Dopamine and Motor Learning in Cerebral Palsy

Background:

Cerebral palsy (CP) is the most common childhood motor disability. The neurotransmitter dopamine (DA) is important in cognition and emotions/behavior. DA may also be important in motor skill learning. Genes that relate to DA function may affect a person s ability to learn new cognitive or motor skills. Some children with CP can learn motor skills easily while others have trouble. Researchers want to find out if DA gene variations cause some of this variability.

Objectives:

To learn more about how DA and its related genes affect motor and cognitive learning in people with and without CP.

Eligibility:

People ages 5 25 with and without CP who can:

Follow the protocol

Attend and perform the training sessions

Design:

Participants will be screened with:

Medical history

Physical exam

Blood draw for genetic tests

The study has 2 parts. Participants with CP can join both. Those without can join only Part 1.

All participants will have a baseline assessment: short motor skills test and blood draw.

Part 1:

Two 10-session training programs over 2 weeks. Cognitive training will be 2 sessions at the clinic, 8 at home. Participants will perform memory tasks on a computer. All 10 motor training sessions are at the clinic. Participants will step on lines in a virtual reality environment.

Part 2:

Two lab training sessions at least 1 week apart. Participants will perform tasks on a

computer.

Participants with CP may have a brain MRI at 1 visit. They will lie on a table that slides into a machine that takes pictures. They will be in the scanner about 45 minutes. They may have a

Study Overview

• Status: Recruiting
• Conditions: Cerebral Palsy

Detailed Description

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 those with and without CP, to preliminarily assess how behavioral manipulations of the DA system may affect learning.

Study Population: A maximum of 120 ambulatory children and young adults 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 and controls 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.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Mayra J Medrano; Phone Number: (301) 451-7529; Email: mayra.medrano@nih.gov
• Study Contact Backup: Name: Diane L Damiano, Ph.D.; Phone Number: (301) 451-7544; Email: damianod@cc.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY8664111010 800-411-1222; Email: prpl@cc.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 25 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

A maximum of 120 ambulatory children and young adults with and without CP (ages 5-25 inclusive) will be enrolled in this protocol.

Description

• 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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Cerebral Palsy; Children and young adults with Cerebral Palsy.
Healthy Volunteer; Children and young adults healthy volunteer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Learning (specific measures vary by task)	There will be two tasks : 1 a motor task which involves walking across a horizontal ladder. 2. Computer base tasks targeting working memory and procedural learning	measure of learning of each training task across the entire training period
Genetic testing (for dopamine and activity-related genes)	COMT, BDNF, DAT, and DRD1, DRD2, DRD3	genetic analyses of individual variations

Collaborators and Investigators

• Sponsor: National Institutes of Health Clinical Center (CC)
• Investigators: Principal Investigator: Diane L Damiano, Ph.D., National Institutes of Health Clinical Center (CC)

Publications and helpful links

General Publications

• Qian Y, Chen M, Forssberg H, Diaz Heijtz R. Genetic variation in dopamine-related gene expression influences motor skill learning in mice. Genes Brain Behav. 2013 Aug;12(6):604-14. doi: 10.1111/gbb.12062. Epub 2013 Jul 17.
• Pearson-Fuhrhop KM, Minton B, Acevedo D, Shahbaba B, Cramer SC. Genetic variation in the human brain dopamine system influences motor learning and its modulation by L-Dopa. PLoS One. 2013 Apr 17;8(4):e61197. doi: 10.1371/journal.pone.0061197. Print 2013.
• Molina-Luna K, Pekanovic A, Rohrich S, Hertler B, Schubring-Giese M, Rioult-Pedotti MS, Luft AR. Dopamine in motor cortex is necessary for skill learning and synaptic plasticity. PLoS One. 2009 Sep 17;4(9):e7082. doi: 10.1371/journal.pone.0007082.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2017
• Primary Completion (Estimated): May 22, 2025
• Study Completion (Estimated): May 22, 2025

Study Registration Dates

• First Submitted: July 19, 2016
• First Submitted That Met QC Criteria: July 20, 2016
• First Posted (Estimated): July 21, 2016

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 28, 2024

More Information

Terms related to this study

• Keywords: Children; Natural History; Adult; Brain Imaging; DNA Testing
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Damage, Chronic; Cerebral Palsy
• Other Study ID Numbers: 160149; 16-CC-0149

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No