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Improving Hand Function in Chronic Stroke
Wolf Muellbacher, MD;
Coletta Richards, MD;
Ulf Ziemann, MD;
George Wittenberg, MD;
Deborah Weltz, MD;
Babak Boroojerdi, MD;
Leonardo Cohen, MD;
Mark Hallett, MD
Arch Neurol. 2002;59:1278-1282.
ABSTRACT
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Background Recovery of function following stroke plateaus in about 1 year, typically
leaving upper arm function better than that in the hand. Since there is competition
among body parts for territory in the sensorimotor cortex, even limited activity
of the upper arm might prevent the hand from gaining more control, particularly
when the territory is reduced in size because of the stroke. Deafferentation
of a body part in a healthy brain enhances cortical representations of adjacent
body parts, and this effect is markedly increased by voluntary activity of
the adjacent part.
Objective To explore whether deafferentation of the upper arm, produced by a new
technique of regional anesthesia during hand motor practice, helps recovery
of hand function in patients with long-term stable weakness of their hand
following stroke.
Methods and Results Deafferentation, produced by a new technique of regional anesthesia
of the upper arm during hand motor practice, dramatically improved hand motor
function including some activities of daily living. The improvement was associated
with an increase in transcranial magnetic stimulation–evoked motor output
to the practice hand muscles.
Conclusion This is a novel therapeutic strategy that may help improve hand function
in patients with long-term weakness after stroke.
INTRODUCTION
RECOVERY OF function after stroke may occur, but it is unclear whether
interventions can improve function beyond the spontaneous process. In particular,
recovery of hand function plateaus in about 1 year, and common knowledge is
that the patient will remain at that level for the rest of his or her life.1-2 Typically in such situations, upper
arm function is better than that in the hand.3
An emerging concept in neural plasticity is that there is competition among
body parts for territory in the brain.4-9
Thus, even limited activity of the upper arm might prevent the hand from gaining
more control, particularly when the territory is reduced in size because of
the stroke. Work in our laboratory and elsewhere has indicated that deafferentation
(with deefferentation) of a body part in a healthy brain enhances cortical
representations of adjacent body parts,10-17
an effect that is markedly increased by voluntary activity of that adjacent
part.18-19 Based on these findings,
we explored whether deafferentation of the upper arm, produced by a new technique
of regional anesthesia during hand motor practice, helps recovery of hand
function in patients with chronic stable weakness of their hand following
stroke.
PATIENTS AND METHODS
PATIENTS
The study protocol was approved by the National Institutes of Neurological
Disorders and Stroke institutional review board. Seven patients (6 men and
1 woman; mean age, 58 years; age range, 51-63 years) with right or left hemiparesis
gave their written informed consent to participate in the experiments that
were started on average 37 months after stroke onset (range, 13-57 months).
EXPERIMENTS
Two experiments were conducted—hand motor practice (experiment
1, "practice"), and hand motor practice during regional anesthesia of the
upper arm (experiment 2, "practice and anesthesia"). In experiment 1, we explored
the effects of motor practice on hand function. This experiment included 3
practice episodes. Practices 1 and 2 were 30 minutes each with a 15-minute
break for rest and test measurements. Practice 3 was 15 minutes every day
for an average of 35 days (range, 7-71 days) and was started the day after
practices 1 and 2 were completed and continued until the beginning of experiment
2. Practice 3 was performed at home after the patient received instruction;
the patients were otherwise under continuous supervision. In experiment 2,
we aimed to enhance the effects of motor practice by depriving the motor cortex
representations of the upper arm from their sensory inputs by using a new
technique of regional anesthesia. This experiment included 2 practice episodes.
Practices 4 and 5 were 30 minutes each with a 15-minute break for rest and
test measurements and included 6 patients from experiment 1 (patient 1 withdrew
from invasive procedures). The final follow-up measures were completed 14
days after practice 5 was completed.
PRACTICING
The practice task was a metronome-paced pinch between the index finger
and the thumb of the impaired hand (frequency individualized between 0.3 and
0.5 Hz). The patient aimed to do the pinching as quickly as possible because
previous experiments in healthy volunteers showed that practicing such accelerated
movements can result in improved hand function.20
BEHAVIORAL MEASURES
Maximal pinch force of the index finger and thumb was measured with
a pinch gauge (model 5083; AliMed Inc, Dedham, Mass) according to a standardized
procedure described in detail elsewhere.20
The acceleration of each thumb flexion during practicing (up to 1200 movements)
was taken with a miniature, high-output charge, piezoelectric accelerometer
with integral electronics (model 25A, ISOTRON PE Accelerometer, 4.575 mV/g
sensitivity; Endevco Corp, San Juan Capistrano, Calif) firmly fixed to the
proximal phalanx of the thumb with tape. The signal was amplified by a battery-powered,
low-noise signal conditioner (model 4416B ISOTRON Signal Conditioner; Endevco).
The signal was digitized using a PCI-MIO-16E4 board (National Instruments
Corp, Austin, Tex) at a rate of 2000 Hz.
MEASUREMENT OF MOTOR EXCITABILITY
Surface electromyogram was recorded (bandpass, 0.1-2.5 kHz) from the
left flexor pollicis brevis muscle using an electromyographic machine (Counterpoint
Electromyograph; Dantec Dynamics A/S, Skovlunde, Denmark). The motor cortex
was excited with a figure 8–shaped stimulation coil connected to a magnetic
stimulator (Magstim 200; MagstimCo Ltd; Whitland, South West Wales). Motor
threshold was defined as the minimum stimulus intensity required to produce
motor evoked potentials (MEPs) exceeding 50 µV in at least 5 of 10 trials.
Peak-to-peak MEP amplitude was determined at a stimulus intensity of 20% of
maximum stimulator output above the individual motor threshold.
REGIONAL ANESTHESIA
A needle was inserted into the interscalene groove and electrical stimulation
was delivered to localize the upper brachial plexus roots. Then, 10 to 20
mL of 1.5% lidocaine hydrochloride was injected. The regional effects of this
procedure were determined 15 minutes after injection by (1) skin anesthesia
of shoulder and upper arm (defined as no response to touch in at least 3 of
4 trials) with sparing of forearm and hand; (2) increase in sensory threshold
in shoulder and upper arm with sparing of forearm and hand, which was expressed
as an increase in monofilament diameter size (in millimeters; the diameters
provide a logarithmic scale of force exerted, and, thus, a linear and interval
scale of perceived intensity) (Semmes-Weinstein Von Frey Monofilaments; Stoelting
Co, Wood Dale, Ill) necessary to produce sensation to touch in at least 3
of 4 trials; (3) decreased strength (Medical Research Council [MRC] Scale)
of shoulder and upper arm muscles, with sparing of forearm and hand muscles;
(4) no change in pinch force (pinch gauge) because of regional anesthesia;
and (5) no change in MEP amplitude in the practice flexor pollicis brevis
muscle because of regional anesthesia. The effects of anesthesia were assessed
15 minutes after the injection of the anesthetic (evaluation of anesthesia)
and at the end of the final practice episode (end of anesthesia) (Figure 1).
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Figure 1. Effects of regional anesthesia
on sensory threshold (A) and muscle strength in different body parts (B).
Changes (during [first bar] and after [second bar] anesthesia) were expressed
as difference in monofilament diameter size (A) and as difference in muscle
strength (Medical Research Council [MRC] Scale) (B). Ches indicates upper
chest; Shou, shoulder; Uarm, upper arm; Farm, forearm; Hdors, dorsal side
of the hand; Hvol, volar surface of the hand; Tvol, volar surface of the thumb;
Ivol, volar surface of the index finger; Uabd, upper arm abduction; Fflex,
forearm flexion; Fext, forearm extension; Hgrip, handgrip; Fiext, finger extension;
Wext, wrist extension; asterisks, P<.05; and error bar, SEM.
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DATA ANALYSIS
The effects of practice and anesthesia on force, motor threshold, MEP
amplitude, and sensory measures were assessed separately with analysis of
variance using a model of repeated measures. For each time point, changes
were expressed as ratio (postpracticex/prepractice1). Conditional to statistically significant (P<.05)
values, post hoc paired t tests were performed. Simple
regression analyses were done to study correlation between the practice-induced
changes in motor behavior and motor excitability.
REPORT OF CASES
CASE 1
A 51-year-old, right-handed woman who had a right capsular stroke was
studied 57 months after the ictus. She had left-sided hemiparesis, moderate
spasticity of the arm and leg, and a discrete hemihypesthesia. Her hand grasp
was weak (MRC Scale, 4-) with full-active mass flexion and some mass
extension of all fingers. Assessment scale scores were Modified Rankin Scale,
2 (slight disability: unable to carry out all previous activities, but able
to look after own affairs without assistance; mean [SD] score, 2.1 [0.4];
range, 2-3); Barthel Activities of Daily Living (ADL) Index, 100 (range 0
[worse]-100 [best]; mean score [SD], 98 [3.9]; range, 90 [worse]-100 [best]);
National Institutes of Health Stroke Scale (NIHSS), 3 (mean score [SD], 3.4
[1.4]; range, 2 [best]-6 [worse]); and Fugl-Meyer Hand Scale, 3 (mean score
[SD], 8.4 [5.3]; range, 3 [best]-14 [worse]).
CASE 2
A 62-year-old man who had a left capsular stroke was studied 44 months
after the ictus. He had a right-sided hemiparesis, with moderate spasticity
in his arm and leg including sustained ankle clonus. He could raise his arm
and hand against gravity, but his hand grasp was weak (MRC Scale, 4-);
he had full-active finger flexion and could release from an active mass flexion
grasp. Assessment scale scores were Modified Rankin Scale, 2; Barthel ADL
Index, 100; NIHSS, 3; and Fugl-Meyer Hand Scale, 3.
CASE 3
A 57-year-old, right-handed man who had a right-sided pontine stroke
was studied 48 months after the ictus. He had slurred speech, left-sided facial
weakness, and left-sided hemiparesis. His hand grasp was weak (MRC Scale,
4-), but he was able to grasp a small cylinder-shaped object; he could
perform a good spherical grasp. Assessment scale scores were Modified Rankin
Scale, 2; Barthel ADL Index, 100; NIHSS, 3; and Fugl-Meyer Hand Scale, 14.
CASE 4
A 63-year-old, right-handed man who had a left-sided anterior pontine
stroke was studied 13 months after the ictus. He had mild right-sided hemiparesis.
Hand grasp was weak (MRC scale, 4-), but he was able to grasp small
objects and could perform a spherical grasp (pick up a small ball with his
fingers). Assessment scale scores were Modified Rankin Scale, 2; Barthel ADL
Index, 100; NIHSS, 6; and Fugl-Meyer Hand Scale, 14.
CASE 5
A 60-year-old, right-handed man who had a left-sided capsular stroke
was studied 20 months after the ictus. He had right-sided facial weakness
and mild weakness and spasticity in the right arm. His hand grasp was weak
(MRC Scale, 4) with full-active mass flexion and some mass extension of all
fingers. He could put his arm through the sleeve of an article of clothing,
and he could carry some objects in his hand. Assessment scale scores were
Modified Rankin Scale, 2; Barthel ADL Index, 100; NIHSS, 4; and Fugl-Meyer
Hand Scale, 4.
CASE 6
A 53-year-old, right-handed man who had a left-sided capsular stroke
was studied 50 months after the ictus. He had right-sided hemiparesis, was
able to grasp a small object, and could perform a spherical grasp. He could
pick up a fork or spoon and use it and was able to button a shirt. Assessment
scale scores were Modified Rankin Scale, 2; Barthel ADL Index, 100; NIHSS,
2; and Fugl-Meyer Hand Scale, 14.
CASE 7
A 61-year-old, right-handed man who had a left-sided capsular stroke
was studied 27 months after the ictus. He had right-sided hemiparesis with
facial weakness and mild paresis of the arm and lower extremity with an almost
normal gait. His hand grasp was weak (MRC Scale, 4), but he was able to grasp
small objects and could perform a spherical grasp. Assessment scale scores
were Modified Rankin Scale, 3; Barthel ADL Index, 90; NIHSS, 2; and Fugl-Meyer
Hand Scale, 5.
RESULTS
No patient experienced any significant adverse effect.
EXPERIMENT 1
Figure 2 shows results of
experiment 1 (Figure 2A) and experiment
2 (Figure 2B). Patients rapidly
improved in peak pinch force and peak pinch acceleration after the first (postpractice
1) and second (postpractice 2) practice episode (peak force, P = .004; peak acceleration, P<.001; Figure 2A). Further practicing (practice
3) did not lead to additional improvement (average change in force because
of practice 3 relative to practice 2 was as follows: 1.15; range, 0.74-2.05; P = .46; no significant correlation was found between motor
performance and the number of training days during practice 3; R = 0.12; P = .82). Transcranial magnetic
stimulation revealed no significant alteration in motor threshold or MEP amplitude
in the practice flexor pollicis brevis muscle (Figure 2A).
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Figure 2. Effects of motor practice (A)
and motor practice and anesthesia (B) on motor behavior and motor excitability
in patients with long-term stroke. Data were normalized to the initial (prepractice
1) measure and given a value of 1.0. The numbers refer to the respective practice
episode. MEP indicates motor evoked potentials; asterisks, P<.05;
error bar, SEM; pre, before the initial practice session; and post, after
each designated practice session.
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EXPERIMENT 2
The regional anesthesia procedure provided a significant proximal (ie,
upper chest, shoulder, and upper arm) but not distal (ie, forearm and hand)
anesthesia (Figure 1): regional
effect of anesthesia on (1) skin anesthesia of shoulder and upper arm was
present in all patients; (2) sensory threshold (Figure 1A), P<.001; (3) regional effect
of anesthesia on strength (Figure 1B), P<.001; (4) effect of anesthesia on pinch force, P = .41 (mean [SD], 1.06 [0.05]; range, 0.94-1.11); and
(5) effect of anesthesia on MEP size, P = .48 (mean
[SD] MEP ratio during anesthesia/preanesthesia, 1.14 [0.43]; range, 0.67-1.74).
Hand motor practice during regional anesthesia produced an additional
improvement in hand function as shown by a further significant increase in
pinch force (P = .02) and pinch acceleration (P<.001) after practices 4 (postpractice 4) and 5 (postpractice
5) (Figure 2B). No significant change
in pinch force was observed in the intact (contralateral) hand (mean [SD],
1.01 [0.06]; range, 0.92-1.06; P = .21). The behavioral
improvement was associated with a significant increase in transcranial magnetic
stimulation–evoked motor output to the practice muscle as indicated
by a significant increase in MEP amplitude in the flexor pollicis brevis (P = .02; Figure 2B),
whereas motor threshold was unchanged. The practice-induced increase in peak
force during regional anesthesia was significantly correlated to the increase
in MEP amplitude (R = 0.86; P<.003).
Patients showed retention of the force gains 2 weeks later (mean [SD] force,
2.43 [1.09]; range, 1.43-4.09). At that time, 5 of the 6 patients reported
significant functional benefits in some of their ADL: for example, "handgrip
better"; "better hand control"; "can now hold pen, cup"; "hand strength better";
"hand feels more normal"; "thumb moves faster and in a new direction"; "can
now hold small objects"; "writing a lot better and much longer"; "previously
no such big steps"; and "helped in daily living."
COMMENT
The main result of this open-label experiment is that regional anesthesia
of the upper arm during hand motor practice potentiates practice-induced improvements
in hand motor function in patients with chronic stroke. In experiment 1 (practice),
patients rapidly improved in hand motor function as indicated by a significant
increase in peak pinch force and pinch acceleration after the first practice
episode. They showed both retention of this improvement and additional improvement
during the second practice episode, but further practicing did not lead to
additional improvement indicating that the behavioral gain had quickly reached
a plateau by the second practice episode.
In experiment 2 (practice and anesthesia), we aimed to enhance the effects
of motor practice on hand function by depriving the motor cortex representations
of the upper arm from their sensory inputs. We hypothesized that regional
deafferentation-deefferentation of the upper arm during hand motor practice
would enhance the cortical motor output to the hand, and that this enhancement
would lead to an additional improvement in hand function that had reached
a plateau by the previous practice episodes. This idea was based on recent
studies that demonstrated that deafferentation-deefferentation of a body part
in a healthy brain enhances cortical representations of adjacent body parts,10-17
and that this effect is increased by motor practice of the adjacent part.18-19 While this is a preliminary and uncontrolled
study, in some sense by its design, the patients served as their own control
group in experiment 1. Moreover, experiment 2 was biased against the anesthesia
effect because if there was a limit to the extent of plasticity, all possible
improvement might well have occurred in the first experiment.
Hand motor practice during regional anesthesia of the upper arm led
to additional improvement in hand function as shown by a further significant
increase in pinch force and pinch acceleration that had reached a plateau
by the previous practice episodes. The failure to demonstrate significant
changes in pinch force in the intact (contralateral) hand rules out nonspecific
influences that are known to influence behavioral test measurements. Patients
showed retention of the behavioral improvement on follow-up 2 weeks later,
and at that time, 5 of the 6 patients reported functional benefits in some
of their ADL.
The behavioral improvement was associated with a significant increase
in transcranial magnetic stimulation–evoked cortical motor output to
the practice muscles as shown by a significant increase in MEP amplitude in
the training muscle, whereas motor threshold remained unchanged. This is analogous
to the results reported in the biceps muscle during acute ischemic hand deafferentation-deefferentation,21 the conventional model to study rapid deafferentation-deefferentation–induced
motor cortical reorganization in humans.14, 22
The cortical changes observed here may result from rapid alterations
in the balance of excitation and inhibition which likely depend on the observation
that neural representations have a larger region of anatomical connectivity
than their territory of usual functional influence. Some motor cortical output
zones may be kept in check by tonic inhibition (eg, via cutaneous inputs),
and if the inhibition is removed (eg, by anesthesia), the region of influence
can be increased rapidly.23 It was shown that,
following application of the  -aminobutyric acid (GABA) antagonist bicuculline
to the forelimb motor cortex area of the rat, stimulation of the adjacent
vibrissa area led to forelimb movements, suggesting that GABAergic neurons
are critical for maintaining motor cortical representations.24
In humans, application of the GABA agonist lorazepam inhibited practice-induced
motor cortex reorganization.18, 25
Another mechanism is strengthening or weakening of existing synapses, such
as or long-term depression, 2 forms of synaptic plasticity described in the
motor cortex26-27 as well as in
other cortical areas. The dissociation of motor threshold (no change) and
MEP amplitude (significant increase) in the present experiments suggests that
the practice-induced changes in motor cortex excitability were primarily caused
by changes in synaptic excitability, since MEP amplitude at suprathreshold
stimulus intensity is particularly sensitive to changes in synaptic and postsynaptic
excitability of cortical neural elements activated by transcranial magnetic
stimulation. This is compatible with an long-term potentiationlike mechanism.
A further possibility of anatomical changes (eg, synaptic proliferation)28 is unlikely because of the rapid time course.
Independent of the precise mechanisms, our results illustrate that the
principles of brain plasticity can have practical applications in stroke rehabilitation.
Further controlled trials are necessary to prove the implications of these
preliminary open-label experiments.
AUTHOR INFORMATION
Accepted for publication March 25, 2002.
Author contributions: Study concept and design (Drs Muellbacher, Wittenberg, Boroojerdi, Cohen, and Hallett); acquisition of data (Drs Muellbacher, Richards,
Ziemann, Weltz, and Boroojerdi); analysis and interpretation of data (Drs Muellbacher and Ziemann); drafting of the manuscript (Drs Muellbacher, Richards, Weltz, Boroojerdi, and Hallett);
critical revision of the manuscript for important intellectual content (Drs Ziemann, Boroojerdi, Cohen, and Hallett); statistical
expertise (Drs Muellbacher and Cohen); obtained funding (Drs Cohen and Hallett); administrative, technical, and
material support (Drs Cohen and Hallett); study supervision (Drs Cohen and Hallett).
This study was supported by the Max-Kade-Foundation, Bonn, Germany (Dr
Muellbacher).
We thank our patients for their cooperation; E. Considine and P. Shelton
for assistance; and D. G. Schoenberg, MSc, for skillful editing.
Corresponding author: Mark Hallett, MD, National Institutes of Health,
National Institute of Neurological Disorders and Stroke, 10 Center Dr, Bldg
10, Room 5N226, Bethesda, MD 20892 (e-mail: hallettm{at}ninds.nih.gov).
From the Human Motor Control Section (Drs Muellbacher, Ziemann, and
Hallett), and the Human Cortical Physiology Section (Drs Ziemann, Wittenberg,
Boroojerdi, and Cohen), National Institute of Neurological Disorders and Stroke,
and the Department of Anesthesia (Drs Richards and Weltz), National Institutes
of Health, Bethesda, Md; Department of Neurology, Ludwig Boltzmann Institute,
Neurological Hospital of Vienna, Vienna, Austria (Dr Muellbacher); and the
Clinic of Neurology, J. W. Goethe–University Frankfurt, Frankfurt am
Main, Germany (Dr Ziemann).
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Arch Neurol 2003;60:640-640.
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