Pushing the plasticity: The role of exercise in the management

of neurological illnessMichael Gaetz Ph.D.

Associate Professor, Kinesiology Department

Faculty of Health Sciences

University of the Fraser Valley

Michael Gaetz Ph.D.

Learning Objectives

• To summarise current science related to the role of exercise in the management of Parkinson’s disease

• To understand the importance of exercise prescription that is effective and appropriate given the stage of illness progression

• To recognise that targeted plasticity may be possible when prescribing a combination of skill-based and aerobic exercise.

Michael Gaetz Ph.D.

Michael Gaetz Ph.D.

Overview

• History of exercise as a treatment for PD

• Clinical symptoms: motor and non-motor symptoms

• Pathophysiology

• The benefit of exercise to improve functioning in PD:• Aerobic

• Balance training

• Resistance Training

• Skills based training

• Plasticity

• Conclusions

Michael Gaetz Ph.D.

History• James Parkinson noted moderately advanced patients as

“being, at the same time, irresistibly impelled to take much quicker and shorter steps, and thereby to adopt unwillingly a running pace”

• Slowness of gait, small and variable step length have since been considered classic clinical features in Parkinson’s disease (PD)• Bayle et al. (2016) PLoS ONE 11(4): e0152469.

• Since the 1950s, physical activity (PA) was already foreseen as a way of minimizing the limitations induced by the disease • Bilowit DS (1956) Establishing physical objectives in the rehabilitation of

patients with Parkinson’s disease; gymnasium activities. Phys Ther Rev, 36, 176-178.

Michael Gaetz Ph.D.

Clinical Symptoms (Motor)

• Tremor, rigidity, and gait disorders• Cusso et al., 2016. Front. Med. 3:35.

• Tremor, bradykinesia, rigidity and postural instability

• Other typical motor symptoms can be observed such as altered gait pattern, freezing of gait and motor coordination deficits • Lauzé et al., 2016. Journal of Parkinson’s Disease 6 (2016) 685–698.

• Step length has been correlated with time since diagnosis• Bayle et al., 2016. PLoS ONE 11(4): e0152469.

Michael Gaetz Ph.D.

Clinical Symptoms (Non-Motor)

• Hyposmia, constipation, cognitive impairment, anxiety, and depression• Cusso et al., 2016. Front. Med. 3:35.

• Cognitive impairment and dementia, insomnia, depression and anxiety, apathy, bladder dysfunction, pain, and fatigue• Lauzé et al., 2016. Journal of Parkinson’s Disease 6 (2016) 685–698.

Michael Gaetz Ph.D.

Pathophysiology• Classical pathophysiological model: the loss of dopamine in the dorsal

lateral striatum leads to imbalance of the dopamine D1 receptor containing the “direct” pathway and the dopamine D2 receptor “indirect” pathway• Jakowec et al., 2016. Journal of Human Kinetics volume 52/2016, 35-51

• Recently, a widespread supraspinal locomotor network has been described, including premotor cortical, motor cortical, basal nuclei, cerebellar, and brain stem structures

• This model can be used to understand three primary gait impairments: 1) gait slowness (pace, rhythm), 2) increased variability and asymmetry, and 3) poor postural control• Petersen D.S. & Horak F.B. Physiology 31: 95–107, 2016.

Michael Gaetz Ph.D.

Pathophysiology – Gait Slowness

• The primary causes of gait slowness are:• 1) hypokinesia (reduced step size)/bradykinesia (increased step duration)

• 2) rigidity/hypertonia

• Excessive flexor muscle actively pulls the hips, knees, and ankles into flexion, resulting in flexed spinal abnormalities, stooped posture, and reduced lower limb joint torques

• This abnormal posture also pushes the center of mass forward over the feet and contributes to short, shuffling steps common in this population• Petersen D.S. & Horak F.B. Physiology 31: 95–107, 2016

Michael Gaetz Ph.D.

Pathophysiology – Gait Slowness

• The “rate model” of basal nuclei pathophysiology suggests that neural degeneration of the substantia nigra pars compacta results in increased inhibition of the globus pallidus external segment and reduced inhibition of the globus pallidus internal segment

• Together, this leads to over excitation of the globus pallidus internal segment and thus more inhibition of the thalamus and pedunculopontine nucleus (PPN)

• These alterations in basal ganglia output result in over-inhibition of the ventral anterior/ventral lateral thalamus and reduced excitation of cortical motor structures such as the supplementary motor area (SMA) and primary motor cortex resulting in gait slowness.

Michael Gaetz Ph.D.

Petersen D.S. & Horak F.B. Neural Control of Walking in People with Parkinsonism. PHYSIOLOGY 31: 95–107, 2016. Published February 17, 2016; doi:10.1152/physiol.00034.2015

Petersen D.S. & Horak F.B. Neural Control of Walking in People with Parkinsonism. PHYSIOLOGY 31: 95–107, 2016. Published February 17, 2016; doi:10.1152/physiol.00034.2015

Pathophysiology – Gait Asymmetry/Variability

• Gait variability includes “stride-to-stride fluctuations in walking” and is consistently elevated in people with PD

• Variability of steps is larger in people with PD in both the anterior-posterior and medio-lateral directions• Petersen D.S. & Horak F.B. Physiology 31: 95–107, 2016

Michael Gaetz Ph.D.

Pathophysiology – Gait Asymmetry/Variability

• People with PD exhibit larger than normal cortical activity during upper extremity motor tasks, both when the task is new and after overlearning has occurred suggesting more voluntary control of tasks in this population

• Even highly overlearned tasks, such as walking, may rely more heavily on cortical structures in people with PD

• This shift toward increased voluntary locomotor control may partially compensate for dysfunction of the basal ganglia and brain stem automatic pathways but may also increase variability• Petersen D.S. & Horak F.B. Physiology 31: 95–107, 2016

Michael Gaetz Ph.D.

Pathophysiology – Poor Postural Control

• Postural control involves maintaining, achieving, and restoring a state of balance during movements and posture

• All three components of postural control are impaired in people with PD• Petersen D.S. & Horak F.B. Physiology 31: 95–107, 2016

Michael Gaetz Ph.D.

Pathophysiology – Poor Postural Control

• Research is pointing toward an important role of non-dopaminergic structures such as the PPN in postural dysfunction of people with PD

• ACh in the thalamus, supplied primarily by the PPN, seems to be related to postural control (e.g., postural sway and sway variability), whereas cortical cholinergic function, supplied by the Nucleus Basalis of Meynert (nbM), may be related to gait speed and hypokinesia

• Petersen D.S. & Horak F.B. Physiology 31: 95–107, 2016

Michael Gaetz Ph.D.

Exercise

• Aerobic

• Balance Training

• Resistance Training

• Skills Based Training

Michael Gaetz Ph.D.

Aerobic

• Nadeau et al., 2017: e.g. significant increases in walking speed and cadence but not step length following training on a cycle ergometer

• Rosenfeldt et al., 2016: e.g. aerobic exercise may be altering central nervous system pathways that regulate the physiologic or cognitive processes controlling olfaction in individuals with PD

• Animal models have shown that aerobic exercise was related to an increase in the density of blood capillaries in the brain’s motor regions, without an increase in synaptic numbers (as measured by dendritic spine density) (Black et al., 1990; Garcia et al., 2012)

Michael Gaetz Ph.D.

Balance Training

• e.g. Significant improvements in postural control were observed for a balance training group for single-leg stance on a force platform

• The standardized mean difference between groups was significantly higher with 36% improvement for balance training and 0.07% for resistance training• Santos et al. Eur J Phys Rehabil Med. 2016 Nov 23

• e.g. Partnered dancing interventions have consistently improved balance performance without focusing on balance deficits (Earhart, 2009; deDreu et al., 2012, 2014; Sharp and Hewitt, 2014; Shanahan et al., 2015b).

Michael Gaetz Ph.D.

Resistance Training

• Saltychev et al., 2016: In a systematic review of 12 RCTs, no evidence was found on the superiority of progressive resistance training in the rehabilitation of people with idiopathic Parkinson’s disease when compared to other types of training or to usual activities

• Specialized strength training programs that have a significant learning component (e.g. focus on high effort functional movements; Millage et al., 2017) or coupling resistance training with transcranial direct current stimulation (Hendy et al., 2016) are being considered

• Resistance training may benefit specific sub-classes of PD such as “akinetic-rigid” (Santos et al., 2017)

Michael Gaetz Ph.D.

Skills based exercise

• Skill-based exercise can be defined as a form of goal-oriented movement in which temporal and/or spatial accuracy is important for achieving predetermined objectives such as movements in yoga, Tai Chi or amplitude training in patients with PD

• Animals models have shown that learned new motor skills (skilled-based exercise) resulted in a greater number of synapses per neuron, without an increase in the density of blood capillaries

• Examples include Tango dancing and boxing

Michael Gaetz Ph.D.

Skills based exercise – Tango dancing• Most studies on dance in patients

with PD have investigated Tango dancing

• Partnered dancing combines exercise with cognitive challenges in an enriched environment with (somato) sensory cues from the music as well as from the dance partner (Bläsing et al., 2012)

• The sensory cues from physical contact with the partner are specifically important during Tango and Salsa dancing

Michael Gaetz Ph.D.

Michael Gaetz Ph.D.

Plasticity

• Physical activity has been found to result in upregulation of neurotrophins such as brain-derived nerve factor (BDRF) and nerve growth factor (NGF) in animal models

• BDRF has been suggested to increase turnover rate of dopamine in vitro and provide a neuroprotective role in nigral dopamine neurons

• Endorphins are hypothesized to improve mood through binding to opioid receptors in the frontal cortex and limbic regions and by interacting with other neurotransmitters, such as dopamine, which also partake in improvement of mood• Cusso et al. 2016. Front. Med. 3:35. doi: 10.3389/fmed.2016.00035

Michael Gaetz Ph.D.

Plasticity – Jakowec et al., 2016

• Aerobic exercise or the aerobic component of the physical activity plays a critical role in making the neuronal environment conducive for the selection and optimization of necessary neuronal circuits

• For example, there is evidence that neurotrophic factors such as the brain BDNF or NGF can lower the threshold by which physiological changes can take place to strengthen synaptic connectivity, and therefore allow specific neuronal pathways to be reinforced for long-term utilization (Adlard and Cotman, 2004; Berchtold et al., 2005)

Michael Gaetz Ph.D.

Plasticity – Jakowec et al., 2016

• Once these circuits are established, practice may be necessary to maintain their integrity at a high level and to avoid the “use-it-or-lose-it” phenomena that could result

• This leads us to better understand that cognition and motor behavior are not mutually exclusive systems, but are closely integrated to control movement and to make basic motor behaviors automatic.

Michael Gaetz Ph.D.

Plasticity – Jakowec et al., 2016

• The elevated activity of neurons within corticostriatal circuits during exercise leads to an increase in metabolic demand, primarily through reduced levels of cellular oxygen

• Such a hypoxic metabolic state leads to the activation of factors including hypoxia-inducible factor 1 alpha (HIF-1α), a transcription factor that targets the expression of hundreds of genes involved functions ranging from the metabolism, mitochondria integrity, signaling cascades such as those involving nitric oxide synthase (NOS) and glutamate, synaptogenesis, and morphology (Correia and Moreira, 2010).

Michael Gaetz Ph.D.

Plasticity

• Duchesne et al. 2016: Magnetic Resonance Imaging (fMRI) to assess the effect of a 3-month AET program on the neural correlates of implicit motor sequence learning (MSL)

• 20 healthy controls (HC) and 19 early PD individuals participated in a supervised, high-intensity, stationary recumbent cycle training program (3 times/week for 12 weeks)

• Increases in functional activity were observed in the hippocampus, striatum and cerebellum in booth groups

• Importantly, the functional brain changes in PD individuals correlated with changes in aerobic fitness: a positive relationship was found with increased activity in the hippocampus and striatum, while a negative relationship was observed with the cerebellar activity

Michael Gaetz Ph.D.

Duchesne et al., 2016. Influence of aerobic exercise training on the neural correlates of motor learning in Parkinson's disease individuals. NeuroImage: Clinical 12 (2016) 559–569

Duchesne et al., 2016. Influence of aerobic exercise training on the neural correlates of motor learning in Parkinson's disease individuals. NeuroImage: Clinical 12 (2016) 559–569

Conclusion• It is not the type of exercise that matters but rather the

parameters within the physical activity itself

• These parameters include:• Task intensity (it must be high such that one may have to break a sweat)

• The task must be difficult to challenge the participant such that they are learning from the experience

• The task must be specific to the motor circuits affected by disease

• The task must be complex enough to engage the individual• Jakowec et al., 2016. Journal of Human Kinetics volume 52/2016, 35-51

Michael Gaetz Ph.D.

Conclusion

• Putting these parameters together indicates that physical activity and exercise, to maximize benefit for the patient, must be a learning modality with goal oriented targets and cognitive engagement

• Cognition makes motor behaviors automatic

• Deficits in cognition can create deficits in motor behavior, since the cognitive load and its demands on the brain can, in fact, be maladaptive

Michael Gaetz Ph.D.

Thanks for your attention!

Michael Gaetz Ph.D.