Intra-individual variability in cognitive performance predicts functional decline in Parkinson's disease.

BACKGROUND: Cognitive deficits contribute to disability in Parkinson's disease (PD). Cognitive intra-individual variability (IIV) is associated with cognitive decline in age-related disorders, but IIV has not been related to functional ability in PD. We examined IIV in predicting functional ability in participants with PD. METHODS: De-identified National Alzheimer's Coordinating Center data (N = 1,228) from baseline and follow-up visits included participants with PD propensity score matched to control participants at baseline on age (M = 72), education (M = 15), and gender (28% female). PD symptom duration averaged 6 years. Outcome measures included the Functional Ability Questionnaire (FAQ), overall test battery mean (OTBM) of ten cognitive variables, IIV calculated as the standard deviation of cognitive data for each participant, Geriatric Depression Scale (GDS), and Unified PD Rating Scale gait and posture items. Baseline FAQ status in the PD group was predicted using logistic regression with age, education, cognition, GDS, and motor function as predictors. We compared baseline characteristics of PD participants with and without functional impairment at follow up. RESULTS: PD participants showed lower OTBM and greater IIV, GDS, and motor dysfunction than controls (p < .0001). Education, OTBM, IIV, GDS, and gait predicted functional status (77% overall classification; AUC = .84). PD participants with functional impairment at follow up showed significantly lower OTBM and greater IIV, GDS, and motor dysfunction at baseline (p < .001). CONCLUSION: IIV independently predicts functional status in participants with PD while controlling for other variables. PD participants with functional impairment at follow up showed greater IIV than those without functional impairment at follow up.

A Systematic Review on the Effects of Acute Aerobic Exercise on Neurophysiological, Molecular, and Behavioral Measures in Chronic Stroke.

BACKGROUND: A single bout of aerobic exercise (AE) can produce changes in neurophysiological and behavioral measures in healthy individuals and those with stroke. However, the effects of AE-priming effects on neuroplasticity markers and behavioral measures are unclear. OBJECTIVES: This systematic review aimed to examine the effects of AE on neuroplasticity measures, such as corticomotor excitability (CME), molecular markers, cortical activation, motor learning, and performance in stroke. METHODS: A literature search was performed in MEDLINE, CINAHL, Scopus, and PsycINFO databases. Randomized and non-randomized studies incorporating acute AE in stroke were selected. Two reviewers independently assessed the risk of bias and methodological rigor of the studies and extracted data on participant characteristics, exercise interventions, and neuroplasticity related outcomes. The quality of transcranial magnetic stimulation reported methods was assessed using a standardized checklist. RESULTS: A total of 16 studies were found suitable for inclusion. Our findings suggest mixed evidence for the effects of AE on CME, limited to no effects on intracortical inhibition and facilitation and some evidence for modulating brain derived neurotrophic factor levels, motor learning, and cortical activation. Exercise intensities in the moderate to vigorous range showed a trend towards better effects on neuroplasticity measures. CONCLUSION: It appears that choosing a moderate to vigorous exercise paradigm for at least 20 to 30 minutes may induce changes in some neuroplasticity parameters in stroke. However, these findings necessitate prudent consideration as the studies were diverse and had moderate methodological quality. There is a need for a consensus on an exercise priming paradigm and for good-quality, larger controlled studies.

Commentary: Remote assessments of gait and balance - Implications for research during and beyond Covid-19.

The COVID-19 pandemic has disrupted non-essential in-person research activities that require contact with human subjects. While guidelines are being developed for ramping up human subjects research, one component of research that can be performed remotely is participant screening for lower limb function and gait impairments. In this commentary, we summarize evidence-supported clinical assessments that have potential to be conducted remotely in a safe manner, to make an initial determination of the functional mobility status of persons with neurological disorders. We present assessments that do not require complex or costly equipment, specialized software, or trained personnel to administer. We provide recommendations to implement remote functional assessments for participant recruitment and continuation of lower limb neurorehabilitation research as a rapid response to the COVID-19 pandemic and for utilization beyond the current pandemic. We also highlight critical research gaps related to feasibility and measurement characteristics of remote lower limb assessments, providing opportunities for future research to advance tele-assessment and tele-rehabilitation.

Reliability of transcallosal inhibition measurements for the lower limb motor cortex in stroke.

Transcallosal inhibition (TCI) is a measure of between-hemisphere inhibitory control that can be evaluated with the ipsilateral silent period (iSP) transcranial magnetic stimulation (TMS) paradigm. The study of iSP for the lower extremity has been limited possibly due to the close orientation of the lower extremity motor representations. Change in TCI can provide insights into pathophysiological mechanisms underlying the asymmetry in corticomotor excitability in stroke. Here, we describe a method for iSP quantification and report reliability of iSP parameters for the tibialis anterior (TA) muscle in stroke. 26 individuals with stroke attended three sessions where single pulse TMS was used to measure TCI from the lesioned to non-lesioned hemisphere. A double cone coil was used for stimulating the ipsilateral motor cortex while the participant maintained an isometric contraction of the non-paretic TA. Absolute and relative reliability were computed for iSP latency, duration and area. iSP latency showed the lowest measurement error (absolute reliability) and iSP latency, duration and area showed good relative reliability (intraclass correlation coefficients > 0.6). This study suggests that iSP parameters for the tibialis anterior are reliable and attempts to provide a guideline for evaluating TCI for the lower extremity in stroke and other clinical populations.

Combining transcranial direct current stimulation with aerobic exercise to optimize cortical priming in stroke.

Aerobic exercise (AE) and transcranial direct current stimulation (tDCS) are priming techniques that have been studied for their potential neuromodulatory effects on corticomotor excitability (CME); however, the synergistic effects of AE and tDCS are not explored in stroke. Here we investigated the synergistic effects of AE and tDCS on CME, intracortical and transcallosal inhibition, and motor control for the lower limb in stroke. Twenty-six stroke survivors participated in 3 sessions: tDCS, AE, and AE+tDCS. AE included moderate-intensity exercise and tDCS included 1 mA of anodal tDCS to the lower limb motor cortex with or without AE. Outcomes included measures of CME, short-interval intracortical inhibition (SICI), ipsilateral silent period (iSP) (an index of transcallosal inhibition) for the tibialis anterior, and ankle reaction time. Ipsilesional CME significantly decreased for AE compared with AE+tDCS and tDCS. No differences were noted in SICI, iSP measures, or reaction time between all 3 sessions. Our findings suggest that a combination of exercise and tDCS, and tDCS demonstrate greater excitability of the ipsilesional hemisphere compared with exercise only; however, these effects were specific to the descending corticomotor pathways. No additive priming effects of exercise and tDCS over tDCS was observed. Novelty: An exercise and tDCS paradigm upregulated the descending motor pathways from the ipsilesional lower limb primary motor cortex compared with exercise. Exercise or tDCS administered alone or in combination did not affect intracortical or transcallosal inhibition or reaction time.

Cortical priming strategies for gait training after stroke: a controlled, stratified trial.

BACKGROUND: Stroke survivors experience chronic gait impairments, so rehabilitation has focused on restoring ambulatory capacity. High-intensity speed-based treadmill training (HISTT) is one form of walking rehabilitation that can improve walking, but its effectiveness has not been thoroughly investigated. Additionally, cortical priming with transcranial direct current stimulation (tDCS) and movement may enhance HISTT-induced improvements in walking, but there have been no systematic investigations. The objective of this study was to determine if motor priming can augment the effects of HISTT on walking in chronic stroke survivors. METHODS: Eighty-one chronic stroke survivors participated in a controlled trial with stratification into four groups: 1) control-15 min of rest (n = 20), 2) tDCS-15 min of stimulation-based priming with transcranial direct current stimulation (n = 21), 3) ankle motor tracking (AMT)-15 min of movement-based priming with targeted movements of the ankle and sham tDCS (n = 20), and 4) tDCS+AMT-15 min of concurrent tDCS and AMT (n = 20). Participants performed 12 sessions of HISTT (40 min/day, 3 days/week, 4 weeks). Primary outcome measure was walking speed. Secondary outcome measures included corticomotor excitability (CME). Outcomes were measured at pre, post, and 3-month follow-up assessments. RESULTS: HISTT improved walking speed for all groups, which was partially maintained 3 months after training. No significant difference in walking speed was seen between groups. The tDCS+AMT group demonstrated greater changes in CME than other groups. Individuals who demonstrated up-regulation of CME after tDCS increased walking speed more than down-regulators. CONCLUSIONS: Our results support the effectiveness of HISTT to improve walking; however, motor priming did not lead to additional improvements. Upregulation of CME in the tDCS+AMT group supports a potential role for priming in enhancing neural plasticity. Greater changes in walking were seen in tDCS up-regulators, suggesting that responsiveness to tDCS might play an important role in determining the capacity to respond to priming and HISTT. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03492229. Registered 10 April 2018 - retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03492229 .

Stimulus Intensity Affects Variability of Motor Evoked Responses of the Non-Paretic, but Not Paretic Tibialis Anterior Muscle in Stroke.

BACKGROUND: Transcranial magnetic stimulus induced motor evoked potentials (MEPs) are quantified either with a single suprathreshold stimulus or using a stimulus response curve. Here, we explored variability in MEPs influenced by different stimulus intensities for the tibialis anterior muscle in stroke. METHODS: MEPs for the paretic and non-paretic tibialis anterior (TA) muscle representations were collected from 26 participants with stroke at seven intensities. Variability of MEP parameters was examined with coefficients of variation (CV). RESULTS: CV for the non-paretic TA MEP amplitude and area was significantly lower at 130% and 140% active motor threshold (AMT). CV for the paretic TA MEP amplitude and area did not vary with intensity. CV of MEP latency decreased with higher intensities for both muscles. CV of the silent period decreased with higher intensity for the non-paretic TA, but was in reverse for the paretic TA. CONCLUSION: We recommend a stimulus intensity of greater than 130% AMT to reduce variability for the non-paretic TA. The stimulus intensity did not affect the MEP variability of the paretic TA. Variability of MEPs is affected by intensity and side tested (paretic and non-paretic), suggesting careful selection of experimental parameters for testing.

Remotely supervised transcranial direct current stimulation: A feasibility study for amyotrophic lateral sclerosis.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been investigated as a therapeutic neuromodulation tool in several neurological disorders. However, evidence supporting its efficacy in disorders such as amyotrophic lateral sclerosis (ALS) is limited possibly due to limited patient accessibility for research, particularly for individuals with advanced disease progression. Telerehabilitation using home-based protocols allows for remote supervision of tDCS over longer durations, thereby increasing participation, compliance and adherence. In this study, we explored the safety, feasibility and preliminary effects of a remotely supervised tDCS (RS-tDCS) protocol in ALS. MATERIAL AND METHODS: In this pre-post case series study, two individuals with ALS completed 24 remotely supervised anodal tDCS sessions (20 minutes, 2 mA). Outcomes included adherence, compliance, disease progression, walking speed, risk of fall, endurance, fatigue and depression. RESULTS: Both participants successfully completed the study without any major adverse effects. Minor side effects included mild sensations of itching and throbbing under the electrodes during stimulation. Clinical outcomes showed minimal to no change for any of the measures. CONCLUSIONS: Preliminary findings suggest that the RS-tDCS protocol is safe and feasible in individuals with ALS. Our protocol serves as a model for future long-term studies to evaluate the clinical and neurophysiological effects of tDCS using a telerehabilitation protocol in ALS.

Recumbent stepping aerobic exercise in amyotrophic lateral sclerosis: a pilot study.

OBJECTIVES: Aerobic exercise can promote neuroplastic responses in the healthy and injured brain. Although the role of exercise in amyotrophic lateral sclerosis (ALS) is debated, new evidence suggests that exercise may reduce disease progression. While common exercise modalities such as the treadmill and cycle ergometer have been explored in ALS, the safety and feasibility of a total body recumbent stepper have not been investigated. Additionally, the functional and neurophysiological effects of recumbent stepping in ALS are still unknown. Here, we investigated the safety and feasibility of a 4-week recumbent stepping program to slow disease progression in ALS and possibly facilitate neuroplasticity. METHOD: Nine individuals with ALS performed moderate intensity recumbent stepping for four weeks. Outcomes included participation satisfaction questionnaire, ALS Functional Rating Scale Revised (ALSFRS-R), clinical tests of walking and endurance, fatigue severity scale, Beck depression inventory, SF-12, and transcranial magnetic stimulation-induced motor evoked potentials (MEPs). All measurements were collected at baseline, post-intervention, and at the 1-month follow-up. RESULTS: Eight participants completed the study without any adverse events. The ALSFRS-R scores were similar at the end of the study and at follow-up. No significant differences were noted for any of the clinical outcomes. MEPs were present only in two participants and changes in corticomotor excitability after exercise were minimal. CONCLUSIONS: Results from this preliminary study support the safety and feasibility of 12 sessions of total body recumbent stepping in individuals with ALS.

Effects of high intensity speed-based treadmill training on ambulatory function in people with chronic stroke: A preliminary study with long-term follow-up.

High intensity treadmill training has shown to be beneficial for stroke survivors, yet the feasibility and long-term effects remain unclear. In this study, we aimed to determine whether a 4-week high intensity speed-based treadmill training (HISTT) is feasible for chronic stroke survivors, and we examined its effects on ambulatory function, and long-term retention. Sixteen individuals post-stroke participated in 40 minutes of HISTT for four weeks at a frequency of three sessions per week. Gait speed was measured using the 10-meter walk test, endurance was measured using the 6-minute walk test, and quality of life was assessed using the Stroke Impact Scale (SIS) at baseline, post-training, and at 3-month follow-up. All participants successfully completed the training without any serious adverse events. Participants significantly increased fastest walking speed by 19%, self-selected walking speed by 18%, and walking endurance by 12% after the training. These improvements were maintained for 3 months after the intervention. Our results indicate that this modified speed-based high intensity walking program has the potential to be a feasible and effective method of gait training for stroke survivors. However, the small sample size and lack of a control group warrant caution in interpretation of results. Further studies are recommended to better understand effectiveness of this protocol in combination with other physical therapy interventions for functional recovery after stroke.

Safety and feasibility of transcranial direct current stimulation in amyotrophic lateral sclerosis - a pilot study with a single subject experimental design.

INTRODUCTION: Transcranial direct current stimulation (tDCS) has been explored as a neuromodulatory tool to prime motor function in several neurological disorders. Studies using tDCS in amyotrophic lateral sclerosis (ALS) are limited. We investigated the safety, feasibility and effects of long-term tDCS in an individual with ALS. METHODS: A 36-year-old male diagnosed with clinically definite ALS received 12 sessions each of anodal, sham, and cathodal tDCS. Outcome measures included disease progression (revised ALS functional rating scale (ALSFRS-R)), clinical measures of endurance and mobility, and corticomotor excitability. RESULTS: No adverse events or change in disease progression were noticed during the study. Small improvement in gait speed (15% increase) was noticed with anodal tDCS only. CONCLUSIONS: This case study demonstrates the safety and feasibility of long-term facilitatory and inhibitory tDCS on a single participant with ALS. This study serves as a guideline for implementing tDCS in future ALS trials.

Absence of a Transcranial Magnetic Stimulation-Induced Lower Limb Corticomotor Response Does Not Affect Walking Speed in Chronic Stroke Survivors.

Background and Purpose- Transcranial magnetic stimulation is used to measure the functional integrity of the corticomotor system via motor evoked potentials (MEPs) in stroke. The association between corticomotor mechanisms and walking recovery is still not completely understood. This study determined the association between transcranial magnetic stimulation-induced MEPs and walking outcomes and examined the contribution of the contralesional hemisphere to walking recovery. Methods- Contralateral and ipsilateral transcranial magnetic stimulation responses from the contralesional and ipsilesional hemispheres were collected from 61 chronic stroke survivors. Clinical assessments included gait speeds, 6-minute walk distance, Timed Up and Go test, Fugl Meyer lower extremity scale, and strength measurements. Results- Stroke participants were classified based on the presence (MEP+ [n=28]) or absence (MEP- [n=33]) of MEPs in the paretic tibialis anterior and rectus femoris muscles. A between-group analyses showed no significant differences for any gait variable. MEP+ group showed significantly higher Fugl Meyer lower extremity and ankle dorsiflexor strength. Ipsilateral conductivity was not significantly different between groups. Finally, in the MEP+ group, MEP parameters did not predict gait recovery. Conclusions- Our study investigated the association between walking outcomes and neurophysiological parameters of lower limb function in a large cohort of stroke survivors. We did not find an associations between transcranial magnetic stimulation-induced tibialis anterior and rectus femoris MEPs and walking speeds. Further work is required to develop more comprehensive models in stroke for predicting walking recovery.

Comparison of transcutaneous electrical nerve stimulation (TENS) and functional electrical stimulation (FES) for spasticity in spinal cord injury - A pilot randomized cross-over trial.

OBJECTIVE: Spasticity following spinal cord injury (SCI) can impair function and affect quality of life. This study compared the effects of transcutaneous electrical nerve stimulation (TENS) and functional electrical stimulation (FES) on lower limb spasticity in patients with SCI. DESIGN: Double blind randomized crossover design. SETTING: Neuro-rehabilitation unit, Manipal University, India. PARTICIPANTS: Ten participants (age: 39 ± 13.6 years, C1-T11, 1-26 months post SCI) with lower limb spasticity were enrolled in this study. INTERVENTIONS: Participants were administered electrical stimulation with TENS and FES (duration - 30 minutes) in a cross over manner separated by 24 hours. OUTCOME MEASURES: Spasticity was measured using modified Ashworth scale (MAS) [for hip abductors, knee extensors and ankle plantar flexors] and spinal cord assessment tool for spastic reflexes (SCATS). Assessments were performed at baseline, immediately, 1 hour, 4 hours, and 24 hours post intervention. RESULTS: A between group analysis did not show statistically significant differences between FES and TENS (P > 0.05). In the within group analyses, TENS and FES significantly reduced spasticity up to 4 hours in hip adductors and knee extensors (P < 0.01). SCATS values showed significant reductions at 1 hour (P = 0.01) following TENS and 4 hours following FES (P = 0.01). CONCLUSION: A single session of electrical stimulation with FES and TENS appears to have similar anti-spasticity effects that last for 4 hours. The findings of this preliminary study suggest that both TENS and FES have the potential to be used as therapeutic adjuncts to relieve spasticity in the clinic. In addition, FES may have better effects on patients presenting with spastic reflexes.

Spatial localization and distribution of the TMS-related 'hotspot' of the tibialis anterior muscle representation in the healthy and post-stroke motor cortex.

Transcranial magnetic stimulation (TMS) is a type of noninvasive brain stimulation used to study corticomotor excitability of the intact and injured brain. Identification of muscle representations in the motor cortex is typically done using a procedure called 'hotspotting', which involves establishing the optimal location on the scalp that evokes a maximum TMS response with minimum stimulator intensity. The purpose of this study was to report the hotspot locations for the tibialis anterior (TA) muscle representation in the motor cortex of healthy and post stroke individuals. A retrospective data analyses from 42 stroke participants and 32 healthy participants was conducted for reporting TMS hotspot locations and their spatial patterns. Single pulse TMS, using a 110mm double cone coil, was used to identify the motor representation of the TA. The hotspot locations were represented as x and y-distances from the vertex for each participant. The mediolateral extent of the loci from the vertex (x-coordinate) and anteroposterior extent of the loci from the vertex (y-coordinate) was reported for each hemisphere: non-lesioned (XNLes, YNLes), lesioned (XLes, YLes) and healthy (XH, YH). We found that the mean hotspot loci for TA muscle from the vertex were approximately: 1.29cm lateral and 0.55cm posterior in the non-lesioned hemisphere, 1.25cm lateral and 0.5cm posterior in the lesioned hemisphere and 1.6cm lateral and 0.8cm posterior in the healthy brain. There was no significant difference in the x- and y-coordinates between the lesioned and non-lesioned hemispheres. However, the locations of the XNLes (p=0.01) and XLes (p=0.004) were significantly different from XH. The YNLes and YLes showed no significant differences from YH loci. Analyses of spatial clustering patterns using the Moran's I index showed a negative autocorrelation in stroke participants (NLes: Moran's I=-0.09, p<0.001; Les: Moran's I=-0.14, p=0.002), and a positive autocorrelation in healthy participants (Moran's I=0.16, p<0.001), suggesting that individuals with stroke demonstrated a more dispersed pattern of hotspot locations than healthy individuals. Our results suggest that the hotspot loci show different spatial patterns in healthy and stroke individuals. The hotspot locations from this study has the potential to provide a guideline for optimal stimulation locations for the TA muscle in healthy and post stroke individuals for neuromodulation procedures such as transcranial direct current stimulation.