Dopamine and Motor Learning in Cerebral Palsy

Objective

The broad objective of this study is to determine the relationship between variations in
genes related to dopamine (DA) neurotransmission in areas of the brain associated with motor
leaning (e.g. DRD1, DRD2, DRD3, COMT, DAT) and/or to activity-dependent brain plasticity
(e.g. BDNF) and differences in motor learning rates and cognitive processing abilities in
persons with and without cerebral palsy (CP). We hypothesize that individual genetic
differences will be related to the ability to learn new motor and cognitive skills and may
thus provide a potential explanation for the often reported response variability to
rehabilitative therapies seen in CP. We will also explore whether motor and cognitive
learning abilities are correlated within individuals which could suggest similar underlying
neural mechanisms. Finally we would like to evaluate the effect of rewards on procedural
learning in CP, to preliminarily assess how behavioral manipulations of the DA system may
affect learning across individuals.

Study Population: A maximum of 100 ambulatory children and young adults including pregnant
women with and without CP (ages 5-25 inclusive) will be enrolled in this protocol.

Design: This protocol will consist of two separate but related studies: Study #1 is an
observational trial whereby subjects with and without CP will participate in two different
training paradigms, 10 sessions each, one that involves learning novel working memory tasks
and one that involves motor skill learning in the lower extremities, adapted from the
horizontal ladder task utilized in rodent studies. All will have blood draws for genetic
analyses at baseline, the results of which will be related to changes in performance
(learning) per task after training.

Study #2 will be a within-subjects evaluation in CP only on the effects of reward (versus
no-reward) during learning, which is presumed to increase dopamine transmission. Mean and
individual responses to reward-based learning will be assessed and related to genetic
variations in dopamine transmission.

For subjects with CP, we would like to obtain brain MRI but this is optional and if they are
unable or unwilling to do this portion, they can still participate in this protocol.

Outcome Measures: Primary outcomes are changes in performance (learning) on each task after
training which will be related to presence or absence of polymorphisms that have been
associated with brain plasticity or with deficits in working memory and/or motor learning.
Individual responses to rewards will also be related to variations related to high versus low
dopamine transmission in the brain.

- INCLUSION CRITERIA:

For all subjects:

1. Ages 5-25 inclusive

2. Able to follow the study protocol

3. Able to attend or perform the training sessions as scheduled

Additional criteria for subjects with CP:

1. Diagnosis of cerebral palsy

2. Gross Motor Functional Classification Scale Level I-II (able to walk at least 10
meters without an assistive device)

EXCLUSION CRITERIA:

For all subjects:

1. Presence of an injury or other medical condition (besides CP) that would affect motor
function or the ability to perform the motor training program.

Additional criteria for subjects with CP:

1. Less than 6 months after major surgery to their legs

2. Currently taking levodopa, trihexyphenidyl, methylphenidate or baclofen since these
may affect dopamine transmission or neuroplasticity.

Additional criteria for those with CP who choose to have an MRI:

1. Have any of the following contraindications to having an MRI scan:

1. Pregnancy

2. A ventriculo-peritoneal shunt

3. Have claustrophobia and not comfortable in small enclosed spaces

4. Have metal that would make an MRI scan unsafe such as: cardiac pacemaker, insulin
infusion pump, implanted drug infusion devise, cochlear or ear implant, transdermal
medication patch (nitroglycerine), any metallic implants or objects, body piercing
that cannot be removed, bone or joint pin, screw, nail, plate, wire sutures or
surgical staples, shunts, cerebral aneurysms clips, shrapnel or other metal embedded
(such as from war wounds or accidents or previous work in metal fields or machines
that may have left any metallic fragments in or near your eyes).

5. Excessive startle reaction to or fear of loud noises