Improvement Of Motor Impairment Research Articles

Telerehabilitation for Lower Extremity Recovery Post-Stroke: A Systematic Review and Meta-Analysis

<h3>Objective(s)</h3> To describe telerehabilitation interventions for lower extremity recovery following stroke; and to quantitatively assess their effects on lower extremity recovery among individuals with stroke. <h3>Data Sources</h3> MEDLINE, EMBASE, PsycINFO, Cochrane databases from inception to May 2021. <h3>Study Selection</h3> All interventional studies investigating telerehabilitation, defined as the provision of rehabilitation remotely, using technology, for lower extremity recovery post-stroke were included in this review. <h3>Data Extraction</h3> Two reviewers independently extracted data on study design, participant characteristics, intervention description, outcomes, and results. Methodological quality was assessed using the Physiotherapy Evidence Database and Cochrane Risk of Bias 2 Tool (RCTs), JBI Critical Appraisal Tool (Non-Randomized Controlled Trial), and the NIH Study Quality Assessment Tool (Single Group Pre-Post Study). <h3>Data Synthesis</h3> 21 studies (732 participants) were included in the quantitative synthesis; 12 RCTs were included for meta-analysis. Technology used ranged from video conferencing, phones, specialized devices or software, and virtual reality. Most interventions were delivered asynchronously, and length of intervention ranged from 20 days to 12 weeks. Overall, quality of studies was moderate, with three RCTs deemed high risk of bias. Meta-analyses revealed improvements in motor impairment using Fugl-Meyer Assessment (MD = 3.73 [95% CI = 2.12, 5.33], p < 0.00001) and balance using Berg Balance Scale (MD = 1.67 [95% CI = 0.52, 2.82], p = 0.004). There were no effects observed for strength, mobility, activities of daily living, or social participation. <h3>Conclusions</h3> RCTs addressing telerehabilitation for lower extremity recovery post-stroke include a broad range of interventions, explored mainly in pilot and feasibility studies. Positive outcomes in the areas of motor impairment and balance are noted, however, larger RCTs are required. <h3>Author(s) Disclosures</h3> None.

Abstract 1: Vagus Nerve Stimulation Paired With Rehabilitation For Upper Limb Motor Function After Ischaemic Stroke: Sub-group Analysis Of The Randomised, Blinded, Pivotal, Vns-Rehab Device Trial.

Background: Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomised, blinded, sham-controlled trial. Here we report post-hoc sub-group analyses from the VNS Rehab trial. We aimed to determine whether treatment effects were consistent across subgroups. Methods: VNS Rehab included 108 participants with moderate to severe arm /hand weakness, at least nine months after ischaemic stroke. They were randomised to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in iFugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of in-clinic therapy. The trial was registered on ClinicalTrials.gov (NCT03131960). We explored the effect of VNS treatment by sex (n=70 males; n=38 females), age (≤ 65 or &gt;65 years)), time from stroke (median time, 2 years) and baseline FMA-UE score (&lt;=33 severe, &gt;33 moderate). We assessed whether there was any interaction with treatment. No hypotheses were specified prior to this analysis and no formal adjustment was made for multiplicity. Findings: On the first day after completion of in-clinic therapy, the mean (±SD) FMA-UE score increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (p=0.001, between group difference 2.6, 95% CI 1.03 to 4.2). The between group difference was similar across all subgroups (figure). No significant treatment interactions were observed with baseline characteristics. Interpretation: Participants with moderate to severe arm and hand impairment after ischaemic stroke showed clinically meaningful improvements in motor impairment and function with rehabilitation paired with VNS compared to rehabilitation with sham VNS. The response appeared similar across pre-defined subgroups of interest.

Balance between competing spectral states in subthalamic nucleus is linked to motor impairment in Parkinson's disease.

Exaggerated local field potential bursts of activity at frequencies in the low beta band are a well-established phenomenon in the subthalamic nucleus of patients with Parkinson’s disease. However, such activity is only moderately correlated with motor impairment. Here we test the hypothesis that beta bursts are just one of several dynamic states in the subthalamic nucleus local field potential in Parkinson’s disease, and that together these different states predict motor impairment with high fidelity.Local field potentials were recorded in 32 patients (64 hemispheres) undergoing deep brain stimulation surgery targeting the subthalamic nucleus. Recordings were performed following overnight withdrawal of anti-parkinsonian medication, and after administration of levodopa. Local field potentials were analysed using hidden Markov modelling to identify transient spectral states with frequencies under 40 Hz.Findings in the low beta frequency band were similar to those previously reported; levodopa reduced occurrence rate and duration of low beta states, and the greater the reductions, the greater the improvement in motor impairment. However, additional local field potential states were distinguished in the theta, alpha and high beta bands, and these behaved in an opposite manner. They were increased in occurrence rate and duration by levodopa, and the greater the increases, the greater the improvement in motor impairment. In addition, levodopa favoured the transition of low beta states to other spectral states. When all local field potential states and corresponding features were considered in a multivariate model it was possible to predict 50% of the variance in patients’ hemibody impairment OFF medication, and in the change in hemibody impairment following levodopa. This only improved slightly if signal amplitude or gamma band features were also included in the multivariate model. In addition, it compares with a prediction of only 16% of the variance when using beta bursts alone.We conclude that multiple spectral states in the subthalamic nucleus local field potential have a bearing on motor impairment, and that levodopa-induced shifts in the balance between these states can predict clinical change with high fidelity. This is important in suggesting that some states might be upregulated to improve parkinsonism and in suggesting how local field potential feedback can be made more informative in closed-loop deep brain stimulation systems.

Immediate and Short-term Outcome of Acute Disseminated Encephalomyelitis (ADEM) after corticosteroid therapy

Background : Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating disorder of the central nervous system (CNS) occurring predominantly but not exclusively in children. The presence of severe disturbance of consciousness together with multifocal neurological symptoms and signs especially in a child under 10 years of age; favours a diagnosis of ADEM. Neuroimaging is essential investigation for establishing the diagnosis of ADEM. High-dose steroid treatment frequently results in a dramatic clinical improvement.&#x0D; Objective: This study aimed to describe our experience with Acute Disseminated Encephalomyelitis (ADEM) focusing on the clinical features, neuroimaging, and outcome after treatment with high-dose steroid.&#x0D; Method: This retrospective observational study was conducted in children who were admitted as inpatients in Paediatric Neurosciences Department of Dhaka Shishu Hospital (DSH) with the diagnosis of ADEM during the period of 2017- 2019. All patients got high dose IV methylprednisolone for 5 days followed by 2 weeks tapering dose of steroid. Outcome was observed on the 7th day of treatment and 6 months after discharge from hospital.&#x0D; Result: A total of 16 patients who were diagnosed as ADEM were included in this study. Twelve children (75%) had a recent upper respiratory tract illness. Patients presented most often with motor deficits (88%) and secondly with altered consciousness (63% ) followed by seizure ( 50% ). MRI brain was the preferable neuroimaging which mostly (41.7%) showed multifocal symmetrical demyelination patch. On the 7th day of steroid treatment, significant improvement in motor function and level of consciousness occurred (p values were 0.001% and 0.014% respectively). After 6 months of discharge from hospital; no motor deficit, age-appropriate cognitive level and no seizure in 71%, 57% and 71% respectively.&#x0D; Conclusion: High dose corticosteroid treatment in ADEM is significantly effective in improvement of motor impairment and consciousness level on immediate follow up.&#x0D; Northern International Medical College Journal Vol.11 (2) Jan 2020: 468-470

Effect of Levodopa Initiation on the Gut Microbiota in Parkinson's Disease.

Background: The impact of Levodopa on the gut microbiota of Parkinson's disease (PD) patients has not been sufficiently addressed.Methods: We conducted a longitudinal study to examine the impact of Levodopa initiation on the gut microbiota composition of 19 PD patients who had not previously been exposed to Levodopa. Patients provided two stool samples prior to and two samples 90 days after starting Levodopa. Motor impairment (MDS-UPDRS Part III), diet, and other patient characteristics were assessed. 16S rRNA gene amplicon sequencing was used to characterize the microbiota. We examined, cross-sectionally and longitudinally, the associations between Levodopa use and alpha and beta diversity and performed feature-wise, multivariate modeling to identify taxa associated longitudinally with Levodopa use and with improvement in motor function after Levodopa administration.Results: We did not observe significant differences in alpha or beta diversity before vs. after initiation of Levodopa. In longitudinal feature-wise analyses, at the genus level, no taxa were significantly associated with Levodopa use after false discovery rate (FDR) correction (q < 0.05). We observed a marginally lower relative abundance of bacteria belonging to Clostridium group IV in PD patients who experienced a medium or large improvement in motor impairment in response to Levodopa compared to those with a small response [β = −0.64 (SE: 0.18), p-trend: 0.00015 p-FDR: 0.019].Conclusions: In this study, Levodopa was not associated with changes in microbiota composition in this longitudinal analysis. The association between abundance of Clostridium group IV and short-term motor symptom response to Levodopa is preliminary and should be investigated in larger, longer-term studies, that include a control group.

Constraint-induced movement therapy for upper extremities in people with stroke.

In people who have had a stroke, upper limb paresis affects many activities of daily life. Reducing disability is therefore a major aim of rehabilitative interventions. Despite preserving or recovering movement ability after stroke, sometimes people do not fully realise this ability in their everyday activities. Constraint-induced movement therapy (CIMT) is an approach to stroke rehabilitation that involves the forced use and massed practice of the affected arm by restraining the unaffected arm. This has been proposed as a useful tool for recovering abilities in everyday activities. To assess the efficacy of CIMT, modified CIMT (mCIMT), or forced use (FU) for arm management in people with hemiparesis after stroke. We searched the Cochrane Stroke Group trials register (last searched June 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library Issue 1, 2015), MEDLINE (1966 to January 2015), EMBASE (1980 to January 2015), CINAHL (1982 to January 2015), and the Physiotherapy Evidence Database (PEDro; January 2015). Randomised control trials (RCTs) and quasi-RCTs comparing CIMT, mCIMT or FU with other rehabilitative techniques, or none. One author identified trials from the results of the electronic searches according to the inclusion and exclusion criteria, three review authors independently assessed methodological quality and risk of bias, and extracted data. The primary outcome was disability. We included 42 studies involving 1453 participants. The trials included participants who had some residual motor power of the paretic arm, the potential for further motor recovery and with limited pain or spasticity, but tended to use the limb little, if at all. The majority of studies were underpowered (median number of included participants was 29) and we cannot rule out small-trial bias. Eleven trials (344 participants) assessed disability immediately after the intervention, indicating a non-significant standard mean difference (SMD) 0.24 (95% confidence interval (CI) -0.05 to 0.52) favouring CIMT compared with conventional treatment. For the most frequently reported outcome, arm motor function (28 studies involving 858 participants), the SMD was 0.34 (95% CI 0.12 to 0.55) showing a significant effect (P value 0.004) in favour of CIMT. Three studies involving 125 participants explored disability after a few months of follow-up and found no significant difference, SMD -0.20 (95% CI -0.57 to 0.16) in favour of conventional treatment. CIMT is a multi-faceted intervention where restriction of the less affected limb is accompanied by increased exercise tailored to the person's capacity. We found that CIMT was associated with limited improvements in motor impairment and motor function, but that these benefits did not convincingly reduce disability. This differs from the result of our previous meta-analysis where there was a suggestion that CIMT might be superior to traditional rehabilitation. Information about the long-term effects of CIMT is scarce. Further trials studying the relationship between participant characteristics and improved outcomes are required.

Lack of TNF-alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression.

Changes in the homeostasis of tumor necrosis factor α (TNFα) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFα to the development of ALS is still debated. TNFα is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFα and its receptors in the selective motor neuron death in ALS invitro and invivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1-G93A co-cultures. Deleting TNFR2 from SOD1-G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1-G93A/TNFR2-/- mice showed high phospho-TAR DNA-binding protein 43 (TDP-43) accumulation and low levels of acetyl-tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane-bound TNFα as an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology. We show evidence of the involvement of neuronal and astroglial TNFR2 in the motor neuron degeneration in ALS. Both concur to cause motor neuron death in primary astrocyte/spinal neuron co-cultures. TNFR2 deletion partially protects motor neurons and sciatic nerves in SOD1-G93A mice but does not improve their symptoms and survival. However, TNFR2 could be a new target for multi-intervention therapies.

Structural white matter changes in descending motor tracts correlate with improvements in motor impairment after undergoing a treatment course of tDCS and physical therapy.

Motor impairment after stroke has been related to the structural and functional integrity of corticospinal tracts including multisynaptic motor fibers and tracts such as the cortico-rubral-spinal and the cortico-tegmental-spinal tract. Furthermore, studies have shown that the concurrent use of transcranial direct current stimulation (tDCS) with peripheral sensorimotor activities can improve motor impairment. We examined microstructural effects of concurrent non-invasive bihemispheric stimulation and physical/occupational therapy for 10 days on the structural components of the CST as well as other descending motor tracts which will be referred to here as alternate motor fibers (aMF). In this pilot study, ten chronic patients with a uni-hemispheric stroke underwent Upper-Extremity Fugl-Meyer assessments (UE-FM) and diffusion tensor imaging (DTI) for determining diffusivity measures such as fractional anisotropy (FA) before and after treatment in a section of the CST and aMF that spanned between the lower end of the internal capsule (below each patient’s lesion) and the upper pons region on the affected and unaffected hemisphere. The treated group (tDCS + PT/OT) showed significant increases in the proportional UE-FM scores (+21%; SD 10%), while no significant changes were observed in an untreated comparison group. Significant increases in FA (+0.007; SD 0.0065) were found in the ipsilesional aMF in the treated group while no significant changes were found in the contralesional aMF, in either CST, or in any tracts in the untreated group. The FA changes in the ipsilesional aMF significantly correlated with the proportional change in the UE-FM (r = 0.65; p < 0.05). The increase in FA might indicate an increase in motor fiber alignment, myelination, and overall fiber integrity. Crossed and uncrossed fibers from multiple cortical regions might be one reason why the aMF fiber system showed more plastic structural changes that correlate with motor improvements than the CST.

Preconditioning effect of (S)-3,5-dihydroxyphenylglycine on ischemic injury in middle cerebral artery occluded Sprague–Dawley rats

Glutamate receptors are the integral cellular components associated with excitotoxicity mechanism induced by the ischemic cascade events. Therefore the glutamate receptors have become the major molecular targets of neuroprotective agents in stroke researches. Recent studies have demonstrated that a Group I metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) preconditioning elicits neuroprotection in the hippocampal slice cultures exposed to toxic level of N-methyl-d-aspartate (NMDA). We further investigated the preconditioning effects of (S)-3,5-DHPG on acute ischemic stroke rats. One 10 or 100μM of (S)-3,5-DHPG was administered intrathecally to Sprague–Dawley adult male rats, 2h prior to induction of acute ischemic stroke by middle cerebral artery occlusion (MCAO). After 24h, neurological deficits were evaluated by modified stroke severity scores and grid-walking test. All rats were sacrificed and infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride staining. The serum level of neuron-specific enolase (NSE) of each rat was analyzed by enzyme-linked immunosorbent assay (ELISA). One and 10μM of (S)-3,5-DHPG preconditioning in the stroke rats showed significant improvements in motor impairment (P<0.01), reduction in the infarct volume (P<0.01) and reduction in the NSE serum level (P<0.01) compared to the control stroke rats. We conclude that 1 and 10μM (S)-3,5-DHPG preconditioning induced protective effects against acute ischemic insult in vivo.

Bilateral arm training in the chronic phase of stroke rehabilitation: a systematic review and meta-analysis

Objective: Bilateral arm training (BAT) is an intervention utilized in rehabilitating upper-extremity paresis. The objective of this study was to conduct a systematic review and meta-analysis on the evidence for BAT on upperlimb paresis in the chronic phase of stroke. Methods: A literature search of multiple databases (MEDLINE, CINAHL, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, OT Seeker ) was conducted for relevant randomized controlled trials (RCTs) published in the English language that met inclusion criteria. Studies must have included BAT as part of treatment and participants must have been ≥6 months post stroke. Methodological quality of each study was assessed using the PEDro scale (maximum score=10). Results: Eight RCTs satisfied the inclusion criteria (PEDro scores 1-7) for a total pooled sample size of 131 subjects (88 males and 43 females). The mean age of subjects was 57.6±4.1 years (range 50.7-64.8 years) and the mean time since stroke was 43.8±34.8 months (range 13.9-114.0 months). Among study endpoints, only the Fugl-Meyer Assessment tool showed significant improvement in motor impairment whereby the BAT groups improved, on average, 3.77 points whereas the control group improved just 1.23 points (Difference of Means = 1.46±0.662; p=0.028). Conclusion: Overall, BAT showed a general trend in improvement over standard therapy, although it was not statistically significant. Future studies with improved methodological quality (e.g., strict inclusion criteria, protocol standardization) and larger sample sizes are needed to appropriately assess the benefit of BAT in stroke patients.

Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury: An Observational Study Involving 629 Consecutive Patients Treated with Perispinal Etanercept

Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood-CSF barrier.The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI.After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed.The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13-97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5-419); for TBI the mean interval was 115.2 ± 160.22 months (range 4-537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced.Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury.Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response.

Effects of Mobilization and Tactile Stimulation on Chronic Upper-Limb Sensorimotor Dysfunction After Stroke

ObjectiveTo explore the effects of Mobilization and Tactile Stimulation (MTS) and patterns of recovery in chronic stroke (>12mo) when upper limb (UL) “performance” has reached a clear plateau. DesignReplicated single-system experimental study with 8 single cases using A-B-A design (baseline-intervention-withdrawal phases); length of baseline randomly determined; intervention phase involved 6 weeks of daily MTS to the contralesional UL. SettingCommunity setting, within participants' place of residence. ParticipantsIndividual stroke survivors (N=8; male-to-female ratio, 3:1; age range, 49–76y; 4 with left hemiplegia, 4 with right hemiplegia) discharged from ongoing therapy, more than 1 year post stroke (range, 14–48mo). Clinical presentations were varied across the sample. InterventionsParticipants received up to 1 hour of daily (Monday to Friday) treatment with MTS to the UL for 6 weeks during the intervention (B) phase. Main Outcome MeasuresMotor function (Action Research Arm Test [ARAT]) and motor impairment (Motricity Index [MI] arm section) of the UL. ResultsUL performance was stable during baseline for all participants. On visual analysis, improvements in motor impairment were seen in all participants, and clinically significant improvements in motor function were seen in 4 of 8 participants during the intervention phase. Latency between onset of intervention and improvement ranged from 5 to 31 days (ARAT) and from 0 to 28 days (MI). Improvements in performance were maintained on withdrawal of the intervention. Randomization tests were not significant. ConclusionsMTS appears to improve UL motor impairment and functional activity many months, even years, after stroke onset. Improvement can be immediate, but more often there is latency between the start of intervention and improvement; recovery can be distal to proximal.

Relationship Between Body Mass Index and Rehabilitation Outcomes in Chronic Stroke

The aim of this study was to evaluate the relationship between body mass index (BMI) and change in motor impairment and functional mobility after a gait rehabilitation intervention in chronic stroke subjects. Correlation and linear regression analyses of pretreatment and end-of-treatment Fugl-Meyer scores and modified Emory Functional Ambulation Profile scores from hemiparetic subjects (n = 108, >3 mos post stroke) who participated in a randomized controlled trial comparing two 12-wk ambulation training treatments were generated. A series of linear regression models that controlled for age, sex, stroke type, interval post-stroke, and training device found the change in the Fugl-Meyer score to be significantly negatively associated with pretreatment BMI (β = -0.207, P = 0.036) and the change in the "up and go" modified Emory Functional Ambulation Profile score to be significantly positively associated with BMI (β = 0.216, P = 0.03). Changes in modified Emory Functional Ambulation Profile scores in floor, carpet, obstacles, or stair climbing were not significantly associated with BMI. Chronic stroke subjects with a higher BMI were less likely to demonstrate improvement in motor impairment and up and go functional mobility performance in response to ambulation training, irrespective of treatment intervention. Stroke rehabilitation clinicians should consider BMI when formulating rehabilitation goals. Further studies are necessary to determine whether obesity is a predictor of longer-term post-stroke motor and functional recovery.

Selective TNF Inhibition for Chronic Stroke and Traumatic Brain Injury

Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood–CSF barrier. The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI. After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed. The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years ± 13.15 (range 13–97). The mean interval between treatment with PSE and stroke was 42.0 ± 57.84 months (range 0.5–419); for TBI the mean interval was 115.2 ± 160.22 months (range 4–537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced. Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury. Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response.

Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion

High mobility group box 1 (HMGB1) is an endogenous danger signal molecule. In a previous report, we showed that HMGB1 is massively released during NMDA-induced acute damaging process in the postischemic brain and triggers inflammatory processes, like microglial activation. siRNA-mediated HMGB1 knockdown markedly reduced infarct volumes, confirming the crucial role played by HMGB1 in the postischemic brain. In the present study, we showed neuroprotective effects of glycyrrhizin (GL) in the postischemic rat brain after middle cerebral artery occlusion (MCAO). GL, a triterpene present in the roots and rhizomes of licorice, Glycyrrhiza glabra, has been shown to have anti-inflammatory and anti-viral effects. It has been reported that GL binds directly to HMGB1, and inhibits its chemoattractant and mitogenic activities. The administration of GL (10mg/kg) intravenously at 3 or 6h after MCAO reduced infarct volumes to 12.9±4.2% and 46.2±9.9%, respectively, of untreated control. This neuroprotective effect was accompanied by improvements in motor impairment and neurological deficits and suppressions of microglia activation and proinflammatory cytokine induction. Interestingly, GL almost completely blocked HMGB1 secretion in the postischemic brain and in lipopolysaccharide (LPS)-treated microglia cells. Furthermore, HMGB1 phosphorylation, which is the initial step for HMGB1 secretion, and the interaction between HMGB1 and protein kinase C (PKC) or calcium/calmodulin-dependent protein kinase IV (CaMKIV) were suppressed dose-dependently by GL. Here, we hypothesized that the blockage for the putative phosphorylation sites in HMGB1 by GL might be attributed to this suppression. In addition to the anti-inflammatory effects, we found that GL has anti-excitotoxic and anti-oxidative effects in neurons. Together these results indicate that GL has neuroprotective efficacy in the postischemic brain via its anti-inflammatory, anti-excitotoxic, and anti-oxidative effects and in particular, it exerts anti-inflammatory effect, at least in part, by inhibiting HMGB1 secretion.

Virtual Reality in Stroke Rehabilitation

Approximately two thirds of stroke survivors continue to experience motor deficits of the arm resulting in diminished quality of life. Conventional rehabilitation provides modest and sometimes delayed effects. Virtual reality (VR) technology is a novel adjunctive therapy that could be applied in neurorehabilitation. We performed a meta-analysis to determine the added benefit of VR technology on arm motor recovery after stroke. We searched Medline, EMBASE, and Cochrane literature from 1966 to July 2010 with the terms "stroke," "virtual reality," and "upper arm/extremity." We evaluated the effect of VR on motor function improvement after stroke. From the 35 studies identified, 12 met the inclusion/exclusion criteria totaling 195 participants. Among them, there were 5 randomized clinical trials and 7 observational studies with a pre-/postintervention design. Interventions were delivered within 4 to 6 weeks in 9 of the studies and within 2 to 3 weeks in the remaining 3. Eleven of 12 studies showed a significant benefit toward VR for the selected outcomes. In the pooled analysis of all 5 randomized controlled trials, the effect of VR on motor impairment (Fugl-Meyer) was OR=4.89 (95% CI, 1.31 to 18.3). No significant difference was observed for Box and Block Test or motor function. Among observational studies, there was a 14.7% (95% CI, 8.7%-23.6%) improvement in motor impairment and a 20.1% (95% CI, 11.0%-33.8%) improvement in motor function after VR. VR and video game applications are novel and potentially useful technologies that can be combined with conventional rehabilitation for upper arm improvement after stroke.

The use of Stronger Neo-Minophagen C, a glycyrrhizin-containing preparation, in robust neuroprotection in the postischemic brain

Stronger Neo-Minophagen C (SNMC) is a glycyrrhizin-containing preparation that is approved in Japan for the treatment of chronic hepatic diseases and is marketed in Japan, China, Korea, Taiwan, and India. Glycyrrhizin, a triterpene present in the roots and rhizomes of licorice (Glycyrrhiza glabra) has been shown to have anti-inflammatory, anti-oxidative, and anti-viral effects. In the present study, we demonstrated the marked neuroprotective effects of SNMC in the postischemic rat brain after middle cerebral artery occlusion (MCAO). We used 1 ml/kg of SNMC, which is within the dose range used for the treatment of patients with chronic hepatic disease. The administration of SNMC intravenously at 30 minutes before or 30 minutes and 3 hours after MCAO (60 minutes) reduces mean infarct volumes to 27.0±4.2%, 37.1±12.4%, and 67.8±5.8% of that of untreated controls, respectively. This neuroprotective effect is accompanied by improvements in motor impairment and neurological deficits. The administration of SNMC is shown to suppress microglia activation and neutrophil infiltration in the postischemic brain. In addition, SNMC suppresses lipopolysaccharide-induced nitrite production and proinflammatory cytokine induction in a microglia cell line, BV2. This indicates that the neuroprotective effect of SNMC might be due, at least in part, to an anti-inflammatiory effect. Interestingly, SNMC shows significantly higher neuroprotective potency compared to an equivalent dose of pure glycyrrhizin, in terms of reducing infarct volume and improving neurological deficits. Together these results indicate that SNMC, a glycyrrhizin-containing preparation developed for chronic liver disease, has a marked neuroprotective function in the postischemic brain via its anti-inflammatory effects.

The effect of cueing therapy on single and dual-task gait in a drug naïve population of people with Parkinson's disease in northern Tanzania

The incidence of Parkinson's disease (PD) in sub-Saharan Africa (SSA) is greater than thought however, is largely undiagnosed and untreated. This study aimed to evaluate a nonpharmacological approach using cueing therapy to improve gait in drug-naïve PD and the feasibility of delivering rehabilitation in northern Tanzania. In this study, twenty-one people with PD aged 76.4 years (12.9 SD) with varying disease severity participated. They received 9 x 30 min sessions of cueing therapy for gait problems over 3 weeks from a trained therapist delivered in their home environment. Cueing therapy consisted of walking in time to a metronome beat to correct step amplitude and step frequency during a range of functional activities. Gait was recorded on video before and after therapy, and videos were analyzed in the UK by an assessor not involved in data collection. Disease severity (UPDRS) and balance were also measured. Patients were assessed in their nearest clinic. Data were analyzed in Minitab and a P value of 0.05 was considered significant. Cueing therapy significantly improved single and dual task walking speed, step amplitude, and single task step frequency. There was also a significant improvement in motor impairment (UPDRS III) and activities of daily living (UPDRS II). The results provide promising evidence for the role of cueing therapy in PD for symptom management to reduce or delay medication onset. This study also supports the feasibility of rehabilitation in PD in community environments in SSA, which may be applicable to other developing regions.

Fluoxetine affords robust neuroprotection in the postischemic brain via its anti‐inflammatory effect

Fluoxetine is a selective serotonin reuptake inhibitor that is widely used in the treatment of major depression including after stroke. In this study, we tested whether fluoxetine protects neuronal death in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO). The administration of fluoxetine intravenously (10 mg/kg) at 30 min, 3 hr, or 6 hr after MCAO reduced infarct volumes to 21.2+/-6.7%, 14.5+/-3.0%, and 22.8+/-2.9%, respectively, of that of the untreated control. Moreover, the neuroprotective effect of fluoxetine was evident when it was administered as late as 9 hr after MCAO/reperfusion. These neuroprotective effects were accompanied by improvement of motor impairment and neurological deficits. The fluoxetine-treated brain was found to show marked repressions of microglia activation, neutrophil infiltration, and proinflammatory marker expressions. Moreover, fluoxetine suppressed NF-kappaB activity dose-dependently in the postischemic brain and also in lipopolysaccharide-treated primary microglia and neutrophil cultures, suggesting that NF-kappaB activity inhibition explains in part its anti-inflammatory effect. These results demonstrate that curative treatment of fluoxetine affords strong protection against delayed cerebral ischemic injury, and that these neuroprotective effects might be associated with its anti-inflammatory effects.

Reduction in subthalamic 8–35 Hz oscillatory activity correlates with clinical improvement in Parkinson's disease

Strong synchronization of neuronal activity occurs in the 8-35 Hz band in the subthalamic nucleus (STN) of patients with Parkinson's disease (PD) and is evident as oscillatory local field potential (LFP) activity. To test whether such synchronization may contribute to bradykinesia and rigidity, we sought correlations between the suppression of synchronization at 8-35 Hz in STN and the reduction in Parkinsonism with levodopa. LFPs were recorded on and off medication from STN deep-brain stimulation electrodes in nine PD patients. LFP power was calculated over the frequencies of the most prominent spectral peak within the 8-35 Hz frequency band on each of 17 sides (off medication), and over the frequencies of any peak in the 60-90 Hz band, if present (seven sides, on medication). Levodopa-induced reduction of LFP power over these two frequency ranges was then correlated with improvement in motor impairment as assessed by the Unified Parkinson's Disease Rating Scale (UPDRS). The reduction in peak activity in the 8-35 Hz band with levodopa positively correlated with the improvement in the contralateral hemibody motor UPDRS score with levodopa (r = 0.811, P < 0.001) as well as with hemibody subscores of akinesia-rigidity (r = 0.835, P < 0.001), but not tremor. A trend for negative correlations was found between peak 60-90 Hz LFP power and UPDRS hemibody score, suggesting that positive correlations were relatively frequency-specific. Our results support a link between levodopa-induced improvements in bradykinesia and rigidity and reductions in population synchrony at frequencies < 35 Hz in the region of the STN in patients with PD.