Use of a New Smartphone Application to Determine Changes in Eyeblink Conditioning from Home Training in Individuals with Spinocerebellar Ataxia

Spinocerebellar ataxias are a group of disorders that cause severe disability and can be fatal. There are currently no known disease-modifying treatments available for use, and there is a critical need to find treatments that slow disease progression and allow affected individuals to live more functional lives. Aerobic training show promise as a treatment for these diseases, but it is unclear if training induces neuroplastic changes within the damaged cerebellum to enhance motor learning, or if improvements are primarily caused by changes in leg strength, fatigue, and endurance. It is crucial to understand how the training impacts the brain, and particularly the cerebellum, in order to determine the most effective training regimen.

To examine the impact of aerobic exercise on the brain, we propose using eyeblink conditioning, a form of motor learning that is dependent on the cerebellum. We will utilize BlinkLab, a newly developed smartphone application, that overcomes the typical barriers of testing eyeblink conditioning by allowing in-home assessments without the need for expensive equipment. We hypothesize that: 1) individuals with spinocerebellar ataxia will have impaired eyeblink conditioning, and 2) aerobic exercise, but not balance training, will improve eyeblink conditioning in this population. If these hypotheses are found to be true, it would further support that aerobic exercise is able to enhance motor learning in individuals with cerebellar damage.

In AIM 1, we will test eyeblink conditioning in individuals with ataxias and follow them over time to see if eyeblink conditioning might be a biomarker for cerebellar ataxia disease progression. We will then use these preliminary results to devise a larger study to further validate eyeblink conditioning as a biomarker for ataxia disease progression. In AIM 2, we will determine the impact of training on eyeblink conditioning. We expect that aerobic training, but not balance training, will enhance eyeblink conditioning in spinocerebellar ataxia. Finally, in AIM 3, we will explore the use of eyeblink conditioning as a biomarker of neuroplasticity.

Spinocerebellar ataxias are a group of disorders that cause severe disability due to progressive incoordination. With no FDA approved medications, there is a critical need to find effective treatments.1,2 Our research team has shown that high intensity aerobic training, defined as 30-minute training sessions, 5x per week at above 80% maximum heart rate, is a potential treatment, causing clinically significant improvements in ataxia symptoms at 6-months compared to home balance training.3-5 However, it is unclear whether aerobic training induces neuroplastic changes within the damaged cerebellum, or if improvements are primarily due to increased leg strength and endurance which help compensate for ataxia and balance deficits.6 We hypothesize that aerobic training causes improvements for people with spinocerebellar ataxias by inducing neuroplastic changes within the cerebellum whereas balance training does not. Our hypothesis is supported by: 1) Research that balance training in individuals with spinocerebellar ataxia causes increased grey matter volume in the premotor cortex, but no statistically significant changes in the cerebellum.7 2) Although not verified in humans, aerobic exercise rescues motor coordination deficits in ataxic mice and improvements correlate with restored cerebellar BDNF levels.8 3) TrkB, the BDNF receptor, was vital for improved motor function and reduced Purkinje cell degeneration seen in ataxic rats that performed endurance exercise.9 Thus, we propose that aerobic training increases cerebellar BDNF levels which enhances responsivity to neurotransmitters and downregulates GABA-inhibition.10-14 This response, in turn, leads to a fertile environment in the cerebellum with one consequence being improved motor learning.15,16 In order to investigate the impact of aerobic training on cerebellar dependent motor learning, we propose using eyeblink conditioning. In this task, individuals learn to blink in response to a conditioned stimulus that is paired with an unconditioned stimulus. Unfortunately, eyeblink conditioning is costly, requires multiple in-person visits to measure learning, and produces data that necessitates extensive programing and data management skills to interpret. To overcome these barriers, our collaborators recently developed BlinkLab, an application for the smartphone that can test eyeblink conditioning remotely. This application is low cost, straight-forward for participants to use at home, and produces easily interpretable data. Moreover, our research team has shown that BlinkLab can be used to determine changes in eyeblink conditioning due to aerobic training in healthy individuals. Thus, the goal of this pilot study will be to use the BlinkLab application to study the impact of exercise on eyeblink conditioning serving as a proxy for neuroplastic changes within the cerebellum.

Aim 1) To determine if eyeblink conditioning is a useful biomarker for spinocerebellar ataxias. Our preliminary work with BlinkLab indicates that individuals with ataxia have deficits in eyeblink conditioning compared to healthy controls. We will recruit 40 individuals with spinocerebellar ataxia and compare changes in ataxia symptoms to changes in eyeblink conditioning over 6-months. We hypothesize that eyeblink conditioning will worsen as disease progresses.

Aim 2) Impact of aerobic exercise on eyeblink conditioning in spinocerebellar ataxias. Thirty individuals with spinocerebellar ataxias will be randomized to either home balance or aerobic training for 3-months. Participants will undergo eyeblink conditioning using BlinkLab at baseline, 3- and 4-months. Secondary outcome measures will include ataxia severity, leg strength, endurance, fitness, balance, and abilities to do activities of daily living. We hypothesize that individuals in the aerobic group will have improved eyeblink conditioning compared to the balance training group. Furthermore, we expect that improvements in ataxia symptoms will correlate with improvements in eyeblink conditioning.

Exploratory Aim 3) Correlation of eyeblink conditioning changes induced by aerobic training with functional connectivity changes in the cerebellum. Resting state fMRI scans will be taken before and after individuals with spinocerebellar ataxia participate in the 3-month training programs in Aim 2. We will then use the cerebellum as our region of interest to analyze how training impacts functional cerebellar connections.17-22 We will explore the relationship between eyeblink conditioning and functional cerebellar changes caused by training to assess the use of eyeblink conditioning as a biomarker of neuroplasticity.

Eligibility Criteria:
Inclusion Criteria:

* Diagnosed with spinocerebellar ataxia
* Cerebellar atrophy on MRI
* Prevalence of ataxia on clinical exam (SARA \>2)\*
* Ability to safely ride a stationary exercise bike (SARA sitting sub-score \<3)

Exclusion Criteria:

* Parkinson's Disease
* Traumatic Brain Injury
* Stroke
* Alzheimer's Disease
* Heart disease
* Dementia
* Medical instability
* Inability to walk without assistance (SARA gait sub-score \>6).

  * Individuals with SARA \<3 (pre-symptomatic) are eligible to participate in AIM 1 of this study (home eyeblink conditioning only), but not AIM 2 and 3 (exercise study). Please inquire if you fall into this category.