The Big Picture
Our research group is involved in both basic and clinical research that is focused on exploring the underlying mechanisms by which experience, in the form of different exercise modalities is able to enhance neuroplasticity.
The following section highlights the ongoing and recent research in our group from both the basic science laboratory and clinical research in patients with Parkinson's disease. For manuscript on any and all these projects please visit the Publications page of this website. If you have any questions or comments please contact us and/or leave a comment on our Blog page. Thank you for your interest.
Current Basic Research Focus
Exercise-enhanced Neuroplasticity in Rodent Models of Parkinson's Disease
Prior to 2002 the primary focus of the basic research group was to better understand the mechanisms involved in intrinsic neuroplasticity in animal models of Parkinson's disease; specifically the MPTP-lesioned model. Both mice and monkeys rendered parkinsonian by the dopamine-depleting agent MPTP show significant recovery in terms of behavior (nonhuman primates) and behavior and dopamine (mice). The hypothesis at the time was that this phenomena of neuroplasticity in adult animal models may provide insight into potential novel therapeutic modalities in treating Parkinson's disease. Could we tap into the natural intrinsic neuroplasticity in the human brain suffering from Parkinson's disease. When Beth Fisher joined the lab as a postdoctoral fellow in 2002 we through we could apply her expertise and PhD topic in stroke neurorehabiiitation to animal models of Parkinson's disease. We hypothesized that mice that were rendered parkinsonian due to exposure to MPTP could in fact be enhanced in terms of recovery by intensive treadmill running. On the treadmill, MPTP-lesioned mice are slower than normal mice indicating the effects of dopamine-depletion on motor behavior. We were interested in the effects of exercise on neuro-restoration and not neuroprotection. A number of other groups at the time were exploring the effects of exercise, either on treadmill or on voluntary running wheels, on protecting against the dopamine-depleting and cell death mediated effects of neurotoxins used in PD research including MPTP and 6-OHDA. While it was not evident at the time our work wold later show that exercise when administered during exercise actually alters the bio-availability of these toxins by changing the uptake into dopaminergic neurons and thus resulting in a lesion of less severity. Since we were interested in neuro-restoration we initiated exercise 5 to 7 days after MPTP-mediated when cell death is completed. Our thought was to treat mice like patients; they come to the clinic when parkinsonian features are evident. Another important experimental design was to use intensive treadmill running to actively engage the mice and force them to run at increasing speed and duration. This is no unlike the engagement by a physical therapist or trainer. Mice ran 5 days per week for 6 weeks for 1 hour achieving speeds up to 24 meters/minute. we also investigated any signs of stress by mice when subjected to intensive treadmill running. While there was elevated stress in the first couple of days this quickly dissipated and mice showed no evidence of shying away from the treadmill regimen. By 3 weeks those MPTP-lesioned mice that were initially slower on the treadmill were able to catch-up to normal mice and match their motor behaviors in terms of speed and duration. We then examined the restoration of the integrity of the basal ganglia since we speculated that exercise would accelerate the recovery of dopamine. We examined the channel responsible for dopamine uptake (the dopamine transporter DAT), the enzyme responsible for synthesizing dopamine (tyrosine hydroxylase TH), and levels of dopamine and its metabolites in tissues analyzed using HPLC. Contrary to our expectation we found that DAT and TH were down-regulated and expressed levels lower than those seen in MPTP-lesioned mice that did not exercise but were sedentary. When examining the degree of expression of the Dopamine D1 and D2 receptors mRNA transcripts using in situ hybridization histochemistry we did not see any change in the D1 receptor between MPTP-lesioned sedentary and exercise mice, but interestingly we did see elevated expression of the D2 receptor; a receptor that is important in cognitive and motor behaviors and that displays a remarkable degree of neuroplasticity in response to experience. And finally we observed changes in the distribution of the neurotransmitter glutamate in the basal ganglia raising the suspicion that glutamatergic neurotransmission is altered indicating that exercise may influence non-dopaminergic pathways as part of the system wide changes in neuronal circuits underlying the exercise-enhanced restoration of motor behavior we observed. The results of this initial findings were published in Fisher et al 2004 (available in the Publications section of this Web Site.
Metabolism and Neurorehabilitation
Astrocytic Response to Aerobic Exercise
Effects of Exercise on Regional Cerebral Blood Flow (rCBF) in Animal Models
Effects of Exercise in a Rodent Model of Huntington's disease
Potential Role of Purinergic Receptors and the Regulation of Dopamine Neurotransmission
Current Clinical Research
Investigating Exercise-Induced Neuroplasticity and its Mechanisms in Parkinson's disease: Targeting Executive Function and Brain Circuitry (Department of Defense Grant Starting July 2018
Principal Investigator: Giselle Petzinger, MD.
Background: Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder of old age and diminishes the quality of life in over 630,000 people in the USA, with numbers projected to double by the year 2040. Estimates of the direct financial burden are in excess of $14.4 billion (2010). There is a growing consensus that pesticides and herbicides exposure, as well as traumatic brain injury in military populations can increase the risk of developing PD. A common problem in PD is cognitive impairment. There are no effective treatments. Impairment in executive function (EF) is the most common subtype of cognitive impairment and leads to challenges in daily function, including decision making, multi-tasking, as well as significant social and psychological burdens all impacting quality of life. Studies from the aging field point to the benefits of physical activity, particularly high intensity exercise (HIE), in improving cognitive performance and brain connectivity (neuroplasticity). Relevant to PD, these exercise effects have been seen in EF and key brain regions subserving EF. More recent studies in aging have demonstrated an association between exercise type, fitness level, and EF. In total these studies support that skill-based exercise (e.g. yoga, boxing) and level of motor fitness (e.g. coordination and agility) are associated with greater EF compared to aerobic exercise (e.g. walking, cycling) and level of cardiovascular fitness (e.g. V02max). In published work from our labs using cerebral perfusion mapping, we have also shown that skill-based versus aerobic exercise in a rodent model of PD results in greater connectivity of the prefrontal cortex (PFC) to the basal ganglia (BG), brain regions subserving EF. While, a wide range of exercise modalities have shown to improve motor performance in PD patients, investigations of the relationship between exercise and EF in PD and mechanisms of neuroplasticity remain a significant gap in knowledge. This application will address this gap through complementary translational studies in humans and animals.
Hypothesis, Specific Aims and Research Strategy: The overall goal of this application is to examine exercise-induced neuroplasticity on EF in PD. We hypothesize that high intensity exercise (HIE) and skill-based exercise (i.e., yoga, Tai Chi) as well as motor fitness (coordination/agility) will have a significantly greater association with EF and increased efficiency in cortical-striatal neural networks subserving EF compared to low intensity exercise (LIE), aerobic exercise (i.e. walking), or cardiovascular fitness (V02max). These goals will be accomplished through two complementary projects. Project 1 will involve an 18-month longitudinal observational study in individuals with PD to test the hypothesis that exercise, intensity and dose (e.g., amount of physical activity), and fitness level is associated with EF performance. To identify mechanisms underlying this association, alterations in functional brain connectivity in neural networks sub-serving EF (e.g., mental flexibility, working memory) will be measured using resting state fMRI to determine their potential role in mediating exercise effects on EF. Project 2 will utilize the 6-hydroxydopamine (6-OHDA) rat model of PD to investigate mechanisms by which the type of exercise (skill-based vs aerobic) enhances circuit-specific neuroplasticity as demonstrated through changes in regional cerebral blood flow, EF, and molecular analysis of neurotransmission (dopamine) and synaptic function (synaptogenesis and metabolism). These projects will address (i) parameters of exercise (e.g. intensity), and predictors of exercise benefit (e.g., fitness level) to help delineate a personalized approach to exercise prescription in PD.
Impact: How exercise impacts EF and brain connectivity in PD remains poorly understood. The current proposal represents a much needed ‘next step’ for the field of rehabilitative medicine and PD as it moves forward into personalized medicine that allows treatment of cognitive disability, as well as potential disease modification. Understanding the impact of exercise, (including intensity, the role of fitness and exercise type) on prefrontal-basal ganglia circuitry and related connections represents a paradigm shift for the field of brain repair in PD in that the novel focus is on circuitry and behavior and mechanisms of neuroplasticity. This proposal provides a framework for guiding future human trials aimed at optimizing specific, cost-effective rehabilitation strategies and reducing the burden of disease, as well as the potential for identifying novel therapeutic targets in PD.
Relevance: This application is a direct response to Funding Opportunity Number: W81XWH-17-PRP-IIRA Parkinson’s Research Program, Investigator-Initiated Research Award, Department of Defense, Congressionally Directed Medical Research Programs specifically target the request “Mechanisms of neuroplasticity in the Parkinson’s disease brain”. This application is timely in light of the growing size of the US military population and the increase in the number of aging individuals not only within the VA system but also the general population of the US, who are at risk for dementia and PD. This application addresses a major gap in knowledge regarding the relationship between exercise, cognition, and the mechanisms of exercise-induced neuroplasticity through translational and complementary studies in both individuals with PD and animal models of dopamine deafferentation.
Title: Exercise targeting cognitive impairment in Parkinson’s disease
National Parkinson's Foundation (2014-2017) Principal investigator: Giselle Petzinger MD.
Specific Aims: Mild cognitive impairment (MCI), particularly of the executive function (EF) subtype, is common in Parkinson's disease (PD) and transitions to dementia, increased fall risk, and poor quality of life. EF is a set of processes that include mental flexibility and attention that are needed to learn and optimize performance of complex cognitive and motor skills. Such skills include the ability to generalize a learned motor task performance under different conditions (context processing) and to perform two tasks simultaneously termed dual-task (DT) performance. Deficits in EF lead to problems in daily functioning and loss of independence and create psychosocial and economic burdens on patients and caregivers. Currently, there is no effective treatment in PD to address EF deficits. Our animal and clinical studies in PD demonstrate that skilled exercise facilitates neuroplasticity of the basal ganglia (BG), a brain region sub-serving EF, and supports the hypothesis that exercise will reverse EF deficits in PD. Furthermore, while many exercise studies in healthy aging support the role of aerobic exercise on EF, recent studies in healthy aging support that skill-based exercise that specifically promotes motor skill fitness (MSF), compared with aerobic exercise that promotes cardiovascular fitness (CF), has a greater impact on EF and related basal ganglia circuits.
The aim of this application is to compare and elucidate the effects of skill-based versus aerobic exercise versus control on MCI of the EF subtype in PD; we hypothesize that skill-based exercise will result in the greatest improvement in EF and lead to modification of underlying neural substrates. Patients will be assigned to 1 of 3 groups (N = 20/group) involving 36 1-hr sessions over 12 weeks including either: (i) skill-based exercise; (ii) aerobic exercise or (iii) social-contact control. All assessments, that include MSF and CF, will be made at baseline and at 12 weeks (post-intervention); a 3-month follow up for EF in SA1 will be done.
Specific Aim 1 tests the hypothesis that skilled-based exercise will lead to greater improvement in EF as indexed by standardized neurocognitive measures of EF. We hypothesize that skill-based exercise will improve EF to a greater extent than aerobic exercise or a control group through improving MSF by comparing pre-post exercise related changes on MSF and neurocognitive measures of EF. We will also compare pre-post exercise related changes on CF and EF. Secondary outcome measures will compare pre-post exercise effects on self-efficacy, quality of life (PDQ39) and Parkinson disease severity (MDS-UPDRS).
Specific Aim 2 tests the hypothesis that skill-based exercise will lead to greater gains in EF, compared to aerobic exercise or a control group on the ability to generalize a learned motor task performance as indexed by a validated context-dependent motor learning (CDML) task. Utilizing this CDML task, we found that PD patients are impaired in the ability to generalize a learned motor task and transfer it to a different contextual setting, which can adversely affect everyday functioning.
Specific Aim 3 tests the hypothesis that skill-based exercise will lead to greater gains in EF compared to aerobic exercise or a control group by examining improved DT performance and the corresponding more efficient neural activity of brain regions sub-serving EF DT capability during an fMRI scan.