Calcium channel α2δ1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis.

To investigate a potential mechanism underlying trigeminal nerve injury-induced orofacial hypersensitivity, we used a rat model of chronic constriction injury to the infraorbital nerve (CCI-ION) to study whether CCI-ION caused calcium channel α2δ1 (Cavα2δ1) protein dysregulation in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 cervical dorsal spinal cord (Vc/C2). Furthermore, we studied whether this neuroplasticity contributed to spinal neuron sensitization and neuropathic pain states. CCI-ION caused orofacial hypersensitivity that correlated with Cavα2δ1 up-regulation in trigeminal ganglion neurons and Vc/C2. Blocking Cavα2δ1 with gabapentin, a ligand for the Cavα2δ1 proteins, or Cavα2δ1 antisense oligodeoxynucleotides led to a reversal of orofacial hypersensitivity, supporting an important role of Cavα2δ1 in orofacial pain processing. Importantly, increased Cavα2δ1 in Vc/C2 superficial dorsal horn was associated with increased excitatory synaptogenesis and increased frequency, but not the amplitude, of miniature excitatory postsynaptic currents in dorsal horn neurons that could be blocked by gabapentin. Thus, CCI-ION-induced Cavα2δ1 up-regulation may contribute to orofacial neuropathic pain states through abnormal excitatory synapse formation and enhanced presynaptic excitatory neurotransmitter release in Vc/C2

Identifying the Neural Correlates of Anticipatory Postural Control: A Novel fMRI Paradigm

Altered postural control in the trunk/hip musculature is a characteristic of multiple neurological and musculoskeletal conditions. Previously it was not possible to determine if altered cortical and subcortical sensorimotor brain activation underlies impairments in postural control. This study used a novel fMRI-compatible paradigm to identify the brain activation associated with postural control in the trunk and hip musculature. BOLD fMRI imaging was conducted as participants performed two versions of a lower limb task involving lifting the left leg to touch the foot to a target. For the supported leg raise (SLR) the leg is raised from the knee while the thigh remains supported. For the unsupported leg raise (ULR) the leg is raised from the hip, requiring postural muscle activation in the abdominal/hip extensor musculature. Significant brain activation during the SLR task occurred predominantly in the right primary and secondary sensorimotor cortical regions. Brain activation during the ULR task occurred bilaterally in the primary and secondary sensorimotor cortical regions, as well as cerebellum and putamen. In comparison with the SLR, the ULR was associated with significantly greater activation in the right premotor/SMA, left primary motor and cingulate cortices, primary somatosensory cortex, supramarginal gyrus/parietal operculum, superior parietal lobule, cerebellar vermis, and cerebellar hemispheres. Cortical and subcortical regions activated during the ULR, but not during the SLR, were consistent with the planning, and execution of a task involving multisegmental, bilateral postural control. Future studies using this paradigm will determine mechanisms underlying impaired postural control in patients with neurological and musculoskeletal dysfunction

Structural Sensorimotor Adaptations in Young Adults with Low Back Pain

Chronic low back pain (CLBP) is the largest cause of disability worldwide. There is evidence for regional structural brain adaptation in CLBP. Most studies have investigated middle-aged adults and show decreased grey matter density in pain processing regions. It is not clear if these adaptations are evident early in the lifespan of individuals with CLBP. The purpose of the study was to compare sensorimotor gray matter density in young adults with a history of CLBP with back-healthy controls. 53 young adults with a greater than 1-year history of CLBP and 29 young adults with no history of LBP participated. Clinical characteristics of the LBP group were quantified with measures of pain duration and intensity as well as pain-related fear and disability. Gray matter density was quantified with voxel-based morphometry. Whole brain and sensorimotor region of interest (ROI) comparisons between groups were made after covarying for age, sex, and total intracranial volume. ROIs were determined a priori. Associations between clinical characteristics and average gray matter density in sensorimotor ROI comparisons were explored with Pearson\u27s correlation coefficients. Individuals with CLBP reported an average duration of pain of 4.9 (+/- 2.2 years) and average pain intensity of 5.0/10. The LBP group had greater gray matter in the right primary somatosensory cortex, right inferior parietal lobule, and right midcingulate cortex (all p \u3c 0.05 FWE corrected). There were significant positive associations between average gray matter and clinical characteristics in the anterior, mid, and posterior cingulate cortices, the supramarginal gyrus, superior parietal lobule and supplementary motor area (all p \u3c 0.05). We demonstrate that in young adults, CLBP is associated with structural neuroplasticity in regions involved in sensory processing, motor control, and the sensory and emotional aspects of pain experience. Increased grey matter density early in the lifespan of individuals with CLBP may reflect an adaptation to ongoing nociceptive input

Effect of Overground Training Augmented by Mental Practice on Gait Velocity in Chronic, Incomplete Spinal Cord Injury

OBJECTIVE: To compare efficacy of a regimen combining mental practice (MP) with overground training with the efficacy of a regimen comprised of overground training only on gait velocity and lower extremity motor outcomes in individuals with chronic (> 12 months post injury), incomplete, spinal cord injury (SCI). DESIGN: Randomized controlled, single blinded, study SETTING: Outpatient rehabilitation laboratories located in the Midwestern and Western United States PARTICIPANTS: 18 subjects with chronic, incomplete SCI INTERVENTIONS: Subjects were randomly assigned to receive: (a) Overground Training only (OT), occurring 3 days/week for 8 weeks; or (b) OT augmented by MP (MP + OT), during which randomly assigned subjects listened to a mental practice audio recording directly following OT sessions. MAIN OUTCOME MEASURES: Subjects were administered a test of gait velocity as well as the Tinetti Performance Oriented Mobility Assessment (POMA), Spinal Cord Injury Independence Measure (SCIM), and Satisfaction with Life Scale (SWLS) on 2 occasions before intervention, 1 week after intervention, and 12 weeks after intervention. RESULTS: A significant increase in gait velocity was exhibited across subjects at both 1 week post-therapy (p=0.0046) and at 12 weeks post-therapy (p=0.0056). However, no differences were seen in intervention response at either 1 or 12 weeks post intervention among subjects in the MP + OT versus the OT groups. CONCLUSION: Overground training was associated with significant gains in gait velocity, and that these gains were not augmented by further addition of mental practice

Bilateral cervical contusion spinal cord injury in rats

There is increasing motivation to develop clinically relevant experimental models for cervical SCI in rodents and techniques to assess deficits in forelimb function. Here we describe a bilateral cervical contusion model in rats. Female Sprague-Dawley rats received mild or moderate cervical contusion injuries (using the Infinite Horizons device) at C5, C6, or C7/8. Forelimb motor function was assessed using a grip strength meter (GSM); sensory function was assessed by the von Frey hair test; the integrity of the corticospinal tract (CST) was assessed by biotinylated dextran amine (BDA) tract tracing. Mild contusions caused primarily dorsal column (DC) and gray matter (GM) damage while moderate contusions produced additional damage to lateral and ventral tissue. Forelimb and hindlimb function was severely impaired immediately post-injury, but all rats regained the ability to use their hindlimbs for locomotion. Gripping ability was abolished immediately after injury but recovered partially, depending upon the spinal level and severity of the injury. Rats exhibited a loss of sensation in both fore- and hindlimbs that partially recovered, and did not exhibit allodynia. Tract tracing revealed that the main contingent of CST axons in the DC was completely interrupted in all but one animal whereas the dorsolateral CST (dlCST) was partially spared, and dlCST axons gave rise to axons that arborized in the GM caudal to the injury. Our data demonstrate that rats can survive significant bilateral cervical contusion injuries at or below C5 and that forepaw gripping function recovers after mild injuries even when the main component of CST axons in the dorsal column is completely interrupted

A re-assessment of long distance growth and connectivity of neural stem cells after severe spinal cord injury

As part of the NIH "Facilities of Research Excellence-Spinal Cord Injury" project to support independent replication, we repeated key parts of a study reporting robust engraftment of neural stem cells (NSCs) treated with growth factors after complete spinal cord transection in rats. Rats (n=20) received complete transections at thoracic level 3 (T3) and 2weeks later received NSC transplants in a fibrin matrix with a growth factor cocktail using 2 different transplantation methods (with and without removal of scar tissue). Control rats (n=9) received transections only. Hindlimb locomotor function was assessed with the BBB scale. Nine weeks post injury, reticulospinal tract axons were traced in 6 rats by injecting BDA into the reticular formation. Transplants grew to fill the lesion cavity in most rats although grafts made with scar tissue removal had large central cavities. Grafts blended extensively with host tissue obliterating the astroglial boundary at the cut ends, but in most cases there was a well-defined partition within the graft that separated rostral and caudal parts of the graft. In some cases, the partition contained non-neuronal scar tissue. There was extensive outgrowth of GFP labeled axons from the graft, but there was minimal ingrowth of host axons into the graft revealed by tract tracing and immunocytochemistry for 5HT. There were no statistically significant differences between transplant and control groups in the degree of locomotor recovery. Our results confirm the previous report that NSC transplants can fill lesion cavities and robustly extend axons, but reveal that most grafts do not create a continuous bridge of neural tissue between rostral and caudal segments

Increased Brain Sensorimotor Network Activation after Incomplete Spinal Cord Injury.

After complete spinal cord injury (SCI), activation during attempted movement of paralyzed limbs is sharply reduced, but after incomplete SCI-the more common form of human injury-it is unknown how attempts to move voluntarily are accompanied by activation of brain motor and sensory networks. Here, we assessed brain activation during ankle movement in subjects with incomplete SCI, among whom voluntary motor function is partially preserved. Adults with incomplete SCI (n = 20) and healthy controls (n = 15) underwent functional magnetic resonance imaging that alternated rest with 0.3-Hz right ankle dorsiflexion. In both subject groups, ankle movement was associated with bilateral activation of primary and secondary sensory and motor areas, with significantly (p < 0.001) greater activation in subjects with SCI within right hemisphere areas, including primary sensorimotor cortex and pre-motor cortex. This result was further evaluated using linear regression analysis with respect to core clinical variables. Poorer locomotor function correlated with larger activation within several right hemisphere areas, including pre- and post-central gyri, possibly reflecting increased movement complexity and effort, whereas longer time post-SCI was associated with larger activation in left post-central gyrus and bilateral supplementary motor area, which may reflect behaviorally useful adaptations. The results indicate that brain adaptations after incomplete SCI differ sharply from complete SCI, are related to functional behavioral status, and evolve with increasing time post-SCI. The results suggest measures that might be useful for understanding and treating incomplete SCI in human subjects