J Rehabil Med 2003; Suppl. 41: 20–26
TRANSCRANIAL MAGNETIC STIMULATION TO ASSESS CORTICAL PLASTICITY:
A CRITICAL PERSPECTIVE FOR STROKE REHABILITATION
Andrew J. Butler and Steven L. Wolf
From the Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, USA
Transcranial magnetic stimulation has gained increasing tissue, producing a depolarization of nerve cells resulting in the
visibility as an evaluative and interventional tool during stimulation or disruption of brain activity. When performed over
the past 15 years. Within the context of rehabilitation, the primary motor cortex at low stimulus intensities, TMS is
transcranial magnetic stimulation has been applied to dif- thought to stimulate the corticospinal tract indirectly (trans-
ferentiate excitatory and inhibitory mechanisms and to synaptically) via horizontal fiber depolarization (8, 9). The re-
assess cortical reorganization following specific interven- sultant efferent volleys can then be recorded as motor-evoked
tions. This article reviews some of the more salient fea- potentials (MEPs) via surface or indwelling electrodes at periph-
tures of transcranial magnetic stimulation applications eral target muscles.
relevant to stroke rehabilitation, highlighting the strengths TMS may be applied as a single stimulus or repeated many
and weaknesses in this approach. Data derived from such times per second, with variation in intensity, site and orientation
studies may be profoundly over-interpreted. Information of the magnetic field. The brain response produced with TMS
is provided showing the importance of utilizing fundamen- will depend on all of these variables as well as the shape of the
tal principles of electrode placement and kinesiological stimulating coil. In most studies, either round or figure-of-8 coils
electromyography to more accurately reflect and interpret are used. Figure-of-8 coils consist of two round coils placed side
data emerging from transcranial magnetic stimulation by side, producing more focal stimulation. Coils with a reduced
mapping studies, particularly as they apply to the inter- diameter have a more focused field of stimulation but require
pretation of cortical reorganization following application greater stimulation intensity to produce similar depth of field pene-
of neurorehabilitative procedures. tration. Highly focused stimulation is essential for many research
applications although uncertainty exists about whether this prop-
Key words: upper extremity, forced use, constraint-induced erty will prove clinically useful, when less focused stimulation
movement therapy may better compensate for variation in location of pathological
lesions and inter-individual anatomy.
J Rehabil Med 2003; suppl. 41: 20–26. The delivery of TMS is often described by the frequency of the
cortical stimulation. Rapid rate or repetitive TMS (rTMS) usu-
Correspondence address: Andrew J. Butler, Ph.D., PT, Assis-
ally refers to the application of TMS at frequencies above 1 Hz
tant Professor, Department of Rehabilitation Medicine, Emory
and is often applied in treatment studies. TMS at 1 Hz and below
University School of Medicine, 1441 Clifton Road NE, At-
lanta, GA 30322, USA. E-mail: email@example.com. may be referred to as slow or low frequency TMS and is often
used in mapping procedures (10).
Different TMS parameters are used to investigate motor sys-
tem excitability. The resting motor threshold intensity is the low-
INTRODUCTION est stimulator output intensity applied with the target muscle in a
relaxed state that can induce MEPs of a least 50 µV peak-to-peak
Transcranial magnetic stimulation (TMS) was introduced by
amplitude in at least 50% of up to ten trials (11). Other important
Barker and colleagues in 1985 (1) and has since gained recogni-
measures include the location of the “hot spot” (the most active
tion as a safe, relatively painless and noninvasive method for
scalp position for the target muscle), the excitability threshold
mapping cortical motor representation, both in normal and patho-
(measured at the hot spot), the area of motor output representa-
logic cases (2–7). Recently, TMS has been used to investigate the
tion, the MEP latency, the amplitude-weighted center of gravity
possible mechanisms underlying both spontaneous and therapy-
(CoG) (4), MEP amplitudes (at rest and sometimes with facilita-
induced post-stroke motor recovery.
tion) and MEP recruitment curves (12–14).
TMS is based upon the principle of electromagnetic induction.
This article reviews therapeutic studies where TMS-evoked mo-
Electrical current is directed through a hand-held copper-stimu-
tor mapping has been applied in rehabilitation. We examined
lating coil, with the consequent production of a transient mag-
strengths and weaknesses in this approach as they relate to our
netic field. When held over the scalp, the rapidly changing mag-
interpretation of cortical reorganization following application of
netic field induces a small electrical current in underlying brain
J Rehabil Med Suppl 41, 2003 DOI 10.1080/16501960310010106
Transcranial magnetic stimulation to assess cortical plasticity 21
THE EMERGENCE OF TMS TO EVALUATE that enlargement in the AH area was due to increased excitability
MOTOR REORGANIZATION AFTER STROKE at the edges of the map. The rapid change detected in the TMS-
derived maps after brief training epochs suggests that functional,
Several investigators have examined the correlation between rather than structural, mechanisms were involved. Potential
TMS-evoked motor map characteristics after stroke and the ex- mechanisms discussed include the modulation of inhibitory
tent of motor recovery in humans (15–17). Pennisi et al. (18) dem- GABA-ergic transmission at the borders of the motor map and
onstrated that complete hand paralysis in association with ab- alteration in glutamate transmission (23). Classen et al. (12, 29)
sence of early MEPs (within 48 h of ictus) predicted poor neuro- have suggested that the “motor cortex builds up, and then loses,
logic recovery at one year in 15 subjects post-stroke (middle ce- in a short time, memory traces of movements retaining the
rebral artery infarct). Conversely, the preservation of TMS evoked subject’s recent history of performance” (29, p. 168).
MEPs in the early post-stroke period may portend good func-
tional recovery (9, 19). Other investigators have reported rela-
tionships between the rate and extent of post-stroke recovery and
changes in the following: presence of MEP, conduction time from
TMS MAPPING IN CONSTRAINT-INDUCED
cortex to muscle, MEP latency, excitability threshold and MEP THERAPY
amplitude (9, 18, 20, 21). In mono-hemispheric infarctions, de- Recent studies have employed TMS motor mapping to investi-
creased affected hemisphere (AH) motor output area and increased gate the effect of constraint-induced (CI) movement therapy for
excitability thresholds for paretic muscles have been repeatedly the more affected UE. Liepert et al. (30) used focal TMS to con-
observed in TMS-derived maps performed in post-stroke patients struct cortical output maps to the APB in 6 chronic stroke pa-
during the sub-acute and chronic phases (22, 23). These tients before and after 10 days of CI therapy. As noted in prior
electrophysiologic changes are presumably related to the motor studies of post-stroke subjects, significantly higher motor thresh-
impairment and may be secondary to neuronal damage, disuse, olds, smaller amplitudes and a smaller area of excitable cortex
unbalanced transcallosal inhibition from the less affected hemi- were observed in the AH. After CI therapy, TMS parameters
sphere, or other unidentified mechanisms (24). showed no change in thresholds, but significant increases in MEP
amplitude and APB motor output area in the AH, possibly indi-
cating increased excitability of surrounding neuronal networks.
RESPONSE TO REPETITIVE TASK PRACTICE The UH output areas were smaller after the training period, pre-
sumably because of decreased use of the less affected UE, nor-
Results from recent work with animal models have suggested malization of the UH APB representation, or increased transcal-
that the specificity and difficulty of training may impact the ex- losal inhibition of the UH by the AH. CoG shifts were significant
tent of use-dependent cortical plasticity (25–28). Similar find- (in the mediolateral axis) only for the AH, suggesting possible
ings have been reported in motor recovery in human subjects post- recruitment of adjacent areas along the motor cortex. All subjects
stroke. Leipert et al. (23) examined the effect of one intensive improved significantly in their use of the affected extremity, but
session of physical therapy in 9 subjects, 4-8 weeks post-stroke. scores on the Motor Activity Log (MAL), a six-point subjective
Participants received 1.5 h of manual dexterity exercises, in ad- impression of how well and how often movement is observed in
dition to ongoing “standard” therapy. TMS mapping of the ab- the affected arm during basic activities of daily living, did not
ductor pollicis brevis (APB) representation was performed one correlate to the degree of map change. The Leipert group sug-
week before, immediately before, immediately after and one day gests that “physiotherapy induces use-dependent reorganization
after the training session. Measures of motor output area, excit- which supports recovery-associated plastic changes” (23, p. 321).
ability threshold at the APB hot spot, (location at which an evoked In another study (22), clinical (MAL) and TMS measures were
muscle response greater than 50 µV in amplitude is seen at mini- made at multiple time points before and after CI therapy in 13
mal stimulus intensity), and CoG for the APB muscle of the AH chronic stroke patients. Neither baseline measure showed appre-
and unaffected hemispheres (UH) did not significantly change ciable change at 2 weeks and 1 day prior to CI therapy, suggest-
between the two pre-training measures, indicating that signifi- ing little spontaneous recovery and good test-retest reliability.
cant changes did not occur because of spontaneous recovery or Again, the AH showed a smaller APB representation area at
nonspecific training. The area of APB representation in the AH baseline, with a near doubling of the area post-CI therapy. MAL
area increased significantly immediately after training, but then improvements were maintained at the later measurement points.
decreased toward baseline after one day. Increased AH motor out- However, a return toward baseline in the AH APB representation
put area was associated with improved dexterity on a clinical area was seen at the 4 week and 6 month TMS sessions, indicat-
measure (the Nine Hole Peg Test) in 7 of the subjects, although ing a possible “normalization after therapy-induced hyper-excit-
the amount of clinical improvement did not correlate with the ability” (22, p. 1214) via improved synaptic efficiency or the rel-
extent of change in area. The excitability threshold at the hot spot egation of motor function to TMS-inaccessible regions.
and the CoG were unchanged after training, possibly signifying
J Rehabil Med Suppl 41, 2003
22 A.J. Butler and S.L. Wolf
EXAMINING MECHANISMS TO EXPLAIN TMS the amplitude of the evoked response (7), the amplitude and la-
MAP CHANGES tency of the response as well as the area of the map (3), the loca-
tion and area of the map (5) and its area, volume and average
Changes in cortical motor representation areas have been docu- amplitude of the evoked response (24).
mented in TMS mapping investigations of motor recovery after One critical area that has been overlooked is the relationship of
stroke with and without specific therapeutic intervention. Sug- electrode placements to the specificity of muscle response and
gested mechanisms for these map changes can include: i) resolu- subsequent interpretation of data. Often TMS mapping experi-
tion of edema and removal of necrotic tissue after CNS injury ments do not describe the details of surface electrode placement
(31); ii) restitution of damaged pathways (22); iii) modulation of (4, 7, 37, 38). Traditionally surface electromyograms (EMG) are
GABA-ergic intracortical inhibition (22, 32, 33); iv) changes in recorded with silver-silver chloride electrodes using a tendon-
synaptic efficacy (22, 29); v) alteration of transcallosal inhibition belly montage in which the active electrode is placed over the
(22); vi) substitution from ipsi-lesional parallel pathways (22, 34); belly of the muscle and the reference electrode over the interpha-
vii) activation of ipsilateral (contra-lesional) pathways (30); viii) langeal joint of the muscle being tested or other bony landmark.
short-term potentiated responses after terminating repetitive stimu- This type of electrode placement has been described for TMS
lation (29); and ix) long-term potentiation (13, 35). mapping for many muscles of the upper extremity including the:
APB (5, 22, 24, 39–41), abductor digiti minimi (ADM) (24, 42,
43), first dorsal interosseous (36, 44), ADM (5, 45), and extensor
ALTERNATIVE EXPLANATIONS FOR digitorum communis (EDC) (46).
OBSERVED CHANGES IN MAP AREA Use of the belly-tendon method has a distinguished history,
emanating from evoked muscle responses to peripheral nerve
Changes in the excitable surface area derived from TMS-evoked stimulation, at which time the emphasis is simply in examining
motor maps to an individual muscle have been linked to changes responsiveness of many muscles to estimate nerve-to-muscle in-
in motor function and interpreted as a reflection of alterations in tegrity. However, when determining functional recovery in many
the cortical representation for that muscle. However, the mea- intrinsic muscles or larger muscle masses, such as the forearm
sured surface area of these TMS maps seems to exceed the likely extensors, there may be increased concern over electrode place-
cortical volume that is dedicated to a single muscle representa- ment.
tion, or even a single movement. Thickbroom et al. (36) employed Stroke survivors often have impairment upon attempting voli-
excitability curves at each scalp location that elicited responses tional movement into extension (out of flexion synergy) to grasp
in the first dorsal interosseous and found that the shape of the and reach for an object. Thus, when exploring responses from a
curves remained similar at each scalp site (with a similar slope muscle functionally relevant to regaining the ability to manipu-
and saturation level), but was shifted along the intensity axis. late objects in the environment, such as the EDC, there are disad-
This finding suggests that a small population of motor cortical vantages to using the montage placement.
neurons, perhaps deeply situated, may be stimulated by current For the more detailed study of connections to muscles relating
spread with gradually less responsiveness as the TMS coil is to function, a “close-spaced” electrode placement may be pre-
moved away from the epicenter of the representation. Therefore ferred. By using a close-spaced recording electrode array, the cli-
changes in the surface area may represent increased excitability nician can better relate the functional movement to the specific
to current spread, without reflecting a true expansion or contrac- action of the underlying muscle, thus leading to a better determi-
tion of the cortical representation area. The center of the map nation (understanding) of the mechanisms observed following an
may be a more stable measure of map change, and should be intervention.
included in future mapping studies. A few recent TMS mapping To examine this contention carefully, MEP amplitudes from a
studies in post-stroke subjects have revealed medio-lateral shifts wide-spaced electrode array were compared to a close-spaced
in the CoG associated with improvements in motor function of electrode array from the same forearm muscle in a normal healthy
the target muscle (22, 30). individual. The MEPs were recorded using two 7×4 mm silver-
silver chloride surface electrodes (Medtronic, Inc., Minneapolis,
MN). The interelectrode distance for the close-spaced electrode
array was approximately 1.5 cm, while the wide-spaced array
CRITICAL ASSESSMENT OF MEPS AS THEY
was approximately 18 cm. The skin surface over the EDC on the
RELATE TO FUNCTIONAL CHANGE
forearms was shaved and abraded with alcohol until an erythemic
The degree of reproducibility of TMS-evoked motor maps is a response appeared. Recording electrodes were placed on the skin
key issue when attempting to detect subtle plastic changes in a over the EDC muscle bellies (close-spaced array) and EDC muscle
given individual or when comparing results from different labo- belly and ulnar head (wide-spaced array). A ground electrode was
ratories; yet, few investigators have studied this question. So far, applied ipsilaterally and proximally to the recording electrodes
reproducibility has been accessed in terms of the variability of at the level of the olecranon process of the ulna, to reduce EMG
J Rehabil Med Suppl 41, 2003
Transcranial magnetic stimulation to assess cortical plasticity 23
1.0 T (EDC) 0,8
1 21 41 61 81 101 121 141 161 181 201
0 5 10 15 20 Fig. 1. Amplitude of extensor
Trial number digitorum communis (EDC)
(MEP) at motor threshold (A)
and 110% motor threshold
1.1 T (EDC) 0.5 (B) in 20 trials for one
1 subject. Diamonds represent
closely spaced electrode
0.8 Wide 0.3
array, while squares represent
0.6 widely spaced electrode
array. Inserts in upper right
1 21 41 61 81 101 121 141 161 181 201
corner denote a represen-
0.2 -0.1 tative MEP of a single trial
Time (ms) from the subject, with the
light trace derived from the
0 5 10 15 20 wide spaced electrode array.
Trial number Note reduced sensitivity at
1.1 threshold (T).
root-mean-square voltage with wide-spaced electrodes (Fig. 2).
noise levels. Skin impedance between recording electrodes, mea-
MEP is more variable at lower stimulus intensities and vari-
sured with an ohmmeter (Simpson 260 series 8, Simpson Elec-
ability in MEP size is a direct function of the proportion of moto-
tric Co., Elgin IL), was kept below 5 kilo-ohms (K ).
neurons in the total pool recruited by each cortical stimulus. There-
The study was performed with a 70 mm figure-of-8 coil using
fore the same protocol was repeated using stimulus intensities of
a single MAGSTIM 200 stimulator (Magstim Company Ltd.,
110% of motor threshold (1.1T), as is commonly done in TMS
Whitland, Dyfed, UK) and delivered in a systematic fashion at
studies (22, 30). At higher stimulus intensities there are more
approximately 0.2 Hz. The magnetic coil was oriented tangen-
motoneurons stimulated and, therefore, fewer are available to
tially to the scalp, with the handle of the coil in line with the
spontaneously reach threshold and discharge. Again, larger MEP
sagittal plane. EMG signals were amplified (×1000) using a James
amplitudes were observed for the wide-placed electrode array
Long Isolated Bioelectric Amplifier (SA Instrumentation Com-
when compared to the closely spaced electrodes (Fig. 1B). When
pany, Encinitas, CA) and band-pass filtered (10–1000 Hz) before
averaged over twenty trials a similar pattern was observed for
being digitized at 1000 Hz for 200 ms following each stimulus.
MEP amplitude, root-mean-square voltage and area under the
Further signal processing, analysis and storage were performed
curve (Fig. 3).
using a PC system containing custom-established routines cre-
The intention of mapping the evoked responses in EDC to TMS
ated in LabView 6.0 (National Instruments, Austin, TX). An au-
of motor cortex is to gain insight into changes in finger extensor
dio amplifier was used to monitor pre-activation EMG activity
representation following specific therapeutic interventions for
from each EDC muscle to assure minimal muscle activity prior
patients with stroke. This concern is particularly relevant since
training should focus on improving motor control by stressing
The scalp overlying the motor cortex was stimulated at motor
selective (out-of-synergy) movement patterns (48). Wider elec-
threshold (1.0 T), while recording MEPs from EDC. As expected
trode placements, including those used in a study on EDC (47),
larger MEP amplitudes were consistently observed for the wide
may actually record motions, such as finger and wrist flexion,
placed electrode array when compared to the closely spaced elec-
that are counterproductive to the very therapy being instituted.
trodes (Fig. 1A). Some potentials recorded from the widely spaced
This possibility was confirmed by recording surface EMG over-
arrangement used by Wittenberg et al. (47) were considerably
lying EDC while performing finger flexion/extension and wrist
larger than the accompanying close-spaced array. We also ob-
served larger average MEP amplitude, area under the curve and
J Rehabil Med Suppl 41, 2003
24 A.J. Butler and S.L. Wolf
close wide close wide
Fig. 2. Average transcranial magnetic stimulation response characteristics Fig. 3. Average transcranial magnetic stimulation response characteristics
at 1.0 threshold for extensor digitorum communis as a function of inter- at 1.1 threshold for extensor digitorum communis as a function of inter-
electrode distance over 20 trials. Motor-evoked potential Amplitude (A), electrode distance over 20 trials. Motor-evoked potential Amplitude (A),
root mean square (RMS) (B) and area under curve (AUC) (C). The bars root mean square (RMS) (B) and area under curve (AUC) (C). The bars
indicate standard error. indicate standard error.
A EDC FF (0°–70°) B EDC FE (70°–0°)
Time (ms) Time (ms)
Fig. 4. Examples of single trials from the subject showing the effect of finger flexion from a neutral position (A) and finger extension to the neutral
position (B) on extensor digitorum communis electromyographic activity. Traces from close spaced (thick-dark line) electrode arrays are superimposed
on traces from wide spaced (thin-light line) electrode arrays for comparison.
J Rehabil Med Suppl 41, 2003
Transcranial magnetic stimulation to assess cortical plasticity 25
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RQ, et al. Non-invasive electrical and magnetic stimulation of the
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