Patrick Kitzman

Alteration in axial motoneuronal morphology in the spinal cord injured spastic rat.

Following spinal cord injury (SCI), exaggerated reflexes and muscle tone emerge that contribute to a general spastic syndrome in humans. At present, the underlying mechanisms involved with the development of spasticity following traumatic spinal cord injury, especially with regard to axial musculature, remains unclear. The purpose of the present study was to examine the temporal changes in sacrocaudal motoneuronal morphology following complete transection of the sacral spinal cord and to correlate these changes with the onset and progression of spasticity within the tail musculature. The spinal cords of rats were transected at the upper sacral (S(2)) level. Animals were behaviorally tested for the onset and progression of spasticity in the tail and at 1, 2, 4, or 12 weeks postinjury were sacrificed. At these time points, the animals demonstrated stage 1, 2, 3, or 4 spastic behavior, respectively. Sacrocaudal motoneurons innervating selected flexor muscles within the tail were retrogradely labeled with cholera toxin beta-subunit and neuronal morphology was analyzed using a combination of immunocytochemistry and standard microscopy. Initially over the first 2 weeks postinjury, a transient increase in the lengths of primary and secondary dendrites occurred. However, a progressive decrease in the overall number of dendritic branches was observed between 2 and 12 weeks postinjury, which parallels the time frame for the progressive increase in spastic behavior in the tail musculature. Following spinal cord injury, there is an alteration in the morphology of tail flexor motoneurons, which may be relevant to the development of spasticity within the tail.

Latest Approaches for the Treatment of Spasticity and Autonomic Dysreflexia in Chronic Spinal Cord Injury

SummaryTwo of the most prevalent secondary complications following spinal cord injury (SCI), besides loss of function and/or sensation below the level of injury, are uncontrolled muscle spasticity and hypertensive autonomic dysreflexia. Despite the desires of the SCI community, there have been few advances in the treatment and/or management of these fundamental impediments to the quality of life associated with chronic SCI. Therefore, the purpose of this review is to focus on current drug treatment strategies that alleviate symptoms of spasticity and autonomic dysfunction. Subsequently, looking ahead, we discuss whether individuals suffering from autonomic dysreflexia and/or muscle spasms can take certain compounds that specifically and rapidly block the neurotransmission of pain into the injured spinal cord to get rapid relief for both aberrant reflexes for which painful stimuli below the level of SCI are common precipitants.

Effectiveness of riluzole in suppressing spasticity in the spinal cord injured rat

UNLABELLED Spasticity poses a major detrimental impact on the quality of life in a significant number of people with spinal cord injury (SCI). Recent observations in our laboratory suggest that spinal transection at the sacral S(2) level induces a significant increase in glutamatergic input to sacrocaudal motoneurons during the time spasticity is present in the tail muscles. The present study examined the effectiveness of riluzole, an agent that has been shown to reduce glutamate release, in managing spasticity within the tail musculature. In this blinded, cross-over study animals with S(2) spinal transections were tested behaviorally for the progression of spasticity in the tail musculature using our established system. When the animals demonstrated a significant level of spastic behavior (e.g. increased response to quick stretch, noxious and non-noxious cutaneous stimuli), they received either saline or riluzole (8 or 10 mg/kg i.p.) and assessed behaviorally at 1, 3, 6, and 12 post-injection. RESULTS riluzole at 8 mg/kg significantly decreased the response of the tail muscle to noxious and non-noxious cutaneous stimuli for the first 3 h post-administration, while administration of riluzole at 10 mg/kg significantly decreased the responsiveness of the tail to all of the behavioral assessments. However, a significant percentage of the animals displayed motor impairments at this higher dosage. CONCLUSION suppression of glutamate release by the administration of riluzole can reduce several, but not all, aspects of spastic activity in the tail muscles at concentrations that do not elicit negative side-effects.

Changes in vesicular glutamate transporter 2, vesicular GABA transporter and vesicular acetylcholine transporter labeling of sacrocaudal motoneurons in the spastic rat

Spasticity of the midline musculature can significantly hinder performing transfers and lead to development of pressure sores. Currently, significant gaps exist in our knowledge of the pathophysiology involved in spasticity development following SCI, especially regarding the axial musculature. The goals of this study were: (1) to determine the effects of S(2) transection on the number and distribution of glutamatergic, GABAergic and cholinergic inputs on more caudal motoneurons, (2) to correlate these changes with the development of spasticity within the tail musculature, which are the caudal counterparts to the axial musculature. Animals with S(2) spinal transection were tested behaviorally for the progression of spasticity within the tail musculature. At 1, 2, 4, or 12 weeks post-injury, the animals were sacrificed and temporal changes in glutamatergic, GABAergic, and cholinergic inputs to sacrocaudal motoneurons were assessed using antibodies for the specific vesicular transporter of each neurotransmitter and confocal microscopy. At 1 week post-injury, when the tail musculature demonstrated decreased responsiveness, an overall increase in the ratio of excitatory to inhibitory input to sacrocaudal motoneurons was observed. From 2 to 12 weeks post-injury, when the tail musculature demonstrated increased reflex behavior, an overall decrease in the ratio of excitatory to inhibitory inputs was observed. Additionally, from 2 to 12 weeks following spinal transection, a progressive loss of cholinergic labeling of sacrocaudal motoneurons was observed. The increase in the overall level of excitation with a concomitant loss of cholinergic influence following spinal transection could, in part, explain the development of spasticity within the tail musculature.

VGLUT1 and GLYT2 labeling of sacrocaudal motoneurons in the spinal cord injured spastic rat.

Spasticity of the midline (axial) musculature may hinder (1) performing transfers, (2) efficient extremity and head movements, and (3) efficient respiration. Currently, gaps exist in our knowledge of the pathophysiology involved in spasticity development within the axial musculature. The goals of this study were (1) to study the effects of S(2) transection on the number and distribution of glutamatergic inputs, arising from primary afferents, and glycinergic inputs to sacrocaudal motoneurons; and (2) to correlate changes in these synaptic inputs with the development of spasticity within the tail musculature, which are the caudal counterparts to the trunk axial musculature. Animals with S(2) spinal transection were tested behaviorally using our established system. At 1, 2, 4, and 12 weeks post-injury, sacrocaudal motoneurons were retrogradely labeled with cholera toxin beta-subunit (CTB), and temporal changes in vesicular glutamate transporter 1 (VGLUT1) and glycine transporter 2 (GlyT2) inputs to CTB-labeled motoneurons were visualized using antibodies specific for each synaptic type and confocal microscopy. These time points correspond to each of 4 stages of spasticity development. There was no significant change in either VGLUT1 or GlyT2 labeling of sacrocaudal motoneurons at any of the time points examined. Spinal cord injury-induced spasticity, in the tail musculature, does not appear to involve either an increase in monosynaptic glutamatergic inputs from myelinated afferents or a decrease in glycinergic inputs to sacrocaudal motoneurons.

Effects of gabapentin on muscle spasticity and both induced as well as spontaneous autonomic dysreflexia after complete spinal cord injury

We recently reported that the neuropathic pain medication, gabapentin (GBP; Neurontin), significantly attenuated both noxious colorectal distension (CRD)-induced autonomic dysreflexia (AD) and tail pinch-induced spasticity compared to saline-treated cohorts 2–3 weeks after complete high thoracic (T4) spinal cord injury (SCI). Here we employed long-term blood pressure telemetry to test, firstly, the efficacy of daily versus acute GBP treatment in modulating AD and tail spasticity in response to noxious stimuli at 2 and 3 weeks post-injury. Secondly, we determined whether daily GBP alters baseline cardiovascular parameters, as well as spontaneous AD events detected using a novel algorithm based on blood pressure telemetry data. At both 14 and 21 days after SCI, irrespective of daily treatment, acute GBP given 1 h prior to stimulus significantly attenuated CRD-induced AD and pinch-evoked tail spasticity; conversely, acute saline had no such effects. Moreover, daily GBP did not alter 24 h mean arterial pressure (MAP) or heart rate (HR) values compared to saline treatment, nor did it reduce the incidence of spontaneous AD events compared to saline over the three week assessment period. Power spectral density (PSD) analysis of the MAP signals demonstrated relative power losses in mid frequency ranges (0.2–0.8 Hz) for all injured animals relative to low frequency MAP power (0.02–0.08 Hz). However, there was no significant difference between groups over time post-injury; hence, GBP had no effect on the persistent loss of MAP fluctuations in the mid frequency range after injury. In summary, the mechanism(s) by which acute GBP treatment mitigate aberrant somatosensory and cardiophysiological responses to noxious stimuli after SCI remain unclear. Nevertheless, with further refinements in defining the dynamics associated with AD events, such as eliminating requisite concomitant bradycardia, the objective repeatability of automatic detection of hypertensive crises provides a potentially useful tool for assessing autonomic function pre- and post-SCI, in conjunction with experimental pharmacotherapeutics for neuropathic pain, such as GBP.

Level of p75 receptor expression in sensory ganglia is modulated by NGF level in the target tissue.

Neurotrophins play an essential role in sensory development by providing trophic support to neurons that innervate peripheral targets. Nerve growth factor (NGF), neurotrophin-3, neurotrophin-4, and brain-derived neurotrophin exert their survival effect by binding to two transmembrane receptor types: trk receptors, which exhibit binding specificity, and the p75NTR receptor, which binds all neurotrophins. To determine how target-derived neurotrophins affect sensory neuron development and function, we used transgenic mice that overexpress NGF in the skin to examine the impact of NGF overexpression on receptor expression. Previous studies of trk expression in trigeminal ganglia of adult NGF transgenics showed that the percentage of trkA neurons doubled and their number increased fivefold. The present study focused on the p75 receptor and shows that the percentage of neurons expressing p75NTR also increase in NGF ganglia, but only by 10%. This increase did not encompass the small, BS-IB-4 isolectin-positive cells as they remained p75 negative in transgenic ganglia. Interestingly, levels of trkA protein were not increased on a per-cell level, whereas levels of p75NTR increased nearly threefold. These results show that in sensory systems, target-derived NGF modulates the level of p75NTR receptor expression, and in so doing, may act to regulate the formation of functional receptor complexes and subsequent trophic action.

Investigating the Mechanisms of Massage Efficacy: The Role of Mechanical Immunomodulation

Massage has the potential to attenuate the inflammatory process, facilitate early recovery, and provide pain relief from muscular injuries. In this hypothesis-driven paper, we integrate the concept of mechanotransduction with the application of massage to explore beneficial mechanisms. By altering signaling pathways involved with the inflammatory process, massage may decrease secondary injury, nerve sensitization, and collateral sprouting, resulting in increased recovery from damage and reduction or prevention of pain. Our goal is to provide a framework that describes our current understanding of the mechanisms whereby massage therapy activates potentially beneficial immunomodulatory pathways.

The risks of polypharmacy following spinal cord injury

Objective: The purpose of this study was to examine the overall prevalence of polypharmacy within the spinal cord injury (SCI) population, the level of polypharmacy with respect to seven classes of high-risk drugs commonly used to treat secondary conditions in the SCI population, and the overall risks for drug-related problems (DRP) related to polypharmacy. Design: A retrospective case–control design. Setting: A commercially available claims dataset that included patient cases from 4800 hospitals in the USA between 2007 and 2009. Participants: Individuals with tetraplegia, paraplegia, and those with SCI but not specified as either tetraplegia or paraplegia as well as a control population of randomly selected, age- and sex-matched individuals without a diagnosis of SCI. Outcome measures: The overall prevalence of polypharmacy, the prevalence of commonly prescribed high-risk medications, and the prevalence of reported DRPs. Results: Overall, the patients in the SCI population were prescribed significantly more medications than their control counterparts. There was a higher rate of individuals being prescribed medications from multiple high-risk classes (e.g. analgesic-narcotics, anticonvulsant, antidepressant, and skeletal muscle relaxer), as well as multiple medications within each class (e.g. multiple analgesic-narcotics). The SCI group had a higher incidence of DRPs. Conclusion: Our results are some of the first to demonstrate the extent of polypharmacy in individuals with SCI, including commonly prescribed high-risk medications, leading to a higher rate of DPRs. The higher rate of polypharmacy and DRPs can impact rehabilitation goals and community integration following neurologic injury.

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.