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% VO 2peak 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 (BDNF resting) and after a graded exercise test (BDNF response) and insulin-like growth factor-1 at the same timepoints (IGF-1 rest , IGF-1 response). 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-1 response at baseline predicted 40% of the variance in cognitive improvement. There was no effect of the interventions on BDNF resting or BDNF response ; 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.

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.

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.

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