Thoracolumbar fascia mobility and chronic low back pain: Phase 1 of a pilot and feasibility study assessing repeated measures and the influence of paraspinal muscle contraction.

BACKGROUND: Differential movement, or shear strain (SS), between layers of thoracolumbar fascia is reduced with chronic low back pain. To provide a foundation for clinical research involving SS, this study assessed temporal stability and the effect of paraspinal muscle contraction on SS in persons with chronic low back pain. METHODS: We used ultrasound imaging to measure SS in adults self-reporting low back pain ≥1 year. Images were obtained by placing a transducer 2-3 cm lateral to L2-3 with participants lying prone and relaxed on a table moving the lower extremities downward 15°, for 5 cycles at 0.5 Hz. To assess paraspinal muscle contraction effects, participants raised the head slightly from the table. SS was calculated using 2 computational methods. Method 1 averaged the maximum SS from each side during the third cycle. Method 2 used the maximum SS from any cycle (2-4) on each side, prior to averaging. SS was also assessed after a 4-week no manual therapy period. RESULTS: Of 30 participants (n = 14 female), mean age was 40 years; mean BMI 30.1. Mean (SE) SS in females with paraspinal muscle contraction was 66% (7.4) (method 1) and 78% (7.8) (method 2); 54% (6.9) (method 1) and 67% (7.3) (method 2) in males. With muscles relaxed, mean SS in females was 77% (7.6) (method 1) or 87% (6.8) (method 2); 63% (7.1) (method 1) and 78% (6.4) (method 2) in males. Mean SS decreased 8-13% in females and 7-13% in males after 4-weeks CONCLUSION: Mean SS in females was higher than males at each timepoint. Paraspinal muscle contraction temporarily reduced SS. Over a 4-week no-treatment period, mean SS (with paraspinal muscles relaxed) decreased. Methods less likely to induce muscle guarding and enabling assessment with broader populations are needed.

Thoracolumbar fascia mobility and chronic low back pain: Phase 2 of a pilot and feasibility study including multimodal chiropractic care.

BACKGROUND: Thoracolumbar fascia mobility observed with ultrasound imaging and calculated as shear strain is lower in persons with chronic low back pain. This pilot and feasibility trial assessed thoracolumbar shear strain in persons with chronic low back pain following spinal manipulation and over an 8-week course of multimodal chiropractic care. METHODS: Adults self-reporting chronic low back pain ≥ 1 year participated between September 2019 and April 2021 in a trial using ultrasound imaging to measure thoracolumbar shear strain. Ultrasound imaging occurred 2-3 cm lateral to L2-3 while participants relaxed prone on an automated table moving the lower extremities downward 15 degrees, for 5 cycles at 0.5 Hz. Pain intensity on an 11-point numerical rating scale, disability, pain interference, and global improvement were also collected. Participants received 8-weeks of twice-weekly chiropractic care including spinal manipulation, education, exercise, self-management advice and myofascial therapies. Shear strain was computed using 2 methods. The highest shear strain from movement cycles 2, 3, or 4 was averaged over right and left sides for each participant. Alternately, the highest shear strain from movement cycle 3 was used. All data were analyzed over time using mixed-effects models. Estimated mean changes are reported. RESULTS: Of 20 participants completing 8-weeks of chiropractic care (female n = 11), mean (SD) age was 41 years (12.6); mean BMI was 28.5 (6.2). All clinical outcomes improved at 8-weeks. Mean (95% confidence interval) pain intensity decreased 2.7 points (- 4.1 to - 1.4) for females and 2.1 points (- 3.7 to 0.4) for males. Mean Roland-Morris disability score decreased by 5 points (- 7.2 to - 2.8) for females, 2.3 points (- 4.9 to 0.2) for males. Mean PROMIS pain interference T-score decreased by 8.7 points (- 11.8 to - 5.5) for females, 5.6 points (- 9.5 to - 1.6) for males. Mean shear strain at 8-weeks increased in females 5.4% (- 9.9 to 20.8) or 15% (- 0.5 to 30.6), decreasing in males 6.0% (- 24.2 to 12.2) or 2% (- 21.0 to 16.8) depending on computational method. CONCLUSION: Spinal manipulation does not likely disrupt adhesions or relax paraspinal muscles enough to immediately affect shear strain. Clinical outcomes improved in both groups, however, shear strain only increased in females following 8-weeks of multimodal chiropractic care. Trial registration ClinicalTrials.gov registration is NCT03916705.

Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction.

Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague-Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed.

Role for Endocannabinoids in Spinal Manipulative Therapy Analgesia?

Chronic pain is quite prevalent and causes significant disabilities and socioeconomic burdens. Spinal manipulative therapy and other manipulative therapies are used to manage chronic pain. There is a critical knowledge gap about mechanisms and sites of action in spinal manipulative therapy pain relief, especially the short-term analgesia that occurs following a treatment. Endocannabinoids are an activity-dependent neurotransmitter system that acts as a short-term synaptic circuit breaker. This review describes both clinical research and basic research evidence suggesting that endocannabinoids contribute to short-term manipulative therapy analgesia. Determining endocannabinoids involvement in spinal manipulative therapy will improve its clinical efficacy when results from basic science and clinical research are translated.

Spinal manipulative therapy reduces peripheral neuropathic pain in the rat.

Spinal manipulative therapy, including low-velocity variable-amplitude spinal manipulation (LVVA-SM), relieves chronic low back pain, especially in patients with neuropathic radiating leg pain following peripheral nervous system insult. Understanding the underlying analgesic mechanisms requires animal models. The aim of the current study was to develop an animal model for the analgesic actions of LVVA-SM in the setting of peripheral neuropathic pain. Adult male Sprague-Dawley rat sciatic nerve tibial and common peroneal branches were transected, sparing the sural branch (spared nerve injury, SNI). After 15-18 days, rats were assigned randomly to one of three groups (n=9 each group): LVVA-SM at 0.15-or 0.16-Hz or Control. LVVA-SM (20° flexion at the L5 vertebra with an innovative motorized treatment table) was administered in anesthetized rats for 10 min. Control rats were administered anesthesia and positioned on the treatment table. After 10, 25, and 40 min, the plantar skin of the hindpaw ipsilateral to SNI was tested for mechanical sensitivity (paw withdrawal threshold to a logarithmic series of Semmes-Weinstein monofilaments) and cold sensitivity (duration of paw lifting, shaking, and/or licking to topical acetone application). SNI produced behavioral signs of mechanical and cold allodynia. LVVA-SM reduced mechanical, but not cold, hypersensitivity compared with Control (0.15-Hz: P=0.04 at 10 min; 0.16-Hz: P<0.001 at 10 min, P=0.04 at 25 min). The analgesic effect of LVVA-SM in chronic low back pain patients with neuropathic leg pain can be reverse-translated to a rat model Video abstract: http://links.lww.com/WNR/A453.

Decreased spontaneous activity and altered evoked nociceptive response of rat thalamic submedius neurons to lumbar vertebra thrust.

The thalamus is a central structure important to modulating and processing all mechanoreceptor input destined for the cortex. A large number of diverse mechanoreceptor endings are stimulated when a high velocity low amplitude thrust is delivered to the lumbar spine during spinal manipulation. The objective of this study was to determine if a lumbar thrust alters spontaneous and/or evoked nociceptive activity in medial thalamic submedius (Sm) neurons. Extracellular recordings were obtained from 94 thalamic Sm neurons in 54 urethane-anesthetized adult Wistar rats. Spontaneous activity was recorded 5 min before and after an L5 control (no thrust) and thrust (85% rat body weight; 100 ms) procedure. In a subset of responsive nociceptive-specific neurons, mean changes in noxious-evoked response (10-s pinch with clip; 795 g) at three sites (tail, contra- and ipsilateral hindpaw) were determined following an L5 thrust. Mean changes in Sm spontaneous activity (60 s bins) and evoked noxious response were compared using a mixed model repeated measures ANOVA with Bonferroni post hoc t tests and paired t tests, respectively. Compared to control, spontaneous Sm activity decreased 180-240 s following the lumbar thrust (p < 0.005). Inhibitory evoked responses were attenuated in the contralateral hindpaw following an L5 thrust compared to control (p < 0.05). No other changes in spontaneous or noxious-evoked Sm activity were found. A delayed, but prolonged suppression of spontaneous Sm activity along with changes in noxious-evoked inhibitory responses in the contralateral hindpaw following lumbar vertebra thrust suggest that thalamic submedius neurons may play a role in central pain modulation related to manual therapy intervention.

Antinociceptive Effects of Spinal Manipulative Therapy on Nociceptive Behavior of Adult Rats during the Formalin Test.

Optimizing pain relief resulting from spinal manipulative therapies, including low velocity variable amplitude spinal manipulation (LVVA-SM), requires determining their mechanisms. Pain models that incorporate simulated spinal manipulative therapy treatments are needed for these studies. The antinociceptive effects of a single LVVA-SM treatment on rat nociceptive behavior during the commonly used formalin test were investigated. Dilute formalin was injected subcutaneously into a plantar hindpaw. Licking behavior was video-recorded for 5 minutes. Ten minutes of LVVA-SM at 20° flexion was administered with a custom-made device at the lumbar (L5) vertebra of isoflurane-anesthetized experimental rats (n = 12) beginning 10 minutes after formalin injection. Hindpaw licking was video-recorded for 60 minutes beginning 5 minutes after LVVA-SM. Control rats (n = 12) underwent the same methods except for LVVA-SM. The mean times spent licking the formalin-injected hindpaw of both groups 1-5 minutes after injection were not different. The mean licking time during the first 20 minutes post-LVVA-SM of experimental rats was significantly less than that of control rats (P < 0.001). The mean licking times of both groups during the second and third 20 minutes post-LVVA-SM were not different. Administration of LVVA-SM had a short-term, remote antinociceptive effect similar to clinical findings. Therefore, mechanistic investigations using this experimental approach are warranted.

Effect of spinal manipulation thrust duration on trunk mechanical activation thresholds of nociceptive-specific lateral thalamic neurons.

OBJECTIVE: The objective of this preliminary study was to determine if high-velocity, low-amplitude spinal manipulation (HVLA-SM) thrust duration alters mechanical trunk activation thresholds of nociceptive-specific (NS) lateral thalamic neurons. METHODS: Extracellular recordings were obtained from 18 NS neurons located in 2 lateral thalamic nuclei (ventrolateral [n = 12] and posterior [n = 6]) in normal anesthetized Wistar rats. Response thresholds to electronic von Frey anesthesiometer (rigid tip) mechanical trunk stimuli applied in 3 lumbar directions (dorsal-ventral, 45° caudal, and 45° cranial) were determined before and immediately after the delivery of 3 HVLA-SM thrust durations (time control 0, 100, and 400 milliseconds). Mean changes in mechanical trunk activation thresholds were compared using a mixed model analysis of variance. RESULTS: High-velocity, low-amplitude spinal manipulation duration did not significantly alter NS lateral thalamic neurons' mechanical trunk responses to any of the 3 directions tested with the anesthesiometer. CONCLUSIONS: This study is the first to examine the effect of HVLA-SM thrust duration on NS lateral thalamic mechanical response thresholds. High-velocity, low-amplitude spinal manipulation thrust duration did not affect mechanical trunk thresholds.

Cutaneous and electrically evoked glutamate signaling in the adult rat somatosensory system.

Glutamate neurotransmission plays critical roles in normal central nervous system (CNS) function, neurodegenerative diseases, and neurotrauma. We determined whether glutamate signaling could be evoked within the anesthetized normal adult rat CNS with clinically relevant peripheral stimulation and recorded (at >1Hz) with glutamate-sensitive, ceramic microelectrode arrays (MEAs). Basal glutamate levels and both forelimb cutaneous and electrical stimulation-evoked glutamate release were measured within the cuneate nucleus, a relay of the mammalian dorsal columns somatosensory system. The MEAs with triangular, sharp-point tips were more effective at tissue penetration than the flat, blunt tips. Basal glutamate levels of 2.1±4.4µM (mean±SD, n=10 animals) were detected from 150µm to 1200µm below the brainstem dorsal surface. Cutaneous evoked glutamate signals showed an amplitude of 1.1±1.1µM and a duration of 7.3±6.5s (26 signals, n=6). Electrically evoked signals, like cutaneous ones, were both rapid and slowly rising. Electrically evoked signals, especially those evoked by stimulation trains, were more reproducible and had an amplitude of 1.2±1.4µM, duration of 19.4±17.3s, and latency from stimulus onset of 21.3±21.5s (25 signals, n=4). In contrast to cutaneous stimulation, glutamate signals evoked by electrical stimulation had longer durations and were recorded primarily in the middle and ventral cuneate nuclei. Importantly, both cutaneous and electrical stimulation of the contralateral forelimb and hindlimbs did not evoke glutamate signaling. With the use of MEAs, these results show, for the first time, somatosensory-pathway specific changes in glutamate levels during peripheral cutaneous and electrical stimulation.

Horizontal ladder task-specific re-training in adult rats with contusive thoracic spinal cord injury.

PURPOSE: Using the horizontal ladder task, we examined some issues that need to be resolved before task-specific rehabilitative training can be employed clinically for the frequent contusive spinal cord injury (SCI). We hypothesized that improving recovery in task performance after contusive thoracic SCI requires frequent re-training and initiating the re-training early during spontaneous recovery. METHODS: Contusive SCI was produced at the adult female Sprague Dawley rat T10 vertebra. Task re-training was initiated one week later when occasional weight-supported plantar steps were taken overground (n = 8). It consisted of 2 repetitions each day, 5 days each week, for 3 weeks. Task performance and overground locomotion were assessed weekly. Neurotransmission through the SCI ventrolateral funiculus was examined. SCI morphometry was determined. RESULTS: Re-training did not improve task performance recovery compared to untrained Controls (n = 7). Untrained overground locomotion and neurotransmission through the SCI did not change. Lesion area at the injury epicenter as a percentage of the total spinal cord area as well as total tissue, lesion, and spared tissue, white matter, or gray matter volumes did not differ. CONCLUSIONS: For the horizontal ladder task after contusive thoracic SCI, earlier re-training sessions with more repetitions and critical neural circuitry may be necessary to engender a rehabilitation effect.

Plasticity after spinal cord injury: relevance to recovery and approaches to facilitate it.

Motor, sensory, and autonomic functions can spontaneously return or recover to varying extents in both humans and animals, regardless of the traumatic spinal cord injury (SCI) level and whether it was complete or incomplete. In parallel, adverse and painful functions can appear. The underlying mechanisms for all of these diverse functional changes are summarized under the term plasticity. Our review will describe what is known regarding this phenomenon after traumatic SCI and focus on its relevance to motor and sensory recovery. Although it is still somewhat speculative, plasticity can be found throughout the neuraxis and includes various changes ranging from alterations in the properties of spared neuronal circuitries, intact or lesioned axon collateral sprouting, and synaptic rearrangements. Furthermore, we will discuss a selection of potential approaches for facilitating plasticity as possible SCI treatments. Because a mechanism underlying spontaneous plasticity and recovery might be motor activity and the related neuronal activity, activity-based therapies are being used and investigated both clinically and experimentally. Additional pharmacological and gene-delivery approaches, based on plasticity being dependent on the delicate balance between growth inhibition and promotion as well as the basic intrinsic growth ability of the neurons themselves, have been found to be effective alone and in combination with activity-based therapies. The positive results have to be tempered with the reality that not all plasticity is beneficial. Therefore, a tremendous number of questions still need to be addressed. Ultimately, answers to these questions will enhance plasticity's potential for improving the quality of life for persons with SCI.

Construction of pathways to promote axon growth within the adult central nervous system.

Inducing significant axon growth or regeneration after spinal cord injury has been difficult, primarily due to the poor growth supportive environment and low intrinsic growth ability of neurons within the CNS. Neurotrophins alone have been shown to readily induce regeneration of sensory axons after dorsal root lesions, however if neurotrophin gradients are expressed within the spinal cord these axons fail to terminate within appropriate target regions. Under such conditions, addition of a "stop" signal reduces growth into deeper dorsal laminae to support more specific targeting. Such neurotrophin gradients alone lose their effectiveness when lesions are within the spinal cord, requiring a combined treatment regime. Construction of pathways using combined treatments support good regeneration when they increase the intrinsic growth properties of neurons, provide a bridge across the lesion site, and supply a growth supportive substrate to induce axon growth out of the bridge and back into the host. Neurotrophin gradients distal to the bridge greatly enhance axon outgrowth. In disorders where neuronal circuits are lost, construction of preformed growth supportive pathways sustain long distance axon growth from a neuronal transplant to distal target locations.

Anterograde labeling of ventrolateral funiculus pathways with spinal enlargement connections in the adult rat spinal cord.

The ventrolateral funiculus in the spinal cord has been identified as containing important ascending and descending pathways related to locomotion and interlimb coordination. The purpose of this descriptive study was to investigate the patterns of axon termination of long ascending and descending ventrolateral pathways within the cervical and lumbar enlargements of the adult rat spinal cord. To accomplish this, we made discrete unilateral injections of the tracer biotinylated dextran-amine (BDA) into the ventrolateral white matter at T9. Although some BDA-labeled axons with varicosities were found bilaterally at all cervical levels, particularly dense BDA labeling was observed in laminae VIII and IX ipsilaterally at the C6 and C8 levels. In the same animals, dense terminal labeling was found in the lumbar enlargement in medial lamina VII and ventromedial laminae VIII and IX contralaterally. This labeling was most apparent in the more rostral lumbar segments. These observations continue the characterization of inter-enlargement (long propriospinal) pathways, illustrating a substantial and largely reciprocal inter-enlargement network with large numbers of both ascending and descending ventrolateral commissural neurons. These pathways are anatomically well-suited to the task of interlimb coordination and to participate in the remarkable recovery of locomotor function seen in the rat following thoracic spinal cord injuries that spare as little as 20% of the total white matter cross sectional area.

Transplantation-mediated strategies to promote axonal regeneration following spinal cord injury.

Devastating central nervous system injuries and diseases continue to occur in spite of the tremendous efforts of various prevention programs. The enormity and annual escalation of healthcare costs due to them require that therapeutic strategies be responsibly developed. The dysfunctions that occur after injury and disease are primarily due to neurotransmission damage. The last two decades of both experimental and clinical research have demonstrated that neural and non-neural tissue and cell transplantation is a viable option for ameliorating dysfunctions to markedly improve quality of life. Moreover, significant progress has been made with tissue and cell transplantation in studies of pathophysiology, plasticity, sprouting, regeneration, and functional recovery. This article will review information about the ability and potential, particularly for traumatic spinal cord injury, that neural and non-neural tissue and cell transplantation has to replace lost neurons and glia, to reconstruct damaged neural circuitry, and to restore neurotransmitters, hormones, neurotrophic factors, and neurotransmission. Donor tissues and cells to be discussed include peripheral nerve, fetal spinal cord and brain, central and peripheral nervous systems' glia, stem cells, those that have been genetically engineered, and non-neural ones. Combinatorial approaches and clinical research are also reviewed.

Rolipram attenuates acute oligodendrocyte death in the adult rat ventrolateral funiculus following contusive cervical spinal cord injury.

Rolipram, an inhibitor of phosphodiesterase 4 (PDE4) proteins that hydrolyze cAMP, increases axonal regeneration following spinal cord injury (SCI). Recent evidence indicate that rolipram also protects against a multitude of apoptotic signals, many of which are implicated in secondary cell death post-SCI. In the present study, we used immunohistochemistry and morphometry to determine potential spinal cord targets of rolipram and to test its protective potential in rats undergoing cervical spinal cord contusive injury. We found that 3 PDE4 subtypes (PDE4A, B, D) were expressed by spinal cord oligodendrocytes. OX-42 immunopositive microglia only expressed the PDE4B subtype. Oligodendrocyte somata were quantified within the cervical ventrolateral funiculus, a white matter region critical for locomotion, at varying time points after SCI in rats receiving rolipram or vehicle treatments. We show that rolipram significantly attenuated oligodendrocyte death at 24 h post-SCI continuing through 72 h, the longest time point examined. These results demonstrate for the first time that spinal cord glial cells express PDE4 subtypes and that the PDE4 inhibitor rolipram protects oligodendrocytes from secondary cell death following contusive SCI. They also indicate that further investigations into neuroprotection and axonal regeneration with rolipram are warranted for treating SCI.

Labeling stem cells in vitro for identification of their differentiated phenotypes after grafting into the CNS.

Grafting neural stem cells is a widely used experimental approach to central nervous system (CNS) repair after trauma or neurodegeneration. It is likely to be a realistic clinical therapy for human CNS disorders in the near future. One of the challenges of this approach is the ability to identify both the survival and differentiated phenotype of various stem cell populations after engraftment into the CNS. There is no single protocol that will work for all cell types and all applications. Labeling stem cells for CNS grafting is an empirical process. The type of stem cell, its fate after engraftment, and the context in which it is anatomically and histologically evaluated all contribute to a decision as to the best approach to take. We have provided the range of conditions under which various labels have been successfully used in CNS grafting studies and delineated the parameters that have to be empirically established. Given a clear understanding of the limitations of the respective labels and the expected outcome of the grafting experiment, these labeling guidelines should enable any investigator to develop a successful approach. Our own personal bias is to use labels that cannot be transferred to host cells. Initially, we preferred 5-bromo-2'-deoxyuridine, or retrovirally delivered enhanced green fluorescent protein or lacZ. More recently, we have found syngeneic grafts of human placental alkaline phosphatase stem cells to work very well. However, each investigator will have to decide what is optimal for his or her cell population and experimental design. We summarize the various approaches to labeling and identifying stem cells, pointing out both the limitations and strengths of the various approaches delineated.

Identification of penile inputs to the rat gracile nucleus.

Neurons in the medullary reticular formation (MRF) of the rat receive a vast array of urogenital inputs. Using select acute and chronic spinal cord lesions to identify the location of the ascending neural circuitries providing either direct or indirect inputs to MRF from the penis, our previous studies demonstrated that the dorsal columns and dorsal half of the lateral funiculus convey low- and high-threshold inputs, respectively. In the present study, the gracile nucleus was targeted as one of the likely sources of low-threshold information from the penis to MRF. Both electrophysiological recordings and neuroanatomical tracing [injection of cholera toxin B subunit (CTB) into a dorsal nerve of the penis] were used. After discrimination of a single neuron responding to penile stimulation, testing for somatovisceral convergence was done (mechanical stimulation of the distal colon and the skin over the entire hindquarters). In 12 rats, a limited number of neurons (43 in total) responded to penile stimulation. Many of these neurons also responded to scrotal stimulation (53.5%, dorsal and/or ventral scrotum) and/or prepuce stimulation (46.5%). Histological reconstruction of the electrode tracks showed that the majority of neurons responding to penile stimulation were located ventrally within the medial one-third of the gracile nucleus surrounding obex. This location corresponded to sparse innervation by CTB-immunoreactive primary afferent terminals. These results indicate that neurons in the gracile nucleus are likely part of the pathway that provides low-threshold penile inputs to MRF, a region known to play an important role in mating processes.

Cortical and subcortical plasticity in the brains of humans, primates, and rats after damage to sensory afferents in the dorsal columns of the spinal cord.

The failure of injured axons to regenerate following spinal cord injury deprives brain neurons of their normal sources of activation. These injuries also result in the reorganization of affected areas of the central nervous system that is thought to drive both the ensuing recovery of function and the formation of maladaptive neuronal circuitry. Better understanding of the physiological consequences of novel synaptic connections produced by injury and the mechanisms that control their formation are important to the development of new successful strategies for the treatment of patients with spinal cord injuries. Here we discuss the anatomical, physiological and behavioral changes that take place in response to injury-induced plasticity after damage to the dorsal column pathway in rats and monkeys. Complete section of the dorsal columns of the spinal cord at a high cervical level in monkeys and rats interrupts the ascending axon branches of low threshold mechanoreceptor afferents subserving the forelimb and the rest of the lower body. Such lesions render the corresponding part of the somatotopic representation of primary somatosensory cortex totally unresponsive to tactile stimuli. There are also behavioral consequences of the sensory loss, including an impaired use of the hand/forelimb in manipulating small objects. In monkeys, if some of the afferents from the hand remain intact after dorsal column lesions, these remaining afferents extensively reactivate portions of somatosensory cortex formerly representing the hand. This functional reorganization develops over a postoperative period of 1 month, during which hand use rapidly improves. These recoveries appear to be mediated, at least in part, by the sprouting of preserved afferents within the cuneate nucleus of the dorsal column-trigeminal complex. In rats, such functional collateral sprouting has been promoted by the post-lesion digestion of the perineuronal net in the cuneate nucleus. Thus, this and other therapeutic strategies have the potential of enhancing sensorimotor recoveries after spinal cord injuries in humans.

Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3.

Increased chondroitin sulfate proteoglycan (CSPG) expression in the vicinity of a spinal cord injury (SCI) is a primary participant in axonal regeneration failure. However, the presence of similar increases of CSPG expression in denervated synaptic targets well away from the primary lesion and the subsequent impact on regenerating axons attempting to approach deafferented neurons have not been studied. Constitutively expressed CSPGs within the extracellular matrix and perineuronal nets of the adult rat dorsal column nuclei (DCN) were characterized using real-time PCR, Western blot analysis and immunohistochemistry. We show for the first time that by 2 days and through 3 weeks following SCI, the levels of NG2, neurocan and brevican associated with reactive glia throughout the DCN were dramatically increased throughout the DCN despite being well beyond areas of trauma-induced blood brain barrier breakdown. Importantly, regenerating axons from adult sensory neurons microtransplanted 2 weeks following SCI between the injury site and the DCN were able to regenerate rapidly within white matter (as shown previously by Davies et al. [Davies, S.J., Goucher, D.R., Doller, C., Silver, J., 1999. Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J. Neurosci. 19, 5810-5822]) but were unable to enter the denervated DCN. Application of chondroitinase ABC or neurotrophin-3-expressing lentivirus in the DCN partially overcame this inhibition. When the treatments were combined, entrance by regenerating axons into the DCN was significantly augmented. These results demonstrate both an additional challenge and potential treatment strategy for successful functional pathway reconstruction after SCI.