Facilitators of Stroke Recovery

Gottfried Schlaug, M.D., Ph.D.

Beth Israel Deaconess Medical Center and Harvard Medical School , Boston, MA

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

April 2002, for 3 years

Funding Amount:

$100,000

Abstract

Facilitators of Stroke Recovery

Of the 350,000 people surviving stroke each year in the United States, approximately 200,000 have persistent and disabling deficits. The mechanisms of stroke recovery are unknown and therefore poorly manipulated by existing therapeutic interventions. Modulatory therapies such as forced-use or constraint-induced therapy, pharmaco-therapy, and cell transplantation have been employed in stroke recovery over recent years; however, these therapies are commonly investigated in selected groups of chronic stroke subjects, and the appropriate timing for such interventions is largely unknown and in most cases is not based on anatomic or physiologic information.

In this proposal, we combine a brain imaging technique, functional magnetic resonance imaging (fMRI), with an electrophysiological technique, transcranial magnetic stimulation (TMS), to investigate how the anatomical and physiological processes interact following injury during the active recovery period and to determine their functional importance for recovery. This combined technology approach to stroke recovery is the most innovative aspect of this proposal, and it permits us to gather data unavailable by employing each technology alone. In the current literature, there is contradictory evidence over whether following stroke, during motor recovery, the ipsilateral, unaffected, sensorimotor cortex and its uncrossed corticospinal tract take over the role of the contralateral, affected, sensorimotor cortex and/or corticospinal tract. In two sequential experiments, we propose to use the combined fMRI and TMS approach to address this specific question and to examine other candidate regions in motor recovery following stroke.

Our specific aims are, in experiment one, to determine at clinically-defined stages of recovery a) the activation pattern of recovering movements using fMRI and correlate it to b) the integrity of ipsi- and contralateral corticospinal tracts and the measures of cortico-cortical excitability using TMS and, in experiment two, to determine whether inhibition of the ipsilateral sensorimotor cortex activation with repetitiveTMS (rTMS) temporarily affects motor performance in the recovering hand. We hypothesize that ipsilateral motor cortex, although activated on movement of the recovering hand, is non-functional and perhaps hinders recovery and that other activated cortical areas are associated with return of good hand function.

Identifying the critical areas and interactions of the motor network that enable recovery and the critical time points during which they become important, will direct the application of existing and the development of new modulatory therapies to improve outcome and reduce disabilities for stroke survivors.

Investigator Biographies

Gottfried Schlaug, M.D., Ph.D.

Assistant Professor of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School

Hypothesis

Hypothesis:
Ipsilateral primary sensorimotor cortex activation seen in movements of the recovering hand does not a) execute or b) facilitate movements of the recovered hand, but is due to loss of normal transcallosal inhibition. The emergence of activation of the remaining contralateral motor cortex and the non-primary, premotor areas facilitate the recovery process.

Goals:
1. To determine the presence and time course of ipsilateral primary and non-primary sensorimotor cortex activation during movement of the recovering hand using functional magnetic resonance imaging.
2. To determine the presence and time course of motor evoked potentials (MEPs) and TMS-derived excitability measures by stimulating ipsilateral and contralateral primary sensorimotor cortex using transcranial magnetic stimulation.
3. To determine whether temporary inhibition of the ipsilateral primary sensorimotor cortex activation using subthreshold, low frequency repetitive TMS (rTMS) facilitates motor recovery.

Methods:
1. Functional MRI
2. TMS

Findings:
Eighteen right-handed stroke patients and eleven age-matched control subjects underwent functional Magnetic Resonance Imaging (fMRI) while performing index finger and wrist movements of their recovered and unaffected hand. A subset of these patients underwent Transcranial Magnetic Stimulation (TMS) to elicit ipsilateral and contralateral motor evoked potentials (MEP). Patients showed more activation of the primary sensorimotor cortex (SM1) in the affected hemisphere than control subjects, during movements of the recovered hand. A larger motor network activation was recruited for recovered index finger movements than wrist movements.

Compared to movements that recover earlier, movements that return later after the stroke and those that involve fine motor control are represented by a larger network including the SM1, SMA and cerebellum. TMS of the affect hemisphere but not of the non-affected hemisphere induced MEPs in the recovered hand. TMS parameters also revealed greater transcallosal inhibition, from the non-affected to the affected hemisphere than in the reverse direction. Persistent disinhibition of the contralesional hemisphere even after recovery suggests altered intracortical and transcortical interactions and that recovery utilizes both ipsi- and contralesional resources.

In a small pilot study, we have used this information of a persistent disinhibition to temporarily block the contralesional motor cortex using trancranial direct current stimulation in order to interfere with the assumed unbalanced inhibition onto the lesional motor cortex. Patients that have been enrolled so far in our study showed a significant improvement in motor function of their affected hand after this intervention. After 5 days of stimulation (30 minutes per day), we found a positive motor effect that lasted 1 week.

Selected Publications

Nair D.G., Hutchinson S., Fregni F., Alexander M., Pascual-Leone A., and Schlaug G. Imaging correlates of motor recovery from cerebral infarction and their physiological significance in well-recovered patients. Neuroimage. 2007 Jan 1;34(1):253-63 .

Boggio P.S., Alonso-Alonso M., Mansur C.G., Rigonatti S.P., Schlaug G., Pascual-Leone A., and Fregni F. Hand function improvement with low-frequency repetitive transcranial magnetic stimulation of the unaffected hemisphere in a severe case of stroke. Am J Phys Med Rehabil. 2006 Nov;85(11):927-30.

Vines B.W., Nair D.G., and Schlaug G. Contralateral and ipsilateral motor effects after transcranial direct current stimulation. Neuroreport. 2006 Apr 24;17(6):671-4 .

Duhamel G., Schlaug G., and Alsop D.C. Measurement of arterial input functions for dynamic susceptibility contrast magnetic resonance imaging using echoplanar images: comparison of physical simulations with in vivo results. Magn Reson Med. 2006 Mar;55(3):514-23 .

Kobayashi M., Hutchinson S., Théoret H., Schlaug G., and Pascual-Leone A. Repetitive TMS of the motor cortex improves ipsilateral sequential simple finger movements. Neurology. 2004 Jan 13;62(1):91-8 .

Kobayashi M., Hutchinson S., Schlaug G., and Pascual-Leone A. Ipsilateral motor cortex activation on functional magnetic resonance imaging during unilateral hand movements is related to interhemispheric interactions. Neuroimage. 2003 Dec;20(4):2259-70.

Hutchinson S., Kobayashi M., Horkan C.M., Pascual-Leone A., Alexander M.P., and Schlaug G. Age-related differences in movement representation. Neuroimage. 2002 Dec;17(4):1720-8 .