NMDA Receptors in Motor Learning in Humans

Disability after a stroke is common, leaving 65% of patients unable to use their affected hand in daily activities after 6 months. Frequently, these limitations can cause a decreased quality of life. The current standard for intense physical therapy most commonly consists of neurofacilitation techniques and/or task-specific training. Labor-intensive and costly therapy methods are critical barriers to achieving optimal functional outcomes in stroke survivors with motor impairments. Thus, there is a great need to find new ways to enhance the effectiveness of upper limb rehabilitation in patients following stroke.

A promising approach to improving upper extremity motor function utilizing repetitive task practice (RTP) and behavioral shaping along with constraint of the less affected limb is constraint-induced movement therapy (CIMT). Two fundamental limitations of CIMT are the time necessary to deliver and oversee training and the excessive time in which the less affected limb must be constrained. RTP, in the context of CIMT appears to be effective in improving upper extremity motor function of patients with stroke. Alternative approaches such as robotic assisted therapy have been investigated. Recent evidence suggests that improvements in upper-extremity motor function, functional performance in daily tasks and quality of life are seen during a robotic-assisted physical therapy regimen.

Activation of N-methyl-D-aspartate (NMDA) receptors is important for inducing various forms of synaptic plasticity. Application of D-cycloserine (a antibiotic for treating tuberculosis) can enhance certain models of plasticity, such as long-term potentiation. Pharmacologic strategies that enhance NMDA neurotransmission and working memory represent a promising adjuvant therapy in motor rehabilitation of patients after stroke.

The researchers for this study have brought these observations together to generate a working hypothesis that D-cycloserine will enhance certain features of motor learning, information processing speed, episodic and working memory and that this effect can be coupled with physical therapy to facilitate retraining of patients to use impaired limbs to a greater extent and faster than they otherwise might be able to do. The researchers specifically hypothesize that motor (re)learning and cognition can be improved in people with post-stroke hemiparesis by increasing the excitability and synaptic activity of the motor cortex by combining D-cycloserine and robotic-assisted physical therapy.

The purpose of this study is to understand the important factors in rehabilitation therapy that help improve arm function after stroke. This information may help to ultimately reduce disability and improve quality of life in patients with stroke.

Inclusion criteria

• between the ages of 18 and 95 years
• of either sex
• of diverse ethnic background
• have experienced a single unilateral hemispheric or brainstem stroke 3 or more months prior
• if have experienced more than one stroke, will be accepted only if all strokes are on the same side of the brain, there is no history of a clinical ischemic or hemorrhagic event affecting the other hemisphere, and there is no CT or MRI evidence of more than one a lacune or minor ischemic demyelination affecting the other hemisphere.
• active motions of the wrist and hand: 10 of wrist extension from a relaxed flexed position; 10 of extension of any two digits at any joint, and 10 of thumb extension at either joint. All active motions must be repeated 3 times within one minute.
• passive range of motion: 90 of flexion and abduction and 45 external and internal rotation at the shoulder; 45 elbow supination and pronation; elbow extension limited by no more than 30; wrist extension to at least neutral; and digit extension limited by no more than 30.
• participants will not be required to exhibit any active shoulder or elbow motion
• ability to sit independently for at least 2 minutes
• Mini Mental Status Examination score greater than 24
• Motor Activity Log score less than 3
• Prospective participants who qualify but who have profound postural instability will undergo the intervention while walking with contact guarding or, when feasible, using their leg and more involved arm to propel a wheelchair.
• must have a score below 16 on the Center for Epidemiologic Studies Depression Scale
• must receive a score greater than 25 on the Folstein Mini Mental State Exam.

Exclusion criteria

• any history of more than minor head trauma, subarachnoid hemorrhage, dementia or any other neurodegenerative disease, multiple sclerosis, HIV infection, drug or alcohol abuse, serious medical illness, schizophrenia, major refractory depression
• insufficient cardiopulmonary function to participate in low-intensity sustained upper extremity exercise
• severe visual impairment
• pregnancy
• breast feeding
• participation in intensive physical therapy within the prior 12 months
• inability to understand the potential risks and benefits of the study, personally provide informed consent, and understand and cooperate with treatment
• participating in other upper extremity rehabilitation, clinical or experimental, during the course of this trial.
• a score of less than 24 on the Folstein Mini-Mental State Exam
• a score of less than10 on the Boston Naming Test
• a first stroke less than 3 months or more than 48 months prior to the initiation of therapeutic intervention
• less than 18 years old
• clinical judgment of excessive frailty or lack of stamina
• serious uncontrolled medical conditions
• excessive pain in any joint of the more affected extremity that could limit ability to cooperate with the intervention
• passive range of motion less than 45 degrees for: abduction, flexion or external rotation at shoulder, or pronation of forearm
• greater than 30 degrees flexion contracture at any finger joint
• unable to stand independently for 2 min., transfer independently to and from the toilet or perform sit-to-stand
• current participation in other pharmacological or physical intervention studies, or have received injections of anti-spasticity drugs into upper extremity musculature within the past 3 months, or wish to have drugs injected in the foreseeable future
• receiving any anti-spasticity drugs orally at the time of expected participation
• received phenol injections less than 12 months prior to receiving therapy
• contemplating a move from proximity to the treatment site in less than 6 months from the randomization date.