Transcranial magnetic stimulation enhances the specificity of multiple sclerosis diagnostic criteria: a critical narrative review.

Background: Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease that involves attacks of inflammatory demyelination and axonal damage, with variable but continuous disability accumulation. Transcranial magnetic stimulation (TMS) is a noninvasive method to characterize conduction loss and axonal damage in the corticospinal tract. TMS as a technique provides indices of corticospinal tract function that may serve as putative MS biomarkers. To date, no reviews have directly addressed the diagnostic performance of TMS in MS. The authors aimed to conduct a critical narrative review on the diagnostic performance of TMS in MS. Methods: The authors searched the Embase, PubMed, Scopus, and Web of Science databases for studies that reported the sensitivity and/or specificity of any reported TMS technique compared to established clinical MS diagnostic criteria. Studies were summarized and critically appraised for their quality and validity. Results: Seventeen of 1,073 records were included for data extraction and critical appraisal. Markers of demyelination and axonal damage-most notably, central motor conduction time (CMCT)-were specific, but not sensitive, for MS. Thirteen (76%), two (12%), and two (12%) studies exhibited high, unclear, and low risk of bias, respectively. No study demonstrated validity for TMS techniques as diagnostic biomarkers in MS. Conclusions: CMCT has the potential to: (1) enhance the specificity of clinical MS diagnostic criteria by "ruling in" true-positives, or (2) revise a diagnosis from relapsing to progressive forms of MS. However, there is presently insufficient high-quality evidence to recommend any TMS technique in the diagnostic algorithm for MS.

A naturalistic study comparing the efficacy of unilateral and bilateral sequential theta burst stimulation in treating major depression - the U-B-D study protocol.

BACKGROUND: Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD. METHODS: In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4-6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals. DISCUSSION: Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD. TRIAL REGISTRATION: The trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).

Age and asymmetry of corticospinal excitability, but not cardiorespiratory fitness, predict cognitive impairments in multiple sclerosis.

Background: Cognitive impairment is a disabling and underestimated consequence of multiple sclerosis (MS), with multiple determinants that are poorly understood. Objectives: We explored predictors of MS-related processing speed impairment (PSI) and age-related mild cognitive impairment (MCI) and hypothesized that cardiorespiratory fitness and corticospinal excitability would predict these impairments. Methods: We screened 73 adults with MS (53 females; median [range]: Age 48 [21-70] years, EDSS 2.0 [0.0-6.5]) for PSI and MCI using the Symbol Digit Modalities Test and Montréal Cognitive Assessment, respectively. We identified six persons with PSI (No PSI, n = 67) and 13 with MCI (No MCI, n = 60). We obtained clinical data from medical records and self-reports; used transcranial magnetic stimulation to test corticospinal excitability; and assessed cardiorespiratory fitness using a graded maximal exercise test. We used receiver operator characteristic (ROC) curves to discern predictors of PSI and MCI. Results: Interhemispheric asymmetry of corticospinal excitability was specific for PSI, while age was both sensitive and specific for MCI. MS-related PSI was also associated with statin prescriptions, while age-related MCI was related to progressive MS and GABA agonist prescriptions. Cardiorespiratory fitness was associated with neither PSI nor MCI. Discussion: Corticospinal excitability is a potential marker of neurodegeneration in MS-related PSI, independent of age-related effects on global cognitive function. Age is a key predictor of mild global cognitive impairment. Cardiorespiratory fitness did not predict cognitive impairments in this clinic-based sample of persons with MS.

Lower corticospinal excitability and greater fatigue among people with multiple sclerosis experiencing pain.

Introduction: Persons with multiple sclerosis (MS) frequently report pain that negatively affects their quality of life. Evidence linking pain and corticospinal excitability in MS is sparse. We aimed to (1) examine differences in corticospinal excitability in MS participants with and without pain and (2) explore predictors of pain. Methods: Sixty-four participants rated their pain severity on a visual analog scale (VAS). Transcranial magnetic stimulation (TMS) and validated clinical instruments characterized corticospinal excitability and subjective disease features like mood and fatigue. We retrieved information on participants' prescriptions and disability status from their clinical records. Results: Fifty-five percent of participants reported pain that affected their daily functioning. Persons with pain had significantly greater fatigue and lower area under the excitatory motor evoked potential (MEP) recruitment curve (eREC AUC), a measure of total corticospinal excitability. After controlling for age, disability status, and pain medications, increased fatigue and decreased eREC AUC together explained 40% of the variance in pain. Discussion: Pain in MS is multifactorial and relates to both greater fatigue and lesser corticospinal excitability. Future work should better characterize relationships between these outcomes to develop targeted pain interventions such as neuromodulation. Summary: We examined pain in MS. Individuals with pain had higher fatigue and lower corticospinal excitability than those without pain. These outcomes significantly predicted self-reported pain.

Multiple sclerosis-related heat sensitivity linked to absence of DMT prescription and subjective hand impairment but not autonomic or corticospinal dysfunction.

OBJECTIVES: Heat sensitivity (HS) describes a temporary worsening of multiple sclerosis (MS) symptoms with increased body temperature. The pathophysiology may relate to central nervous system conduction deficits and autonomic dysfunction. We conducted deep clinical phenotyping of a cohort of persons with MS to identify predictors of HS. METHODS: We recruited 59 MS participants with HS or No HS. Participants self-reported symptom severity (Hospital Anxiety and Depression Scale, Multiple Sclerosis Impact Scale, and fatigue visual analog scale) and underwent maximal exercise and transcranial magnetic stimulation testing to characterize autonomic and corticospinal function. We examined associations with HS using binomial logistic regression. RESULTS: People with HS (36/59) had significantly greater disability, depression, fatigue, and physical and psychological functional effects of MS. They also had significantly lower corticospinal excitability but not conduction. After controlling for disease-modifying therapy (DMT), disability, and disease type, self-reported difficulty using hands in everyday tasks was significantly associated with a large increase in the odds of HS. Autonomic and corticospinal dysfunction were not associated with HS. Lack of DMT use alone was also associated with a large increase in the odds of HS. DISCUSSION: Following a comprehensive assessment of plausible contributors to HS, HS was most strongly associated with lack of a DMT prescription and self-reported hand dysfunction. Surprisingly, objective measurement of autonomic and corticospinal integrity did not contribute to HS.

Sex-specific disruption in corticospinal excitability and hemispheric (a)symmetry in multiple sclerosis.

Multiple Sclerosis (MS) is a neurodegenerative disease in which pathophysiology and symptom progression presents differently between the sexes. In a cohort of people with MS (n = 110), we used transcranial magnetic stimulation (TMS) to investigate sex differences in corticospinal excitability (CSE) and sex-specific relationships between CSE and cognitive function. Although demographics and disease characteristics did not differ between sexes, males were more likely to have cognitive impairment as measured by the Montreal Cognitive Assessment (MoCA); 53.3% compared to females at 26.3%. Greater CSE asymmetry was noted in females compared to males. Females demonstrated higher active motor thresholds and longer silent periods in the hemisphere corresponding to the weaker hand which was more typical of hand dominance patterns in healthy individuals. Males, but not females, exhibited asymmetry of nerve conduction latency (delayed MEP latency in the hemisphere corresponding to the weaker hand). In males, there was also a relationship between delayed onset of ipsilateral silent period (measured in the hemisphere corresponding to the weaker hand) and MoCA, suggestive of cross-callosal disruption. Our findings support that a sex-specific disruption in CSE exists in MS, pointing to interhemispheric disruption as a potential biomarker of cognitive impairment and target for neuromodulating therapies.

Task-Oriented Circuit Training as an Alternative to Ergometer-Type Aerobic Exercise Training after Stroke.

Moderate-intensity aerobic exercise training is an important treatment strategy to enhance functional recovery and decrease cardiometabolic risk factors after stroke. However, stroke related impairments limit access to ergometer-type exercise. The aims of the current study were (1) to evaluate whether our task-oriented circuit training protocol (intermittent functional training; IFT) could be used to sustain moderate-intensity aerobic workloads over a 10-week intervention period, and (2) to investigate its preliminary effects on cardiorespiratory fitness and metabolic profiles compared to constant-load ergometer-type exercise (CET). Forty chronic hemiparetic stroke survivors were randomized to receive 30 sessions of IFT or CET over ten weeks. Similar proportions of participants were randomized to IFT (7/19) and CET (9/18) sustained workloads associated with moderate-intensity aerobic exercise over the study period (p = 0.515). However, CET was associated with more substantial changes in maximal oxygen uptake (MD = 2.79 mL min-1 kg-1 CI: 0.84 to 4.74) compared to IFT (MD = 0.62 mL min-1 kg-1 CI: -0.38 to 1.62). Pre to post changes in C-reactive protein (-0.9 mg/L; p =0.017), short-term glycemia (+14.7 mol/L; p = 0.026), and resting whole-body carbohydrate oxidation (+24.2 mg min-1; p = 0.046) were observed when considering both groups together. Accordingly, IFT can replicate the aerobic intensities sustained during traditional ergometer-type exercise training. More work is needed to evaluate the dose-response effects of such task-oriented circuit training protocols on secondary prevention targets across the continuum of stroke recovery.

Probing the Brain-Body Connection Using Transcranial Magnetic Stimulation (TMS): Validating a Promising Tool to Provide Biomarkers of Neuroplasticity and Central Nervous System Function.

Transcranial magnetic stimulation (TMS) is a non-invasive method used to investigate neurophysiological integrity of the human neuromotor system. We describe in detail, the methodology of a single pulse TMS protocol that was performed in a large cohort of people (n = 110) with multiple sclerosis (MS). The aim was to establish and validate a core-set of TMS variables that predicted typical MS clinical outcomes: walking speed, hand dexterity, fatigue, and cognitive processing speed. We provide a brief and simple methodological pipeline to examine excitatory and inhibitory corticospinal mechanisms in MS that map to clinical status. Delayed and longer ipsilateral silent period (a measure of transcallosal inhibition; the influence of one brain hemisphere's activity over the other), longer cortical silent period (suggestive of greater corticospinal inhibition via GABA) and higher resting motor threshold (lower corticospinal excitability) most strongly related to clinical outcomes, especially when measured in the hemisphere corresponding to the weaker hand. Greater interhemispheric asymmetry (imbalance between hemispheres) correlated with poorer performance in the greatest number of clinical outcomes. We also show, not surprisingly, that TMS variables related more strongly to motor outcomes than non-motor outcomes. As it was validated in a large sample of patients with varying severities of central nervous system dysfunction, the protocol described herein can be used by investigators and clinicians alike to investigate the role of TMS as a biomarker in MS and other central nervous system disorders.

Walking Training Enhances Corticospinal Excitability in Progressive Multiple Sclerosis-A Pilot Study.

Background: Inflammatory lesions and neurodegeneration lead to motor, cognitive, and sensory impairments in people with multiple sclerosis (MS). Accumulation of disability is at least partially due to diminished capacity for neuroplasticity within the central nervous system. Aerobic exercise is a potentially important intervention to enhance neuroplasticity since it causes upregulation of neurotrophins and enhances corticospinal excitability, which can be probed using single-pulse transcranial magnetic stimulation (TMS). Whether people with progressive MS who have accumulated substantial disability could benefit from walking rehabilitative training to enhance neuroplasticity is not known. Objective: We aimed to determine whether 10 weeks of task-specific walking training would affect corticospinal excitability over time (pre, post, and 3-month follow-up) among people with progressive MS who required walking aids. Results: Eight people with progressive MS (seven female; 29-74 years old) with an Expanded Disability Status Scale of 6-6.5 underwent harness-supported treadmill walking training in a temperature controlled room at 16°C (10 weeks; three times/week; 40 min at 40-65% heart rate reserve). After training, there was significantly higher corticospinal excitability in both brain hemispheres, reductions in TMS active motor thresholds, and increases in motor-evoked potential amplitudes and slope of the recruitment curve (REC). Decreased intracortical inhibition (shorter cortical silent period) after training was noted in the hemisphere corresponding to the stronger hand only. These effects were not sustained at follow-up. There was a significant relationship between increases in corticospinal excitability (REC, area under the curve) in the hemisphere corresponding to the stronger hand and lessening of both intensity and impact of fatigue on activities of daily living (Fatigue Severity Scale and Modified Fatigue Impact Scale, respectively). Conclusion: Our pilot results support that vigorous treadmill training can potentially improve neuroplastic potential and mitigate symptoms of the disease even among people who have accumulated substantial disability due to MS.

Exercise-Induced Brain Excitability Changes in Progressive Multiple Sclerosis: A Pilot Study.

BACKGROUND AND PURPOSE: Even a single bout of aerobic exercise (AE) enhances corticospinal excitability (CSE), a biomarker of neuroplasticity. Because neurodegeneration limits capacity for neuroplasticity, it is not clear whether AE would induce CSE changes in people with progressive multiple sclerosis (MS). METHODS: People with progressive MS (n = 10) requiring ambulatory assistive devices completed a graded maximal exercise test. Dual-energy x-ray absorptiometry was used to quantify body fat and lean mass. Before and following one 40-minute AE session using body weight-supported (<10% support) treadmill at moderate intensity, CSE was measured using transcranial magnetic stimulation. Variables included resting and active motor thresholds, motor evoked potential (MEP) amplitudes, recruitment curves, and length of the cortical silent period (CSP). RESULTS: Aerobic exercise reduced inhibition (shorter CSP) and increased excitation (increased MEP amplitude) only in the hemisphere corresponding to the stronger hand. Controlling for age, higher fitness and lower body fat significantly predicted exercise-induced reduction in resting motor threshold (ΔR = +0.458, P = 0.046) and CSP (ΔR = +0.568, P = 0.030), respectively. DISCUSSION AND CONCLUSIONS: Despite high levels of disability, capacity for exercise-induced neuroplasticity was retained among people with progressive MS. The hemisphere contralateral to the weaker hand was resistant to exercise-induced CSE changes, suggesting less neuroplastic potential. Lower fitness and higher body fat were associated with diminished exercise-induced CSE benefits, suggesting that therapists should consider interventions aimed at improving fitness and combating sedentarism to ultimately enhance the benefits of exercise on the brain.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A302).

Vigorous cool room treadmill training to improve walking ability in people with multiple sclerosis who use ambulatory assistive devices: a feasibility study.

BACKGROUND: Aerobic training has the potential to restore function, stimulate brain repair, and reduce inflammation in people with Multiple Sclerosis (MS). However, disability, fatigue, and heat sensitivity are major barriers to exercise for people with MS. We aimed to determine the feasibility of conducting vigorous harness-supported treadmill training in a room cooled to 16 °C (10 weeks; 3times/week) and examine the longer-term effects on markers of function, brain repair, and inflammation among those using ambulatory aids. METHODS: Ten participants (9 females) aged 29 to 74 years with an Expanded Disability Status Scale ranging from 6 to 7 underwent training (40 to 65% heart rate reserve) starting at 80% self-selected walking speed. Feasibility of conducting vigorous training was assessed using a checklist, which included attendance rates, number of missed appointments, reasons for not attending, adverse events, safety hazards during training, reasons for dropout, tolerance to training load, subjective reporting of symptom worsening during and after exercise, and physiological responses to exercise. Functional outcomes were assessed before, after, and 3 months after training. Walking ability was measured using Timed 25 Foot Walk test and on an instrumented walkway at both fast and self-selected speeds. Fatigue was measured using fatigue/energy/vitality sub-scale of 36-Item Short-Form (SF-36) Health Survey, Fatigue Severity Scale, modified Fatigue Impact Scale. Aerobic fitness (maximal oxygen consumption) was measured using maximal graded exercise test (GXT). Quality-of-life was measured using SF-36 Health Survey. Serum levels of neurotrophin (brain-derived neurotrophic factor) and cytokine (interleukin-6) were assessed before and after GXT. RESULTS: Eight of the ten participants completed training (attendance rates ≥ 80%). No adverse events were observed. Fast walking speed (cm/s), gait quality (double-support (%)) while walking at self-selected speed, fatigue (modified Fatigue Impact Scale), fitness (maximal workload achieved during GXT), and quality-of-life (physical functioning sub-scale of SF-36) improved significantly after training, and improvements were sustained after 3-months. Improvements in fitness (maximal respiratory exchange ratio and maximal oxygen consumption during GXT) were associated with increased brain-derived neurotrophic factor and decreased interleukin-6. CONCLUSION: Vigorous cool room training is feasible and can potentially improve walking, fatigue, fitness, and quality-of-life among people with moderate to severe MS-related disability. TRIAL REGISTRATION: The study was approved by the Newfoundland and Labrador Health Research Ethics Board (reference number: 2018.088) on 11/07/2018 prior to the enrollment of first participant (retrospectively registered at ClinicalTrials.gov: NCT04066972. Registered on 26 August 2019.

Transcranial Magnetic Stimulation as a Potential Biomarker in Multiple Sclerosis: A Systematic Review with Recommendations for Future Research.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. Disease progression is variable and unpredictable, warranting the development of biomarkers of disease status. Transcranial magnetic stimulation (TMS) is a noninvasive method used to study the human motor system, which has shown potential in MS research. However, few reviews have summarized the use of TMS combined with clinical measures of MS and no work has comprehensively assessed study quality. This review explored the viability of TMS as a biomarker in studies of MS examining disease severity, cognitive impairment, motor impairment, or fatigue. Methodological quality and risk of bias were evaluated in studies meeting selection criteria. After screening 1603 records, 30 were included for review. All studies showed high risk of bias, attributed largely to issues surrounding sample size justification, experimenter blinding, and failure to account for key potential confounding variables. Central motor conduction time and motor-evoked potentials were the most commonly used TMS techniques and showed relationships with disease severity, motor impairment, and fatigue. Short-latency afferent inhibition was the only outcome related to cognitive impairment. Although there is insufficient evidence for TMS in clinical assessments of MS, this review serves as a template to inform future research.

Synergistic Benefits of Combined Aerobic and Cognitive Training on Fluid Intelligence and the Role of IGF-1 in Chronic Stroke.

BACKGROUND: Paired exercise and cognitive training have the potential to enhance cognition by "priming" the brain and upregulating neurotrophins. METHODS: Two-site randomized controlled trial. Fifty-two patients >6 months poststroke with concerns about cognitive impairment trained 50 to 70 minutes, 3× week for 10 weeks with 12-week follow-up. Participants were randomized to 1 of 2 physical interventions: Aerobic (>60% VO2peak using <10% body weight-supported treadmill) or Activity (range of movement and functional tasks). Exercise was paired with 1 of 2 cognitive interventions (computerized dual working memory training [COG] or control computer games [Games]). The primary outcome for the 4 groups (Aerobic + COG, Aerobic + Games, Activity + COG, and Activity + Games) was fluid intelligence measured using Raven's Progressive Matrices Test administered at baseline, posttraining, and 3-month follow-up. Serum neurotrophins collected at one site (N = 30) included brain-derived neurotrophic factor (BDNF) at rest (BDNFresting) and after a graded exercise test (BDNFresponse) and insulin-like growth factor-1 at the same timepoints (IGF-1rest, IGF-1response). RESULTS: At follow-up, fluid intelligence scores significantly improved compared to baseline in the Aerobic + COG and Activity + COG groups; however, only the Aerobic + COG group was significantly different (+47.8%) from control (Activity + Games -8.5%). Greater IGF-1response at baseline predicted 40% of the variance in cognitive improvement. There was no effect of the interventions on BDNFresting or BDNFresponse; nor was BDNF predictive of the outcome. CONCLUSIONS: Aerobic exercise combined with cognitive training improved fluid intelligence by almost 50% in patients >6 months poststroke. Participants with more robust improvements in cognition were able to upregulate higher levels of serum IGF-1 suggesting that this neurotrophin may be involved in behaviorally induced plasticity.

Prolonged cortical silent period is related to poor fitness and fatigue, but not tumor necrosis factor, in Multiple Sclerosis.

OBJECTIVE: Poor fitness among people with Multiple Sclerosis (MS) aggravates disease symptoms. Whether low fitness levels accompany brain functioning changes is unknown. METHODS: MS patients (n = 82) completed a graded maximal exercise test, blood was drawn, and transcranial magnetic stimulation determined resting and active motor thresholds, motor evoked potential latency, and cortical silent period (CSP). RESULTS: Sixty-two percent of participants had fitness levels ranked below 10th percentile. Fitness was not associated with disability measured using the Expanded Disability Status Scale (EDSS). Regression analyses revealed that, cardiorespiratory fitness, when controlling for disease demographics, contributed 23.7% (p < 0.001) to the model explaining variance in CSP. Regression analysis using cardiorespiratory fitness and CSP as predictors showed that CSP alone explained 19.9% of variance in subjective fatigue (p = 0.002). Tumor necrosis factor was not associated with any variable. CONCLUSION: Low fitness was associated with longer CSP in MS. Longer CSP was, in turn, related to greater MS fatigue. SIGNIFICANCE: MS patients had extremely low levels of cardiorespiratory fitness. Poor fitness predicted longer CSP, a marker of greater intracortical inhibition, which was linked to MS fatigue. Future research should examine whether aerobic training could shorten CSP and potentially lessen inhibition of cortical networks.

Asymmetry of Brain Excitability: A New Biomarker that Predicts Objective and Subjective Symptoms in Multiple Sclerosis.

OBJECTIVES: Investigate whether asymmetrical corticospinal excitability exists in Multiple Sclerosis (MS) and its association with MS symptoms. METHODS: Bilateral resting and active motor thresholds (RMT, AMT) were gathered using transcranial magnetic stimulation among 82 MS patients. Corticospinal excitability (CSE) asymmetry was expressed as the ratio between weaker and stronger sides' RMT and AMT. Stronger and weaker side was determined by pinch and grip strength. We examined whether CSE asymmetry predicted symptoms. RESULTS: AMT asymmetry ratio revealed atypical CSE asymmetry whereby the hemisphere associated with the weaker hand was more excitable in early MS. After controlling for MS disease demographics, shifting of CSE asymmetry towards greater excitability in the stronger side significantly predicted more severe symptoms including Expanded Disease Severity Scale, nine-hole peg test, cognitive processing speed, walking speed, heat sensitivity, fatigue, and subjective impact of MS. CONCLUSION: CSE asymmetry significantly predicted the severity of MS-related physical and objective cognitive symptoms. The phenomenon may be related to neuroinflammation-mediated hyperexcitability. Shifting of asymmetry toward less excitability on the weaker side may suggest the onset of a more neurodegenerative phase of the disease. SIGNIFICANCE: Shifting of hemispheric excitability, detected using a CSE asymmetry ratio, may be a useful biomarker to track disease progression and understand the benefits of treatments.

A Bout of High Intensity Interval Training Lengthened Nerve Conduction Latency to the Non-exercised Affected Limb in Chronic Stroke.

Objective: Evaluate intensity-dependent effects of a single bout of high intensity interval training (HIIT) compared to moderate intensity constant-load exercise (MICE) on corticospinal excitability (CSE) and effects on upper limb performance in chronic stroke. Design: Randomized cross-over trial. Setting: Research laboratory in a tertiary rehabilitation hospital. Participants: Convenience sample of 12 chronic stroke survivors. Outcome measures: Bilateral CSE measures of intracortical inhibition and facilitation, motor thresholds, and motor evoked potential (MEP) latency using transcranial magnetic stimulation. Upper limb functional measures of dexterity (Box and Blocks Test) and strength (pinch and grip strength). Results: Twelve (10 males; 62.50 ± 9.0 years old) chronic stroke (26.70 ± 23.0 months) survivors with moderate level of residual impairment participated. MEP latency from the ipsilesional hemisphere was lengthened after HIIT (pre: 24.27 ± 1.8 ms, and post: 25.04 ± 1.8 ms, p = 0.01) but not MICE (pre: 25.49 ± 1.10 ms, and post: 25.28 ± 1.0 ms, p = 0.44). There were no significant changes in motor thresholds, intracortical inhibition or facilitation. Pinch strength of the affected hand decreased after MICE (pre: 8.96 ± 1.9 kg vs. post: 8.40 ± 2.0 kg, p = 0.02) but not after HIIT (pre: 8.83 ± 2.0 kg vs. post: 8.65 ± 2.2 kg, p = 0.29). Regardless of type of aerobic exercise, higher total energy expenditure was associated with greater increases in pinch strength in the affected hand after exercise (R2 = 0.31, p = 0.04) and decreases in pinch strength of the less affected hand (R2 = 0.26 p = 0.02). Conclusion: A single bout of HIIT resulted in lengthened nerve conduction latency in the affected hand that was not engaged in the exercise. Longer latency could be related to the cross-over effects of fatiguing exercise or to reduced hand spasticity. Somewhat counterintuitively, pinch strength of the affected hand decreased after MICE but not HIIT. Regardless of the structure of exercise, higher energy expended was associated with pinch strength gains in the affected hand and strength losses in the less affected hand. Since aerobic exercise has acute effects on MEP latency and hand strength, it could be paired with upper limb training to potentiate beneficial effects.

Intensifying Functional Task Practice to Meet Aerobic Training Guidelines in Stroke Survivors.

Objective: To determine whether stroke survivors could maintain workloads during functional task practice that can reach moderate levels of cardiometabolic stress (i.e., ≥40% oxygen uptake reserve ([Formula: see text]O2R) for ≥20 min) without the use of ergometer-based exercise. Design: Cross-sectional study using convenience sampling. Setting: Research laboratory in a tertiary rehabilitation hospital. Participants: Chronic hemiparetic stroke survivors (>6-months) who could provide consent and walk with or without assistance. Intervention: A single bout of intermittent functional training (IFT). The IFT protocol lasted 30 min and involved performing impairment specific multi-joint task-oriented movements structured into circuits lasting ~3 min and allowing 30-45 s recovery between circuits. The aim was to achieve an average heart rate (HR) 30-50 beats above resting without using traditional ergometer-based aerobic exercise. Outcome measures: Attainment of indicators for moderate intensity aerobic exercise. Oxygen uptake ([Formula: see text]O2), carbon dioxide production ([Formula: see text]CO2), and HR were recorded throughout the 30 min IFT protocol. Values were reported as percentage of [Formula: see text]O2R, HR reserve (HRR) and HRR calculated from predicted maximum HR (HRRpred), which were determined from a prior maximal graded exercise test. Results: Ten (3-female) chronic (38 ± 33 months) stroke survivors (70% ischemic) with significant residual impairments (NIHSS: 3 ± 2) and a high prevalence of comorbid conditions (80% ≥ 1) participated. IFT significantly increased all measures of exercise intensity compared to resting levels: [Formula: see text]O2 (Δ 820 ± 290 ml min-1, p < 0.001), HR (Δ 42 ± 14 bpm, p < 0.001), and energy expenditure (EE; Δ 4.0 ± 1.4 kcal min-1, p < 0.001). Also, mean values for percentage of [Formula: see text]O2R (62 ± 19), HRR (55 ± 14), and HRRpred (52 ± 18) were significantly higher than the minimum threshold (40%) indicating achievement of moderate intensity aerobic exercise (p = 0.004, 0.016, and 0.043, respectively). Conclusion: Sufficient workloads to achieve moderate levels of cardiometabolic stress can be maintained in chronic stroke survivors using impairment-focused functional movements that are not dependent on ergometers or other specialized equipment.