Early intensive hand rehabilitation is not more effective than usual care plus one-to-one hand therapy in people with sub-acute spinal cord injury ('Hands On'): a randomised trial.

QUESTION: What is the effect of adding an intensive task-specific hand-training program involving functional electrical stimulation to a combination of usual care plus three 15-minute sessions per week of one-to-one hand therapy in people with sub-acute tetraplegia? DESIGN: A parallel group, randomised, controlled trial. Participants were randomly assigned (1:1) via a computer-generated concealed block randomisation procedure to either a control or experimental intervention. PARTICIPANTS: Seventy people with C2 to T1 motor complete or incomplete tetraplegia within 6 months of injury. Participants were recruited from seven spinal units in Australia and New Zealand. INTERVENTION: Experimental participants received intensive training for one hand. Intensive training consisted of training with an instrumented exercise workstation in conjunction with functional electrical stimulation for 1hour per day, 5 days per week for 8 weeks. Both groups received usual care and 15minutes of one-to-one hand therapy three times per week without functional electrical stimulation. OUTCOME MEASURES: The primary outcome was the modified Action Research Arm Test reflecting arm and hand function, which was assessed at the end of the intervention, that is, 11 weeks after randomisation. Secondary outcomes were measured at 11 and 26 weeks. RESULTS: Sixty-six (94%) participants completed the post-intervention assessment and were included in the primary intention-to-treat analysis. The mean (SD) modified Action Research Arm Test score for experimental and control participants at the post-intervention assessment was 36.5 points (SD 16.0) and 33.2 points (SD 17.5), respectively, with an adjusted mean between-group difference of 0.9 points (95% CI -4.1 to 5.9). CONCLUSION: Adding an intensive task-specific hand-training program involving functional electrical stimulation to a combination of usual care plus three 15-minute sessions per week of one-to-one hand therapy does not improve hand function in people with sub-acute tetraplegia. REGISTRATION: Australian and New Zealand Trial Registry ACTRN12609000695202 and ClinicalTrials.gov NCT01086930. [Harvey LA, Dunlop SA, Churilov L, Galea MP, Spinal Cord Injury Physical Activity (SCIPA) Hands On Trial Collaborators (2017) Early intensive hand rehabilitation is not more effective than usual care plus one-to-one hand therapy in people with sub-acute spinal cord injury ('Hands On'): a randomised trial. Journal of Physiotherapy 63: 197-204].

Early intensive hand rehabilitation is not more effective than usual care plus one-to-one hand therapy in people with sub-acute spinal cord injury ('Hands On'): a randomised trial.

QUESTION: What is the effect of adding an intensive task-specific hand-training program involving functional electrical stimulation to a combination of usual care plus three 15-minute sessions per week of one-to-one hand therapy in people with sub-acute tetraplegia? DESIGN: A parallel group, randomised, controlled trial. Participants were randomly assigned (1:1) via a computer-generated concealed block randomisation procedure to either a control or experimental intervention. PARTICIPANTS: Seventy people with C2 to T1 motor complete or incomplete tetraplegia within 6 months of injury. Participants were recruited from seven spinal units in Australia and New Zealand. INTERVENTION: Experimental participants received intensive training for one hand. Intensive training consisted of training with an instrumented exercise workstation in conjunction with functional electrical stimulation for 1 hour per day, 5 days per week for 8 weeks. Both groups received usual care and 15 minutes of one-to-one hand therapy three times per week without functional electrical stimulation. OUTCOME MEASURES: The primary outcome was the modified Action Research Arm Test reflecting arm and hand function, which was assessed at the end of the intervention, that is, 11 weeks after randomisation. Secondary outcomes were measured at 11 and 26 weeks. RESULTS: Sixty-six (94%) participants completed the post-intervention assessment and were included in the primary intention-to-treat analysis. The mean modified Action Research Arm Test score for experimental and control participants at the post-intervention assessment was 36.5 points (SD 16.0) and 33.2 points (SD 17.5), respectively, with an adjusted mean between-group difference of 0.9 points (95% CI -4.1 to 5.9). CONCLUSION: Adding an intensive task-specific hand-training program involving functional electrical stimulation to a combination of usual care plus three 15-minute sessions per week of one-to-one hand therapy does not improve hand function in people with sub-acute tetraplegia. REGISTRATION: Australian and New Zealand Trial Registry ACTRN12609000695202 and ClinicalTrials.gov NCT01086930.

Early exercise after spinal cord injury ('Switch-On'): study protocol for a randomised controlled trial.

BACKGROUND: Spinal cord injury (SCI) leads to a profound muscular atrophy, bone loss and bone fragility. While there is evidence that exercising paralysed muscles may lead to reversal of muscle atrophy in the chronic period after SCI, there is little evidence that exercise can prevent muscle changes early after injury. Moreover, whether exercise can prevent bone loss and microarchitectural decay is not clear. METHODS/DESIGN: A multi-centre, parallel group, assessor-blinded randomised controlled trial will be conducted. Fifty participants with acute spinal cord injury will be recruited from four SCI units in Australia and New Zealand. Participants will be stratified by site and AIS status and randomised to an experimental or control group. Experimental participants will receive a 12-week programme of functional electrical stimulation (FES)-assisted cycling. Control participants will receive a 12-week programme of passive cycling. The primary outcome is muscle cross-sectional area of the thigh and calf measured using magnetic resonance images (MRI) of the leg. Secondary outcomes include serum biomarkers of SCI osteoporosis (sclerostin, P1NP and ß-CTX), markers of immune function (IL-6, IL-10, FGF2, INF-γ, TNF-α), neurological function, body composition, depression and quality of life. Leg MRIs will be measured by a single blinded assessor based in Melbourne. Serum samples will be analysed in a central laboratory. All other characteristics will be measured at baseline and 12 weeks by blinded and trained assessors at each site. The first participant was randomised on 27 November 2012. DISCUSSION: The results of this trial will determine the relative effectiveness of a 12-week programme of FES-assisted cycling versus passive cycling in preventing muscle atrophy and maintaining skeletal integrity after spinal cord injury. TRIAL REGISTRATION: ACTRN12611001079932 (18 October 2011).

Intensive exercise program after spinal cord injury ("Full-On"): study protocol for a randomized controlled trial.

BACKGROUND: Rehabilitation after spinal cord injury (SCI) has traditionally involved teaching compensatory strategies for identified impairments and deficits in order to improve functional independence. There is some evidence that regular and intensive activity-based therapies, directed at activation of the paralyzed extremities, promotes neurological improvement. The aim of this study is to compare the effects of a 12-week intensive activity-based therapy program for the whole body with a program of upper body exercise. METHODS/DESIGN: A multicenter, parallel group, assessor-blinded randomized controlled trial will be conducted. One hundred eighty-eight participants with spinal cord injury, who have completed their primary rehabilitation at least 6 months prior, will be recruited from five SCI units in Australia and New Zealand. Participants will be randomized to an experimental or control group. Experimental participants will receive a 12-week program of intensive exercise for the whole body, including locomotor training, trunk exercises and functional electrical stimulation-assisted cycling. Control participants will receive a 12-week intensive upper body exercise program. The primary outcome is the American Spinal Injuries Association (ASIA) Motor Score. Secondary outcomes include measurements of sensation, function, pain, psychological measures, quality of life and cost effectiveness. All outcomes will be measured at baseline, 12 weeks, 6 months and 12 months by blinded assessors. Recruitment commenced in January 2011. DISCUSSION: The results of this trial will determine the effectiveness of a 12-week program of intensive exercise for the whole body in improving neurological recovery after spinal cord injury. TRIAL REGISTRATION: NCT01236976 (10 November 2010), ACTRN12610000498099 (17 June 2010).

Paranode Abnormalities and Oxidative Stress in Optic Nerve Vulnerable to Secondary Degeneration: Modulation by 670 nm Light Treatment.

Secondary degeneration of nerve tissue adjacent to a traumatic injury results in further loss of neurons, glia and function, via mechanisms that may involve oxidative stress. However, changes in indicators of oxidative stress have not yet been demonstrated in oligodendrocytes vulnerable to secondary degeneration in vivo. We show increases in the oxidative stress indicator carboxymethyl lysine at days 1 and 3 after injury in oligodendrocytes vulnerable to secondary degeneration. Dihydroethidium staining for superoxide is reduced, indicating endogenous control of this particular reactive species after injury. Concurrently, node of Ranvier/paranode complexes are altered, with significant lengthening of the paranodal gap and paranode as well as paranode disorganisation. Therapeutic administration of 670 nm light is thought to improve oxidative metabolism via mechanisms that may include increased activity of cytochrome c oxidase. Here, we show that light at 670 nm, delivered for 30 minutes per day, results in in vivo increases in cytochrome c oxidase activity co-localised with oligodendrocytes. Short term (1 day) 670 nm light treatment is associated with reductions in reactive species at the injury site. In optic nerve vulnerable to secondary degeneration superoxide in oligodendrocytes is reduced relative to handling controls, and is associated with reduced paranode abnormalities. Long term (3 month) administration of 670 nm light preserves retinal ganglion cells vulnerable to secondary degeneration and maintains visual function, as assessed by the optokinetic nystagmus visual reflex. Light at a wavelength of 670 nm may serve as a therapeutic intervention for treatment of secondary degeneration following neurotrauma.

Early intensive hand rehabilitation after spinal cord injury ("Hands On"): a protocol for a randomised controlled trial.

BACKGROUND: Loss of hand function is one of the most devastating consequences of spinal cord injury. Intensive hand training provided on an instrumented exercise workstation in conjunction with functional electrical stimulation may enhance neural recovery and hand function. The aim of this trial is to compare usual care with an 8-week program of intensive hand training and functional electrical stimulation. METHODS/DESIGN: A multicentre randomised controlled trial will be undertaken. Seventy-eight participants with recent tetraplegia (C2 to T1 motor complete or incomplete) undergoing inpatient rehabilitation will be recruited from seven spinal cord injury units in Australia and New Zealand and will be randomised to a control or experimental group. Control participants will receive usual care. Experimental participants will receive usual care and an 8-week program of intensive unilateral hand training using an instrumented exercise workstation and functional electrical stimulation. Participants will drive the functional electrical stimulation of their target hands via a behind-the-ear bluetooth device, which is sensitive to tooth clicks. The bluetooth device will enable the use of various manipulanda to practice functional activities embedded within computer-based games and activities. Training will be provided for one hour, 5 days per week, during the 8-week intervention period. The primary outcome is the Action Research Arm Test. Secondary outcomes include measurements of strength, sensation, function, quality of life and cost effectiveness. All outcomes will be taken at baseline, 8 weeks, 6 months and 12 months by assessors blinded to group allocation. Recruitment commenced in December 2009. DISCUSSION: The results of this trial will determine the effectiveness of an 8-week program of intensive hand training with functional electrical stimulation. TRIAL REGISTRATION: NCT01086930 (12th March 2010)ACTRN12609000695202 (12th August 2009).

Manual stimulation, but not acute electrical stimulation prior to reconstructive surgery, improves functional recovery after facial nerve injury in rats.

UNLABELLED: The outcome of peripheral nerve injuries requiring surgical repair is poor. Recent work suggested that electrical stimulation (ES) of the proximal nerve stump to produce repeated discharges of the parent motoneurons for one hour could be a beneficial therapy if delivered immediately prior to reconstructive surgery of mixed peripheral nerves. PURPOSE: We tested whether ES has a positive influence on functional recovery after repair of a purely motor nerve, the facial nerve. METHODS: Electrical stimulation (20 Hz) was delivered to the proximal nerve stump of the transected facial nerve for 1 hour prior to nerve reconstruction by end-to-end suture (facial-facial anastomosis, FFA). For manual stimulation (MS), animals received daily rhythmic stroking of the whisker pads. Restoration of vibrissal motor performance following ES or MS was evaluated using video-based motion analysis. We also assessed the degree of collateral axonal branching at the lesion site, by counting motoneuronal perikarya after triple retrograde labeling, and estimated the quality of motor end-plate reinnervation in the target musculature. Outcomes at 4 months were compared to animals receiving sham stimulation (SS) or MS. RESULTS: Neither protocol reduced the degree of collateral sprouting. ES did not improve functional outcome and failed to reduce the proportion of polyinnervated motor end-plates. By contrast, MS restored normal whisking function and reduced polyinnervation. CONCLUSION: Whereas acute ES is not beneficial for facial nerve repair, MS provides long-term benefits.

Bone marrow-derived mesenchymal stem cell transplantation does not improve quality of muscle reinnervation or recovery of motor function after facial nerve transection in rats.

Recently, we devised and validated a novel strategy in rats to improve the outcome of facial nerve reconstruction by daily manual stimulation of the target muscles. The treatment resulted in full recovery of facial movements (whisking), which was achieved by reducing the proportion of pathologically polyinnervated motor endplates. Here, we posed whether manual stimulation could also be beneficial after a surgical procedure potentially useful for treatment of large peripheral nerve defects, i.e., entubulation of the transected facial nerve in a conduit filled with suspension of isogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) in collagen. Compared to control treatment with collagen only, entubulation with BM-MSCs failed to decrease the extent of collateral axonal branching at the lesion site and did not improve functional recovery. Post-operative manual stimulation of vibrissal muscles also failed to promote a better recovery following entubulation with BM-MSCs. We suggest that BM-MSCs promote excessive trophic support for regenerating axons which, in turn, results in excessive collateral branching at the lesion site and extensive polyinnervation of the motor endplates. Furthermore, such deleterious effects cannot be overridden by manual stimulation. We conclude that entubulation with BM-MSCs is not beneficial for facial nerve repair.

Manual stimulation of facial muscles improves functional recovery after hypoglossal-facial anastomosis and interpositional nerve grafting of the facial nerve in adult rats.

The facial nerve in humans is often prone to injuries requiring surgical intervention. In the best case, nerve reconstruction is achieved by a facial-facial anastomosis (FFA), i.e. suture of the proximal and distal stumps of the severed facial nerve. Although a method of choice, FFA rarely leads to a satisfactory functional recovery. We have recently devised and validated, in an established experimental paradigm in rats, a novel strategy to improve the outcome of FFA by daily manual stimulation (MS) of facial muscles. This treatment results in full recovery of facial movements (whisking) and is achieved by reducing the proportion of functionally detrimental poly-innervated motor end-plates. Here we asked whether MS could also be beneficial after two other commonly used surgical methods of clinical facial nerve reconstruction namely hypoglossal-facial anastomosis (HFA) and interpositional nerve grafting (IPNG) which, however, seem to have a poorer outcome compared to FFA. Compared to FFA, daily MS for 2 months after HFA and IPGN did not completely restore function but, nevertheless, significantly improved the amplitude of whisker movements by 50% compared with untreated animals. Functional improvement was associated with a reduction in the proportion of polyinnervated end-plates. MS did not reduce the extent of axonal branching at the lesion site nor the subsequent misdirected axonal regrowth to inappropriate targets. Our data show that a simple approach leading to improved quality of muscle fiber reinnervation is functionally beneficial after different types of clinically relevant surgical interventions.