Pushing the plasticity: The role of exercise in the management of neurological illness

Pushing the plasticity: The role of exercise in the management of neurological illness Michael Gaetz Ph.D. Associate Professor, Kinesiology Department Faculty of Health Sciences University of the Fraser Valley

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.

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

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.

Clinical Symptoms (Motor) Michael Gaetz Ph.D. 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.

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.

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.

Pathophysiology Gait Slowness Michael Gaetz Ph.D. 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

Pathophysiology Gait Slowness Michael Gaetz Ph.D. 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.

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 anteriorposterior and medio-lateral directions Petersen D.S. & Horak F.B. Physiology 31: 95 107, 2016

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

Pathophysiology Poor Postural Control Michael Gaetz Ph.D. 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

Pathophysiology Poor Postural Control Michael Gaetz Ph.D. 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

Exercise Michael Gaetz Ph.D. Aerobic Balance Training Resistance Training Skills Based Training

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)

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).

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)

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 (skilledbased 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

Skills based exercise Tango dancing Michael Gaetz Ph.D. 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

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

Plasticity Jakowec et al., 2016 Michael Gaetz Ph.D. 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 longterm utilization (Adlard and Cotman, 2004; Berchtold et al., 2005)

Plasticity Jakowec et al., 2016 Michael Gaetz Ph.D. Once these circuits are established, practice may be necessary to maintain their integrity at a high level and to avoid the use-it-or-loseit 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.

Plasticity Jakowec et al., 2016 Michael Gaetz Ph.D. 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).

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

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

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

Thanks for your attention! Michael Gaetz Ph.D.