Enhancement of Post-Stroke Neural Plasticity with Atomoxetine: A Pilot Study

Lumy Sawaki, M.D., Ph.D.

University of Kentucky

Funded in June, 2006: $100000 for 2 years
LAY SUMMARY . ABSTRACT . HYPOTHESIS . SELECTED PUBLICATIONS .

LAY SUMMARY

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Pilot-Testing a Potential New Therapy for Improving Motor Rehabilitation in Stroke Patients

Investigators will undertake a small-scale pilot study of the drug atomoxetine in adults undergoing rehabilitation following a stroke.  They will use a technique called Transcranial Magnetic Stimulation (TMS) to determine whether the drug, combined with rehabilitation, shows promise in promoting cortical plasticity associated with improved motor functioning. 

The ability to regain movement following ischemic stroke (impaired blood flow to the brain) remains challenging.  The drug amphetamine showed promise for enhancing recovery by increasing levels of the neurotransmitter norepinephrine, which was associated with increased brain plasticity.  But it has cardiovascular and addictive side effects. Another drug that increases norepinephrine called atomoxetine does not appear to have these side effects. This drug has been federally approved for treating attention deficit hyperactivity disorder, and the investigators recently studied its effects in ten healthy volunteers and found that it significantly increased use-dependent plasticity in the brain.  Now the researchers will test whether physical therapy plus atomoxetine, compared to rehabilitation alone, works better to increase neorepinephrine, brain plasticity, and motor recovery, in 20 adult stroke patients.

The researchers will use TMS, a non-invasive method for mapping brain activity, to assess the extent of plasticity that occurs in the patients receiving atoxoxetine and motor therapy, compared to patients receiving physical therapy alone.  The research also should advance understanding of the potential role of norepinephrine in promoting motor recovery. If both plasticity and motor improvement are greater in the TMS group, the investigators will seek larger-scale funding from others to undertake a clinical trial.

Significance:  If atomoxetine shows preliminary evidence of enhanced promotion of brain plasticity in association with motor recovery in stroke patients, the study could lead to a large-scale trial and, potentially, improved outcomes in patients recovering from stroke.

ABSTRACT

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Enhancement of Post-Stroke Neural Plasticity with Atomoxetine: A Pilot Study

Stroke is one of the most devastating and prevalent modern diseases, but efforts to limit the amount of tissue damaged in the acute phase have been disappointing, highlighting the need for effective therapeutic interventions after neurologic damage has occurred. Recently, data from animal models and clinical trials have suggested that certain medications can up- or down-regulate plastic changes and recovery after stroke, possibly by influencing specific neurotransmitters in the brain. The most extensively studied drug in post-ischemic brain injury is amphetamine, which has produced promising results in animals and humans.

The proposed mechanism by which amphetamine enhances recovery is increased central levels of norepinephrine. While a growing body of evidence suggests that amphetamine has beneficial effects in stroke recovery, the limitations and side effects of this drug preclude its widespread use.The cardiovascular side effects and interaction of amphetamine with other drugs exclude approximately 80% of stroke patients from clinical trials of this drug. Furthermore, the addictive effects of amphetamine preclude its daily administration.

Given these limitations of amphetamine use in stroke patients, we propose in this pilot study to evaluate the efficacy of a selective inhibitor of norepinephrine reuptake, atomoxetine, known to be less toxic, more specific, and better tolerated than amphetamine. Atomoxetine is newly approved by the Food and Drug Administration for attention deficit hyperactivity disorder (ADHD), is a potent and selective inhibitor of presynaptic norepinephrine transporter and, unlike amphetamine, it has no drug abuse potential. We recently successfully completed a double-blind, randomized, placebo-controlled, cross-over study of atomoxetine in 10 healthy subjects. We found that atomoxetine significantly increased use-dependent plasticity. However, there are no available data on the effects of atomoxetine on motor learning in stroke subjects in a clinical setting.

In this pilot study, we propose to collect sufficient data to evaluate the potential of atomoxetine plus physical therapy to promote beneficial effects in 20 chronic stroke patients, compared to physical therapy alone. The results of this proposed pilot study will allow us to a) study the effects of atomoxetine in stroke patients in a clinical setting, b) provide preliminary data that would support a large clinical trial of the effects of this drug in enhancing motor recovery in acute and chronic stroke patients, and c) better understand the role of neurotransmitters underlying post-ischemic recovery of motor function.

HYPOTHESIS

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Hypothesis:
Stroke patients treated with atomoxetine paired with task-oriented therapy will have improved motor function compared to patients receiving therapy plus placebo, and the degree of this behaviorally-measured effect will correlate with the increase of training-dependent cortical plasticity measured by transcranial magnetic stimulation (TMS).

Goals:
The adult brain is capable of degrees of reorganization (known as plasticity) that were formerly thought to occur only during the early post-natal period. It is believed that these plastic changes play a crucial role in learning and memory processes as well as recovery of function after brain injury. Therefore the goals for this study are (a) up-modulate cortical plasticity, (b) maximize the restoration of hand motor function after stroke, and (b) determine the impact of this intervention in activities of daily living and quality of life.

Methods:
Stroke patients will participate in 3 assessment sessions and 10 consecutive weekdays of task-oriented therapy. Assessment sessions will consist of TMS and behavioral motor function evaluation. Patients will be randomized to atomoxetine (intervention group) or placebo (control group). TMS procedures will be performed at baseline, one day after completion of intervention, and at 1-month follow-up. The primary TMS outcome measure will be the increase of cortical motor map volume.

SELECTED PUBLICATIONS

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Foster D.J., Good D.C., Fowlkes A., and Sawaki L.  Atomoxetine enhances a short-term model of plasticity in humans.  Arch Phys Med Rehabil. 2006 Feb;87(2):216-21.

Sawaki L., Yaseen Z., Kopylev L., and Cohen L.G.  Age-dependent changes in the ability to encode a novel elementary motor memory. Ann Neurol. 2003 Apr;53(4):521-4.

Sawaki L., Werhahn K.J.,  Barco R., Kopylev L., and Cohen L.G.  Effect of an α1-adrenergic blocker on plasticity elicited by motor training. Exp Brain Res. 2003 Feb;148(4):504-8.

Donchin O., Sawaki L., Madupu G., Cohen L.G., and Shadmehr R.  Mechanisms influencing acquisition and recall of motor memories.   J Neurophysiol. 2002 Oct;88(4):2114-23.

Sawaki L., Cohen L.G.,  Classen J., Davis B.C., and Butefisch C.M.  Enhancement of use-dependent plasticity by d-amphetamine. Neurology. 2002 Oct 22; 59(8): 1262-4.