Functional and Structural Imaging and Motor Control in Spinocerebellar Ataxia

Thirty individuals who have been diagnosed with either Spinocerebellar Ataxia - 1 (SCA1),
Spinocerebellar Ataxia - 3 (SCA3), or Spinocerebellar Ataxia - 6 (SCA6) will be recruited for
this study. Participants will be randomly assigned to a best medical management (BMM /
control) group and an error-reduction group. All participants will visit the lab twice for
testing one month apart. Participants in the control group will not train between the pre-
and post-test time.

The error-reduction intervention will be a 4-week home-based program. Investigators will use
a novel, custom designed computer interface. Participants will perform goal-directed
movements with each leg to targets in a 3D virtual environment designed to emphasize accurate
movements. The goal-directed leg movements (similar to leg press) will be performed seated
and require hip, knee, and ankle joint control. Leg movement will be detected using the
LeapMotion sensor (Leap Motion Inc. San Francisco, CA), a device that supports hand, and
finger / tool motions as input, similar to a mouse, but requiring no contact. Spatial
endpoint errors will be quantified in 3D space by comparing the endpoint location of the foot
trajectory (extending from the big toe) and the virtual location of the target. Time endpoint
errors will be quantified by comparing the timing of the foot trajectory and the required
time to target.

The length of the intervention will be 4 weeks. Each participant will train 4 days a week for
~1 hour per day. Within a week the task difficulty will increase by changing the presentation
of the target from a predictable to an unpredictable location, by increasing movement speed
requirements and by changing target size. Targets will be made predictable by identifying
them prior to the cue for movement onset (target turning green). Specifically, there will be
a flashing dotted line around the target prior to the target turning green. Targets will be
made unpredictable by not providing any indication of the target location prior to the target
turning green. Movement speed will be quantified from the voluntary movement onset of the leg
(no reaction time) to the movement end.The movement speed requirements will be increased
within a week and participants will learn to execute faster movements from the feedback after
each trial. The size of the target will be progressively reduced during the 4 weeks.

All individuals in the study will receive a pre- and post-test assessment using the
International Cooperative Ataxia Rating Scale (ICARS) and the Scale for the Assessment and
Rating of Ataxia (SARA). The individual sections of the ICARS (e.g. Kinetic section) and SARA
will be quantified.

In addition, leg dysmetria will be quantified using a custom-made goal-directed movement
protocol. Specifically, participants will perform unloaded ankle dorsiflexion movements and
attempt to reach a space-time target. The primary outcomes will be position and time errors.

Biomechanics of overground walking in SCA will be monitored using the APDM mobility lab
(APDM, Inc. Mobility Lab, Oregon, USA). Participants will wear APDM's wireless sensors on the
hands, legs, trunk and forehead and walk overground a distance of 7 meters for 2 minutes.
APDM quantifies 80 common biomechanical outcomes of gait (e.g. stride length variability).

The neurophysiology of SCA will be quantified with functional Magnetic Resonance Imaging
(fMRI) and motor unit pool activity. Brain activity will be quantified with task-based fMRI
using a 32-channel head coil. During fMRI force tasks, ankle dorsiflexion will be measured
from the most affected lower limb using customized fiber optic sensors, as has been done in
the past. Real-time feedback of force performance will be provided to the subject. During the
rest blocks, subjects will fixate on a stationary target but do not produce force. During
task blocks, subjects will complete 2 second pulse-hold contractions to 15% maximum voluntary
contraction(MVC) of ankle dorsiflexion followed by 1 second of rest. There will be 10 pulses
per block. The knee will be supported by a pillow to flex the knee so that the forces applied
by the ankle do not cause head movement.

Inclusion Criteria:

- DNA diagnosis of SCA1, SCA3, or SCA6

- phenotype consistent with the DNA diagnosis

- ability to walk 7 meters

- the age of 21-85 years

- capable of providing informed consent and complying with the trial procedures

Exclusion Criteria:

- Known recessive, X-linked or mitochondrial ataxias or any other type of ataxia

- Concomitant disorder(s) that affect ataxia measures used in this study

- Cognitive status on the Montreal Cognitive Assessment < 24

- Patients who have any type of implanted electrical device (such as a cardiac pacemaker
or a neurostimulator), or a certain type of metallic clip in their body (i.e., an
aneurysm clip in the brain), and are not eligible for participation in the MRI portion
of the study

- Individuals who are claustrophobic

- Women who are or might be pregnant and nursing mothers

- Individuals with psychiatric disorders or dementia, along with other neurological and
orthopedic problems that impair hand movements and walking