The Effect of Dopamine on Motor Skills Training
Condition: Cerebrovascular Accident
MeSH terms: Stroke
Study type: Observational

Summary: 
      This study will examine how dopamine, a brain chemical, affects motor training. Taken by
      mouth, dopamine can enhance motor training, especially during rehabilitation after brain
      damage. The study will also examine whether Sinemet, a drug containing a precursor of
      dopamine, can improve motor training.

      Healthy normal volunteers and stroke patients between 18 and 80 years of age may be eligible
      for this study. Healthy volunteers must be right-handed. Stroke patients must have had a
      stroke that caused weakness in one hand, from which they have recovered enough to be able to
      move the thumb in different directions. Participants will have up to three study sessions, as
      follows:

      Prestudy 1 (MRI, TMS with motor training)

        -  Session 1: Magnetic resonance imaging (MRI) of the brain. This procedure uses a strong
           magnetic field and radio waves to show structural and chemical changes in tissues.
           During the scan, the patient lies on a table in a narrow cylinder containing a magnetic
           field. He or she can communicate with the staff administering the test at all times.

        -  Session 2: Transcranial magnetic stimulation (TMS) - The subject sits in a comfortable
           chair with the right forearm held still at the side and the head held still by an
           aluminum frame. A magnetic coil is placed over the head, and a small probe is attached
           to the thumb to measure thumb movement. Magnetic pulses are occasionally delivered over
           the scalp, likely inducing a mild thumb movement. After this test, the subject takes a
           tablet of either Sinemet or placebo (a look-alike pill with no active ingredient). Fifty
           minutes after taking the pill, the subject undergoes motor training that involves
           performing brisk thumb movements at a rate of 1 movement per second. At the end of the
           training, TMS is repeated.

        -  Session 3: Identical to session 2, except subjects who took Sinemet in session 2 now
           take placebo, and vice versa.

      Prestudy 2 (MRI, PET without motor training, no TMS)

        -  Session 1: MRI of the brain if the subject has not had one within the last 12 months.

        -  Session 2: Positron emission tomography (PET) scanning - This procedure provides
           information on brain chemistry and function. First, the subject is given either Sinemet
           or placebo. The subject lies on a bed in a doughnut-shaped machine with a custom-molded
           plastic mask placed over the face and head to support the head and hold it still during
           the scanning. A catheter (plastic tube) is placed in each arm-one to inject
           [11C]raclopride-a radioactive substance that competes with dopamine for binding in
           certain parts of the brain and can be detected by the PET scanner-and one to draw blood
           samples for measuring the level of Sinemet in the blood.

        -  Session 3: Identical to session 2, except subjects who took Sinemet in session 2 now
           take placebo, and vice versa.

      Main Study (MRI, TMS, PET with motor training)

        -  Session 1: MRI of the brain, if one has not been done within the last 12 months.

        -  Session 2: TMS, followed by administration of Sinemet or placebo and PET scanning with
           motor training. The subject lies quietly during the first half of the PET session and
           performs brisk thumb movements during the second half. After completing the PET scan,
           the subject undergoes TMS again.

        -  Session 3: Identical to session 2, except subjects who took Sinemet in session 2 now
           take placebo, and vice versa.
    

Detailed description: 
      It has been proposed that the nigrostriatal and cortical dopaminergic systems are involved in
      motor learning in health and disease. However, it is not known to which extent dopamine
      influences use-dependent plasticity (UDP), one of the crucial functions that mediate recovery
      of motor function after stroke. Understanding the role of dopamine on UDP in healthy
      volunteers and patients with stroke may impact the development of rationale strategies to
      promote functional recovery after this condition.

      The aim of the present protocol is to provide evidence for the influence of dopaminergic
      function on UDP in health and disease. We plan to address this issue in two different,
      complementary ways (main experiment): (a) determine if UDP is positively correlated with the
      decrease in raclopride binding potential (RAC-BP) in the contralateral dorsal striatum
      (primary outcome measure), and (b) determine if administration of a dopaminergic drug will
      enhance UDP and elicit a decrease in RAC-BP in the contralateral dorsal striatum.

      Before the main experiment, we will assess the ability of a dopaminergic drug to enhance UDP
      (prestudy 1, motor training only), and the effects of a dopaminergic drug on RAC-BP during
      resting condition (prestudy 2, RAC-PET during resting condition only).

      UDP will be assessed using a technique developed in our lab, in which we have extensive
      experience. In short, we will evaluate TMS-evoked thumb movement directions after a period of
      motor training consisting of performance of voluntary thumb movements for 30 minutes.
      Striatal and cortical dopamine release will be assessed with positron emission tomography
      using the dopamine-D2 receptor radioligand [(11)C]raclopride, after administration of
      placebo, and after administration of a dopaminergic drug. The study will be initially done in
      a group of healthy volunteers and then in a group of patients with chronic subcortical stroke
      who experienced good motor recovery.
    

Keywords: Stroke; Motor Training; Positron Emission Tomograhy; Plasticity; Transcranial Magnetic Stimulation; Healthy Volunteer; HV