Learned Motor Patterns Are Replayed in Human Motor Cortex during Sleep.

Consolidation of memory is believed to involve offline replay of neural activity. While amply demonstrated in rodents, evidence for replay in humans, particularly regarding motor memory, is less compelling. To determine whether replay occurs after motor learning, we sought to record from motor cortex during a novel motor task and subsequent overnight sleep. A 36-year-old man with tetraplegia secondary to cervical spinal cord injury enrolled in the ongoing BrainGate brain-computer interface pilot clinical trial had two 96-channel intracortical microelectrode arrays placed chronically into left precentral gyrus. Single- and multi-unit activity was recorded while he played a color/sound sequence matching memory game. Intended movements were decoded from motor cortical neuronal activity by a real-time steady-state Kalman filter that allowed the participant to control a neurally driven cursor on the screen. Intracortical neural activity from precentral gyrus and 2-lead scalp EEG were recorded overnight as he slept. When decoded using the same steady-state Kalman filter parameters, intracortical neural signals recorded overnight replayed the target sequence from the memory game at intervals throughout at a frequency significantly greater than expected by chance. Replay events occurred at speeds ranging from 1 to 4 times as fast as initial task execution and were most frequently observed during slow-wave sleep. These results demonstrate that recent visuomotor skill acquisition in humans may be accompanied by replay of the corresponding motor cortex neural activity during sleep.SIGNIFICANCE STATEMENT Within cortex, the acquisition of information is often followed by the offline recapitulation of specific sequences of neural firing. Replay of recent activity is enriched during sleep and may support the consolidation of learning and memory. Using an intracortical brain-computer interface, we recorded and decoded activity from motor cortex as a human research participant performed a novel motor task. By decoding neural activity throughout subsequent sleep, we find that neural sequences underlying the recently practiced motor task are repeated throughout the night, providing direct evidence of replay in human motor cortex during sleep. This approach, using an optimized brain-computer interface decoder to characterize neural activity during sleep, provides a framework for future studies exploring replay, learning, and memory.

Measuring consciousness in severely damaged brains.

Significant advances have been made in the behavioral assessment and clinical management of disorders of consciousness (DOC). In addition, functional neuroimaging paradigms are now available to help assess consciousness levels in this challenging patient population. The success of these neuroimaging approaches as diagnostic markers is, however, intrinsically linked to understanding the relationships between consciousness and the brain. In this context, a combined theoretical approach to neuroimaging studies is needed. The promise of such theoretically based markers is illustrated by recent findings that used a perturbational approach to assess the levels of consciousness. Further research on the contents of consciousness in DOC is also needed.

Restoring cortical control of functional movement in a human with quadriplegia.

Millions of people worldwide suffer from diseases that lead to paralysis through disruption of signal pathways between the brain and the muscles. Neuroprosthetic devices are designed to restore lost function and could be used to form an electronic 'neural bypass' to circumvent disconnected pathways in the nervous system. It has previously been shown that intracortically recorded signals can be decoded to extract information related to motion, allowing non-human primates and paralysed humans to control computers and robotic arms through imagined movements. In non-human primates, these types of signal have also been used to drive activation of chemically paralysed arm muscles. Here we show that intracortically recorded signals can be linked in real-time to muscle activation to restore movement in a paralysed human. We used a chronically implanted intracortical microelectrode array to record multiunit activity from the motor cortex in a study participant with quadriplegia from cervical spinal cord injury. We applied machine-learning algorithms to decode the neuronal activity and control activation of the participant's forearm muscles through a custom-built high-resolution neuromuscular electrical stimulation system. The system provided isolated finger movements and the participant achieved continuous cortical control of six different wrist and hand motions. Furthermore, he was able to use the system to complete functional tasks relevant to daily living. Clinical assessment showed that, when using the system, his motor impairment improved from the fifth to the sixth cervical (C5-C6) to the seventh cervical to first thoracic (C7-T1) level unilaterally, conferring on him the critical abilities to grasp, manipulate, and release objects. This is the first demonstration to our knowledge of successful control of muscle activation using intracortically recorded signals in a paralysed human. These results have significant implications in advancing neuroprosthetic technology for people worldwide living with the effects of paralysis.

Distinct Corticospinal and Reticulospinal Contributions to Voluntary Control of Elbow Flexor and Extensor Muscles in Humans with Tetraplegia.

Humans with cervical spinal cord injury (SCI) often recover voluntary control of elbow flexors and, to a much lesser extent, elbow extensor muscles. The neural mechanisms underlying this asymmetrical recovery remain unknown. Anatomical and physiological evidence in animals and humans indicates that corticospinal and reticulospinal pathways differentially control elbow flexor and extensor motoneurons; therefore, it is possible that reorganization in these pathways contributes to the asymmetrical recovery of elbow muscles after SCI. To test this hypothesis, we examined motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation over the arm representation of the primary motor cortex, maximal voluntary contractions, the StartReact response (a shortening in reaction time evoked by a startling stimulus), and the effect of an acoustic startle cue on MEPs elicited by cervicomedullary stimulation (CMEPs) on biceps and triceps brachii in males and females with and without chronic cervical incomplete SCI. We found that SCI participants showed similar MEPs and maximal voluntary contractions in biceps but smaller responses in triceps compared with controls, suggesting reduced corticospinal inputs to elbow extensors. The StartReact and CMEP facilitation was larger in biceps but similar to controls in triceps, suggesting enhanced reticulospinal inputs to elbow flexors. These findings support the hypothesis that the recovery of biceps after cervical SCI results, at least in part, from increased reticulospinal inputs and that the lack of these extra inputs combined with the loss of corticospinal drive contribute to the pronounced weakness found in triceps.SIGNIFICANCE STATEMENT Although a number of individuals with cervical incomplete spinal cord injury show limited functional recovery of elbow extensors compared with elbow flexor muscles, to date, the neural mechanisms underlying this asymmetrical recovery remain unknown. Here, we provide for the first time evidence for increased reticulospinal inputs to biceps but not triceps brachii and loss of corticospinal drive to triceps brachii in humans with tetraplegia. We propose that this reorganization in descending control contributes to the asymmetrical recovery between elbow flexor and extensor muscles after cervical spinal cord injury.

Cortical and Subcortical Effects of Transcutaneous Spinal Cord Stimulation in Humans with Tetraplegia.

An increasing number of studies supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes functional recovery in humans with spinal cord injury (SCI). However, the neural mechanisms contributing to these effects remain poorly understood. Here we examined motor-evoked potentials in arm muscles elicited by cortical and subcortical stimulation of corticospinal axons before and after 20 min of TESS (30 Hz pulses with a 5 kHz carrier frequency) and sham-TESS applied between C5 and C6 spinous processes in males and females with and without chronic incomplete cervical SCI. The amplitude of subcortical, but not cortical, motor-evoked potentials increased in proximal and distal arm muscles for 75 min after TESS, but not sham-TESS, in control subjects and SCI participants, suggesting a subcortical origin for these effects. Intracortical inhibition, elicited by paired stimuli, increased after TESS in both groups. When TESS was applied without the 5 kHz carrier frequency both subcortical and cortical motor-evoked potentials were facilitated without changing intracortical inhibition, suggesting that the 5 kHz carrier frequency contributed to the cortical inhibitory effects. Hand and arm function improved largely when TESS was used with, compared with without, the 5 kHz carrier frequency. These novel observations demonstrate that TESS influences cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. We hypothesized that these parallel effects contribute to further the recovery of limb function following SCI.SIGNIFICANCE STATEMENT Accumulating evidence supports the view that transcutaneous electrical stimulation of the spinal cord (TESS) promotes recovery of function in humans with spinal cord injury (SCI). Here, we show that a single session of TESS over the cervical spinal cord in individuals with incomplete chronic cervical SCI influenced in parallel the excitability cortical and spinal networks, having an excitatory effect at the spinal level and an inhibitory effect at the cortical level. Importantly, these parallel physiological effects had an impact on the magnitude of improvements in voluntary motor output.

Sensing and decoding the neural drive to paralyzed muscles during attempted movements of a person with tetraplegia using a sleeve array.

Motor neurons convey information about motor intent that can be extracted and interpreted to control assistive devices. However, most methods for measuring the firing activity of single neurons rely on implanted microelectrodes. Although intracortical brain-computer interfaces (BCIs) have been shown to be safe and effective, the requirement for surgery poses a barrier to widespread use that can be mitigated by instead using noninvasive interfaces. The objective of this study was to evaluate the feasibility of deriving motor control signals from a wearable sensor that can detect residual motor unit activity in paralyzed muscles after chronic cervical spinal cord injury (SCI). Despite generating no observable hand movement, volitional recruitment of motor units below the level of injury was observed across attempted movements of individual fingers and overt wrist and elbow movements. Subgroups of motor units were coactive during flexion or extension phases of the task. Single digit movement intentions were classified offline from the electromyogram (EMG) power [root-mean-square (RMS)] or motor unit firing rates with median classification accuracies >75% in both cases. Simulated online control of a virtual hand was performed with a binary classifier to test feasibility of real-time extraction and decoding of motor units. The online decomposition algorithm extracted motor units in 1.2 ms, and the firing rates predicted the correct digit motion 88 ± 24% of the time. This study provides the first demonstration of a wearable interface for recording and decoding firing rates of motor units below the level of injury in a person with motor complete SCI.NEW & NOTEWORTHY A wearable electrode array and machine learning methods were used to record and decode myoelectric signals and motor unit firing in paralyzed muscles of a person with motor complete tetraplegia. The myoelectric activity and motor unit firing rates were task specific, even in the absence of visible motion, enabling accurate classification of attempted single-digit movements. This wearable system has the potential to enable people with tetraplegia to control assistive devices through movement intent.

Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.

The conserved transport protein particle (TRAPP) complexes regulate key trafficking events and are required for autophagy. TRAPPC4, like its yeast Trs23 orthologue, is a core component of the TRAPP complexes and one of the essential subunits for guanine nucleotide exchange factor activity for Rab1 GTPase. Pathogenic variants in specific TRAPP subunits are associated with neurological disorders. We undertook exome sequencing in three unrelated families of Caucasian, Turkish and French-Canadian ethnicities with seven affected children that showed features of early-onset seizures, developmental delay, microcephaly, sensorineural deafness, spastic quadriparesis and progressive cortical and cerebellar atrophy in an effort to determine the genetic aetiology underlying neurodevelopmental disorders. All seven affected subjects shared the same identical rare, homozygous, potentially pathogenic variant in a non-canonical, well-conserved splice site within TRAPPC4 (hg19:chr11:g.118890966A>G; TRAPPC4: NM_016146.5; c.454+3A>G). Single nucleotide polymorphism array analysis revealed there was no haplotype shared between the tested Turkish and Caucasian families suggestive of a variant hotspot region rather than a founder effect. In silico analysis predicted the variant to cause aberrant splicing. Consistent with this, experimental evidence showed both a reduction in full-length transcript levels and an increase in levels of a shorter transcript missing exon 3, suggestive of an incompletely penetrant splice defect. TRAPPC4 protein levels were significantly reduced whilst levels of other TRAPP complex subunits remained unaffected. Native polyacrylamide gel electrophoresis and size exclusion chromatography demonstrated a defect in TRAPP complex assembly and/or stability. Intracellular trafficking through the Golgi using the marker protein VSVG-GFP-ts045 demonstrated significantly delayed entry into and exit from the Golgi in fibroblasts derived from one of the affected subjects. Lentiviral expression of wild-type TRAPPC4 in these fibroblasts restored trafficking, suggesting that the trafficking defect was due to reduced TRAPPC4 levels. Consistent with the recent association of the TRAPP complex with autophagy, we found that the fibroblasts had a basal autophagy defect and a delay in autophagic flux, possibly due to unsealed autophagosomes. These results were validated using a yeast trs23 temperature sensitive variant that exhibits constitutive and stress-induced autophagic defects at permissive temperature and a secretory defect at restrictive temperature. In summary we provide strong evidence for pathogenicity of this variant in a member of the core TRAPP subunit, TRAPPC4 that associates with vesicular trafficking and autophagy defects. This is the first report of a TRAPPC4 variant, and our findings add to the growing number of TRAPP-associated neurological disorders.

Is Guillain-Barrè syndrome triggered by SARS-CoV-2? Case report and literature review.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the infectious agent responsible for coronavirus disease 2019 (COVID-19). Respiratory and gastrointestinal manifestations of SARS-CoV-2 are well described, less defined is the clinical neurological spectrum of COVID-19. We reported a case of COVID-19 patient with acute monophasic Guillain-Barré syndrome (GBS), and a literature review on the SARS-CoV-2 and GBS etiological correlation. CASE DESCRIPTION: A 68 years-old man presented to the emergency department with symptoms of acute progressive symmetric ascending flaccid tetraparesis. Oropharyngeal swab for SARS-CoV-2 tested positive. Neurological examination showed bifacial nerve palsy and distal muscular weakness of lower limbs. The cerebrospinal fluid assessment showed an albuminocytologic dissociation. Electrophysiological studies showed delayed distal latencies and absent F waves in early course. A diagnosis of Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP) subtype of GBS was then made. CONCLUSIONS: Neurological manifestations of COVID-19 are still under study. The case we described of GBS in COVID-19 patient adds to those already reported in the literature, in support of SARS-CoV-2 triggers GBS. COVID-19 associated neurological clinic should probably be seen not as a corollary of classic respiratory and gastrointestinal symptoms, but as SARS-CoV-2-related standalone clinical entities. To date, it is essential for all Specialists, clinicians and surgeons, to direct attention towards the study of this virus, to better clarify the spectrum of its neurological manifestations.

An investigation into the validity and reliability of the Chinese version of Spinal Cord Independence Measure III (SCIM III).

OBJECTIVE: To investigate the validity and reliability of a Chinese version of Spinal Cord Independence Measure III (SCIM III) in individuals with spinal cord injury. DESIGN: Study on psychometric properties. SETTING: An inpatient rehabilitation facility in China. SUBJECTS: 102 participants with spinal cord injury. Mean (SD) age was 48.8 (15.6) years; tetraplegia/paraplegia ratio was 50/52; median time post injury was 2 months. INTERVENTION: SCIM III was translated into Chinese. Chinese versions of Barthel Index and SCIM III were filled out for each participant by Rater 1. SCIM III was then administered by Rater 2 after 24 hours (n = 67) and 7 days (n = 65). MAIN MEASURES: Validity, inter-rater/test-retest reliability, and internal consistency of the Chinese version of SCIM III. RESULTS: The total scores between the two raters were similar (mean ± SD: 33.8 ± 25.8 vs 33.8 ± 25.5, P = 0.95). Total agreement between the raters in each item was >80%, with both Pearson and intraclass correlation coefficients >0.97 (P < 0.01) for each subscale and total score. The Pearson correlation coefficients of the two independent assessments performed by Rater 2 were also >0.97 (P < 0.01) for each subscale and the total score. Cronbach α was >0.7 for each subscale and the total score for both raters. High consistency was found between Barthel Index and SCIM III total scores (Pearson correlation coefficient = 0.88, P < 0.01). CONCLUSION: The Chinese version of SCIM III is valid and reliable for the functional assessment of patients with SCI.

Non-Dolichoectatic Vertebral Artery Compression of the Medulla: A Comprehensive Literature Review.

OBJECTIVE: Vertebral artery compression of the medulla is a rare vascular finding that causes a variety of clinical presentations, from asymptomatic to neurological disability. This article presents the largest literature review to date on medullary compression of the vertebral arteries. METHODS: An English literature search was performed using the PubMed database and the keywords vertebral artery tortuosity, vertebral artery compression, and medullary compression. RESULTS: A comprehensive literature search yielded 68 patients (57% male) with medullary compression by an intracranial vertebral artery (ICVA). The left side of the medulla was compressed in 44, the right side in 19, and bilateral in 7. The most common clinical symptom was weakness - 26 patients (36%) - 6 had quadriparesis and 6 had hemiparesis. 21 patients reported imbalance; 12 various sensory symptoms; 4 patients were asymptomatic. CONCLUSIONS: Understanding the anatomy of the vasculature can help mitigate future debilitating stroke symptoms. Concrete guidelines for revascularization surgery in symptomatic patients may also be effective. Future studies are needed to further clarify the prevalence, natural history, vascular etiology, and treatment of this condition, including asymptomatic patients and the likelihood that they will develop further neurological signs and disability.

Enabling respiratory control after severe chronic tetraplegia: an exploratory case study.

Respiratory dysfunction is one of the most debilitating effects of spinal cord injury (SCI) impacting the quality of life of patients and caregivers. In addition, breathing difficulties impact the rehabilitation routine a patient may potentially undergo. Transcutaneous electrical spinal cord neuromodulation (TESCoN) is a novel approach to reactivate and retrain spinal circuits after paralysis. We demonstrate that acute and chronic TESCoN therapy over the cervical spinal cord positively impacts the breathing and coughing ability in a patient with chronic tetraplegia. ln addition, we show that the improved breathing and coughing ability are not only observed in the presence of TESCoN but persisted for a few days after TESCoN was stopped.NEW & NOTEWORTHY Noninvasive spinal neuromodulation improves breathing and coughing in a patient with severe and complete tetraplegia.

Changes in motoneuron excitability during voluntary muscle activity in humans with spinal cord injury.

The excitability of resting motoneurons increases following spinal cord injury (SCI). The extent to which motoneuron excitability changes during voluntary muscle activity in humans with SCI, however, remains poorly understood. To address this question, we measured F waves by using supramaximal electrical stimulation of the ulnar nerve at the wrist and cervicomedullary motor-evoked potentials (CMEPs) by using high-current electrical stimulation over the cervicomedullary junction in the first dorsal interosseous muscle at rest and during 5 and 30% of maximal voluntary contraction into index finger abduction in individuals with chronic cervical incomplete SCI and aged-matched control participants. We found higher persistence (number of F waves present in each set) and amplitude of F waves at rest in SCI compared with control participants. With increasing levels of voluntary contraction, the amplitude, but not the persistence, of F waves increased in both groups but to a lesser extent in SCI compared with control participants. Similarly, the CMEP amplitude increased in both groups but to a lesser extent in SCI compared with controls. These results were also found at matched absolutely levels of electromyographic activity, suggesting that these changes were not related to decreases in voluntary motor output after SCI. F-wave and CMEP amplitudes were positively correlated across conditions in both groups. These results support the hypothesis that the responsiveness of the motoneuron pool during voluntary activity decreases following SCI, which could alter the generation and strength of voluntary muscle contractions.NEW & NOTEWORTHY How the excitability of motoneurons changes during voluntary muscle activity in humans with spinal cord injury (SCI) remains poorly understood. We found that F-wave and cervicomedullary motor-evoked potential amplitude, outcomes reflecting motoneuronal excitability, increased during voluntary activity compared with rest in SCI participants but to a lesser extent that in controls. These results suggest that the responsiveness of motoneurons during voluntary activity decreases following SCI, which might affect functionally relevant plasticity after the injury.

Locomotor patterns during obstacle avoidance in children with cerebral palsy.

We investigated how early injuries to developing brain affect the interaction of locomotor patterns with the voluntary action required by obstacle clearance. This task requires higher cognitive load and specific anticipatory sensorimotor integration than more automated steady-state gait. To this end, we compared the adaptive gait patterns during obstacle clearance in 40 children with cerebral palsy (CP) (24 diplegic, 16 hemiplegic, 2-12 yr) and 22 typically developing (TD) children (2-12 yr) by analyzing gait kinematics, joint moments during foot elevation, electromyographic (EMG) activity of 11 pairs of bilateral muscles, and muscle modules evaluated by factorization of the EMG signals. The results confirmed generally slower task performance, plus difficulty in motor planning and control in CP. Thus ~30% of diplegic children failed to perform the task. Children with CP demonstrated higher foot lift, smaller range of motion of distal segments, difficulties in properly activating the hamstring muscles at liftoff, and a modified hip strategy when elevating the trailing limb. Basic muscle modules were generally roughly similar to TD patterns, though they showed a limited adaptation. Thus a distinct activation burst in the adaptable muscle module timed to the voluntary task (liftoff) was less evident in CP. Children with CP also showed prolonged EMG burst durations. Impaired obstacle task performance may reflect impaired or less adaptable supraspinal and spinal control of gait when a locomotor task is superimposed with the voluntary movement. Neurorehabilitation of gait in CP may thus be beneficial by adding voluntary tasks such as obstacle clearance during gait performance.NEW & NOTEWORTHY Previous studies mainly evaluated the neuromuscular pattern generation in cerebral palsy (CP) during unobstructed gait. Here we characterized impairments in the obstacle task performance associated with a limited adaptation of the task-relevant muscle module timed to the foot lift during obstacle crossing. Impaired task performance in children with CP may reflect basic developmental deficits in the adaptable control of gait when the locomotor task is superimposed with the voluntary movement.

Expanding traditional tendon-based techniques with nerve transfers for the restoration of upper limb function in tetraplegia: a prospective case series.

BACKGROUND: Loss of upper extremity function after cervical spinal cord injury greatly affects independence, including social, vocational, and community engagement. Nerve transfer surgery offers an exciting new option for the reanimation of upper limb function in tetraplegia. The aim of this study was to evaluate the outcomes of nerve transfer surgery used for the reanimation of upper limb function in tetraplegia. METHODS: In this prospective case series, we consecutively recruited people of any age with early (<18 months post-injury) cervical spinal cord injury of motor level C5 and below, who had been referred to a single centre for upper extremity reanimation and were deemed suitable for nerve transfer. All participants underwent single or multiple nerve transfers in one or both upper limbs, sometimes combined with tendon transfers, for restoration of elbow extension, grasp, pinch, and hand opening. Participants were assessed at 12 months and 24 months post-surgery. Primary outcome measures were the action research arm test (ARAT), grasp release test (GRT), and spinal cord independence measure (SCIM). FINDINGS: Between April 14, 2014, and Nov 22, 2018, we recruited 16 participants (27 limbs) with traumatic spinal cord injury, among whom 59 nerve transfers were done. In ten participants (12 limbs), nerve transfers were combined with tendon transfers. 24-month follow-up data were unavailable for three patients (five limbs). At 24 months, significant improvements from baseline in median ARAT total score (34·0 [IQR 24·0-38·3] at 24 months vs 16·5 [12·0-22·0] at baseline, p<0·0001) and GRT total score (125·2 [65·1-154·4] vs 35·0 [21·0-52·3], p<0·0001) were observed. Mean total SCIM score and mobility in the room and toilet SCIM score improved by more than the minimal detectable change and the minimal clinically important difference, and the mean self-care SCIM score improved by more than the minimal detectable change between baseline and 24 months. Median Medical Research Council strength grades were 3 (IQR 2-3) for triceps and 4 (IQR 4-4) for digital extensor muscles after 24 months. Mean grasp strength at 24 months was 3·2 kg (SD 1·5) in participants who underwent distal nerve transfers (n=5), 2·8 kg (3·2) in those who had proximal nerve transfers (n=9), and 3·9 kg (2·4) in those who had tendon transfers (n=8). There were six adverse events related to the surgery, none of which had any ongoing functional consequences. INTERPRETATION: Early nerve transfer surgery is a safe and effective addition to surgical techniques for upper limb reanimation in tetraplegia. Nerve transfers can lead to significant functional improvement and can be successfully combined with tendon transfers to maximise functional benefits. FUNDING: Institute for Safety, Compensation, and Recovery Research (Australia).

Impact of respiratory muscle training on respiratory muscle strength, respiratory function and quality of life in individuals with tetraplegia: a randomised clinical trial.

BACKGROUND: Respiratory complications remain a leading cause of morbidity and mortality in people with acute and chronic tetraplegia. Respiratory muscle weakness following spinal cord injury-induced tetraplegia impairs lung function and the ability to cough. In particular, inspiratory muscle strength has been identified as the best predictor of the likelihood of developing pneumonia in individuals with tetraplegia. We hypothesised that 6 weeks of progressive respiratory muscle training (RMT) increases respiratory muscle strength with improvements in lung function, quality of life and respiratory health. METHODS: Sixty-two adults with tetraplegia participated in a double-blind randomised controlled trial. Active or sham RMT was performed twice daily for 6 weeks. Inspiratory muscle strength, measured as maximal inspiratory pressure (PImax) was the primary outcome. Secondary outcomes included lung function, quality of life and respiratory health. Between-group comparisons were obtained with linear models adjusting for baseline values of the outcomes. RESULTS: After 6 weeks, there was a greater improvement in PImax in the active group than in the sham group (mean difference 11.5 cmH2O (95% CI 5.6 to 17.4), p<0.001) and respiratory symptoms were reduced (St George Respiratory Questionnaire mean difference 10.3 points (0.01-20.65), p=0.046). Significant improvements were observed in quality of life (EuroQol-Five Dimensional Visual Analogue Scale 14.9 points (1.9-27.9), p=0.023) and perceived breathlessness (Borg score 0.64 (0.11-1.17), p=0.021). There were no significant improvements in other measures of respiratory function (p=0.126-0.979). CONCLUSIONS: Progressive RMT increases inspiratory muscle strength in people with tetraplegia, by a magnitude which is likely to be clinically significant. Measurement of baseline PImax and provision of RMT to at-risk individuals may reduce respiratory complications after tetraplegia. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN 12612000929808).

Spinal cord injury alters purinergic neurotransmission to mesenteric arteries in rats.

Complications associated with spinal cord injury (SCI) result from unregulated reflexes below the lesion level. Understanding neurotransmission distal to the SCI could improve quality of life by mitigating complications. The long-term impact of SCI on neurovascular transmission is poorly understood, but reduced sympathetic activity below the site of SCI enhances arterial neurotransmission (1). We studied sympathetic neurovascular transmission using a rat model of long-term paraplegia (T2-3) and tetraplegia (C6-7). Sixteen weeks after SCI, T2-3 and C6-7 rats had lower blood pressure (BP) than sham rats (103 ± 2 and 97 ± 4 vs. 117 ± 6 mmHg, P < 0.05). T2-3 rats had tachycardia (410 ± 6 beats/min), and C6-7 rats had bradycardia (299 ± 10 beats/min) compared with intact rats (321 ± 4 beats/min, P < 0.05). Purinergic excitatory junction potentials (EJPs) were measured in mesenteric arteries (MA) using microlectrodes, and norepinephrine (NE) release was measured using amperometry. NE release was similar in all groups, while EJP frequency-response curves from T2-3 and C6-7 rats were left-shifted vs. sham rats. EJPs in T2-3 and C6-7 rats showed facilitation followed by run-down during stimulation trains (10 Hz, 50 stimuli). MA reactivity to exogenous NE and ATP was similar in all rats. In T2-3 and C6-7 rats, NE content was increased in left cardiac ventricles compared with intact rats, but was not changed in MA, kidney, or spleen. Our data indicate that peripheral purinergic, but not adrenergic, neurotransmission increases following SCI via enhanced ATP release from periarterial nerves. Sympathetic BP support is reduced after SCI, but improving neurotransmitter release might maintain cardiovascular stability in individuals living with SCI.NEW & NOTEWORTHY This study revealed increased purinergic, but not noradrenergic, neurotransmission to mesenteric arteries in rats with spinal cord injury (SCI). An increased releasable pool of ATP in periarterial sympathetic nerves may contribute to autonomic dysreflexia following SCI, suggesting that purinergic neurotransmission may be a therapeutic target for maintaining stable blood pressure in individuals living with SCI. The selective increase in ATP release suggests that ATP and norepinephrine may be stored in separate synaptic vesicles in periarterial sympathetic varicosities.

Brain-Computer Interface-Based Communication in the Completely Locked-In State.

Despite partial success, communication has remained impossible for persons suffering from complete motor paralysis but intact cognitive and emotional processing, a state called complete locked-in state (CLIS). Based on a motor learning theoretical context and on the failure of neuroelectric brain-computer interface (BCI) communication attempts in CLIS, we here report BCI communication using functional near-infrared spectroscopy (fNIRS) and an implicit attentional processing procedure. Four patients suffering from advanced amyotrophic lateral sclerosis (ALS)-two of them in permanent CLIS and two entering the CLIS without reliable means of communication-learned to answer personal questions with known answers and open questions all requiring a "yes" or "no" thought using frontocentral oxygenation changes measured with fNIRS. Three patients completed more than 46 sessions spread over several weeks, and one patient (patient W) completed 20 sessions. Online fNIRS classification of personal questions with known answers and open questions using linear support vector machine (SVM) resulted in an above-chance-level correct response rate over 70%. Electroencephalographic oscillations and electrooculographic signals did not exceed the chance-level threshold for correct communication despite occasional differences between the physiological signals representing a "yes" or "no" response. However, electroencephalogram (EEG) changes in the theta-frequency band correlated with inferior communication performance, probably because of decreased vigilance and attention. If replicated with ALS patients in CLIS, these positive results could indicate the first step towards abolition of complete locked-in states, at least for ALS.

Rituximab in refractory chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a disorder in which early effective treatment is important to minimize disability from axonal degeneration. It has been suggested that some patients with CIDP may benefit from rituximab therapy, but there is no definitive evidence for this. METHODS: Baseline and post-rituximab-therapy neuromuscular Medical Research Council (MRC) sum scores, Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, and functional status were assessed in 11 patients with refactory CIDP. RESULTS: The MRC sum score, INCAT disability score, and functional status improved in all patients after rituximab therapy. DISCUSSION: Our study provides evidence of the efficacy of rituximab therapy in at least some patients with CIDP. A placebo-controlled study to assess the effectiveness of rituximab therapy in CIDP with and without nodal antibodies is required to identify disease markers that predict responsiveness.

Exoskeletal-Assisted Walking During Acute Inpatient Rehabilitation Leads to Motor and Functional Improvement in Persons With Spinal Cord Injury: A Pilot Study.

OBJECTIVE: To explore the potential effects of incorporating exoskeletal-assisted walking (EAW) into spinal cord injury (SCI) acute inpatient rehabilitation (AIR) on facilitating functional and motor recovery when compared with standard of care AIR. DESIGN: A quasi-experimental design with a prospective intervention group (AIR with EAW) and a retrospective control group (AIR only). SETTING: SCI AIR facility. PARTICIPANTS: Ten acute inpatient participants with SCI who were eligible for locomotor training were recruited in the intervention group. Twenty inpatients with SCI were identified as matched controls by reviewing an AIR database, Uniform Data System for Medical Rehabilitation, by an individual blinded to the study. Both groups (N=30) were matched based on etiology, paraplegia/tetraplegia, completeness of injury, age, and sex. INTERVENTION: EAW incorporated into SCI AIR. MAIN OUTCOME MEASURES: FIM score, International Standards for Neurological Classification of Spinal Cord Injury Upper Extremity Motor Score and Lower Extremity Motor Scores (LEMS), and EAW session results, including adverse events, walking time, and steps. RESULTS: Changes from admission to discharge LEMS and FIM scores were significantly greater in the intervention group (LEMS change: 14.3±10.1; FIM change: 37.8±10.8) compared with the control group (LEMS change: 4.6±6.1; FIM change: 26.5±14.3; Mann-Whitney U tests: LEMS, P<.01 and FIM, P<.05). One adverse event (minor skin abrasion) occurred during 42 walking sessions. Participants on average achieved 31.5 minutes of up time and 18.2 minutes of walk time with 456 steps in one EAW session. CONCLUSIONS: Incorporation of EAW into standard of care AIR is possible. AIR with incorporated EAW has the potential to facilitate functional and motor recovery compared with AIR without EAW.

Physical Activity and Sedentary Behavior From Discharge to 1 Year After Inpatient Rehabilitation in Ambulatory People With Spinal Cord Injury: A Longitudinal Cohort Study.

OBJECTIVE: To evaluate changes in duration of physical activity (PA) and sedentary behavior (SB) from discharge to 1 year after inpatient rehabilitation in ambulatory people with spinal cord injury (SCI). DESIGN: Longitudinal cohort study with objective measurements of physical behavior at discharge and at 6 and 12 months post discharge. SETTING: Three rehabilitation centers and the participant's home environment. PARTICIPANTS: Participants (N=47) with ambulatory function were consecutively recruited from the self-management and self-efficacy in patients with SCI cohort (age 18 years or older, recent SCI, expected inpatient stay ≥4wk). Mean age was 54.5±12.9 years, all had incomplete lesions, 53% were men, 49% had tetraplegia, and 51% were community ambulators at discharge. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Duration (min) of PA (summed duration of walking, cycling, running, and wheeling) and SB (sitting/lying). RESULTS: Mean duration of PA increased by 21 min/d (95% confidence interval, 7-35) and SB decreased by 64 min/d (95% confidence interval, -94 to -35) from discharge to 6 months after inpatient rehabilitation. No changes were found in the second half-year. One year after discharge mean PA was 116±59 min/d and mean SB was 665±121 min/d. The increase in PA was the result of an almost doubling of time spent walking. Variability in physical behavior and its change was large. Older age and lower ambulation level were associated with lower PA, lower ambulation level with higher SB, and tetraplegia was associated with a reduced increase in PA. CONCLUSIONS: At group level, duration of PA and SB improved following inpatient rehabilitation in ambulatory people with SCI. However, there were large differences between individuals. Levels 1 year after discharge were still unfavorable, particularly regarding SB.