Neurobiological Principles Applied to the Rehabilitation of Stroke Patients

• Specific Aim 1: Increases of noradrenergic, dopaminergic and serotonergic transmission will enhance use-dependent plasticity in intact M1. [ Time Frame: Study Completion ] [ Designated as safety issue: No ]
• Specific Aim 2: M1 Stimulation is most effective in increasing use-dependent plasticity when the stimulus occurs within 50 ms of M1 pyramidal tract neuron discharge with 0.1 to 0.3 Hx frequency (reminiscent of settings used for Hebbian-type stimulation). [ Time Frame: Study Completion ] [ Designated as safety issue: No ]
• Specific Aim 3: Hebbian-type stimulation of M1 and increase of monoaminergic transmission facilitates training induced changes of motor representation in the lesioned hemisphere of patients post-stroke. [ Time Frame: Study Completion ] [ Designated as safety issue: No ]

Enhance motor cortex reorganization with noradrenergic drugs and non-invasive repetitive transcranial magnetic stimulation.

Previous studies have shown, that when patients learn a new motor movement, it may cause a change in the way the nerves act in the area of the brain that controls movement. This change is called use-dependent plasticity. The ability of that part of the brain, called the motor cortex (M1), to reorganize plays a major role in the recovery of motor deficits post-stroke; hence the importance for further development of rehabilitative strategies that utilize this potential for recovery. In this proposed study we will further examine influences of use-dependent plasticity in the non-injured M1 of healthy subjects and injured M1 of stroke subjects using a combination of non-invasive cortical stimulation, medication, and exercise techniques. In Specific Aim 1, we will test the effect of drugs that interact specifically with different neurotransmitter systems on use-dependent plasticity in intact M1 of healthy humans. In Specific Aim 2, we will identify the parameters for non-invasive TMS stimulation of M1 that are most effective to enhance use-dependent plasticity in intact healthy human M1. Specific Aim 3 will assess the efficacy of plasticity enhancing methods developed in non-injured M1 healthy subjects (Specific Aims 1 & 2) in injured M1 of stroke patients. Our proposal links science to neurorehabilitation practice in stroke patients by applying principles known to enhance practice dependent plasticity in intact human M1 to injured M1 of stroke patients to enhance motor recovery. These newly designed rehabilitation strategies could potentially reduce the morbidity and disability of stroke and, thus, reduce dramatically the costs for long-term ambulatory and nursing home care. The positive impact on the field of neurorehabilitation will be considerable.

• Drug: Sinemet, ritalin, amphetamine, and placebo

  Each subject will take a single dose of the following during Transcranial Magnetic Stimulation sessions:

  Ritalin: 40 mg dose taken 2 hours prior to the baseline measurement. Sinemet: 25/100 mg dose taken 1 hour prior to the baseline measurement. Amphetamine: 10 mg dose taken 2 hours prior to the baseline measurement. Placebo: 1 pill taken 2 hours prior to the baseline measurement.

• Device: Transcranial magnetic stimulation (TMS)
  Subjects will be scheduled for six different sessions using TMS. Applications will include five different stimulation settings and one at no stimulation setting.
• Other: Combined drug treatment and TMS
  Data analysis from the healthy adult subjects participating in Specific Aims 1 and 2 will provide the drug/TMS settings to be used in Specific Aim 3 (Stroke subjects)

• Experimental: Specific Aim 1
  Healthy adult female and male subjects, aged 55 to 80 years of age with no previous history of neurological or psychiatric diseases.
  Intervention: Drug: Sinemet, ritalin, amphetamine, and placebo
• Experimental: Specific Aim 2
  Healthy adult female and male subjects, aged 55 to 80 years with no previous history of neurological or psychiatric diseases.
  Intervention: Device: Transcranial magnetic stimulation (TMS)
• Experimental: Specific Aim 3
  Female and male subjects, aged 55 to 80 years of age with cerebral ischemic infarction more than 12 months prior to entering into the study.
  Intervention: Other: Combined drug treatment and TMS

For Specific Aims 1 and 2

Inclusion Criteria:

• Aged 55 to 80 years
• Normal neurological examination
• Ability to meet criteria of inclusion experiment
• Ability to give informed consent.

Exclusion Criteria:

• History or neurological or psychiatric disease
• Abnormal MRI of brain
• Abnormal neuropsychological testing
• Intake of CNS active drugs
• History of seizure disorder
• History of migraine headaches
• History of anaphylaxis or allergic reactions
• Contraindication to TMS

Specific Aim 3:

Inclusion Criteria:

• Aged 55 to 80 years
• Cerebral ischemic infarction more than 12 months prior to entering the study
• Single lesion as defined by MRI of the brain affecting the primary motor output system of the hand at a cortical (M1) level
• Dense paresis of the hand for more than three days after cerebral infarction
• Good functional recovery of hand function as defined by the ability to perform selective movements of the finger at the time of the study
• Ability to meet criteria of inclusion experiment
• Ability to give informed consent.

Exclusion Criteria:

• History or neurological or psychiatric disease, including bipolar disorder
• Intake of CNS active drugs
• History of seizure disorder
• History of migraine headaches
• History of anaphylaxis or allergic reactions
• Contraindication to TMS

• National Institutes of Health (NIH)
• National Institute of Neurological Disorders and Stroke (NINDS)