Proprioception: A New Era Set in Motion by Emerging Genetic and Bionic Strategies?

The generation of an internal body model and its continuous update is essential in sensorimotor control. Although known to rely on proprioceptive sensory feedback, the underlying mechanism that transforms this sensory feedback into a dynamic body percept remains poorly understood. However, advances in the development of genetic tools for proprioceptive circuit elements, including the sensory receptors, are beginning to offer new and unprecedented leverage to dissect the central pathways responsible for proprioceptive encoding. Simultaneously, new data derived through emerging bionic neural machine-interface technologies reveal clues regarding the relative importance of kinesthetic sensory feedback and insights into the functional proprioceptive substrates that underlie natural motor behaviors.

Motor and somatosensory degenerative myelopathy responsive to pantothenic acid in piglets.

This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis.

Dorsal column mapping in resection of intramedullary spinal cord tumors: a prospective comparison of two methods and neurological follow-up.

PURPOSE: In surgery for intramedullary spinal cord tumors (imSCT), distortion of the anatomy challenges the visual identification of dorsal columns (DC) for midline myelotomy. Dorsal column mapping (DCM) and spinal cord stimulation (SCS) can identify DC neurophysiologically. We compare application and feasibility of both methods. METHODS: Patients with surgically treated imSCT were prospectively included between 04/2017 and 06/2019. The anatomical midline (AM) was marked. SSEPs at the DC after stimulation of tibial/median nerve with an 8-channel DCM electrode and cortical SSEP phase reversal at C3/C4 after SCS using a bipolar concentric probe were recorded. Procedural and technical aspects were compared. Standardized neurological examinations were performed preoperatively, 1 week postoperatively and after more than 12 months. RESULTS: The DCM electrode detected the midline in 9/13 patients with handling limitations in the remaining patients. SCS was applicable in all patients with determination of the midline in 9/13. If both recordings could be acquired (6/13), concordance was 100%. If baseline SSEPs were poor, both methods were limited. SCS was less time-consuming (p = 0.001), cheaper, and easier to handle. In 92% of cases, the AM and neurophysiologic midlines were concordant. After myelotomy, 3 patients experienced > 50% reduction in amplitude of SSEPs. Despite early postoperative worsening of DC function, long-term follow-up showed significant recovery and improvement in quality of life. CONCLUSION: DCM and SCS may help confirm and correct the AM for myelotomy in imSCT, leading to a favorable long-term neurological outcome in this cohort. SCS evolved to be superior concerning applicability, cost-effectiveness, and time expenditure.

RFC1-Related Disorder: In Vivo Evaluation of Spinal Cord Damage.

BACKGROUND: RFC1-related disorder is a novel heredodegenerative condition with a broad phenotypic spectrum. Its neuropathological bases are not yet fully understood, particularly regarding the pattern, extent, and clinical relevance of spinal cord (SC) damage. OBJECTIVES: The objectives were to determine the SC structural signature in RFC1-related disorder in vivo and to identify potential clinical correlates for these imaging abnormalities. METHODS: We enrolled 17 subjects with biallelic RFC1 (AAGGG)n expansions and 11 age- and sex-matched healthy controls that underwent multimodal magnetic resonance imaging SC acquisitions in a 3T Philips Achieva scanner. Both global morphometry and tract-specific analyses were then performed across all cervical levels. Between-group comparisons were assessed using nonparametric tests. RESULTS: In the patient group, mean age and disease duration were 62.9 ± 9.3 and 9.3 ± 4.0, respectively. Compared to controls, patients had remarkable SC cross-sectional area reduction along all cervical levels but anteroposterior flattening only in the lower cervical levels. There was also prominent SC gray matter atrophy. Diffusivity abnormalities were identified in the dorsal columns but not in the lateral corticospinal tracts. Disease severity did not correlate with these imaging parameters. CONCLUSION: SC damage is a hallmark of RFC1-related disorder and characterized by gray as well as white matter involvement. In particular, dorsal columns are severely and diffusely affected. The clinical correlates of these imaging abnormalities still deserve additional investigations. © 2022 International Parkinson and Movement Disorder Society.

Longitudinally extensive dorsal column spinal cord lesion with sensory ganglionopathy.

We present a case of a 23-year-old woman with a history of celiac disease who presented with a 2-month history of progressive gait unsteadiness and falls. Neurologic examination exhibited preserved motor strength, diffuse areflexia, and ataxic gait. Autoimmune and infectious workups were unremarkable, including vitamin B12. Electrodiagnostic testing showed absent diffuse sensory responses, consistent with sensory ganglionopathy. Total spine magnetic resonance imaging (MRI) revealed a non-enhancing, posterior cord, hyperintense signal from C1-T11. Partial improvement in her sensory ataxia was noted after 6 months of high-dose steroids without dorsal cord signals change on repeat MRI that suggests Wallerian degeneration of sensory axons.

The muscle evoked potential after epidural electrical stimulation of the spinal cord as a monitor for the corticospinal tract: studies by collision technique and double train stimulation.

To study if spinal motor evoked potentials (SpMEPs), muscle responses after electrical stimulation of the spinal cord, can monitor the corticospinal tract. Study 1 comprised 10 consecutive cervical or thoracic myelopathic patients. We recorded three types of muscle responses intraoperatively: (1) transcranial motor evoked potentials (TcMEPs), (2) SpMEPs and (3) SpMEPs + TcMEPs from the abductor hallucis (AH) using train stimulation. Study 2 dealt with 5 patients, who underwent paired train stimulation to the spinal cord with intertrain interval of 50-60 ms for recording AH SpMEPs. We will also describe two illustrative cases to demonstrate the clinical value of AH SpMEPs for monitoring the motor pathway. In Study 1, SpMEPs and SpMEPs + TcMEPs recorded from AH measured nearly the same, suggesting the collision of the cranially evoked volleys with the antidromic signals induced by spinal cord stimulation via the corticospinal tracts. In Study 2, the first and second train stimuli elicited almost identical SpMEPs, indicating a quick return of transmission after 50-60 ms considered characteristic of the corticospinal tract rather than the dorsal column, which would have recovered much more slowly. Of the two patients presented, one had no post-operative neurological deteriorations as anticipated by stable SpMEPs, despite otherwise insufficient IONM, and the other developed post-operative motor deficits as predicted by simultaneous reduction of TcMEPs and SpMEPs in the face of normal SEPs. Electrical stimulation of the spinal cord primarily activates the corticospinal tract to mediate SpMEPs.

Effect of Lead Position and Polarity on Paresthesia Coverage in Spinal Cord Stimulation Therapy: A Computational Study.

OBJECTIVES: The effect of lead placement and programming strategies on spinal cord stimulation (SCS) therapy has been widely studied; however, there is a need to optimize these parameters to favor dorsal column (DC) over dorsal root (DR) stimulation in complex pain treatment. This study aimed to determine the optimal lateral distance between two leads and the effect of transverse stimulation using a mathematical model. MATERIALS AND METHODS: A three-dimensional computational SCS and a nerve fiber model were used to determine the effect of the lateral distance between two leads at the same vertebral level T8 and the effect of the addition of anodes with two parallel leads at T8 and three different lateral distances on the model-based results (perception thresholds, activated DC fiber area and depth, and position of the first stimulated fiber). RESULTS: With two parallel leads programmed with symmetrical polarities, the maximal DC fiber area stimulated was found for a lateral distance of 5 mm. The results also show a higher preference for DR stimulation as the lateral distance increased. The addition of positive contacts at the same level of active contacts in the second lead produces a displacement of the first stimulated fiber laterally. CONCLUSIONS: A lateral distance of 5 mm shows a DC stimulated fiber area greater than when leads are placed contiguously. The addition of anodes creates an effect whereby the area of paresthesia is not displaced to the midline, but in the opposite direction. This may be useful when the leads are too close and stimulation of one of the sides is compromised.

Pain in relationship to Tinnitus and Hearing Loss.

INTRODUCTION: Cervical and lower back pain are noteworthy in the manner of development of tinnitus. OBJECTIVES: The focus of this research was to indicate the consequence of the severity of neck pain and pain of the lower back and/or lower limbs in tinnitus patients. DESIGN: A retrospective analysis of 61 patients with tinnitus as main complaint during a three month period. RESULTS: In this study, we found two groups of tinnitus patients defined by the existence of postural instability. Patients with tinnitus and postural unsteadiness were characterized by predominant female, self-perceived hearing loss, a higher intensity of tinnitus, cervical pain, and pain of the lower back and/or of the lower limbs, and more hearing deficit from 250 Hz to 4 kHz. CONCLUSIONS: In patients with tinnitus one should be aware that hearing loss can be a consequence of high intensity cervical pain. Stimulation of the proprioceptive input pathways due to cervical pain can result in a higher intensity of tinnitus and a hearing loss in the range of 250 Hz to 4 kHz.

Reorganization of the Primate Dorsal Horn in Response to a Deafferentation Lesion Affecting Hand Function.

The loss of sensory input following a spinal deafferentation injury can be debilitating, and this is especially true in primates when the hand is involved. Although significant recovery of function occurs, little is currently understood about the reorganization of the neuronal circuitry, particularly within the dorsal horn. This region receives primary afferent input from the periphery, and cortical input via the somatosensory subcomponent of the corticospinal tract (S1 CST), and is critically important in modulating sensory transmission, both in normal and lesioned states. To determine how dorsal horn circuitry alters to facilitate recovery post-injury, we used an established deafferentation lesion model (dorsal root/dorsal column) in male monkeys to remove sensory input from just the opposing digits (digits 1-3) of one hand. This results in a deficit in fine dexterity that recovers over several months. Electrophysiological mapping, tract tracing, and immunolabeling techniques were combined to delineate specific changes to dorsal horn input circuitry. Our main findings show that (1) there is complementary sprouting of the primary afferent and S1 CST populations into an overlapping region of the reorganizing dorsal horn; (2) S1 CST and primary afferent inputs connect in different ways within this region to facilitate sensory integration; and (3) there is a loss of larger S1 CST terminal boutons in the affected dorsal horn, but no change in the size profile of the spared/sprouted primary afferent terminal boutons post-lesion. Understanding such changes helps to inform new and targeted therapies that best promote recovery.SIGNIFICANCE STATEMENT Spinal injuries that remove sensation from the hand, can be debilitating, though functional recovery does occur. We examined changes to the neuronal circuitry of the dorsal horn in monkeys following a lesion that deafferented three digits of one hand. Little is understood about dorsal horn circuitry, despite the fact that this region loses most of its normal input after such an injury, and is clearly a major focus of reorganization. We found that both the spared primary afferents and somatosensory corticospinal efferents sprouted in an overlapping region of the dorsal horn after injury, and that larger (presumably faster) corticospinal terminals are lost, suggesting a significantly altered cortical modulation of primary afferents. Understanding this changing circuitry is important for designing targeted therapies.

Functional networks in non-human primate spinal cord and the effects of injury.

Spontaneous fluctuations of Blood Oxygenation-Level Dependent (BOLD) MRI signal in a resting state have previously been detected and analyzed to describe intrinsic functional networks in the spinal cord of rodents, non-human primates and human subjects. In this study we combined high resolution imaging at high field with data-driven Independent Component Analysis (ICA) to i) delineate fine-scale functional networks within and between segments of the cervical spinal cord of monkeys, and also to ii) characterize the longitudinal effects of a unilateral dorsal column injury on these networks. Seven distinct functional hubs were revealed within each spinal segment, with new hubs detected at bilateral intermediate and gray commissure regions in addition to the bilateral dorsal and ventral horns previously reported. Pair-wise correlations revealed significantly stronger connections between hubs on the dominant hand side. Unilateral dorsal-column injuries disrupted predominantly inter-segmental rather than intra-segmental functional connectivities as revealed by correlation strengths and graph-theory based community structures. The effects of injury on inter-segmental connectivity were evident along the length of the cord both below and above the lesion region. Connectivity strengths recovered over time and there was revival of inter-segmental communities as animals recovered function. BOLD signals of frequency 0.01-0.033 Hz were found to be most affected by injury. The results in this study provide new insights into the intrinsic functional architecture of spinal cord and underscore the potential of functional connectivity measures to characterize changes in networks after an injury and during recovery.

Spinal Cord Stimulation for Visceral Pain: Present Approaches and Future Strategies.

INTRODUCTION: The introduction of successful neuromodulation strategies for managing chronic visceral pain lag behind what is now treatment of choice in refractory chronic back and extremity pain for many providers in the United States and Europe. Changes in public policy and monetary support to identify nonopioid treatments for chronic pain have sparked interest in alternative options. In this review, we discuss the scope of spinal cord stimulation (SCS) for visceral pain, its limitations, and the potential role for new intradural devices of the type that we are developing in our laboratories, which may be able to overcome existing challenges. METHODS: A review of the available literature relevant to this topic was performed, with particular focus on the pertinent neuroanatomy and uses of spinal cord stimulation systems in the treatment of malignant and nonmalignant gastrointestinal, genitourinary, and chronic pelvic pain. RESULTS: To date, there have been multiple off-label reports testing SCS for refractory gastrointestinal and genitourinary conditions. Though some findings have been favorable for these organs and systems, there is insufficient evidence to make this practice routine. The unique configuration and layout of the pelvic pain pathways may not be ideally treated using traditional SCS implantation techniques, and intradural stimulation may be a viable alternative. CONCLUSIONS: Despite the prevalence of visceral pain, the application of neuromodulation therapies, a standard approach for other painful conditions, has received far too little attention, despite promising outcomes from uncontrolled trials. Detailed descriptions of visceral pain pathways may offer several clues that could be used to implement devices tailored to this unique anatomy.

A Comprehensive Practice Guideline for Magnetic Resonance Imaging Compatibility in Implanted Neuromodulation Devices.

OBJECTIVES: The evolution of neuromodulation devices in order to enter magnetic resonance imaging (MRI) scanners has been one of understanding limitations, engineering modifications, and the development of a consensus within the community in which the FDA could safely administer labeling for the devices. In the initial decades of neuromodulation, it has been contraindicated for MRI use with implanted devices. In this review, we take a comprehensive approach to address all the major products currently on the market in order to provide physicians with the ability to determine when an MRI can be performed for each type of device implant. MATERIALS AND METHODS: We have prepared a narrative review of MRI guidelines for currently marketed implanted neuromodulation devices including spinal cord stimulators, intrathecal drug delivery systems, peripheral nerve stimulators, deep brain stimulators, vagal nerve stimulators, and sacral nerve stimulators. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles, as well as manufacturer-provided information. RESULTS: Guidelines and recommendations for each device and their respective guidelines for use in and around MR environments are presented. CONCLUSIONS: This is the first comprehensive guideline with regards to various devices in the market and MRI compatibility from the American Society of Pain and Neuroscience.

Assessment of axonal recruitment using model-guided preclinical spinal cord stimulation in the ex vivo adult mouse spinal cord.

Spinal cord stimulation (SCS) is used clinically to limit chronic pain, but fundamental questions remain on the identity of axonal populations recruited. We developed an ex vivo adult mouse spinal cord preparation to assess recruitment following delivery of clinically analogous stimuli determined by downscaling a finite element model of clinical SCS. Analogous electric field distributions were generated with 300-µm × 300-µm electrodes positioned 200 µm above the dorsal column (DC) with stimulation between 50 and 200 µA. We compared axonal recruitment using electrodes of comparable size and stimulus amplitudes when contacting the caudal thoracic DC and at 200 or 600 µm above. Antidromic responses recorded distally from the DC, the adjacent Lissauer tract (LT), and in dorsal roots (DRs) were found to be amplitude and site dependent. Responses in the DC included a unique component not seen in DRs, having the lowest SCS recruitment amplitude and fastest conduction velocity. At 200 µm above, mean cathodic SCS recruitment threshold for axons in DRs and LT were 2.6 and 4.4 times higher, respectively, than DC threshold. SCS recruited primary afferents in all (up to 8) caudal segments sampled. Whereas A and C fibers could be recruited at nearby segments, only A fiber recruitment and synaptically mediated dorsal root reflexes were observed in more distant (lumbar) segments. In sum, clinically analogous SCS led to multisegmental recruitment of several somatosensory-encoding axonal populations. Most striking is the possibility that the lowest threshold recruitment of a nonprimary afferent population in the DC are postsynaptic dorsal column tract cells (PSDCs) projecting to gracile nuclei.NEW & NOTEWORTHY Spinal cord stimulation (SCS) is used clinically to control pain. To identify axonal populations recruited, finite element modeling identified scaling parameters to deliver clinically analogous SCS in an ex vivo adult mouse spinal cord preparation. Results showed that SCS first recruited an axonal population in the dorsal column at a threshold severalfold lower than primary afferents. These putative postsynaptic dorsal column tract cells may represent a previously unconsidered population responsible for SCS-induced paresthesias necessary for analgesia.

MiR-20a Plays a Key Regulatory Role in the Repair of Spinal Cord Dorsal Column Lesion via PDZ-RhoGEF/RhoA/GAP43 Axis in Rat.

Spinal cord injury (SCI) causes sensory dysfunctions such as paresthesia, dysesthesia, and chronic neuropathic pain. MiR-20a facilitates the axonal outgrowth of the cortical neurons. However, the role of miR-20a in the axonal outgrowth of primary sensory neurons and spinal cord dorsal column lesion (SDCL) is yet unknown. Therefore, the role of miR-20a post-SDCL was investigated in rat. The NF-200 immunofluorescence staining was applied to observe whether axonal outgrowth of dorsal root ganglion (DRG) neurons could be altered by miR-20a or PDZ-RhoGEF modulation in vitro. The expression of miR-20a was quantized with RT-PCR. Western blotting analyzed the expression of PDZ-RhoGEF/RhoA/GAP43 axis after miR-20a or PDZ-RhoGEF was modulated. The spinal cord sensory conduction function was assessed by somatosensory-evoked potentials and tape removal test. The results demonstrated that the expression of miR-20a decreased in a time-dependent manner post-SDCL. The regulation of miR-20a modulated the axonal growth and the expression of PDZ-RhoGEF/RhoA/GAP43 axis in vitro. The in vivo regulation of miR-20a altered the expression of miR-20a-PDZ-RhoGEF/RhoA/GAP43 axis and promoted the recovery of ascending sensory function post-SDCL. The results indicated that miR-20a/PDZ-RhoGEF/RhoA/GAP43 axis is associated with the pathophysiological process of SDCL. Thus, targeting the miR-20a/PDZ-RhoGEF /RhoA/GAP43 axis served as a novel strategy in promoting the sensory function recovery post-SCI.

Computational Study of the Effect of Electrode Polarity on Neural Activation Related to Paresthesia Coverage in Spinal Cord Stimulation Therapy.

OBJECTIVE: Using computer simulation, we investigated the effect of electrode polarity on neural activation in spinal cord stimulation and propose a new strategy to maximize the activating area in the dorsal column (DC) and, thus, paresthesia coverage in clinical practice. MATERIALS AND METHODS: A new three-dimensional spinal cord model at the T10 vertebral level was developed to simulate neural activation induced by the electric field distribution produced by different typical four-contact electrode polarities in single- and dual-lead stimulation. Our approach consisted of the combination of a finite element model of the spinal cord developed in COMSOL Multiphysics and a nerve fiber model implemented in MATLAB. Five evaluation parameters were evaluated, namely, the recruitment ratio, the perception and discomfort thresholds, and the activating area and depth. The results were compared quantitatively. RESULTS: The dual-guarded cathode presents the maximum activating area and depth in single- and dual-lead stimulation. However, the lowest value of the ratio between the perception threshold in DC and the perception threshold in the dorsal root (DR) is achieved when the guarded cathode is programmed. Although the two versions of bipolar polarity (namely bipolar 1 and bipolar 2) produce higher activating area and depth than the guarded cathode, they are suitable for producing DR stimulation. Similarly, dual-lead stimulation is likely to activate DR fibers because the electrodes are closer to these fibers. CONCLUSIONS: The results suggest that the activating area in the DC is maximized by using the dual-guarded cathode both in single- and dual-lead stimulation modes. However, DC nerve fibers are preferentially stimulated when the guarded cathode is used. According to these results, the new electrode programming strategy that we propose for clinical practice first uses the dual-guarded cathode, but, if the DR nerve fibers are activated, it then uses guarded cathode polarity.

Single S1 Dorsal Root Ganglia Stimulation for Intractable Complex Regional Pain Syndrome Foot Pain After Lumbar Spine Surgery: A Case Series.

INTRODUCTION: Intractable complex regional pain syndrome (CRPS)-related chronic foot pain, is a common therapeutic challenge for interventional pain management physicians and patients alike. Dorsal root ganglia (DRG) stimulation is a very target specific dorsal column stimulation technique with very promising clinical outcomes. Patients with CRPS foot pain and previous back surgery can benefit from DRG stimulation but also run a significant risk of epidural trauma from the DRG sheath advancement. Most sensory innervation to the foot is from L5 and S1 dermatomes. Although there is dual modulation from L5 and S1 DRG, significant "cross talk" exists between these structures such that a DRG lead solely at S1 could provide pain relief for the entire foot. In this case series, we examined the outcomes obtained from placement of solely S1 DRG stimulating electrodes in patients with CRPS-related chronic foot pain, and examine whether this may provide a reduced risk of dural injury. Furthermore, we describe the technical aspects of a S1 DRG placement and discuss relevant anatomical issues pertaining to this approach. MATERIALS AND METHODS: Five patients (four female, one male) with chronic foot pain participated. The oldest was 71 and the youngest 49. Three patients were diagnosed with foot CRPS-1, and two patients with foot CRPS-2. All patients had back surgery in the past and all underwent a trial and subsequent S1 DRG implantation. The patients were evaluated with a numeric rating score (NRS) for pain and function before the procedure and one, two, three, and six months after the procedure. The first patient underwent an L5 and S1 trial and developed CSF leak and postdural puncture headache. Two months later, the patient was re-trialed and implanted with a single S1 electrode. The other four patients were trialed and implanted with single S1 DRG electrodes. RESULTS: All five patients had severe pain (8-10 NRS) and significant loss of function and quality of life (2-4 NRS) before the procedure. All five patients had excellent (0-3 NRS) pain relief and functional restoration (8-10 NRS) with a single S1 electrode trial, and all five proceeded with permanent implantation. The pain relief from the S1 DRG stimulation extended to the entire foot without any sparing. All patients were able to discontinue or significantly reduce their oral pain medications. The one-, two-, three-, and six-month follow-up showed preservation of therapeutic efficacy. CONCLUSIONS: A single S1 DRG electrode placement in patients diagnosed with CRPS of the foot and who had previous back surgery is therapeutically effective and can minimize the risk of dural trauma and CSF leak.

Afferent input and sensory function after human spinal cord injury.

Spinal cord injury (SCI) often disrupts the integrity of afferent (sensory) axons projecting through the spinal cord dorsal columns to the brain. Examinations of ascending sensory tracts, therefore, are critical for monitoring the extent of SCI and recovery processes. In this review, we discuss the most common electrophysiological techniques used to assess transmission of afferent inputs to the primary motor cortex (i.e., afferent input-induced facilitation and inhibition) and the somatosensory cortex [i.e., somatosensory evoked potentials (SSEPs), dermatomal SSEPs, and electrical perceptual thresholds] following human SCI. We discuss how afferent input modulates corticospinal excitability by involving cortical and spinal mechanisms depending on the timing of the effects, which need to be considered separately for upper and lower limb muscles. We argue that the time of arrival of afferent input onto the sensory and motor cortex is critical to consider in plasticity-induced protocols in humans with SCI. We also discuss how current sensory exams have been used to detect differences between control and SCI participants but might be less optimal to characterize the level and severity of injury. There is a need to conduct some of these electrophysiological examinations during functionally relevant behaviors to understand the contribution of impaired afferent inputs to the control, or lack of control, of movement. Thus the effects of transmission of afferent inputs to the brain need to be considered on multiple functions following human SCI.

Dorsal Column Stimulation vs. Dorsal Root Ganglion Stimulation for Complex Regional Pain Syndrome Confined to the Knee: Patients' Preference Following the Trial Period.

BACKGROUND AND OBJECTIVES: Patients with complex regional pain syndrome (CRPS) confined to the knee are often therapy resistant. Neurostimulation is an accepted treatment for CRPS. Although results with dorsal column (DC) stimulation in patients with CRPS confined to the knee are often disappointing, the availability of dorsal root ganglion (DRG) stimulation may provide new opportunities for this complaint. Therefore, this study explores patients' preference for DC stimulation vs. DRG stimulation in treating chronic pain due to CRPS confined to the knee. METHODS: A prospective, observational crossover cohort study was conducted comparing 2 methods of neurostimulation, in randomized order, in patients with CRPS confined to the knee. After receiving DC and DRG stimulation during a trial period of 16 days, patients were asked which of the 2 methods they preferred. Patients with a successful trial period with one or both stimulation methods received a fully implantable system. RESULTS: Twelve patients were included. After finishing the trial period, 10 patients (83.3%) preferred DRG stimulation and 2 (16.7%) preferred DC stimulation (P = 0.04). CONCLUSION: To our knowledge, this is the first study to compare these 2 neurostimulation methods in patients with CRPS confined to the knee. Results show that the probability of the preference for either neurostimulation treatment significantly deviates from chance in favor of DRG stimulation.

Characterisation and functional mapping of surface potentials in the rat dorsal column nuclei.

KEY POINTS: The brainstem dorsal column nuclei (DCN) process sensory information arising from the body before it reaches the brain and becomes conscious. Despite significant investigations into sensory coding in peripheral nerves and the somatosensory cortex, little is known about how sensory information arising from the periphery is represented in the DCN. Following stimulation of hind-limb nerves, we mapped and characterised the evoked electrical signatures across the DCN surface. We show that evoked responses recorded from the DCN surface are highly reproducible and are unique to nerves carrying specific sensory information. ABSTRACT: The brainstem dorsal column nuclei (DCN) play a role in early processing of somatosensory information arising from a variety of functionally distinct peripheral structures, before being transmitted to the cortex via the thalamus. To improve our understanding of how sensory information is represented by the DCN, we characterised and mapped low- (<200 Hz) and high-frequency (550-3300 Hz) components of nerve-evoked DCN surface potentials. DCN surface potentials were evoked by electrical stimulation of the left and right nerves innervating cutaneous structures (sural nerve), or a mix of cutaneous and deep structures (peroneal nerve), in 8-week-old urethane-anaesthetised male Wistar rats. Peroneal nerve-evoked DCN responses demonstrated low-frequency events with significantly longer durations, more high-frequency events and larger magnitudes compared to responses evoked from sural nerve stimulation. Hotspots of low- and high-frequency DCN activity were found ipsilateral to stimulated nerves but were not symmetrically organised. In conclusion, we find that sensory inputs from peripheral nerves evoke unique and characteristic DCN activity patterns that are highly reproducible both within and across animals.

Modulation of activity and conduction in single dorsal column axons by kilohertz-frequency spinal cord stimulation.

Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a potential paresthesia-free treatment for chronic pain. However, the effects of KHF-SCS on spinal dorsal column (DC) axons and its mechanisms of action remain unknown. The objectives of this study were to quantify activation and conduction block of DC axons by KHF-SCS across a range of frequencies (1, 5, 10, or 20 kHz) and waveforms (biphasic pulses or sinusoids). Custom platinum electrodes delivered SCS to the T10/T11 dorsal columns of anesthetized male Sprague-Dawley rats. Single DC axons and compound action potentials were recorded during KHF-SCS to evaluate SCS-evoked activity. Responses to KHF-SCS in DC axons included brief onset firing, slowly accommodating asynchronous firing, and conduction block. The effects of KHF-SCS mostly occurred well above motor thresholds, but isolated units were activated at amplitudes shown to reduce behavioral sensitivity in rats. Activity evoked by SCS was similar across a range of frequencies (5-20 kHz) and waveforms (biphasic and sinusoidal). Stimulation at 1-kHz SCS evoked more axonal firing that was also more phase-synchronized to the SCS waveform, but only at amplitudes above motor threshold. These data quantitatively characterize the central nervous system activity that may modulate pain perception and paresthesia, and thereby provide a foundation for continued investigation of the mechanisms of KHF-SCS and its optimization as a therapy for chronic pain. Given the asynchronous and transient nature of DC activity, it is unlikely that the same mechanisms underlying conventional SCS (i.e., persistent, periodic DC activation) apply to KHF-SCS. NEW & NOTEWORTHY: Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a new mode of SCS that may offer better pain relief than conventional SCS. However, the mechanism of action is poorly characterized, especially the effects of stimulation on dorsal column (DC) axons, which are the primary target of stimulation. This study provides the first recordings of single DC axons during KHF-SCS to quantify DC activity that has the potential to mediate the analgesic effects of KHF-SCS.