Study 1: Transcranial Magnetic Stimulation

Focal transcranial magnetic stimulation (TMS) was used to map the areas of the brain that control arm movement in 6 patients with a chronic upper extremity hemiparesis before and after CI Therapy (Liepert, Miltner, Bauder, Sommer, Dettmers, Taub & Weiller, 1998). The patients were at least 6 months poststroke (mean chronicity = 6 years) and were able to extend at least 20 degrees at the wrist and 10 degrees at the fingers on their impaired extremity prior to therapy. Patients received 14 days of CI Therapy; they were trained to use their paretic arm for 6 hours each day in the clinic and wore a sling on their contralateral arm in the clinic and at home for 90% of waking hours. The amount of arm use at home was measured using the Motor Activity Log (MAL), which is a semi-structured interview that tracks arm use on 20 activities of daily living (Taub & Uswatte, in press; Taub, Miller, Novack, Cook, Fleming, Nepomuceno, Connell, & Crago, 1993). Cortical reorganization was measured by mapping the cortical output area of the abductor pollicis (APB) muscle using TMS with a figure-of-8 coil (Magstim, Dyfed, UK). Several parameters of brain activity were calculated. Data is presented here for the cortical representation area size of the APB muscle, defined as the number of scalp positions from which stimulation (10% above the individual motor threshold) produced at least 1 motor evoked potential (MEP) > 50 µV in a series of 5 stimulations. The ratio of affected to unaffected hemisphere representation area was used as the dependent measure because this ratio had been found to be a more stable measure of cortical representation than the absolute values for the individual hemispheres (Cicinelli, Traversa, & Rossini, 1997).

Study 2: Neuroelectric Source Imaging

Current source density analysis of the steady state electroencephalographic (EEG) motor potential was used to measure brain activity related to arm movement in 4 patients with a chronic upper extremity hemiparesis before, immediately after, and 3 months after CI Therapy (Kopp, Kunkel, Muehlnickel, Villringer, Taub & Flor, submitted). The patients were at least 1 year poststroke (chronicity range = 4-15 years) and were able to extend at least 20 degrees at the wrist and 10 degrees at the fingers on their impaired extremity. As in the first study, patients received 14 days of CI Therapy. The amount of arm use at home was measured using the MAL. Cortical reorganization was measured by dipole modeling of the mean source of steady-state movement-related cortical potentials (Gerloff, Toro, Uenishi, Cohen, Leocani, & Hallet, Electroenceph. Clin. Neurophysiol., pp. 106-113, 1997). The EEG was recorded from an array of 50 scalp Zn-electrodes while patients flexed/extended the digits of either their affected or unaffected hands. Following preprocessing of the data by a principle component analysis (PCA), a fixed dipole model was used for analysis of the first component of the PCA, and a single dipole was reconstructed for the time range from 20 to 400 ms after movement onset.

Study 1: Transcranial Magnetic Stimulation

CI Therapy produced a large and significant increase in the patients' amount of arm use in the real world environment over the 2-week treatment period, going from a 2.3 (2 = sometimes used affected arm, but mostly used other arm) before treatment to 3.8 (4 = almost as much use as before the stroke) after treatment, p < .001. Over the same period, it was found that the cortical region from which EMG responses of the APB muscle could be elicited by TMS more than doubled, p < .01. Figure 1 illustrates this large change in the cortical area controlling affected arm movement associated with the increase in arm use produced by CI Therapy.

Fig. 1. Changes in cortical motor area sizes in the damaged hemisphere of a single subject eliciting responses in abductor pollicis brevis (APB) muscle before and after CI Therapy.

Study 2: Neuroelectric Source Imaging

As in Study 1, Kopp and associates found that CI Therapy produced a large and significant increase in the patients' amount of arm use in the home over the 2-week treatment period, going from a 2.0 (sometimes used affected arm, but mostly used other arm) before treatment to 4.7 (close to as much amount of use as before the stroke) after treatment, p < .001. Before and immediately after treatment, the mean source locations of motor potentials for movement of the affected arm were located in the damaged hemisphere anterior to the motor cortex. However, 3 months after treatment, the mean source locations for the affected arm had shifted from the stroke-damaged hemisphere to the undamaged hemisphere for all 4 patients and clustered in all three dimensions with the sources, presumably in primary motor cortex, that were activated by movements of the unaffected hand in the stroke patients and of the corresponding hand in 20 healthy control subjects. The fact that this effect was not in evidence immediately after treatment suggests that the shift in the mean source of affected arm motor potentials was due to the sustained increase in affected arm use over the 3-month follow-up period subsequent to treatment. Figure 2 illustrates the large shift in the mean source of motor potentials for movement of the affected arm from the hemisphere contralateral to the affected arm to the ipsilateral motor cortex, which normally controls movements of the contralateral (unaffected) arm.

Fig.2. Mean source locations superimposed on coronal and sagittal MRI scans of one patient. The source locations are for the left and right (affected) hand movements of subjects with chronic stroke (N = 4) before, immediately after, and 3 months following CI Therapy and for left and right hand movements of healthy subjects (N = 20).

Figure 2

The treatment data from the two studies presented here replicate the finding of Taub and co-workers (Taub et al., 1993; Taub, Pidikiti, DeLuca, & Crago, 1996; Taub & Uswatte, in press) that CI Therapy produces large increases in the amount of real world arm use of persons with a stroke-related paresis of an upper extremity. The two studies present the new finding that the increase in affected arm use produced by CI Therapy is associated with cortical reorganization of the areas controlling arm movement. Liepert and co-workers found that the cortical region from which EMG responses of a hand muscle could be elicited by TMS was more than doubled, while Kopp and associates found that 3 months after treatment the motor cortex ipsilateral to the affected arm, which normally controls movements of the contralateral arm, had been recruited to generate movements of the affected extremity.

These findings suggest that CI Therapy produces a permanent increase in arm use by two mechanisms. First, CI Therapy changes the contingencies of reinforcement (provides opportunities for reinforcement of use of the affected arm by constraining the unaffected arm) so that the learned nonuse of the stroke-affected arm conditioned in the acute and early subacute periods is counter-conditioned or lifted (For a detailed discussion of this mechanism see Taub, 1980 and Taub & Uswatte, in press). Second, the consequent increase in use, involving sustained and repeated practice of functional arm movements, induces expansion of the contralateral cortical area controlling movement of the affected arm and recruitment of new ipsilateral areas. This use-dependent cortical reorganization may serve as the neural basis for the permanent increase in use of the affected arm that results from CI Therapy. Moreover, to the best of our knowledge, these recent studies are the first to demonstrate an alteration in brain structure or function associated with therapy-induced rehabilitation of movement after CNS damage in humans.

Supported by grants from the Deutsche Forschungsgemeinschaft, Grant #HD34273 from the National Institutes of Health, Grants B93-629AP and B95-975R from the Rehabilitation Research and Development Service, U.S. Department of Veterans Affairs, and Grant #94-172 from the Retirement Research Foundation.

1. Liepert, J., Bauder, H., Sommer, M., Miltner, W.H.R., Dettmers, C., Taub, E., & Weiller, C.. (1998). Motor cortex plasticity during Constraint-Induced Movement Therapy in chronic stroke patients. Neuroscience Letters, 250, 5-8.
2. Kopp, B., Kunkel, A., Muehlnickel, W., Villringer, K., Taub, E.,& Flor, H. (1998). Plasticity in the motor system correlated with therapy-induced improvement of movement in human stroke patients. Manuscript submitted for publication.
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6. Taub, E., & Uswatte, G. (in press). A new approach to treatment and measurement in physical rehabilitation: Constraint-Induced (CI) Movement Therapy. In R. G. Frank and T. R. Elliott (Eds.) Handbook of rehabilitation psychology. Washington, DC: American Psychological Association.