13 research outputs found
Targeted vagus nerve stimulation for rehabilitation after stroke
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Vagus nerve stimulation paired with mobility training in chronic ischemic stroke: a case report
Objective The purpose of this case report is to describe pairing vagus nerve stimulation (VNS) with mobility training in an individual after stroke. Methods A 53-year-old man with left hemiparesis 14.2 months after an ischemic stroke participated in a pilot study investigating the safety and feasibility of VNS paired with upper limb rehabilitation. In addition to upper limb impairment, the participant had impaired gait and wanted to improve his mobility. A single-subject design investigation of VNS paired with self-directed mobility training was conducted. Following the conclusion of the pilot study, the participant was instructed to complete daily sessions of self-activated VNS paired with walking or stationary biking. The 10-Meter Walk Test and timed distance (6-Minute Walk Test) were assessed at 4 baseline points and at 3 to 41 months after mobility training. Results The participant had stable baseline values and was classified as a household ambulator with a quad cane. After VNS-paired mobility training, statistically significant improvements were observed in all measures, with the greatest improvements at 9 months exceeding the minimal detectable change: self-selected gait speed from 0.34 (standard deviation [SD] = 0.01) to 0.60 meters/second, fast gait speed from 0.37 (SD = 0.03) to 0.79 meters/second, and 6-Minute Walk Test distance from 106.91 (SD = 6.38) to 179.83 meters. The participant reported increased confidence and balance when walking. No falls or adverse events were reported. Conclusion The participant demonstrated improved gait speed and timed distance after VNS-paired mobility training. Randomized, blinded trials are needed to determine treatment efficacy. Impact This is the first documented case of VNS-paired mobility training in an individual with chronic poststroke gait impairments. VNS paired with mobility training may improve poststroke gait impairments
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Vagus nerve stimulation paired with upper limb rehabilitation after chronic stroke
Background and Purpose:
We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke.
Methods:
We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy.
Results:
All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 postâin-clinic therapy (difference, 2.3 points; CI, â1.8 to 6.4; P=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the
control scores improved by 3.8 (difference, 5.7 points; CI, â1.4 to 11.5; P=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS (P<0.05).
Conclusions:
VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified
Research Priorities in Limb and Task-Specific Dystonias
Dystonia, which causes intermittent or sustained abnormal postures and movements, can present in a focal or a generalized manner. In the limbs, focal dystonia can occur in either the upper or lower limbs and may be task-specific causing abnormal motor performance for only a specific task, such as in writerâs cramp, runnerâs dystonia, or musicianâs dystonia. Focal limb dystonia can be non-task-specific and may, in some circumstances, be associated with parkinsonian disorders. The true prevalence of focal limb dystonia is not known and is likely currently underestimated, leaving a knowledge gap and an opportunity for future research. The pathophysiology of focal limb dystonia shares some commonalities with other dystonias with a loss of inhibition in the central nervous system and a loss of the normal regulation of plasticity, called homeostatic plasticity. Functional imaging studies revealed abnormalities in several anatomical networks that involve the cortex, basal ganglia, and cerebellum. Further studies should focus on distinguishing cause from effect in both physiology and imaging studies to permit focus on most relevant biological correlates of dystonia. There is no specific therapy for the treatment of limb dystonia given the variability in presentation, but off-label botulinum toxin therapy is often applied to focal limb and task-specific dystonia. Various rehabilitation techniques have been applied and rehabilitation interventions may improve outcomes, but small sample size and lack of direct comparisons between methods to evaluate comparative efficacy limit conclusions. Finally, non-invasive and invasive therapeutic modalities have been explored in small studies with design limitations that do not yet clearly provide direction for larger clinical trials that could support new clinical therapies. Given these gaps in our clinical, pathophysiologic, and therapeutic knowledge, we have identified priorities for future research including: the development of diagnostic criteria for limb dystonia, more precise phenotypic characterization and innovative clinical trial design that considers clinical heterogeneity, and limited available number of participants
Vagus nerve stimulation paired with rehabilitation for upper limb motor impairment and function after chronic ischemic stroke: subgroup analysis of the randomized, blinded, pivotal, VNS-REHAB device trial
Background:
Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomized, triple-blind, sham-controlled trial in people with chronic arm weakness after stroke.
Objective:
We aimed to determine whether treatment effects varied across candidate subgroups, such as younger age or less injury.
Methods:
Participants were randomized to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in impairment measured by the FuglâMeyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of 6-weeks in-clinic therapy. We explored the effect of VNS treatment by sex, age (â„62âyears), time from stroke (>2âyears), severity (baseline FMA-UE score >34), paretic side of body, country of enrollment (USA vs UK) and presence of cortical involvement of the index infarction. We assessed whether there was any interaction with treatment.
Findings:
The primary outcome increased by 5.0âpoints (SD 4.4) in the VNS group and by 2.4âpoints (SD 3.8) in the Control group (Pâ=â.001, between group difference 2.6, 95% CI 1.03-4.2). The between group difference was similar across all subgroups and there were no significant treatment interactions. There was no important difference in rates of adverse events across subgroups.
Conclusion:
The response was similar across subgroups examined. The findings suggest that the effects of paired VNS observed in the VNS-REHAB trial are likely to be consistent in wide range of stroke survivors with moderate to severe upper extremity impairment
A functional magnetic resonance imaging study of head movements in cervical dystonia
Cervical dystonia (CD) is a neurological disorder characterized by abnormal movements and postures of the head. The brain regions responsible for these abnormal movements are not well understood, because most imaging techniques for assessing regional brain activity cannot be used when the head is moving. Recently, we mapped brain activation in healthy individuals using functional magnetic resonance imaging (fMRI) during isometric head rotation, when muscle contractions occur without actual head movements. In the current study, we used the same methods to explore the neural substrates for head movements in subjects with CD who had predominantly rotational abnormalities (torticollis). Isometric wrist extension was examined for comparison. Electromyography of neck and hand muscles ensured compliance with tasks during scanning, and any head motion was measured and corrected. Data were analyzed in three steps. First, we conducted within-group analyses to examine task-related activation patterns separately in subjects with CD and in healthy controls. Next, we directly compared task-related activation patterns between participants with CD and controls. Finally, considering that the abnormal head movements in CD occur in a consistently patterned direction for each individual, we conducted exploratory analyses that involved normalizing data according to the direction of rotational CD. The between-group comparisons failed to reveal any significant differences, but the normalization procedure in subjects with CD revealed that isometric head rotation in the direction of dystonic head rotation was associated with more activation in the ipsilateral anterior cerebellum, whereas isometric head rotation in the opposite direction was associated with more activity in sensorimotor cortex. These findings suggest that the cerebellum contributes to abnormal head rotation in CD, whereas regions in the cerebral cortex are involved in opposing the involuntary movements
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Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease.
LeschâNyhan disease (LND) is an inherited disorder with a characteristic neurobehavioral phenotype that includes a movement disorder dominated by generalized dystonia, intellectual disability, and recurrent self-injurious behavior.1â4 The disorder is caused by mutations in the HPRT1 gene, leading to deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt).5,6
The mechanisms by which HGprt deficiency leads to the neurological and behavioral problems are not well understood. However, there is strong evidence that they arise from dysfunction of basal ganglia circuits, and particularly dopaminergic pathways.7,8 Neurochemical studies of LND brains collected at autopsy have revealed 60 to 80% loss of dopamine throughout the basal ganglia.9â11 Positron emission tomography studies have demonstrated similar reductions of dopamine transporters and dopamine uptake.12,13 These studies have led to suggestions that dopamine neurons or their axonal projections are damaged.9,13 However, several histopathological studies of autopsied brains have not revealed any consistent loss of neurons in the substantia nigra.1,11,14 The reason for profound loss of dopamine-related measures with apparently preserved nigral dopamine neurons has never been established.
Dysfunction of dopaminergic pathways also is observed in animal and cell models of HGprt deficiency.15 The HGprt knockout (HGprtâ) mouse model has a 30 to 60% loss of striatal dopamine and associated biochemical markers such as homovanillic acid, dihydroxyphenylacetic acid, tyrosine hydroxylase (TH), aromatic amino acid decarboxylase, and dopamine transporters.16â18
However, quantitative stereological studies of these mutant mice have revealed no loss of midbrain dopamine neurons or their axonal projections.19 Several HGprt-deficient cell models also have shown loss of dopaminergic markers with no apparent loss of viability.20â25 In these cell models, mRNA expression profiling has revealed broad disruption of the neurotransmitter phenotype. These findings from cell and animal models have led to suggestions that HGprt deficiency disrupts early developmental programs that lead to the expression of the dopaminergic neurochemical phenotype. This hypothesis was explored in the current studies by examining the integrity of midbrain dopamine neurons in the brains of 5 LND brains collected at autopsy. Key findings were confirmed in the HGprtâ mouse model19 and the MN9D cell model21 of HGprt deficiency
Vagus nerve stimulation paired with upper-limb rehabilitation after stroke: one-year follow-up
Background. Vagus nerve stimulation (VNS) paired with rehabilitation may improve upper-limb impairment and function after ischemic stroke. Objective. To report 1-year safety, feasibility, adherence, and outcome data from a home exercise program paired with VNS using long-term follow-up data from a randomized double-blind study of rehabilitation therapy paired with Active VNS (n = 8) or Control VNS (n = 9). Methods. All people were implanted with a VNS device and underwent 6 weeks in clinic therapy with Control or Active VNS followed by home exercises through day 90. Thereafter, participants and investigators were unblinded. The Control VNS group then received 6 weeks in-clinic Active VNS (Cross-VNS group). All participants then performed an individualized home exercise program with self-administered Active VNS. Data from this phase are reported here. Outcome measures were Fugl-Meyer AssessmentâUpper Extremity (FMA-UE), Wolf Motor Function Test (Functional and Time), Box and Block Test, Nine-Hole Peg Test, Stroke Impact Scale, and Motor Activity Log. Results. There were no VNS treatmentârelated serious adverse events during the long-term therapy. Two participants discontinued prior to receiving the full crossover VNS. On average, participants performed 200 ± 63 home therapy sessions, representing device use on 57.4% of home exercise days available for each participant. Pooled analysis revealed that 1 year after randomization, the FMA-UE score increased by 9.2 points (95% CI = 4.7 to 13.7; P = .001; n = 15). Other functional measures were also improved at 1 year. Conclusions. VNS combined with rehabilitation is feasible, with good long-term adherence, and may improve arm function after ischemic stroke
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Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke.
Background and Purpose- We assessed safety, feasibility, and potential effects of vagus nerve stimulation (VNS) paired with rehabilitation for improving arm function after chronic stroke. Methods- We performed a randomized, multisite, double-blinded, sham-controlled pilot study. All participants were implanted with a VNS device and received 6-week in-clinic rehabilitation followed by a home exercise program. Randomization was to active VNS (n=8) or control VNS (n=9) paired with rehabilitation. Outcomes were assessed at days 1, 30, and 90 post-completion of in-clinic therapy. Results- All participants completed the course of therapy. There were 3 serious adverse events related to surgery. Average FMA-UE scores increased 7.6 with active VNS and 5.3 points with control at day 1 post-in-clinic therapy (difference, 2.3 points; CI, -1.8 to 6.4; P=0.20). At day 90, mean scores increased 9.5 points from baseline with active VNS, and the control scores improved by 3.8 (difference, 5.7 points; CI, -1.4 to 11.5; P=0.055). The clinically meaningful response rate of FMA-UE at day 90 was 88% with active VNS and 33% with control VNS ( P<0.05). Conclusions- VNS paired with rehabilitation was acceptably safe and feasible in participants with upper limb motor deficit after chronic ischemic stroke. A pivotal study of this therapy is justified. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT02243020