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.

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.

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.