Exercise and Neuroplasticity in Multiple Sclerosis

Robert W. Motl Professor, Department of Physical Therapy Associate Director, REACT Center, UCEM – Rehabilitation Research, UAB/Lakeshore Research Collaborative Overview of Presentation

1. Nervous System Decline in MS: Cognitive Function and Brain MRI as Markers of Neuroplasticity 2. Exercise and the Nervous System in MS: Evidence of Neuroplasticity 3. PRIMERS Model 4. Next Steps Nervous System Decline (Neuroplasticity) in MS: ACT I What is neuroplasticity? • The brain’s ability to reorganize itself by forming new neural connections through life experiences (i.e., brain malleability) – underlies other outcomes.

Zeller & Classen (2014). Neuroscience, 283, 222-230 Pervasive Cognitive Decline in Early MS Particularly in CPS and Learning and Memory Cognitive Decline Associated with Regional CNS Atrophy – I Cognitive Decline Associated with Regional CNS Atrophy – II Cognitive Dysfunction is Poorly Managed in MS Exercise, Cognition, and Brain Plasticity in Aging

Erickson et al, 2011, Proc Natl Acad Sci Walking and Brain Function

Saturday Night Live’s “Weekend Update” Walking and Brain Function

This Week, Researchers at the University of Illinois Reported that Exercise Improves Brain Function. Walking and Brain Function

Unfortunately, there are some exceptions...

Exercise and the Nervous System in MS: ACT II Multiple Sclerosis and Exercise

Motl & Pilutti, Nat Rev Neurol, 2013. Overview of Exercise Benefits Meta-analyses: Systematic Reviews: 1. éAerobic capacity 1. êRelapse rate 2. éMuscle strength 2. êComorbidity 3. éWalking performance 3. éHRQOL 4. éBalance 4. éParticipation 5. êFatigue 6. êDepression 7. éQOL

Motl & Sandroff, Curr Neurol Neurosci Rep, 2015. Letterman’s Top 10 List Aerobic Fitness and Cognition Aerobic Fitness and Brain Structure Physical Activity and Cognition Physical Activity and Brain Structure RCT of Physical Activity and CPS Case Study of Aerobic Exercise, Memory, & Hippocampus

Exercise: 3 d/wk, 30 min/d, cycle ergometry for 12 wk. Control: 3 d/wk, 30 min/d, stretching for 12 wk.

Results: 16.5% hippocampal volume; 55.9% verbal memory (CVLT); 51.3% nonverbal memory (BVMT); 10% aerobic capacity RCT of Aerobic Exercise, Memory, & Hippocampus RCT of Aerobic Exercise, CPS, & RSFC

PRIMERS Model: ACT III Assumptions of the PRIMERS Model • Exercise is a potent stimulus that activates nearly every organ and organ system in human body! • The activation is integrative and involves CNS regulation using feedback and feed-forward processes. • Endless potential for adaptation over time using systematic delivery of acute bouts (i.e., exercise training). PRIMERS (PRocessing, Integration of Multisensory Exercise-Related Stimuli) Framework

Not Efficient More Efficient Efficient

Sensory Motor Sensory Motor Sensory Motor Input Output Input Output Input Output

Sandroff et al., NNR, under review Next Steps: ACT IV Future Research

Phase II and III RCTs

Exercise Alone and Combined with Cognitive Rehabilitation and/or Other Behaviors

Other Markers of CNS Dysfunction

Cognitively Impaired Samples

Mechanisms of Neuroplasticity Why Cognitively-Impaired Persons with MS? • Secondary analysis: N=64 persons with MS • N=64 persons with MS completed IET, SDMT, and modified flanker task • N=50 without PS impairment (PSI); N=14 with PSI (i.e., SDMT > 1.5 SD’s below normative score)

Group Variable Modified Flanker RT ρ p No PSI (n=50) VO 2peak −.20 .08 ρ p PSI (n=14) VO 2peak −.62* .01

40 Sandroff et al., 2017, in press, Med Sci Sports Exerc Directions for Countermeasures Inquiry Summary

1. Exercise is a strong, integrative stimulus 2. Carefully vet other diseases/literatures as a EXERCISE guide AND 3. Learn from lessons/mistakes in RRMS 4. Bottom-up approach for developing line of inquiry 5. Multi-component interventions for optimizing outcomes Thank you!