Impact of Exercise on Eyeblink Conditioning in Spinocerebellar Ataxias

Study Overview
=================
Brief Summary
-----------------
The goal of this project is to evaluate how aerobic training impacts eyeblink conditioning as a proxy for cerebellar dependent motor learning. The newly developed smartphone application, iBlink, will be used to test participants at home in an effort to improve recruitment and increase the sample size of the study. The investigators hypothesize that aerobic training, but not balance training, will improve eyeblink conditioning in participants with spinocerebellar ataxias. The current study focuses on Aim 3 of this project.

Detailed Description
-----------------
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. The 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. However, it is unclear whether aerobic training induces neuroplastic changes within the damaged cerebellum to enhance motor learning, or if improvements are primarily due to increased leg strength and endurance which help compensate for balance deficits. In order to investigate the impact of aerobic training on cerebellar-dependent motor learning, the research team proposes using eyeblink conditioning. In this paradigm, an unconditioned stimulus, such as a flash of light, is used to elicit a reflexive blink. When a neutral conditioned stimulus, such as a tone is paired repeatedly with the flash of light, individuals learn to blink their eyes in response to the tone (conditioned response). The magnitude of learning is gauged by the percentage of trials that result in a conditioned response or the mean change in conditioned response amplitude. Unfortunately, eyeblink conditioning is not often utilized in clinical studies due to the high cost, extensive programing and data management skills needed to interpret data, and the need for multiple in-person visits to ascertain the magnitude of learning. In an effort to overcome these barriers, the research team's collaborators recently developed iBlink, 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, the research team has shown that iBlink 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 iBlink application to study the impact of exercise on eyeblink conditioning as a proxy for motor learning in spinocerebellar ataxias. Aim 1) To determine if individuals with spinocerebellar ataxias have deficits in eyeblink conditioning using iBlink. Prior studies indicate that individuals with spinocerebellar ataxia 3, 6, and Fredrich's ataxia have impaired eyeblink conditioning, but it is unclear whether this is true for other ataxia types. Thus, the investigators will recruit individuals with a variety of spinocerebellar ataxia types and compare eyeblink conditioning to age and sex-matched healthy controls (baseline condition). The investigators hypothesize that all participants with spinocerebellar ataxia will have impaired eyeblink conditioning compared to healthy controls, but participants with spinocerebellar ataxia types that cause oculomotor deficits will have more impairment than individuals with other ataxia types. Aim 2) Impact of acute aerobic exercise on eyeblink conditioning in spinocerebellar ataxias. Acute aerobic exercise enhances the conditioned response rate in healthy individuals, and this enhancement is larger in physically active individuals when compared to sedentary people. For this study, participants with spinocerebellar ataxia will be classified as sedentary or physically active using the Global Physical Activity Questionnaire. Next, participants will be asked to perform 30-minutes of acute aerobic training at moderate intensity ( 75% max heart rate) for 5 consecutive days. Immediately after each training, participants will use iBlink and results will be compared to baseline condition (Aim 1). The investigators hypothesize that all participants with ataxia will have improvement in eyeblink conditioning (increased mean change in conditioned response amplitude) after acute aerobic training, but those who are more physically active will have more enhancement with exercise. Aim 3) Impact of long-term aerobic exercise on eyeblink conditioning in spinocerebellar ataxias. Participants will be randomized to either home balance or aerobic training for 6-months. Participants will undergo eyeblink conditioning using iBlink at baseline, 3-, 6-, and 9-months. Ataxia symptoms will also be determined using the remote video Scale for the Assessment and Rating of Ataxia (SARAhome) at each assessment. The investigators hypothesize that individuals in the aerobic group will have improved eyeblink conditioning compared to the balance training group. Furthermore, the investigators expect that improvements in SARA scores will correlate with improvements in eyeblink conditioning, supporting that the aerobic training is inducing neuroplastic changes within the cerebellum. Clinical Significance: Aerobic training demonstrates promise as a treatment for spinocerebellar ataxias, but the mechanism of improvement is unclear. This study addresses if aerobic training can enhance motor learning in individuals with cerebellar degeneration. It will also help validate the use of the iBlink application as an easy, inexpensive, and remote way to test eyeblink conditioning. Thus, eyeblink conditioning can be more readily used to monitor spinocerebellar ataxias or be used as an outcome measure in future clinical studies.

Official Title
-----------------
Use of a New Smartphone Application, iBlink, to Determine Changes in Eyeblink Conditioning From Home Training in Individuals With Spinocerebellar Ataxias

Conditions
-----------------
Spinocerebellar Ataxias

Intervention / Treatment
-----------------
* Behavioral: Aerobic Training
* Behavioral: Balance Training


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosed with spinocerebellar ataxia Cerebellar atrophy on MRI Prevalence of ataxia on clinical exam Ability to safely ride a stationary exercise bike Exclusion Criteria: Other neurologic conditions Heart disease Cognitive impairment Medical instability

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single blinded randomized controlled trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Balance Training<br>A physical therapist will tailor a home balance training program for each participant based on pre- training capabilities. Participants will be asked to perform exercises five times a week for thirty-minute sessions. Both dynamic and static exercises will be performed in sitting and standing positions. Exercises will start with stabilizing in a challenging static position and progress to dynamic arm and leg movements in the same or modified position. Participants will be contacted weekly by e-mail or phone to answer any questions about the exercise protocol and will be required to log their exercise effort in terms of frequency and level of balance challenge. | Behavioral: Balance Training<br>* Training 5x a week for 30 minutes. Standard of care.<br>|
| Experimental: Aerobic Training<br>Participants will be given a stationary exercise bike for home use. They will be instructed to use the exercise bike five times a week for thirty-minute sessions. The exercise intensity prescription will be based on the subject's VO2max determined on pre-test day. The exercise program will start at 60% of intensity per session, and then will be increased by steps of 5% intensity every 2 sessions until participants reach 30 minutes of training at 80% intensity. Participants will be contacted weekly by e-mail or phone to answer any questions about the exercise protocol and will be instructed to log each training session. Participants will record duration of exercise, perceived exertion, average heart rate, maximum heart rate, and distance. | Behavioral: Aerobic Training<br>* Aerobic training on stationary bike 5x a week for 30 minutes a day<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Conditioned Response (CR) Amplitude | Individual eyelid traces will be normalized by dividing each trace by the maximum signal amplitude of the relevant session. Thus, eyes closed will correspond to a value of 1, and eyes open to a value of 0. A mean baseline Conditioned Response (CR) amplitude will be determined for each participant using the pre-block Conditioned Stimulus (CS) only trials. CR amplitude will then be determined as the maximum signal amplitude value at 430ms, for paired and CS only trials, minus the baseline CR amplitude. | 0, 3, 6, and 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SARAhome Score | Scale for the Assessment and Rating of Ataxia Home (SARAhome) is a validated home measurement of ataxia symptoms with the participants recording 5 tasks (gait, stance, speech, nose-finger test, and fast alternating hand movements) with a smartphone. Scores range from 0 to 28 with higher scores indicating more ataxia symptoms. SARAhome and the conventional SARA were shown to be highly correlated, and this measurement was deemed reliable for home monitoring of ataxia symptoms. Scores will be used to correlate with changes in eyeblink conditioning as a result of training. | 0, 3, 6, and 9 months | 
| PROM of Ataxia Score | The Patient Reported Outcome Measure (PROM) of Ataxia is a 70-item survey that is scored by participants on a 0-4 Likert scale. It asks participants to rate motor domains of gait, lower and upper extremity control, manual dexterity, visual motor control, dysphagia, bowel and bladder function, sleep, fatigue, vertigo, libido, neuropathy, ability to do household chores, driving, self-care, mood, anxiety, motivation, and social interactions. Scores will be used to correlate with changes in eyeblink conditioning as a result of training. Scores range from 0-280 with a higher score indicating a worse outcome. | 0, 3, 6, and 9 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ataxia, Eyeblink Conditioning, Exercise