Mouse Model of Spinal Cord Hypoperfusion with Immediate Paralysis Caused by Endovascular Repair of Thoracic Aortic Aneurysm.

BACKGROUND: A clinically relevant mouse model of thoracic endovascular aortic repair-induced ischemic spinal cord injury has been lacking since the procedure was first employed in 1991. The hypothesis was that ligation of mouse intercostal arteries would simulate thoracic endovascular aortic repair-induced ischemic spinal cord injury and behavioral deficit. The aim was to create a mouse model of thoracic endovascular aortic repair-induced spinal cord hypoperfusion by ligating five pairs of mouse intercostal vessels. METHODS: Mice were divided into sham (n = 53) and ligation (n = 60) groups. The procedures called for double ligation of three pairs and single ligation of two pairs of thoracic intercostal arteries in adult C57BL/6 mice. A laser Doppler probe was used in vivo on the spinal cords and intercostal arteries to document the extent of arterial ligation and spinal cord hypoperfusion. The Basso Mouse Scale for Locomotion, histological studies, and electron microscopy demonstrated postligation locomotive and histopathological changes. RESULTS: Ligation induced a significant and instantaneous drop in blood flow in the intercostal arteries (% change; mean = -63.81; 95% CI, -72.28 to -55.34) and the thoracic spinal cord (% change; mean = -68.55; 95% CI, -80.23 to -56.87). Paralysis onset was immediate and of varying degree, with behavioral deficit stratified into three groups: 9.4% exhibited severe paralysis, 37.5% moderate paralysis, and 53.1% mild paralysis at day 1 (n = 32; P < 0.001). Mild and moderate paralysis was transient, gradually improving over time. Severe paralysis showed no improvement and exhibited a higher mortality rate (83%; n = 15 of 18) compared to moderately (33%; n = 6 of 18) and mildly (24%; n = 6 of 25) paralyzed mice (P < 0.001). The overall ligation group survival rate (84%; n = 46 of 55) was significantly lower than the sham group (100%; n = 48 of 48) with P = 0.003. CONCLUSIONS: The mouse model generates reproducible spinal cord hypoperfusion and accompanying histopathological ischemic spinal cord damage. The resulting anatomical changes and variable behavioral deficits mimic the variability in radiological and clinical findings in human patients.

Microglia Promote Increased Pain Behavior through Enhanced Inflammation in the Spinal Cord during Repeated Social Defeat Stress.

Clinical studies indicate that psychosocial stress contributes to adverse chronic pain outcomes in patients, but it is unclear how this is initiated or amplified by stress. Repeated social defeat (RSD) is a mouse model of psychosocial stress that activates microglia, increases neuroinflammatory signaling, and augments pain and anxiety-like behaviors. We hypothesized that activated microglia within the spinal cord facilitate increased pain sensitivity following RSD. Here we show that mechanical allodynia in male mice was increased with exposure to RSD. This stress-induced behavior corresponded with increased mRNA expression of several inflammatory genes, including IL-1ß, TNF-α, CCL2, and TLR4 in the lumbar spinal cord. While there were several adhesion and chemokine-related genes increased in the lumbar spinal cord after RSD, there was no accumulation of monocytes or neutrophils. Notably, there was evidence of microglial activation selectively within the nociceptive neurocircuitry of the dorsal horn of the lumbar cord. Elimination of microglia using the colony stimulating factor 1 receptor antagonist PLX5622 from the brain and spinal cord prevented the development of mechanical allodynia in RSD-exposed mice. Microglial elimination also attenuated RSD-induced IL-1ß, CCR2, and TLR4 mRNA expression in the lumbar spinal cord. Together, RSD-induced allodynia was associated with microglia-mediated inflammation within the dorsal horn of the lumbar spinal cord.SIGNIFICANCE STATEMENT Mounting evidence indicates that psychological stress contributes to the onset and progression of adverse nociceptive conditions. We show here that repeated social defeat stress causes increased pain sensitivity due to inflammatory signaling within the nociceptive circuits of the spinal cord. Studies here mechanistically tested the role of microglia in the development of pain by stress. Pharmacological ablation of microglia prevented stress-induced pain sensitivity. These findings demonstrate that microglia are critical mediators in the induction of pain conditions by stress. Moreover, these studies provide a proof of principle that microglia can be targeted as a therapeutic strategy to mitigate adverse pain conditions.

Longitudinal Recovery and Reduced Costs After 120 Sessions of Locomotor Training for Motor Incomplete Spinal Cord Injury.

OBJECTIVE: To determine the impact of long-term, body weight-supported locomotor training after chronic, incomplete spinal cord injury (SCI), and to estimate the health care costs related to lost recovery potential and preventable secondary complications that may have occurred because of visit limits imposed by insurers. DESIGN: Prospective observational cohort with longitudinal follow-up. SETTING: Eight outpatient rehabilitation centers that participate in the Christopher & Dana Reeve Foundation NeuroRecovery Network (NRN). PARTICIPANTS: Individuals with motor incomplete chronic SCI (American Spinal Injury Association Impairment Scale C or D; N=69; 0.1-45y after SCI) who completed at least 120 NRN physical therapy sessions. INTERVENTIONS: Manually assisted locomotor training (LT) in a body weight-supported treadmill environment, overground standing and stepping activities, and community integration tasks. MAIN OUTCOME MEASURES: International Standards for Neurological Classification of Spinal Cord Injury motor and sensory scores, orthostatic hypotension, bowel/bladder/sexual function, Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI), Berg Balance Scale, Modified Functional Reach, 10-m walk test, and 6-minute walk test. Longitudinal outcome measure collection occurred every 20 treatments and at 6- to 12-month follow-up after discharge from therapy. RESULTS: Significant improvement occurred for upper and lower motor strength, functional activities, psychological arousal, sensation of bowel movement, and SCI-FAI community ambulation. Extended training enabled minimal detectable changes at 60, 80, 100, and 120 sessions. After detectable change occurred, it was sustained through 120 sessions and continued 6 to 12 months after treatment. CONCLUSIONS: Delivering at least 120 sessions of LT improves recovery from incomplete chronic SCI. Because walking reduces rehospitalization, LT delivered beyond the average 20-session insurance limit can reduce rehospitalizations and long-term health costs.

Consideration of Dose and Timing When Applying Interventions After Stroke and Spinal Cord Injury.

BACKGROUND AND PURPOSE: Nearly 4 decades of investigation into the plasticity of the nervous system suggest that both timing and dose could matter. This article provides a synopsis of our lectures at the IV STEP meeting, which presented a perspective of current data on the issues of timing and dose for adult stroke and spinal cord injury motor rehabilitation. SUMMARY OF KEY POINTS: For stroke, the prevailing evidence suggests that greater amounts of therapy do not result in better outcomes for upper extremity interventions, regardless of timing. Whether or not greater amounts of therapy result in better outcomes for lower extremity and mobility interventions needs to be explicitly tested. For spinal cord injury, there is a complex interaction of timing postinjury, task-specificity, and the microenvironment of the spinal cord. Inflammation appears to be a key determinant of whether or not an intervention will be beneficial or maladaptive, and specific retraining of eccentric control during gait may be necessary. RECOMMENDATIONS FOR CLINICAL PRACTICE: To move beyond the limitations of our current interventions and to effectively reach nonresponders, greater precision in task-specific interventions that are well-timed to the cellular environment may hold the key. Neurorehabilitation that ameliorates persistent deficits, attains greater recovery, and reclaims nonresponders will decrease institutionalization, improve quality of life, and prevent multiple secondary complications common after stroke and spinal cord injury.

Test-retest reliability of the Neuromuscular Recovery Scale.

OBJECTIVE: To determine the test-retest reliability of the Neuromuscular Recovery Scale (NRS), a measure to classify lower extremity and trunk recovery of individuals with spinal cord injury (SCI) to typical preinjury performance of functional tasks without use of external and behavioral compensation. DESIGN: Multicenter observational study. SETTING: Five outpatient rehabilitation clinics. PARTICIPANTS: Physical therapists (N=13), trained and competent in conducting NRS, rated outpatients with SCI (N=69) using the NRS. Testing occurred on 2 days, separated by 24 to 48 hours, on the same patient by the same therapist. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Spearman rank correlation coefficients to compare NRS results. The NRS scores of motor performance were based on normal, preinjury function on 11 items: 4 treadmill-based items (standing and stepping), 7 overground/mat items (sitting, sit-up, reverse sit-up, trunk extension, sit to stand, standing, walking). RESULTS: Test-retest reliability was very strong for the NRS items. Ten of the 11 items exhibited Spearman correlation coefficients ≥.92, and lower bounds of the 95% confidence intervals (CIs) for these items met or exceeded .83. The exception was stand retraining (ρ=.84; 95% CI, .68-.96). The test-retest reliability of the measurement model-derived summary score was very strong (ρ=.99; 95% CI, .96-.99). CONCLUSIONS: The NRS had excellent test-retest reliability when conducted by trained therapists in adults with chronic SCI across all levels of injury severity. All raters had undergone standardized training in use of the NRS. The minimal requirement of training to achieve test-retest reliability has not been established.

Interrater reliability of the Neuromuscular Recovery Scale for spinal cord injury.

OBJECTIVE: To determine the interrater reliability of the Neuromuscular Recovery Scale (NRS), an outcome measure designed to classify people with complete or incomplete spinal cord injury (SCI) into 4 phase-of-injury groups by assessing motor performance based on normal preinjury function and disallowing use of compensation for 4 treadmill-based items and 6 overground/mat items. DESIGN: Masked comparison, multicenter observational study. SETTING: Outpatient rehabilitation. PARTICIPANTS: Raters (N=14) and a criterion standard expert assigned scores to 10 video NRS assessments of persons with SCI. The raters were volunteers from the NeuroRecovery Network. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Interrater reliability measured with the Kendall coefficient of concordance (W). RESULTS: Interrater reliability was generally strong (W=.91-.98; 95% confidence interval [CI], .65-.99), while lower reliability occurred for treadmill stand retraining (W=.87; 95% CI, .06-1) and seated trunk extension (W=.82; 95% CI, .28-.94). Less experienced raters assigned slightly lower scores than the expert for most items, but the difference was less than half a point and did not weaken concordance. CONCLUSIONS: NRS had strong interrater reliability, a necessary first step in establishing its utility as a clinical and research outcome measure.

Validity of the Neuromuscular Recovery Scale: a measurement model approach.

OBJECTIVE: To determine how well the Neuromuscular Recovery Scale (NRS) items fit the Rasch, 1-parameter, partial-credit measurement model. DESIGN: Confirmatory factor analysis (CFA) and principal components analysis (PCA) of residuals were used to determine dimensionality. The Rasch, 1-parameter, partial-credit rating scale model was used to determine rating scale structure, person/item fit, point-measure item correlations, item discrimination, and measurement precision. SETTING: Seven NeuroRecovery Network clinical sites. PARTICIPANTS: Outpatients (N=188) with spinal cord injury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: NRS. RESULTS: While the NRS met 1 of 3 CFA criteria, the PCA revealed that the Rasch measurement dimension explained 76.9% of the variance. Ten of 11 items and 91% of the patients fit the Rasch model, with 9 of 11 items showing high discrimination. Sixty-nine percent of the ratings met criteria. The items showed a logical item-difficulty order, with Stand retraining as the easiest item and Walking as the most challenging item. The NRS showed no ceiling or floor effects and separated the sample into almost 5 statistically distinct strata; individuals with an American Spinal Injury Association Impairment Scale (AIS) D classification showed the most ability, and those with an AIS A classification showed the least ability. Items not meeting the rating scale criteria appear to be related to the low frequency counts. CONCLUSIONS: The NRS met many of the Rasch model criteria for construct validity.

Elevated MMP-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice.

Spinal cord injury results in distant pathology around putative locomotor networks that may jeopardize the recovery of locomotion. We previously showed that activated microglia and increased cytokine expression extend at least 10 segments below the injury to influence sensory function. Matrix metalloproteinase-9 (MMP-9) is a potent regulator of acute neuroinflammation. Whether MMP-9 is produced remote to the injury or influences locomotor plasticity remains unexamined. Therefore, we characterized the lumbar enlargement after a T9 spinal cord injury in C57BL/6 (wild-type [WT]) and MMP-9-null (knock-out [KO]) mice. Within 24 h, resident microglia displayed an activated phenotype alongside increased expression of progelatinase MMP-3 in WT mice. By 7 d, increases in active MMP-9 around lumbar vasculature and production of proinflammatory TNF-α were evident. Deletion of MMP-9 attenuated remote microglial activation and restored TNF-α expression to homeostatic levels. To determine whether MMP-9 impedes locomotor plasticity, we delivered lumbar-focused treadmill training in WT and KO mice during early (2-9 d) or late (35-42 d) phases of recovery. Robust behavioral improvements were observed by 7 d, when only trained KO mice stepped in the open field. Locomotor improvements were retained for 4 weeks as identified using state of the art mouse kinematics. Neither training nor MMP-9 depletion alone promoted recovery. The same intervention delivered late was ineffective, suggesting that lesion site sparing is insufficient to facilitate activity-based training and recovery. Our work suggests that by attenuating remote mechanisms of inflammation, acute treadmill training can harness endogenous spinal plasticity to promote robust recovery.

Dual-task training for balance and mobility in a person with severe traumatic brain injury: a case study.

BACKGROUND AND PURPOSE: Attentional impairments following severe traumatic brain injury (TBI) are common and can lead to decreased functional mobility and balance, as well as deficits in previously automatic movements such as walking and stair climbing. The purpose of this case study was to determine the feasibility and potential value of incorporating a cognitive-motor dual-task training program into physical therapy for a patient with a severe TBI. CASE DESCRIPTION: The patient was a 26-year-old woman who sustained a severe TBI during a motor vehicle accident 46 days prior to physical therapy evaluation. On the 8-level Rancho Los Amigos Cognitive Function Scale, her functioning was classified as level IV. She had impairments in attention, functional mobility, and balance, all of which limited her ability to participate in activities of daily living. INTERVENTION: : Physical therapy was provided over 26 days within the inpatient rehabilitation setting. Interventions included mobility tasks such as walking, balancing, and stair climbing. Mobility training was paired with specific secondary cognitive and motor tasks. OUTCOMES: Dual-task training may have contributed to improvements on outcome measures designed to test divided attention including the Walking While Talking Test and Trail Making Test and a greater rate of improvement in walking speed and time to descend stairs when compared to the baseline phase. DISCUSSION: Addition of cognitive-motor dual-task training to standard physical therapy in the inpatient rehabilitation setting appears to be feasible and may have value for improving function in individuals with severe TBI. VIDEO ABSTRACT AVAILABLE: (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A41) for more insights from the authors.

Relationship between ASIA examination and functional outcomes in the NeuroRecovery Network Locomotor Training Program.

OBJECTIVE: To determine the effects of locomotor training on: (1) the International Standards for Neurological Classification of Spinal Cord Injury examination; (2) locomotion (gait speed, distance); (3) balance; and (4) functional gait speed stratifications after chronic incomplete spinal cord injury (SCI). DESIGN: Prospective observational cohort. SETTING: Outpatient rehabilitation centers in the NeuroRecovery Network (NRN). PARTICIPANTS: Individuals (n=225) with American Spinal Injury Association Impairment Scale (AIS) grade C or D chronic motor incomplete SCI having completed locomotor training in the NRN. INTERVENTION: The NRN Locomotor Training Program consists of manual-facilitated body weight-supported standing and stepping on a treadmill and overground. MAIN OUTCOME MEASURES: AIS classification, lower extremity pin prick, light touch and motor scores, ten-meter walk and six-minute walk tests, and the Berg Balance Scale. RESULTS: Significant gains occurred in lower extremity motor scores but not in sensory scores, and these were only weakly related to gait speed and distance. Final Berg Balance Scale scores and initial lower extremity motor scores were positively related. Although 70% of subjects showed significantly improved gait speed after locomotor training, only 8% showed AIS category conversion. CONCLUSIONS: Locomotor training improves gait speed to levels sufficient for independent in-home or community ambulation after chronic motor incomplete SCI. Changes in lower extremity motor and sensory scores do not capture the full extent of functional recovery, nor predict responsiveness to locomotor training. Functional classification based on gait speed may provide an effective measure of treatment efficacy or functional improvement after incomplete SCI.

Ambulation and balance outcomes measure different aspects of recovery in individuals with chronic, incomplete spinal cord injury.

OBJECTIVE: To evaluate relationships among ambulation and balance outcome measures over time for incomplete spinal cord injury (SCI) after locomotor training, in order to facilitate the selection of effective and sensitive rehabilitation outcomes. DESIGN: Prospective observational cohort. SETTING: Outpatient rehabilitation centers (N=7) from the Christopher and Dana Reeve Foundation NeuroRecovery Network. PARTICIPANTS: Patients with incomplete SCI (N=182) American Spinal Injury Association Impairment Scale level C (n=61) and D (n=121). INTERVENTIONS: Intensive locomotor training, including step training using body weight support and manual facilitation on a treadmill followed by overground assessment and community integration. MAIN OUTCOME MEASURES: Six-minute and 10-meter walk tests, Berg Balance Scale, Modified Functional Reach, and Neuromuscular Recovery Scale collected at enrollment, approximately every 20 sessions, and on discharge. RESULTS: Walking and standing balance measures for all participants were strongly correlated (r≥.83 for all pairwise outcome correlations), standing and sitting balance measures were not highly correlated (r≤.48 for all pairwise outcome correlations), and walking measures were weakly related to sitting balance. The strength of relationships among outcome measures varied with functional status. Correlations among evaluation-to-evaluation changes were markedly reduced from performance correlations. Walk tests, when conducted with different assistive devices, were strongly correlated but had substantial variability in performance. CONCLUSIONS: These results cumulatively suggest that changes in walking and balance measures reflect different aspects of recovery and are highly influenced by functional status and the utilization of assistive devices. These factors should be carefully considered when assessing clinical progress and designing clinical trials for rehabilitation.

Histological Findings After Aortic Cross-Clamping in Preclinical Animal Models.

Spinal cord ischemic injury and paralysis are devastating complications after open surgical repair of thoracoabdominal aortic aneurysms. Preclinical models have been developed to simulate the clinical paradigm to better understand the neuropathophysiology and develop therapeutic treatment. Neuropathological findings in the preclinical models have not been comprehensively examined before. This systematic review studies the past 40 years of the histological findings after open surgical repair in preclinical models. Our main finding is that damage is predominantly in the grey matter of the spinal cord, although white matter damage in the spinal cord is also reported. Future research needs to examine the neuropathological findings in preclinical models after endovascular repair, a newer type of surgical repair used to treat aortic aneurysms.

Eccentric rehabilitation induces white matter plasticity and sensorimotor recovery in chronic spinal cord injury.

Experience-dependent white matter plasticity offers new potential for rehabilitation-induced recovery after neurotrauma. This first-in-human translational experiment combined myelin water imaging in humans and genetic fate-mapping of oligodendrocyte lineage cells in mice to investigate whether downhill locomotor rehabilitation that emphasizes eccentric muscle actions promotes white matter plasticity and recovery in chronic, incomplete spinal cord injury (SCI). In humans, of 20 individuals with SCI that enrolled, four passed the imaging screen and had myelin water imaging before and after a 12-week (3 times/week) downhill locomotor treadmill training program (SCI + DH). One individual was excluded for imaging artifacts. Uninjured control participants (n = 7) had two myelin water imaging sessions within the same day. Changes in myelin water fraction (MWF), a histopathologically-validated myelin biomarker, were analyzed in a priori motor learning and non-motor learning brain regions and the cervical spinal cord using statistical approaches appropriate for small sample sizes. PDGFRα-CreERT2:mT/mG mice, that express green fluorescent protein on oligodendrocyte precursor cells and subsequent newly-differentiated oligodendrocytes upon tamoxifen-induced recombination, were either naive (n = 6) or received a moderate (75 kilodyne), contusive SCI at T9 and were randomized to downhill training (n = 6) or unexercised groups (n = 6). We initiated recombination 29 days post-injury, seven days prior to downhill training. Mice underwent two weeks of daily downhill training on the same 10% decline grade used in humans. Between-group comparison of functional (motor and sensory) and histological (oligodendrogenesis, oligodendroglial/axon interaction, paranodal structure) outcomes occurred post-training. In humans with SCI, downhill training increased MWF in brain motor learning regions (postcentral, precuneus) and mixed motor and sensory tracts of the ventral cervical spinal cord compared to control participants (P < 0.05). In mice with thoracic SCI, downhill training induced oligodendrogenesis in cervical dorsal and lateral white matter, increased axon-oligodendroglial interactions, and normalized paranodal structure in dorsal column sensory tracts (P < 0.05). Downhill training improved sensorimotor recovery in mice by normalizing hip and knee motor control and reducing hyperalgesia, both of which were associated with new oligodendrocytes in the cervical dorsal columns (P < 0.05). Our findings indicate that eccentric-focused, downhill rehabilitation promotes white matter plasticity and improved function in chronic SCI, likely via oligodendrogenesis in nervous system regions activated by the training paradigm. Together, these data reveal an exciting role for eccentric training in white matter plasticity and sensorimotor recovery after SCI.

Bone Marrow-Derived Monocytes Drive the Inflammatory Microenvironment in Local and Remote Regions after Thoracic Spinal Cord Injury.

Spinal cord injury (SCI) produces a toxic inflammatory microenvironment that negatively affects plasticity and recovery. Recently, we showed glial activation and peripheral myeloid cell infiltration extending beyond the epicenter through the remote lumbar cord after thoracic SCI. The presence and role of infiltrating monocytes is important, especially in the lumbar cord where locomotor central pattern generators are housed. Therefore, we compared the inflammatory profile of resident microglia and peripheral myeloid cells after SCI. Bone marrow chimeras received midthoracic contusive SCI, and trafficking was determined 1-7 days later. Fluorescence-activated cell (FAC) sorting showed similar infiltration timing of both neutrophils and macrophages in epicenter and lumbar regions. While neutrophil numbers were attenuated by day 3, macrophages remained unchanged at day 7, suggesting that macrophages have important long-term influence on the microenvironment. Nanostring gene array identified a strong proinflammatory profile of infiltrating macrophages relative to microglia at both epicenter and lumbar sites. Macrophages had elevated expression of inflammatory cytokines (IL-1ß, IFNγ), chemokines (CCL2, CXCL2), mediators (COX-1, MMP-9), and receptors (CCR2, Ly6C), and decreased expression of growth promoting genes (GDNF, BDNF). Importantly, lumbar macrophages had elevated expression of active trafficking genes (CCR2, l-selectin, MMP-9) compared with epicenter macrophages. Further, acute rehabilitation exacerbated the inflammatory profile of infiltrated macrophages in the lumbar cord. Such high inflammatory potential and negative response to rehabilitation of infiltrating macrophages within lumbar locomotor central pattern generators likely impedes activity-dependent recovery. Therefore, limiting active trafficking of macrophages into the lumbar cord identifies a novel target for SCI therapies to improve locomotion.

Influence of feedback schedule in motor performance and learning of a lumbar multifidus muscle task using rehabilitative ultrasound imaging: a randomized clinical trial.

BACKGROUND AND PURPOSE: Low back pain (LBP) may be associated with inadequate multifidus muscle function. Varying the frequency and timing of feedback may enhance acquisition and retention of multifidus muscle recruitment during exercise. SUBJECTS: Subjects without LBP (n=30) were randomly assigned to a constant (CON) or variable (VAR) feedback group. Twenty-eight subjects (mean age=28 years, SD=8.0; mean body mass index=24 kg/m(2), SD=0.70) completed training, and 23 completed retention testing. METHODS: Eight training sessions over 4 weeks included multifidus muscle exercise with rehabilitative ultrasound imaging (RUSI) feedback. Retention was assessed at 1 week and >or=1 month. RESULTS: At the start, both groups had similar performances of multifidus muscle recruitment (Fisher exact test, P=.26). Early in training, the CON group had good success (mean=80%) that was maintained at session 8 (mean=84%), with no difference between sessions 1 and 8 (Wilcoxon signed rank test, P=.19, 95% confidence interval [CI]=-9%, 42%). The VAR group gradually increased success (Wilcoxon signed rank test, P=.002, 95% CI=17%, 59%) between sessions 1 and 8. Both groups sustained their session 8 success when tested for short-term retention at 1 week (CON group: Wilcoxon signed rank test, P=.79; VAR group: Wilcoxon signed rank test, P=.36). At the long-term retention test, the VAR group outperformed the CON group (Wilcoxon score test, P=.04), indicating superior motor learning. DISCUSSION AND CONCLUSION: Variable feedback provided by RUSI resulted in greater success in lumbar multifidus muscle recruitment up to 3 to 4 months after training.

Unique Sensory and Motor Behavior in Thy1-GFP-M Mice before and after Spinal Cord Injury.

Sensorimotor recovery after spinal cord injury (SCI) is of utmost importance to injured individuals and will rely on improved understanding of SCI pathology and recovery. Novel transgenic mouse lines facilitate discovery, but must be understood to be effective. The purpose of this study was to characterize the sensory and motor behavior of a common transgenic mouse line (Thy1-GFP-M) before and after SCI. Thy1-GFP-M positive (TG+) mice and their transgene negative littermates (TG-) were acquired from two sources (in-house colony, n = 32, Jackson Laboratories, n = 4). C57BL/6J wild-type (WT) mice (Jackson Laboratories, n = 10) were strain controls. Moderate-severe T9 contusion (SCI) or transection (TX) occurred in TG+ (SCI, n = 25, TX, n = 5), TG- (SCI, n = 5), and WT (SCI, n = 10) mice. To determine responsiveness to rehabilitation, a cohort of TG+ mice with SCI (n = 4) had flat treadmill (TM) training 42-49 days post-injury (dpi). To characterize recovery, we performed Basso Mouse Scale, Grid Walk, von Frey Hair, and Plantar Heat Testing before and out to day 42 post-SCI. Open field locomotion was significantly better in the Thy1 SCI groups (TG+ and TG-) compared with WT by 7 dpi (p < 0.01) and was maintained through 42 dpi (p < 0.01). These unexpected locomotor gains were not apparent during grid walking, indicating severe impairment of precise motor control. Thy1 derived mice were hypersensitive to mechanical stimuli at baseline (p < 0.05). After SCI, mechanical hyposensitivity emerged in Thy1 derived groups (p < 0.001), while thermal hyperalgesia occurred in all groups (p < 0.001). Importantly, consistent findings across TG+ and TG- groups suggest that the effects are mediated by the genetic background rather than transgene manipulation itself. Surprisingly, TM training restored mechanical and thermal sensation to baseline levels in TG+ mice with SCI. This behavioral profile and responsiveness to chronic training will be important to consider when choosing models to study the mechanisms underlying sensorimotor recovery after SCI.

Caregiver Burden Varies by Sensory Subtypes and Sensory Dimension Scores of Children with Autism.

Understanding characteristics associated with burden in caregivers of children with autism spectrum disorder (ASD) is critical due to negative health consequences. We explored the association between child sensory subtype, sensory dimension scores, and caregiver burden. A national survey of caregivers of children with ASD aged 5-13 years was conducted (n = 367). The relationship between variables of interest and indicators of caregiver burden, including health-related quality of life (HRQOL) and caregiver strain, was examined with canonical correlation analyses. Caregiver strain was, but caregiver HRQOL was not, significantly associated with child sensory subtype and sensory dimension scores. Caregiver age, child age, and household income were also associated with caregiver strain. Potential explanatory mechanisms for these findings, derived from published qualitative studies, are discussed.

Validity of the walking scale for spinal cord injury and other domains of function in a multicenter clinical trial.

OBJECTIVE: To demonstrate criterion (concurrent and predictive) and construct validity of the Walking Index for Spinal Cord Injury (WISCI) scale and other walking measures in the Spinal Cord Injury Locomotor Trial (SCILT). DESIGN: Prospective multicenter clinical trial of a walking intervention for patients with acute traumatic spinal cord injury (SCI). PARTICIPANTS/ METHODS: Body weight-supported treadmill training was compared to overground mobility training in 146 patients with incomplete SCI (C4 to L3) enrolled within 8 weeks of onset and treated for 12 weeks. Primary outcome measures were the Functional Independence Measure (FIM), 50-foot walking speed (50FW-S), and 6-minute walking distance (6MW-D), tested 3, 6, and 12 months after entry. Secondary measures were the Lower Extremity Motor Score (LEMS), Berg Balance Scale (BBS), WISCI, and FIM locomotor score (LFIM), assessed at 6 centers by blinded observers. Data for the 2 arms were combined since no significant differences in outcomes had been found. RESULTS: Correlations with WISCI at 6 months were significant with BBS (r = .90), LEMS (r = .85), LFIM (r = .89), FIM (r = .77), 50FW-S (r = .85), and 6MW-D ( r = .79); similar correlations occurred at 3 and 12 months. Correlations of change scores from baseline WISCI were significant for change scores from baseline of LEMS/BBS/LFIM. Correlation of baseline LEMS and WISCI at 12 months were most significant (r = .73). The R(2) of baseline LEMS explained 57% of variability of WISCI levels at 3 months. CONCLUSION: Concurrent validity of the WISCI scale was supported by significant correlations with all measures at 3, 6, and 12 months. Correlation of change scores supports predictive validity. The LEMS at baseline was the best predictor of the WISCI score at 12 months and explained most of the variance, which supported both predictive and construct validity. The combination of the LEMS, BBS, WISCI, 50FW-S, and LFIM appears to encompass adequate descriptors for outcomes of walking trials for incomplete SCI.

Supraspinal Control Predicts Locomotor Function and Forecasts Responsiveness to Training after Spinal Cord Injury.

Restoration of walking ability is an area of great interest in the rehabilitation of persons with spinal cord injury. Because many cortical, subcortical, and spinal neural centers contribute to locomotor function, it is important that intervention strategies be designed to target neural elements at all levels of the neuraxis that are important for walking ability. While to date most strategies have focused on activation of spinal circuits, more recent studies are investigating the value of engaging supraspinal circuits. Despite the apparent potential of pharmacological, biological, and genetic approaches, as yet none has proved more effective than physical therapeutic rehabilitation strategies. By making optimal use of the potential of the nervous system to respond to training, strategies can be developed that meet the unique needs of each person. To complement the development of optimal training interventions, it is valuable to have the ability to predict future walking function based on early clinical presentation, and to forecast responsiveness to training. A number of clinical prediction rules and association models based on common clinical measures have been developed with the intent, respectively, to predict future walking function based on early clinical presentation, and to delineate characteristics associated with responsiveness to training. Further, a number of variables that are correlated with walking function have been identified. Not surprisingly, most of these prediction rules, association models, and correlated variables incorporate measures of volitional lower extremity strength, illustrating the important influence of supraspinal centers in the production of walking behavior in humans.