An exploratory study of predictors of response to vagus nerve stimulation paired with upper-limb rehabilitation after ischemic stroke

We have previously shown the safety and feasibility of vagus nerve stimulation (VNS) paired with upper-limb rehabilitation after ischemic stroke. In this exploratory study, we assessed whether clinical and brain MRI variables predict response to treatment. We used data from two completed randomised and blinded clinical trials (N = 35). All participants had moderate to severe upper-limb weakness and were randomised to 6-weeks intensive physiotherapy with or without VNS. Participants had 3 T brain MRI at baseline. The primary outcome was change in Fugl-Meyer Assessment, upper-extremity score (FMA-UE) from baseline to the first day after therapy completion. We used general linear regression to identify clinical and brain MRI predictors of change in FMA-UE. VNS-treated participants had greater improvement in FMA-UE at day-1 post therapy than controls (8.63 ± 5.02 versus 3.79 ± 5.04 points, t = 2.83, Cohen’s d = 0.96, P = 0.008). Higher cerebrospinal fluid volume was associated with less improvement in FMA-UE in the control but not VNS group. This was also true for white matter hyperintensity volume but not after removal of an outlying participant from the control group. Responders in the VNS group had more severe arm impairment at baseline than responders to control. A phase III trial is now underway to formally determine whether VNS improves outcomes and will explore whether these differ in people with more severe baseline upper-limb disability and cerebrovascular disease

Observation of Amounts of Movement Practice Provided during Stroke Rehabilitation

Objective To investigate how much movement practice occurred during stroke rehabilitation, and what factors might influence doses of practice provided. Design Observational survey of stroke therapy sessions. Setting Seven inpatient and outpatient rehabilitation sites. Participants We observed a convenience sample of 312 physical and occupational therapy sessions for people with stroke. Interventions Not applicable. Main Outcome Measures We recorded numbers of repetitions in specific movement categories and data on potential modifying factors (patient age, side affected, time since stroke, FIM item scores, years of therapist experience). Descriptive statistics were used to characterize amounts of practice. Correlation and regression analyses were used to determine whether potential factors were related to the amount of practice in the 2 important categories of upper extremity functional movements and gait steps. Results Practice of task-specific, functional upper extremity movements occurred in 51% of the sessions that addressed upper limb rehabilitation, and the average number of repetitions/session was 32 (95% confidence interval [CI]=20–44). Practice of gait occurred in 84% of sessions that addressed lower limb rehabilitation and the average number of gait steps/session was 357 (95% CI=296–418). None of the potential factors listed accounted for significant variance in the amount of practice in either of these 2 categories. Conclusions The amount of practice provided during poststroke rehabilitation is small compared with animal models. It is possible that current doses of task-specific practice during rehabilitation are not adequate to drive the neural reorganization needed to promote function poststroke optimally

Visualizing the Effects of rTMS in a Patient Sample: Small N vs. Group Level Analysis

The use of transcranial magnetic stimulation (TMS) to assess changes in cortical excitability is a tool used with increased prevalence in healthy and impaired populations. One factor of concern with this technique is how to achieve adequate statistical power given constraints of a small number of subjects and variability in responses. This paper compares a single pulse excitability measure using traditional group-level statistics vs single subject analyses in a patient population of subjects with focal hand dystonia, pre and post repetitive TMS (rTMS). Results show significant differences in cortical excitability for 4/5 subjects using a split middle line analysis on plots of individual subject data. Group level statistics (ANOVA), however, did not detect any significant findings. The consideration of single subject statistics for TMS excitability measures may assist researchers in describing the variably of rTMS outcome measures

Clinical and demographic subject information.

<p>R = right, L = left, WC = writer's cramp, MD = musician's dystonia, M = male, F = female.</p

Motor evoked potentials of repeated single pulse stimulations at 130% resting motor threshold (repeated tests occurred at 0.1 Hz).

<p>Arrows indicate a significant decrease in cortical excitability during the intervention phase vs the sham phase for 4 subjects. Symbols on the x axis for s13 (жж) indicate missing data. Inset shows group level outcomes; means and standard deviations, N = 5.</p

Multiple sessions of low-frequency repetitive transcranial magnetic stimulation in focal hand dystonia:clinical and physiological effects

PURPOSE: The ability of low-frequency repetitive transcranial magnetic stimulation (rTMS) to enhance intracortical inhibition has motivated its use as a potential therapeutic intervention in focal hand dystonia (FHD). In this preliminary investigation, we assessed the physiologic and behavioral effects of multiple sessions of rTMS in FHD. METHODS: 12 patients with FHD underwent five daily-sessions of 1Hz rTMS to contralateral dorsal premotor cortex (dPMC). Patients held a pencil and made movements that did not elicit dystonic symptoms during rTMS. We hypothesized that an active but non-dystonic motor state would increase beneficial effects of rTMS. Five additional patients received sham-rTMS protocol. The area under curve (AUC) of the motor evoked potentials and the cortical silent period (CSP) were measured to assess changes in corticospinal excitability and intracortical inhibition, respectively. Behavioral measures included pen force and velocity during handwriting and subjective report. RESULTS: Multiple-session rTMS strengthened intracortical inhibition causing a prolongation of CSP after 3 days of intervention and pen force was reduced at day 1 and 5, leaving other measures unchanged. 68% of patients self-reported as ‘responders’ at day 5, and 58% at follow-up. Age predicted responders. CONCLUSIONS: A strong therapeutic potential of this rTMS paradigm in FHD was not supported but findings warrant further investigation

Effectiveness of rTMS and retraining in the treatment of focal hand dystonia

Though the pathophysiology of dystonia remains uncertain, two primary factors implicated in the development of dystonic symptoms are excessive cortical excitability and impaired sensorimotor processing. The aim of this study was to determine the functional efficacy of a sensorimotor intervention combining rTMS and sensorimotor retraining. A randomized, single-subject, multiple baseline design with crossover was used to examine participants with focal hand dystonia (FHD) (n=9). Intervention: 5 days rTMS + sensorimotor retraining (SMR) vs. 5 days rTMS + control therapy (CTL) (which included stretching and massage). The rTMS was applied to the premotor cortex at 1 Hz at 80% resting motor threshold for 1200 pulses. For sensorimotor retraining, a subset of the Learning-based Sensorimotor Training program was followed. Each session consisted of rTMS followed immediately by 30 minutes of the therapy intervention (SMR or CTL). Group analyses revealed no additional benefit from the SMR training vs CTL, which was contrary to our hypothesis. When analyzed across group however, there was significant improvement from first baseline in several measures, including tests of sensory ability and self-rated changes. The patient rated improvements were accompanied by a moderate effect size suggesting clinical meaningfulness. These results provide encouragement for further investigation of rTMS in FHD with a need to optimized a secondary intervention and determine likely responders vs. non-responders

Laryngeal Dystonia: Multidisciplinary Update on Terminology, Pathophysiology, and Research Priorities.

OBJECTIVE: To delineate research priorities for improving clinical management of laryngeal dystonia, the NIH convened a multidisciplinary panel of experts for a 1-day workshop to examine the current progress in understanding its etiopathophysiology and clinical care. METHODS: The participants reviewed the current terminology of disorder and discussed advances in understanding its pathophysiology since a similar workshop was held in 2005. Clinical and research gaps were identified, and recommendations for future directions were delineated. RESULTS: The panel unanimously agreed to adopt the term laryngeal dystonia instead of spasmodic dysphonia to reflect the current progress in characterizations of this disorder. Laryngeal dystonia was recognized as a multifactorial, phenotypically heterogeneous form of isolated dystonia. Its etiology remains unknown, whereas the pathophysiology likely involves large-scale functional and structural brain network disorganization. Current challenges include the lack of clinically validated diagnostic markers and outcome measures and the paucity of therapies that address the disorder pathophysiology. CONCLUSION: Research priorities should be guided by challenges in clinical management of laryngeal dystonia. Identification of disorder-specific biomarkers would allow the development of novel diagnostic tools and unified measures of treatment outcome. Elucidation of the critical nodes within neural networks that cause or modulate symptoms would allow the development of targeted therapies that address the underlying pathophysiology. Given the rarity of laryngeal dystonia, future rapid research progress may be facilitated by multicenter, national and international collaborations