Recovery of walking after paralysis by regenerating characterized neurons to their natural target region.

Axon regeneration can be induced across anatomically complete spinal cord injury (SCI), but robust functional restoration has been elusive. Whether restoring neurological functions requires directed regeneration of axons from specific neuronal subpopulations to their natural target regions remains unclear. To address this question, we applied projection-specific and comparative single-nucleus RNA sequencing to identify neuronal subpopulations that restore walking after incomplete SCI. We show that chemoattracting and guiding the transected axons of these neurons to their natural target region led to substantial recovery of walking after complete SCI in mice, whereas regeneration of axons simply across the lesion had no effect. Thus, reestablishing the natural projections of characterized neurons forms an essential part of axon regeneration strategies aimed at restoring lost neurological functions.

A high-performance speech neuroprosthesis.

Speech brain-computer interfaces (BCIs) have the potential to restore rapid communication to people with paralysis by decoding neural activity evoked by attempted speech into text1,2 or sound3,4. Early demonstrations, although promising, have not yet achieved accuracies sufficiently high for communication of unconstrained sentences from a large vocabulary1-7. Here we demonstrate a speech-to-text BCI that records spiking activity from intracortical microelectrode arrays. Enabled by these high-resolution recordings, our study participant-who can no longer speak intelligibly owing to amyotrophic lateral sclerosis-achieved a 9.1% word error rate on a 50-word vocabulary (2.7 times fewer errors than the previous state-of-the-art speech BCI2) and a 23.8% word error rate on a 125,000-word vocabulary (the first successful demonstration, to our knowledge, of large-vocabulary decoding). Our participant's attempted speech was decoded  at 62 words per minute, which is 3.4 times as fast as the previous record8 and begins to approach the speed of natural conversation (160 words per minute9). Finally, we highlight two aspects of the neural code for speech that are encouraging for speech BCIs: spatially intermixed tuning to speech articulators that makes accurate decoding possible from only a small region of cortex, and a detailed articulatory representation of phonemes that persists years after paralysis. These results show a feasible path forward for restoring rapid communication to people with paralysis who can no longer speak.

A high-performance neuroprosthesis for speech decoding and avatar control.

Speech neuroprostheses have the potential to restore communication to people living with paralysis, but naturalistic speed and expressivity are elusive1. Here we use high-density surface recordings of the speech cortex in a clinical-trial participant with severe limb and vocal paralysis to achieve high-performance real-time decoding across three complementary speech-related output modalities: text, speech audio and facial-avatar animation. We trained and evaluated deep-learning models using neural data collected as the participant attempted to silently speak sentences. For text, we demonstrate accurate and rapid large-vocabulary decoding with a median rate of 78 words per minute and median word error rate of 25%. For speech audio, we demonstrate intelligible and rapid speech synthesis and personalization to the participant's pre-injury voice. For facial-avatar animation, we demonstrate the control of virtual orofacial movements for speech and non-speech communicative gestures. The decoders reached high performance with less than two weeks of training. Our findings introduce a multimodal speech-neuroprosthetic approach that has substantial promise to restore full, embodied communication to people living with severe paralysis.

Invisible consequences of paralysis.

Neuroprosthetic technologies can control blood pressure and restore walking.

The neurons that restore walking after paralysis.

A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord1-3 applied during neurorehabilitation4,5 (EESREHAB) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencing6-9 and spatial transcriptomics10,11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type12,13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.

The effect of transnasal humidified rapid-insufflation ventilator exchange (THRIVE) versus nasal prongs on safe apnoea time in paralysed obese patients: a randomised controlled trial.

BACKGROUND: Evidence is lacking regarding the efficacy of Optiflow transnasal humidified rapid-insufflation ventilator exchange (THRIVE™) in obese patients. We compared the impact of this technique at 70 L min-1 with 4 L min-1 oxygen via nasal prongs on safe apnoea times of paralysed obese patients. METHODS: We randomised adults with a BMI >35 kg m-2 undergoing elective bariatric surgery. While apnoeic and paralysed, Group T received 70 L min-1 oxygen via Optiflow THRIVE™. Group N received nasal prong oxygen at 4 L min-1. The primary outcome was time to SpO2 ≤95% while apnoeic, with a 360 s cut-off. This was analysed by applying a time-to-event analysis. RESULTS: Forty-two patients were included. The median (inter-quartile range) BMI was 44.8 kg m-2 (40.0-50.0) in Group T and 42.0 kg m-2 (39.3-45.1) in Group N. Median (inter-quartile range) time to SpO2 ≤95% in Group T was 356 (165 to ≥360) s and in Group N, 210 (160-270) s. Using a survival analysis framework, median time-to-event in Group T was 356 s (95% confidence interval 165 s-upper limit not defined) and 210 s (95% confidence interval 160-242 s) (P=0.049) in Group N. CONCLUSIONS: Compared with oxygen delivered via nasal prongs at 4 L min-1, oxygen delivery via Optiflow THRIVE™ at a flow rate of 70 L min-1 can prolong safe apnoea time, however, the results are statistically inconclusive. Optiflow THRIVE™ did decrease the rate of reduction in Pao2 during apnoea. CLINICAL TRIAL REGISTRATION: ANZCTR 12618000445279.

IAPV-Induced Paralytic Symptoms Associated with Tachypnea via Impaired Tracheal System Function.

Although it had been reported that Israeli acute paralysis virus (IAPV) can cause systemic infection in honey bees, little is known about how it establishes this infection and results in the typical symptoms, paralysis and trembling. Here, we used our previously constructed IAPV infectious clone to investigate viral loads in different tissues of honey bees and further identify the relation between tissue tropism and paralytic symptoms. Our results showed that tracheae showed a greater concentration of viral abundance than other tissues. The abundance of viral protein in the tracheae was positively associated with viral titers, and was further confirmed by immunological and ultrastructural evidence. Furthermore, higher viral loads in tracheae induced remarkable down-regulation of succinate dehydrogenase and cytochrome c oxidase genes, and progressed to causing respiratory failure of honey bees, resulting in the appearance of typical symptoms, paralysis and body trembling. Our results showed that paralysis symptoms or trembling was actually to mitigate tachypnea induced by IAPV infection due to the impairment of honey bee tracheae, and revealed a direct causal link between paralysis symptoms and tissue tropism. These findings provide new insights into the understanding of the underlying mechanism of paralysis symptoms of honey bees after viral infection and have implications for viral disease prevention and specific therapeutics in practice.

Does a combination treatment of repetitive transcranial magnetic stimulation and occupational therapy improve upper limb muscle paralysis equally in patients with chronic stroke caused by cerebral hemorrhage and infarction?: A retrospective cohort study.

ABSTRACT: The clinical presentation of stroke is usually more severe in patients with intracerebral hemorrhage (ICH) than in those with cerebral infarction (CI); recovery of stroke-related muscle paralysis is influenced and limited by the type of stroke. To date, many patients have been treated by neurorehabilitation; however, the changes in the recovery of motor paralysis depending on the type of stroke, ICH or CI, have not been established. This study aimed to determine this difference in improvement of upper extremity paralysis using 2-week in-hospital NovEl intervention Using Repetitive transcranial magnetic stimulation combined with Occupational therapy (NEURO).We scrutinized the medical records of all patients with poststroke (ICH or CI) upper extremity muscle paralysis using Fugl-Meyer assessments (FMAs) who had been admitted to 6 hospitals between March 2010 and December 2018 for rehabilitation treatment. This was a multiinstitutional, open-label, retrospective cohort study without control patients. We evaluated the effects of NEURO on patients with CI and ICH by dividing them into 2 groups according to the type of stroke, after adjustment for age, sex, dominant hand, affected hand side, time since stroke, and prediction of recovery capacity in the upper extremity.The study included 1716 (CI [n = 876] and ICH [n = 840]) patients who had undergone at least 2 FMAs and had experienced stroke at least 6 months before. The type of stroke had no effect on the outcomes (changes in the FMA-upper extremity score, F[4,14.0] = 2.05, P = .09, partial η2 = 0.01). Patients from all 5 groups equally benefited from the treatment (improvement in FMA scores) according to the sensitivity analysis-stratified analysis (F = 0.08 to 1.94, P > .16, partial η2 < 0.001).We conclude that NEURO can be recommended for chronic stroke patients irrespective of the type of stroke.

Weakened Effective Connectivity Related to Electroacupuncture in Stroke Patients with Prolonged Flaccid Paralysis: An EEG Pilot Study.

Flaccid paralysis in the upper extremity is a severe motor impairment after stroke, which exists for weeks, months, or even years. Electroacupuncture treatment is one of the most widely used TCM therapeutic interventions for poststroke flaccid paralysis. However, the response to electroacupuncture in different durations of flaccid stage poststroke as well as in the topological configuration of the cortical network remains unclear. The objectives of this study are to explore the disruption of the cortical network in patients in different durations of flaccid stage and observe dynamic network reorganization during and after electroacupuncture. Resting-state networks were constructed from 18 subjects with flaccid upper extremity by partial directed coherence (PDC) analysis of multichannel EEG. They were allocated to three groups according to time after flaccid paralysis: the short-duration group (those with flaccidity for less than two months), the medium-duration group (those with flaccidity between two months and six months), and the long-duration group (those with flaccidity over six months). Compared with short-duration flaccid subjects, weakened effective connectivity was presented in medium-duration and long-duration groups before electroacupuncture. The long-duration group has no response in the cortical network during electroacupuncture. The global network measures of EEG data (sPDC, mPDC, and N) indicated that there was no significant difference among the three groups. These results suggested that the network connectivity reduced and weakly responded to electroacupuncture in patients with flaccid paralysis for over six months. These findings may help us to modulate the formulation of electroacupuncture treatment according to different durations of the flaccid upper extremity.

Contralateral C7 nerve transfer through posterior vertebral approach combined with selective posterior rhizotomy of the affected cervical nerve in the treatment of central upper limb spastic paralysis: A case report.

INTRODUCTION: C7 nerve transfer alone can improve upper limb motor function and partial spasticity. Selective posterior rhizotomy (SPR) of the cervical nerve alone can comprehensively improve spasticity but without neuromotor regeneration. We propose a novel possible improvement of contralateral C7 (CC7) nerve transfer through the posterior vertebral approach, which was combined with SPR of the affected cervical nerve. PATIENT CONCERNS: A 33-year-old male patient presented with cerebral hemorrhage of the left basal ganglia, paralysis of the right limbs, and hypesthesia 8 months earlier. The dysfunction of the affected hand was already present at admission. The patient reported a previous history of hypertension for several years and oral antihypertensive drugs, and blood pressure was controlled within a normal range. DIAGNOSIS: Central upper limb spastic paralysis. The muscle strength of the right lower limb was grade IV. The Fugl-Meyer score of the right upper limb was 7 points, and the modified Ashworth score was 10. INTERVENTIONS: The patient underwent CC7 transfer and SPR. OUTCOMES: The patient successfully underwent CC7 transfer and SPR without complications. On the day after surgery, the left upper limb motions were normal. The Fugl-Meyer score was 9, and the modified Ashworth score of the right upper limb was 2. CONCLUSIONS: CC7 nerve transfer through the posterior vertebral approach combined with SPR of the affected cervical nerve can possibly improve the surgical outcomes of selected patients with upper limb motor dysfunction and partial spasticity. This method has not been reported in the literature before, and additional studies are necessary.

Factors related to daily use of the paretic upper limb in patients with chronic hemiparetic stroke-A retrospective cross-sectional study.

AIMS: The present study aimed to determine factors associated with the frequency of paralyzed upper extremity (UE) use in chronic stroke patients with severe UE functional deficiency. METHODS: We retrospectively reviewed the medical records of 138 consecutive patients, and 117 was analyzed (median age, 55 [range, 18-85] years; median stroke duration, 24.5 [range, 7-302] months) with chronic hemiparetic stroke who were admitted to our hospital for intensive upper extremity rehabilitation. The mean Fugl-Meyer Assessment (FMA) UE score was 28.6. All of them are independent in their activity of daily living (ADL) and without remarkable cognitive deficits. Amount-of-use score of Motor Activity Log-14 (MAL-AOU) was applied as the index of daily use of affected UE. The following parameters were examined as the explanatory variables: demographics, proximal and distal sub-scores of FMA UE, Modified Ashworth Scale (MAS), and sensory function scores in the Stroke Impairment Assessment Set (SIAS). RESULTS: The median MAL-AOU score was 0.57 [range, 0.28-0.80]. Ordinal regression analysis revealed that FMA proximal, FMA distal, and SIAS sensory function (touch) were associated with AOU score of MAL-14 (Pseudo R-square = 0.460). CONCLUSION: Not only motor but also sensory function, especially tactile sensation, play a crucial role in the daily use of affected UE in chronic stroke patients with severe UE hemiparesis.

Lathyrism and Socioeconomic Disparities: A Neglected Public Health Problem in Northeast Ethiopia.

Lathyrism is an incurable neurological disorder, resulting from excessive consumption of grass pea (Lathyrus sativus), which clinically manifests as paralysis of lower limbs. Because of the high production of grass peas, a large number of people are expected to be affected by the disease in Northeast Ethiopia. However, there is no comprehensive study that quantified the magnitude of the problem. Therefore, in this study, we determined the prevalence of lathyrism and socioeconomic disparities in Northeast Ethiopia. A community-based cross-sectional study was used which used a quantitative method of data collection from January to February 2019. Data were collected from a total of 2,307 inhabitants in the study area using structured questionnaires. Lathyrism cases were identified using a case definition of symmetrical spastic leg weakness, and subacute or insidious onset, with no sensory deficit, and with a history of grass pea consumption before and at the onset of paralysis. The majority (56.8%) of participants were male, and 34.7% were aged 45 years or older. Overall, the prevalence of lathyrism was 5.5%, and it was higher in males (7.9%) than in females (2.5%). Moreover, the prevalence was higher among farmers (7.0%) than merchants (0.3%), very poor economic status (7.2%) than very rich (1.1%), who produced (9.6%) grass pea than not produced (0.9%), and those who used clay pottery (6.2%) than metal (4.8%) for cooking. The prevalence of lathyrism in Northeast Ethiopia is remarkably high. Therefore, we recommend lathyrism to be among the list of reportable health problems and incorporated in the national routine surveillance system.

Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.

RATIONALE: Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. PATIENT CONCERNS: We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully. DIAGNOSES: Right vocal fold paralysis was diagnosed with flexible laryngoscopy. INTERVENTIONS: Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. OUTCOMES: Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain. LESSONS: The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.

Three-Year Longitudinal Motor Function and Disability Level of Acute Flaccid Myelitis.

BACKGROUND: We summarize the long-term motor outcome and disability level in a cluster of pediatric patients with acute flaccid myelitis (AFM) associated with the enterovirus D68 outbreak in 2015. METHODS: This is a nationwide follow-up questionnaire analysis study. Clinical data including the motor function (manual muscle strength test) and other neurological symptoms were collected at the acute (nadir), recovery (six months), and chronic (three years) stages. We use the Barthel index, which measures 10 variables describing activity of daily living and mobility to assess the disability level. RESULTS: Clinical data of 33 patients with AFM (13 females, 20 males; median age = 4.1 years) were available. Among patients with tetraplegia or triplegia, paraplegia, and monoplegia at the acute stage, two of seven, four of thirteen, and two of thirteen exhibited complete recovery without paralysis; of those five of seven, eight of thirteen, and two of thirteen showed improvement with lesser limb involvement at the chronic stage, respectively. Nine patients (27%) demonstrated improvement at the recovery-to-chronic period. All six patients with positive isolation of enterovirus D68 from biological samples at the acute stage showed persistent motor deficits. Other neurological findings had better prognosis than motor weakness. Better Barthel index score at the chronic stage was observed (P < 0.001; median difference [95% confidence interval], 53 [40 to 63]), implying an improved disability level even in patients with persistent motor deficits. CONCLUSIONS: AFM has a high rate of persistent motor deficits showing one- to two-limb paralysis. Disability level of patients with AFM, however, generally improved at the three-year time point.

Standardizing fatigue-resistance testing during electrical stimulation of paralysed human quadriceps muscles, a practical approach.

BACKGROUND: Rapid onset of muscular fatigue is still one of the main issues of functional electrical stimulation (FES). A promising technique, known as distributed stimulation, aims to activate sub-units of a muscle at a lower stimulation frequency to increase fatigue-resistance. Besides a general agreement on the beneficial effects, the great heterogeneity of evaluation techniques, raises the demand for a standardized method to better reflect the requirements of a practical application. METHODS: This study investigated the fatigue-development of 6 paralysed quadriceps muscles over the course of 180 dynamic contractions, evaluating different electrode-configurations (conventional and distributed stimulation). For a standardized comparison, fatigue-testing was performed at 40% of the peak-torque during a maximal evoked contraction (MEC). Further, we assessed the isometric torque for each electrode-configuration at different knee-extension-angles (70°-170°, 10° steps). RESULTS: Our results showed no significant difference in the fatigue-index for any of the tested electrode-configurations, compared to conventional-stimulation. We conjecture that the positive effects of distributed stimulation become less pronounced at higher stimulation amplitudes. The isometric torque produced at different knee-extension angles was similar for most electrode-configurations. Maximal torque-production was found at 130°-140° knee-extension-angle, which correlates with the maximal knee-flexion-angles during running. CONCLUSION: In most practical applications, FES is intended to initiate dynamic movements. Therefore, it is crucial to assess fatigue-resistance by using dynamic contractions. Reporting the relationship between produced torque and knee-extension-angle can help to observe the stability of a chosen electrode-configuration for a targeted range-of-motion. Additionally, we suggest to perform fatigue testing at higher forces (e.g. 40% of the maximal evoked torque) in pre-trained subjects with SCI to better reflect the practical demands of FES-applications.

Plug-and-play control of a brain-computer interface through neural map stabilization.

Brain-computer interfaces (BCIs) enable control of assistive devices in individuals with severe motor impairments. A limitation of BCIs that has hindered real-world adoption is poor long-term reliability and lengthy daily recalibration times. To develop methods that allow stable performance without recalibration, we used a 128-channel chronic electrocorticography (ECoG) implant in a paralyzed individual, which allowed stable monitoring of signals. We show that long-term closed-loop decoder adaptation, in which decoder weights are carried across sessions over multiple days, results in consolidation of a neural map and 'plug-and-play' control. In contrast, daily reinitialization led to degradation of performance with variable relearning. Consolidation also allowed the addition of control features over days, that is, long-term stacking of dimensions. Our results offer an approach for reliable, stable BCI control by leveraging the stability of ECoG interfaces and neural plasticity.

Motor neuroprosthesis implanted with neurointerventional surgery improves capacity for activities of daily living tasks in severe paralysis: first in-human experience.

BACKGROUND: Implantable brain-computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore voluntary motor impulses to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. However, reports to date have had limited clinical translation. METHODS: Two participants with amyotrophic lateral sclerosis (ALS) underwent implant in a single-arm, open-label, prospective, early feasibility study. Using a minimally invasive neurointervention procedure, a novel endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. The participants undertook machine-learning-assisted training to use wirelessly transmitted electrocorticography signal associated with attempted movements to control multiple mouse-click actions, including zoom and left-click. Used in combination with an eye-tracker for cursor navigation, participants achieved Windows 10 operating system control to conduct instrumental activities of daily living (IADL) tasks. RESULTS: Unsupervised home use commenced from day 86 onwards for participant 1, and day 71 for participant 2. Participant 1 achieved a typing task average click selection accuracy of 92.63% (100.00%, 87.50%-100.00%) (trial mean (median, Q1-Q3)) at a rate of 13.81 (13.44, 10.96-16.09) correct characters per minute (CCPM) with predictive text disabled. Participant 2 achieved an average click selection accuracy of 93.18% (100.00%, 88.19%-100.00%) at 20.10 (17.73, 12.27-26.50) CCPM. Completion of IADL tasks including text messaging, online shopping and managing finances independently was demonstrated in both participants. CONCLUSION: We describe the first-in-human experience of a minimally invasive, fully implanted, wireless, ambulatory motor neuroprosthesis using an endovascular stent-electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices in two participants with flaccid upper limb paralysis.