Authors:
Paulo S. Boggio, MSc
Miguel Alonso-Alonso, MD, MSc
Carlos G. Mansur, MD
Sergio P. Rigonatti, MD, PhD
Gottfried Schlaug, MD
Alvaro Pascual-Leone, MD, PhD
Felipe Fregni, MD, PhD

Stroke

CASE REPORT

Affiliations:
From the Center for Non-Invasive
Brain Stimulation, Department of
Neurology, Beth Israel Deaconess
Medical Center, Harvard Medical
School, Boston, Massachusetts (MA-A,
GS, AP-L, FF); the Department of
Experimental Psychology and
Department of Psychiatry, University
of Sao Paulo, Sao Paulo, Brazil (PSB,
CGM); and Mackenzie University,
Sao Paulo, Brazil (PSB).

Hand Function Improvement with
Low-Frequency Repetitive Transcranial
Magnetic Stimulation of the
Unaffected Hemisphere in
a Severe Case of Stroke

Disclosures:
This work was supported by a grant
from the Harvard Medical School
Scholars in Clinical Science Program
(NIH K30 HL04095) to Felipe Fregni.
Pascual-Leone is supported by NIH
grants R01-NS20068, R01-EB005047,
and K24-RR018875.

Correspondence:
All correspondence and requests for
reprints should be addressed to Felipe
Fregni, MD, PhD; Harvard Center for
Non-invasive Brain Stimulation, 330
Brookline Ave – KS 452, Boston,
MA 02215.
0894-9115/06/8511-0927/0
American Journal of Physical
Medicine & Rehabilitation
Copyright © 2006 by Lippincott
Williams & Wilkins
DOI: 10.1097/01.phm.0000242635.88129.38

ABSTRACT
Boggio PS, Alonso-Alonso M, Mansur CG, Rigonatti SP, Schlaug G, PascualLeone A, 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;85:927–930.
Previous research has shown that low-frequency rTMS of the unaffected hemisphere can improve motor function in acute and chronic stroke patients. However, these studies only investigated patients with mild or moderate motor deficits.
We report a case of a stroke patient with a severe motor impairment who
underwent sham and active repetitive transcranial magnetic stimulation (rTMS) of
the unaffected hemisphere and had significantly improved motor function after
active, but not after sham, stimulation of the unaffected primary motor cortex. In
an additional session of active rTMS, this patient maintained and further enhanced
the initial motor improvement. This case report shows that inhibitory rTMS of the
unaffected hemisphere can also be beneficial for stroke patients with severe
motor deficits and suggests that this approach of noninvasive brain stimulation
should be further investigated in this population of patients.
Key Words:
Inhibition

Transcranial Magnetic Stimulation, Motor Function, Stroke, Transcallosal

S

troke is a major public health concern in industrialized countries. Despite
its high incidence and prevalence, there are few currently available therapies.
Partial or total recovery can sometimes be achieved, but in a substantial number
of patients, severe deficits in the motor and language function result in a great
burden for patients, their families, and the healthcare system. In the last few
years, several lines of evidence have coalesced around the finding that after a
stroke, the brain undergoes plastic changes involving areas beyond the site of
lesion in an attempt to recover function.1,2 Recent evidence suggests, however,
that the results of some of these changes may not be beneficial but, rather,
maladaptive. In such a circumstance, they can hinder motor recovery.1– 4
Interhemispheric inhibitory interactions through callosal connections seem to
November 2006

Hand Function Improvement with rTMS

927

be dysfunctional in chronic stroke patients.3 In
lesions involving the corticospinal tract, this may
result in an excessive inhibitory drive from intact
M1 over its damaged homologous counterpart, with
negative consequences.3 Two recent studies have
demonstrated an improvement in hand motor function after decreasing excitability of M1 in the unaffected hemisphere, using low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS).5,6
However, these investigations targeted a population
of stroke patients with mild-to-moderate motor
deficits. It is not yet clear whether severely impaired individuals could also benefit from this new
therapeutic approach. Here, for the first time, we
report positive effects of 1-Hz rTMS in a chronic
stroke patient with total paralysis of the affected
hand.

CASE REPORT
A 74-yr-old woman participated in a pilot study
investigating the utility of rTMS for motor recovery. This patient had had a stroke in the right
internal capsule 23 mos before enrollment in the
study. She had no movements in her left hand and
only proximal movements in her left shoulder.
Furthermore, she had moderate spasticity (score of
2 in the modified Ashworth scale) in her left hand.
This patient had had an intensive physical therapy
program in the first year after the stroke, during
which she had recovered some of the proximal but
not distal movements.
On enrollment in the study, using a figureeight coil and a Dantec MagPro Stimulator
(Medtronic, Minneapolis, MN), her motor threshold (MT) was determined to be 60% (maximum
stimulator output) in the right abductor pollicis
brevis, and although small MEPs (smaller than
50uV) could be elicited in the left abductor pollicis
brevis, the MT could not be determined using the
maximum output (100%) in the affected hand. MT
was defined as the stimulus intensity capable of
evoking a motor-evoked response of 50 uV (peak to
peak, using surface electromyography) in the resting abductor pollicis brevis muscle in at least 6 of
10 trials. The angle of movements such as finger
flexion and extension; thumb flexion, extension,
abduction, and adduction; and wrist flexion and
extension were assessed before treatment. Importantly, because muscle synergy is frequently observed in stroke patients, the assessment was performed with the patient having her arm flexed at 90
degrees and rested and fixed at the armrest. No
movements could be elicited (0 degrees) in any of
these muscles of the left, affected hand before the
treatment. Furthermore, we assessed short-term
mood changes using a visual analog scale in which
the patient had to rate her mood from 0 (very

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Boggio et al.

unhappy) to 10 (very happy) before and after treatment. She scored 8 before the stimulation.
Initially, as part of the double-blind pilot study,
the patient received sham rTMS with a frequency of
1 Hz. The stimulation site was the “hot spot” for
the stimulation of the muscle abductor pollicis
brevis (as defined for the MT determination) in the
unaffected hemisphere. The coil handle was positioned at 45 degrees from the parasagittal plane so
that the induced current would be in the optimal
position for the stimulation of the motor cortex
strip; stimulation was applied with an intensity of
100% of MT in a continuous train of 20 mins, 1200
pulses. We used a specially designed sham figureeight stimulation coil (commercially available from
Medtronic, Inc.) that has the same appearance as
the real rTMS coil. This sham rTMS contains a
small copper-wire loop inside a plastic casing and
produces a similar sound artifact and a mechanical
tapping sensation on the subject’s scalp. She had
no improvement in motor function or change in
the MT of the affected and unaffected hemispheres
after this stimulation. After 2 mos, the patient
returned and received real rTMS using identical
parameters compared with the initial sham stimulation session. After this session, the patient was
able to perform small movements with her thumb
(5 degrees of abduction and adduction, and 5 degrees of finger flexion). There was no change in
spasticity or mood. MT in the unaffected hand
increased by 8% compared with baseline (Fig. 1).
After 4 mos, the patient returned for a new
session of active rTMS using the same parameters
of stimulation. The patient maintained the initial
improvement obtained after the first real rTMS
session and also had additional improvements:

FIGURE 1 Motor threshold changes (%) from baseline after sham repetitive transcranial
magnetic stimulation and active repetitive transcranial magnetic stimulation
(first and second session) in the stimulated, unaffected hemisphere. A positive
change indicates motor threshold increase.

Am. J. Phys. Med. Rehabil. ● Vol. 85, No. 11

thumb adduction, 10 degrees, thumb abduction, 5
degrees; finger flexion, 15 degrees; and finger extension, 5 degrees. After this second session of real
rTMS, a further improvement was observed (thumb
adduction, 20 degrees; thumb abduction, 15 degrees; finger flexion, 20 degrees; finger extension,
10 degrees). Similar to the first real rTMS session,
there was no change in spasticity (as evaluated by
the modified Ashworth scale) or mood (as indexed
by visual analog scale), and there was a small increase in MT in the unaffected hemisphere (increase of 5%). No adverse effects were associated
with this treatment.

DISCUSSION
We have shown that a chronic stroke patient
with no movements in the affected hand was able
to partially gain hand motor function after inhibitory 1-Hz rTMS was applied on the unaffected,
contralesional M1. Importantly, there was no
change in spasticity or mood from baseline
through the follow-up period. At the time rTMS
was delivered in our patient, she had already
reached a chronic, stable phase (23 mos poststroke), and thus it seems unlikely that the effects
we observed could have been attributable to spontaneous recovery. According to observational studies, this is not expected beyond 5 mos after the
onset of a stroke.7 In addition, placebo effects can
be reasonably ruled out in this particular case
because no changes were found either immediately
after or during the period of 2 mos after sham
stimulation.
On the other hand, although no voluntary
movements were present in this patient’s affected
hand at baseline, small MEPs could still be elicited
at that level. A number of studies have demonstrated a positive correlation between preserved
MEPs—a physiologic marker of corticospinal integrity—and motor outcome after a stroke.8,9 Additionally, a link has been suggested between high
interhemispheric inhibitory drive from contralesional M1 to damaged M1 and poor motor recovery.3 To date, however, it is not known whether the
presence of MEPs in severely impaired patients
could serve as a predictor of response to 1-Hz rTMS
over the contralesional M1. Based on our results
with this patient, it is tempting to speculate that
this might be the case. Excessive interhemispheric
inhibition might preclude motor improvement despite residual substrate for recovery as revealed by
MEPs. Thus, inhibition of contralesional M1 might
be especially beneficial in these individuals. Further studies are needed to address this hypothesis
in detail.
Our case is in line with two previous studies
documenting beneficial effects of 1-Hz rTMS on
contralesional M1 in patients with upper-limb moNovember 2006

tor deficits after stroke. Mansur et al.5 reported an
improvement in reaction times and motor performance (Purdue pegboard test) in a group of 10
patients after a single session of rTMS (1 Hz, 100%
of the resting MT for 10 mins). Of these patients,
five had mild impairment and three had moderate
impairment. The remaining two patients, who were
severely impaired, were excluded from the study
because they were not able to perform the required
task and did not receive the treatment. Takeuchi
et al.6 recently reported an improvement in hand
function (pinch acceleration) after rTMS, using
different parameters (1 Hz, 90% RMT, 25 mins).
Interestingly, these authors also demonstrated a
correlation between motor improvement after
rTMS and the degree of interhemispheric inhibition. The group of patients included in this study
had a degree of motor performance on the FuglMeyer scale ranging from 21 to 100%. No patients
with total paralysis participated in either of these
two studies.
Despite growing evidence that excessive interhemispheric inhibition is a maladaptive compensation in patients with chronic stroke,3,5,6 some authors have suggested a different role for ipsilateral
motor areas in the process of recovery. A beneficial
effect of the unaffected hemisphere was suggested
by reports of patients who had recovered well after
a stroke, where a second cerebrovascular event on
the undamaged hemisphere led to worsening of the
paresis associated with the first stroke.11 Some
studies have explored the role of contralesional
motor areas using single-pulse TMS or rTMS to
directly disrupt activity during or before motor
tasks in chronic stroke patients (“virtual lesions”);
no relevant changes have been found in these studies. Disruption of ipsilateral M1, either with online
TMS or offline 1-Hz rTMS, did not change simple
reaction times or finger tapping in the paretic
hand.12,13 The study of Werhahn et al.13 applied
1-Hz rTMS over the intact M1 only in patients with
good recovery, although single-pulse TMS did not
interfere with motor performance in either group
(good or poor recovery). The study of JohansenBerg et al.,12 however, found decreased reaction
times in the paretic hand with online single-pulse
TMS applied on the ipsilateral premotor cortex but
not M1. Moreover, the authors found greater disruption associated with more impairment, suggesting that recruitment of this ipsilateral region
might play a functional role. Finally, evidence supporting the negative effect of the unaffected hemisphere is shown in a recent longitudinal study that
found an inverse correlation between the activation
of ipsilateral motor areas and recovery, with this
activation pattern diminishing over time as a function of recovery.10 The discrepancies found in these
studies may be explained by the different tasks

Hand Function Improvement with rTMS

929

employed, the type of lesion, and the time course
(i.e., online vs. offline TMS).
Finally, the duration of the positive motor effects in this patient is remarkable. In contrast, the
study of Takeuchi et al.6 demonstrated a short-lived
effect that lasted less than 30 mins. There is evidence that several rTMS treatment sessions can
lead to long-lasting effects for weeks after stimulation14,15; however, the relatively long-lasting effect
was observed after the first session of real rTMS.
Similar effects have been observed in patients with
epilepsy,16 and it has been hypothesized that a
highly dysfunctional cortical activity can be more
susceptible to the modulatory effects of rTMS.16
This case report has some limitations that
should be considered. First, the arm relaxation
might have changed after active rTMS and, thus,
confounded our results. Because we did not assess
it directly, we cannot rule out that relaxation was a
potential confounder in this study. However, the
long-lasting effects of this treatment make this
hypothesis less likely. Second, because we used an
intensity of stimulation that was 100% of the MT
that induces muscle hand contractions, it is possible that the patient realized the difference between
sham and active rTMS and that the effects were
derived from this perception. We cannot rule out
this potential placebo effect; however, after sham
treatment, the patient reported that she believed
she had received active treatment (she was naı̈ve to
rTMS), and, thus, a placebo effect might have occurred after sham rTMS if placebo played an important role in our study. Third, our hypothesis
that the modulation of transcallosal inhibition was
responsible for the beneficial effects on motor
function should be viewed with caution, considering that we could not measure cortical excitability
in the affected hemisphere because of the small
size of MEPs in this hemisphere. However, in a
recent paper, we showed that low-frequency rTMS
of the unaffected hemisphere decreases cortical
excitability in the unaffected hemisphere and increases it in the contralateral, affected hemisphere.17 Further studies should evaluate brain activity in patients lacking MEPs in the paretic hand
using other tools such as electroencephalography
and neuroimaging.
In sum, we have reported, for the first time,
positive effects of rTMS in a stroke patient with
total paralysis of the upper limb. Our case suggests
that subjects with severe motor deficits may find
benefits from this therapeutic approach. Therefore,
our findings underscore the importance of further
exploration of rTMS in patients with severe motor

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deficits using different parameters of stimulation
and longer, systematic follow-up assessments.
Stroke lesion characteristics that might be more
susceptible to the beneficial effects of rTMS also
should be investigated.
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