smooth pursuits, and vestibulo-ocular reflex), (2) cervicogenic (neck range of motion and spasm), and (3) autonomic/balance (orthostatic intolerance and complex tandem gait). CONCLUSIONS: Although we identified 3 physical examination subtypes, it seemed that physical examination findings alone are not enough to define subtypes that are both statistically supported and clinically relevant, likely because they do not include symptoms, assessment of mood or cognitive problems, or graded exertion testing.

Early Identification and Management of Cervical Impairments in Pediatric Patients With Concussion May Reduce Risk of Delayed Recovery.

OBJECTIVE: Previous research, including high-quality systematic reviews, has found that cervical injury, which often accompanies concussive head injury, can delay recovery from concussion. One pilot randomized controlled trial found that focused cervical assessment and appropriate intervention in children and young adults with persisting postconcussive symptoms (PPCS) improved recovery outcomes. Our sports medicine clinics adopted this approach early (within 2 weeks) in children (aged 10-18 years) after concussion. This study describes our clinical management protocol and compares the recovery trajectories in children after concussion with and without a concomitant cervical injury. DESIGN: Prospective cohort study. SETTING: Three university-affiliated outpatient sports medicine clinics from September 2016 to December 2019. PATIENTS: One-hundred thirty-four concussed children with cervical impairment (mean age 14.9 years, 65% male, and 6.2 days since concussion) were compared with 130 concussed children without cervical impairment (mean age 14.9 years, 57% male, and 6.0 days since concussion). INDEPENDENT VARIABLES: Examination findings related to the cervical spine (range of motion, cervical spasm, and cervical tenderness). MAIN OUTCOME MEASURES: Recovery time (measured in days), concussion symptom burden (Postconcussion Symptom Scale), and incidence of PPCS. RESULTS: Children with cervical impairment reported a higher initial symptom burden; however, there were no differences in recovery time (33.65 [28.20-39.09] days vs 35.98 [27.50-44.45] days, P = 0.651) or incidence of PPCS (40.0% vs 34.3%, P = 0.340). CONCLUSIONS: We conclude that within this pediatric population, early identification and management of cervical injuries concomitant with concussion may reduce the risk of delayed recovery.

Does Physiologic Post-Concussion Disorder Cause Persistent Post-Traumatic Headache?

PURPOSE OF REVIEW: One system classifies patients with symptoms after concussion into physiologic, vestibulo-ocular, cervicogenic, and mood/cognition post-concussion disorders (PCD) based upon the preponderance of specific symptoms and physical impairments. This review discusses physiologic PCD and its potential relationship to the development of persistent post-traumatic headaches (PPTH). RECENT FINDINGS: Headache is the most reported symptom after a concussion. Headaches in physiologic PCD are suspected to be due to abnormal cellular metabolism, subclinical neuroinflammation, and dysfunction of the autonomic nervous system (ANS). These abnormalities have been linked to the development of migraine-like and neuralgia-related PPTH. Physiologic PCD is a potential cause of PPTH after a concussion. Future research should focus on how to prevent PPTH in patients with physiologic PCD.

Neural population dynamics reveal that motor-targeted intraspinal microstimulation preferentially depresses nociceptive transmission in spinal cord injury-related neuropathic pain.

The purpose of this study is to determine whether intraspinal microstimulation (ISMS) intended to enhance voluntary motor output after spinal cord injury (SCI) modulates neural population-level spinal responsiveness to nociceptive sensory feedback. The study was conducted in vivo in three cohorts of rats: neurologically intact, chronic SCI without behavioral signs of neuropathic pain, and chronic SCI with SCI-related neuropathic pain (SCI-NP). Nociceptive sensory feedback was induced by application of graded mechanical pressure to the plantar surface of the hindpaw before, during, and after periods of sub-motor threshold ISMS delivered within the motor pools of the L5 spinal segment. Neural population-level responsiveness to nociceptive feedback was recorded throughout the dorso-ventral extent of the L5 spinal segment using dense multi-channel microelectrode arrays. Whereas motor-targeted ISMS reduced nociceptive transmission across electrodes in neurologically intact animals both during and following stimulation, it was not associated with altered nociceptive transmission in rats with SCI that lacked behavioral signs of neuropathic pain. Surprisingly, nociceptive transmission was reduced both during and following motor-targeted ISMS in rats with SCI-NP, and to an extent comparable to that of neurologically intact animals. The mechanisms underlying the differential anti-nociceptive effects of motor-targeted ISMS are unclear, although they may be related to differences in the intrinsic active membrane properties of spinal neurons across the cohorts. Nevertheless, the results of this study support the notion that it may be possible to purposefully engineer spinal stimulation-based therapies that afford multi-modal rehabilitation benefits, and specifically that it may be possible to do so for the individuals most in need - i.e., those with SCI-related movement impairments and SCI-NP.

Precision neuromodulation: Promises and challenges of spinal stimulation for multi-modal rehabilitation.

Spinal cord injury results in multiple, simultaneous sensorimotor deficits. These include, but are not limited to, full or partial paralysis of muscles below the lesion, muscle spasms, spasticity, and neuropathic pain. Bowel, bladder, and sexual dysfunction are also prevalent. Yet, the majority of emerging spinal stimulation-based therapies focus on a single issue: locomotor rehabilitation. Despite the enormous potential of these translational advances to transform the lives of people living with spinal cord injury, meaningful recovery in other domains deemed critical priorities remains lacking. Here, we highlight the importance of considering the diverse patterns of neural transmission that underlie clinically similar presentations when developing spinal stimulation-based therapies. We also motivate advancement of multi-modal rehabilitation paradigms, which leverage the dense interconnectivity of sensorimotor spinal networks and the unique ability of electrical stimulation to modulate these networks to facilitate and guide simultaneous rehabilitation across domains.