Effects of limb immobilization on brain plasticity

N. Langer, J. Hänggi, N.A. Müller, et al.

Neurology 2012;78;182-188
DOI 10.1212/WNL.0b013e31823fcd9c

This information is current as of January 16, 2012

The online version of this article, along with updated information and services, is
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N. Langer, MSc
J. Hänggi, PhD
N.A. Müller, MD
H.P. Simmen, MD
L. Jäncke, PhD
Correspondence and reprint
requests to N. Langer:
n.langer@psychologie.uzh.ch
or L. Jäncke:
l.jaencke@psychologie.uzh.ch
Supplemental data at
www.neurology.org
Supplemental Data
182
Effects of limb immobilization on
brain plasticity
ABSTRACT
Objective: Little is known about the effects of reduced sensory input and motor output in the
human brain. Therefore, we conducted a longitudinal study to investigate whether limb immobili-
zation after unilateral arm injury is reflected in structural plastic changes in gray matter (cortical
thickness) and white matter (fractional anisotropy [FA]).
Methods: We examined 10 right-handed subjects with injury of the right upper extremity that
required at least 14 days of limb immobilization. Subjects underwent 2 MRI examinations, the
first within 48 hours postinjury and the second after an average time interval of 16 days of
immobilization. Based on the MRI scans, we measured cortical thickness of sensorimotor regions
and FA of the corticospinal tracts.
Results: After immobilization, we revealed a decrease in cortical thickness in the left primary
motor and somatosensory area as well as a decrease in FA in the left corticospinal tract. In addi-
tion, the motor skill of the left (noninjured) hand improved and is related to increased cortical
thickness and FA in the right motor cortex.
Conclusions: The present study illustrates that cortical thickness of the sensorimotor cortex and
FA of the corticospinal tract changed during right arm immobilization and that these changes are
associated with skill transfer from the right to the left hand. Thus, immobilization induces rapid
reorganization of the sensorimotor system. Given that limb immobilization is a standard interven-
tion technique in constraint-induced therapy, therapists should be aware of both the positive and
negative effects of this intervention. Neurology® 2012;78:182–188
GLOSSARY
FA ⫽ fractional anisotropy; FSL ⫽ FMRIB Software Library; MLS ⫽ Motor Performance Series; MNI ⫽ Montreal Neurological
Institute.
Although many studies have focused on functional and structural alterations in response to skill
acquisition, the effects of sensory and motor deprivation in the human brain are still hardly
understood.1,2 In contrast, animal studies have demonstrated the effects of amputation, dener-
vation, or central system lesions on remapping of the somatosensory cortex.3–5 One of the
reasons for this discrepancy is the lack of preinjury data in previous human studies of deaffer-
entation (e.g., due to limb amputation6). The purpose of the present longitudinal study was
therefore to examine the effects of limb immobilization on human brain plasticity. An interest-
ing concomitant effect of immobilization of the right-sided upper extremity is the compensa-
tory usage of the nondeprived left (subdominant) upper extremity for daily life skills such as
dressing, dental hygiene, or operating a computer mouse.
Longitudinal studies of experimental interventions may potentially unveil the dynamic
properties of learning-related plastic changes.7–9 In this study, our goal was to test whether
injury-related transient somatosensory and motor deprivation can induce rapid reorganization
of the adult CNS.
From the Division of Neuropsychology, Institute of Psychology (N.L., J.H., L.J.), and International Normal Aging and Plasticity Imaging Center
(L.J.), University of Zurich, Zurich; and Division of Trauma Surgery (N.A.M., H.P.S.), University Hospital Zurich, Zurich, Switzerland.
Study funding: Supported by the National Centre of Competence in Research on Neural Plasticity and Repair and the Swiss National Science
Foundation (grant SNF 31003A-100109 awarded to L.J.).
Disclosure: Author disclosures are provided at the end of the article.
Copyright © 2012 by AAN Enterprises, Inc.
 Our hypothesis was that immobilization
leads to a cortical thickness decrease in the left
primary somatosensory and motor region and
a decrease in fractional anisotropy (FA)
within the left corticospinal tract, which are
responsible for fine motor movements. In ad-
dition, we expected that enhanced behavioral
performance of the left hand after immobili-
zation is reflected by increased cortical thick-
ness in right hemispheric sensorimotor areas
and increased FA within the right corticospi-
nal tract.
METHODS Subjects. We investigated 10 right-handed (ac-
cording to the Annett handedness questionnaire10) subjects (8
male; mean ⫾ SD age of 31.6 ⫾ 9.81 years), who had an injury
of the right upper extremity and needed immobilization with a
cast or immobilizing sling for at least 14 days. The entire right
arm was immobilized, preventing large and even small move-
ments with this arm and hand. Seven of the participants had a
humerus fracture, and 3 had an elbow fracture. Thus, for this
time period, the motor and somatosensory information flow to
and from the right upper extremity was reduced (or at least sub-
stantially changed). To deal with daily life situations requiring
manual skills (e.g., washing or using a toothbrush, spoon, knife,
fork, or pen), the patients had to use the subdominant left hand
and arm. None of the subjects had traumatic brain injury, neu-
rologic disease, psychiatric disease, or peripheral nerve injury.
Standard protocol approvals, registrations, and patient
consents. The local ethics committee gave ethical approval for
the study (ref. no. StV 13–2009), and we obtained written in-
formed consent from all study participants before examination.
Task. We used a comprehensive fine motor abilities test battery
to assess the alteration of the behavioral performance of the left,
noninjured, subdominant hand. The Motor Performance Series
(MLS) is a test battery developed by Schoppe based on Fleish-
man’s factor analytic examinations of fine motor abilities.11 We
assessed the motor performance of static and dynamic tasks for
fingers, hand, and arm movements. The following 6 factors of
fine motor abilities are analyzed by the MLS: aiming of motion,
hand unrest (tremor), precision of arm-hand movements, man-
ual dexterity and finger dexterity, rate of arm and hand move-
ments, and wrist-finger speed. The MLS work panel is covered
with boreholes, grooves, and contact surfaces. Retest reliability
coefficients ranging between 0.6 and 0.94. Based on the perfor-
mance subtest measures we calculated an overall motor perfor-
mance score by averaging the standardized subtest measures. We
compared the first (within 48 hours after the injury) with the
second examination (after deprivation) with a paired test (thresh-
old was set at p ⬍ 0.05). In addition, we used the difference of
the standardized average performance between the 2 time points
for correlation analysis with the changes in surface- and
diffusion-based measures between the 2 time points.
Surface-based morphometry. All subjects underwent 2
structural MRI examinations, each consisting of 2 T1-weighted
and 1 diffusion-weighted sequence. Two T1-weighted scans pro-
vided a better signal/noise ratio.12 We performed the first exami-
nation within 48 hours after the initial injury (time point 1).
After an average interval of 16 days, during which the subjects’
right arm was sensory and motor deprived, a second MRI exam-
ination was conducted (time point 2) (table e-1 on the Neurol-
ogy® Web site at www.neurology.org). For the details of the MRI
data acquisition and surface-based morphometry, see appendix
e-1. The FreeSurfer image analysis suite was used for cortical
reconstruction (http://surfer.nmr.mgh.harvard.edu/). FreeSurfer
is a sophisticated set of automated tools for reconstruction of the
brain’s cortical surface from structural MRI data.13,14 We con-
ducted all statistical analyses using the general linear model im-
plemented in FreeSurfer (mri_glmfit). In a first step, we
performed a longitudinal cortical thickness analysis using vertex-
wise paired t tests within a predefined region of interest
(figure e-1) to detect regional differences in cortical thickness be-
tween the 2 time points with a resel-based correction for multiple
comparisons.15,16 We applied a statistical threshold of p ⬍ 0.05 (cor-
rected for multiple comparisons). In addition, we performed a
regression analysis to evaluate the neural correlate of the behav-
ioral improvement of the left upper extremity at time point 2
(threshold of p ⬍ 0.05 corrected for multiple comparisons).
Fiber tractography and analysis of fractional aniso-
tropy. For the preprocessing of the fiber tractography and anal-
ysis of fractional anisotropy, we used the FMRIB Software Li-
brary (FSL), version 4.1.617 (www.fmrib.ox.ac.uk/fsl). This
analysis included the following steps: 1) creation of a brain mask
of the reference volume (no diffusion) by segregating brain tissue
from nonbrain tissue using Brain Extraction Tool18; 2) eddy cur-
rent and head movement correction using EDDYCORRECT
from FMRIB’s Diffusion Toolbox17; 3) rotation of the gradients
by taking the corrected parameters from the eddy current and
head movement into account; and 4) local fitting of diffusion
tensors and constructing of individual FA maps using DTIFIT
from FMRIB’s Diffusion Toolbox.17
We performed fiber tractography with the Diffusion Toolkit
0.5 and TrackVis 0.5.119 (www.trackvis.org) based on a standard
protocol for corticospinal tract tractography (for details, see
appendix e-2). The FA of the corticospinal tract was analyzed in
2 different steps. First, we analyzed the mean FA value of the
entire corticospinal tract ranging from the primary sensorimotor
cortex to the brainstem. Second, we used a voxel-based analysis
of the corticospinal tract to identify the particular location with
possible FA difference within the corticospinal tract. For the first
step, the mean FA value was obtained for the left and right corti-
cospinal tract by averaging the FA values of all voxels belonging
to the respective tract. We compared the mean FA value of the
corticospinal tract from the first examination with the mean FA
value from the second examination using a Wilcoxon test (FA
values were not normally distributed: Kolmogorov-Smirnov test,
Z ⫽ 1.425, p ⫽ 0.034) separately for each hemisphere (thresh-
old was set at p ⬍ 0.05). For the second step, we applied a
voxel-based analysis on the FA maps using the statistical para-
metric mapping (SPM8) software package (www.fil.ion.ucl.ac.
uk/spm). In addition to the preprocessing steps applied with FSL
and described above, a linear and nonlinear registration of the
FA maps into a standard space was applied, and these registered
FA maps were smoothed with a Gaussian kernel of full-width at
half-maximum ⫽ 12 mm. We excluded voxels with a FA lower
than 0.2 before analyses because previous studies showed that
this threshold successfully excludes voxels, which are primar-
ily gray matter or CSF in the majority of subjects.20 Because
we were particularly interested in the corticospinal tract, we
restricted the analysis to the probability map of the cortico-
spinal tract.21 We examined differences within the corticospi-
nal tract using paired t tests, which were performed with the
Neurology 78 January 17, 2012 183

Figure 1 Structural change in cortical thickness induced by deprivation of
motor and sensory inputs
We found decreases in cortical thickness only in the left hemisphere between time point 1
and time point 2. A significant decrease was found in the left precentral gyrus, in the supe-
rior postcentral gyrus, and in the inferior postcentral gyrus. In addition, trend plots for the
primary motor area cluster (time point 1: mean ⫽ 2.70 mm; SE ⫽ 0.16 mm; time point 2:
mean ⫽ 2.54 mm; SE ⫽ 0.17 mm) and the average of the 2 primary sensory areas (time
point 1: mean ⫽ 2.35 mm; SE ⫽ 0.18 mm; time point 2: mean ⫽ 2.29 mm; SE ⫽ 0.15 mm)
illustrate cortical thickness for each subject and time point. Note that the trend plots are
only for descriptive purposes and no statistical trend analyses were done on these mean
measures of the significant clusters.
general linear model implemented in SPM8 (threshold of p ⬍
0.05, corrected for multiple comparisons combined with a
cluster extent threshold of k ⫽ 20 voxels).
As for the surface-based morphometry, we evaluated the
neural correlate of the behavioral improvement of the left upper
extremity using a regression analysis. We correlated the differ-
ence of the performances in the MLS between the 2 time points
with the change in mean FA of the corticospinal tract (threshold
of p ⬍ 0.05) and voxel-wise within the corticospinal tract
(threshold of p ⬍ 0.05, corrected for multiple comparisons com-
bined with a cluster extent threshold of k ⫽ 20 voxels).
RESULTS Behavioral data analysis. Comparing the
first (within 48 hours after the injury) with the sec-
ond examination (after an average of 16 days of de-
privation), the analysis of the MLS motor skill
performance revealed a significant performance in-
crease for the left hand (t(df⫽9) ⫽ 4.75; p ⫽
0.00016). We used the difference in the standardized
average performance in the MLS between the 2 time
points for correlation analysis with the surface-based
and diffusion tensor imaging (DTI) data (see below).
Surface-based morphometry analysis. The longitudi-
nal analysis of cortical thickness revealed a decrease
184 Neurology 78 January 17, 2012
only in the left hemisphere, namely in primary motor
area (Montreal Neurological Institute [MNI] coordi-
nates: x ⫽ ⫺35, y ⫽ ⫺21, z ⫽ 53; z score(df⫽9) ⫽
⫺3.61; p ⫽ 0.00015) and 2 clusters in the primary
somatosensory area (cluster 1: x ⫽ ⫺58, y ⫽ ⫺18,
z ⫽ 46; z score(df⫽9) ⫽ ⫺2.86; p ⫽ 0.002; cluster 2:
x ⫽ ⫺50, y ⫽ ⫺21, z ⫽ 57; z score(df⫽9) ⫽ ⫺2.76;
p ⫽ 0.003) (figure 1, table e-2). These regions are
likely to represent the hand area.22,23 When the corti-
cal thickness between the first and the second time
point was compared, there were no significant differ-
ences in the right hemisphere.
The investigation of whether there was a relation-
ship between brain structure and improved behav-
ioral performance of the left (noninjured) upper arm
and hand revealed that better motor proficiency of
the left hand (as measured with the MLS) is associ-
ated with an increase in cortical thickness in the right
primary motor cortex extending into the premotor
cortex (x ⫽ 43, y ⫽ 3, z ⫽ 42; z score(df⫽9) ⫽ 3.10;
p ⫽ 0.00096). In the left hemisphere, in contrast, the
better the behavioral performance of the subdomi-
nant left hand, the larger was the decrease in cortical
thickness in the transition zone between primary mo-
tor and somatosensory cortex (x ⫽ ⫺16, y ⫽ ⫺26,
z ⫽ 57; z score(df⫽9) ⫽ ⫺2.97; p ⫽ 0.0015) (figure
2, table e-3).
Fiber tractography and analysis of fractional aniso-
tropy. We successfully obtained tractographies of the
corticospinal tract in all subjects and in both hemi-
spheres (figure 3, A and B). There was a significant
decrease in mean FA from the first to the second
examination only in the left corticospinal tract (z
score(df⫽9) ⫽ ⫺1.99; p ⫽ 0.024). To specify the ex-
act location of the FA difference within the corticospi-
nal tract, we applied a voxel-based analysis. We
identified a significant decrease in FA, primarily in the
origin of the left corticospinal tract (MNI coordinates:
x ⫽ ⫺14, y ⫽ ⫺43, z ⫽ 69; z score(df⫽9) ⫽
⫺2.92; p ⫽ 0.002) (figure 3D). There were no sig-
nificant differences in FA within the right corticospi-
nal tract between the 2 time points.
Investigating the relationship between improved
behavioral performance of the left (noninjured) up-
per arm and the mean FA changes of the corticospi-
nal tract, we found a positive correlation between
improved performance and mean FA of the left cor-
ticospinal tract, which, however, did not reach statis-
tical significance (Spearman’s correlation coefficient
r ⫽ 0.30; p ⫽ 0.39, two-tailed). The cluster, which
was subsequently identified with the voxel-based
analysis, is located in the upper part of the right cor-
ticospinal tract and showed a significantly positive
correlation between the behavioral improvement and
 Figure 2 Correlation between increased motor skill performance and cortical thickness

Correlation between the change in cortical thickness and the improvement of the behavioral performance is displayed. We found a significant positive
correlation in the left precentral gyrus and a negative relationship between the behavioral performance in the left hand and the right central sulcus. In
addition, correlation graphs illustrate the relationship between change in cortical thickness and the improvement of the behavioral performance. Note that
the correlation graphs are only for descriptive purposes and no statistical analyses were done on these mean measures of the significant cluster. MLS ⫽
Motor Performance Series.

FA (x ⫽ 27, y ⫽ ⫺23, z ⫽ 64; z score(df⫽9) ⫽ 3.54;
p ⫽ 0.0002) (figure e-2).
DISCUSSION The present longitudinal investiga-
tion examined whether a reduction of motor output
and sensory input is reflected in structural plastic
changes in gray and white matter in the human
brain. The cortical thickness decreases are located in
the “inverted omega” shape of the central sulcus
where the somatotopic representation of the hand is
situated22,23 and are in line with similar morphologic
changes in the context of focal hand dystonia in pa-
tients experiencing writer’s cramp.24 The decrease in
FA in the corticospinal tract emphasizes that both
the cortical motor and somatosensory regions and
the afferent and efferent pathways connected to these
cortical regions are affected. There have been similar
findings in animal studies.25 In these studies, con-
straining the use of a forelimb during early develop-
ment affected the topology and morphology of
corticospinal tract axon terminals.26 Restriction of
forelimb activity also reduced the forelimb represen-
tation in the motor cortex.27
The present study used a standard protocol for
corticospinal tract tractography. However, this
method does not allow the afferent and efferent path-
ways to be disentangled. The decreased FA in the
corticospinal tract may therefore reflect changes in
the efferent or afferent fiber tract. However, animal
and human studies showed that the differentiation
between afferent and efferent pathways is indeed
problematic28,29 because these fibers are partly inter-
mingled, making it very difficult to separate them.
Cortical thickness in our study is a measure of the
brain’s gray matter, which contains primarily neu-
rons. The formation of strong local connections
(0 –3 mm) between neurons within this thin sheet,
the thickness of which is just 1.5– 4.5 mm, has pro-
moted the idea of local processing units. Decreased
cortical thickness (as in our study) could be due to a
smaller arborization per neuron, decreased glial vol-
ume, or decreased regional vasculature. Our findings
might therefore suggest that local processing units
within the sensorimotor cortex are changed during
immobilization. Further experiments are needed
to compare imaging results with histologic data for
identification of the structural basis of these
deprivation-dependent structural changes in hu-
man brains, both at the microscopic and macro-
scopic level.

Neurology 78 January 17, 2012 185


Figure 3 Fiber tractography and fractional anisotropy (FA) analysis
Displayed are FA changes in the corticospinal tract induced by deprivation of motor out-
puts and sensory inputs. (A) Illustrative construction of the corticospinal tract for time point
1 and time point 2, with the seed and the target regions of interest. (B) Three supplemental
representative corticospinal tracts for time point 1 and time point 2 are presented. The
colors in A and B indicate the FA values within the corticospinal tract. (C) A trend plot for
the mean FA values of the whole fiber tract for each subject and time point demonstrate the
significant decrease in mean FA (Wilcoxon test: z ⫽ ⫺1.99, p ⫽ 0.024). (D) The subsequent
voxel-based analysis found a decrease in FA in the left hemisphere between time point 1
and time point 2 in the left postcentral gyrus (x ⫽ ⫺14, y ⫽ ⫺43, z ⫽ 69, with z score ⫽
⫺2.92, p ⫽ 0.002) extending into the precentral gyrus.
An interesting associated effect found in the pres-
ent study is the compensatory usage of the nonde-
prived left (subdominant) upper extremity for daily
life skills such as dressing, dental hygiene, or operat-
ing a computer mouse. Previous studies explored
structural plasticity in the context of new skill acqui-
sition (e.g., juggling or musical training).30,31 In these
studies, increases in gray matter volume were ob-
served in brain areas involved in controlling the ex-
pertise task. Our study sought to explicitly test the
motor skill of the unaffected hand to define any com-
pensatory improvement in the performance of the
unaffected hand. We identified substantial perfor-
mance enhancement in various measures of hand
skill of the unaffected subdominant hand tested by a
standard and comprehensive test battery of fine mo-
tor abilities. In particular, the stronger the skill im-
provement is, the stronger are the cortical thickness
increases in the motor and premotor cortex of the
right hemisphere. Previous studies showed that the
premotor cortex is important for visuomotor adapta-
tion and object manipulation, as is the case for the
186 Neurology 78 January 17, 2012
left hand in the present study.32,33 Besides the as-
sumption that the right hemispheric changes reflect
plasticity due to skill acquisition or transfer of skills,
it is also plausible that simply the increased stimula-
tion of the left upper extremity during immobiliza-
tion of the right led to these changes.
Because in mature primary sensory cortices, the
gross morphology of neurons and their circuitry does
not change dramatically under normal condi-
tions,34,35 our findings suggest that the structure of
the human brain is altered by deprivation and by
transfer of skills from the right to the left upper ex-
tremity. The obvious benefit of the CNS’s plastic
capacity is the acquisition of new skills, and it is rea-
sonable to assume that plasticity is a characteristic of
the nervous system that evolved for coping with
changes in the environment as expressed by increases
or decreases in cortical thickness and alterations in
the fiber structure.2,36
Our results might have implications for neuropsy-
chological therapies, especially for interventions such
as constraint-induced therapy approaches. For exam-
ple, the unaffected arm is immobilized during
constraint-induced movement therapy to force mo-
bility of the affected arm.37 As demonstrated in our
study, immobilization of one arm results in cortical
thickness decreases in brain areas involved in process-
ing somatosensory information of the immobilized
arm. Thus, in addition to the positive effects on the
hemisphere ipsilateral to the affected limb, immobili-
zation has, at least temporarily, a substantial negative
effect on cortical thickness and FA in neural net-
works contralateral to the affected limb. However,
because we do not provide follow-up data, we could
make no statement about the functional conse-
quences nor determine whether the decrease in corti-
cal thickness will be long lasting. Nevertheless, recent
studies demonstrated that rehabilitation therapy
without constraining the unaffected arm may also
facilitate therapeutic success, for example, by solely
motivational capacities.38 Further studies have to be
conducted to investigate whether using a restraint in
stroke patients with paralyzed limbs is really a neces-
sity for improving arm and hand motor perfor-
mance. Moreover, based on these findings, the
trauma surgery guidelines39,40 suggesting that an in-
jured extremity should be immobilized “as short as
possible, as long as necessary,” received substantial
support by our findings.
A limitation of our study is the relative low num-
ber of subjects. Increasing the number of participants
could on the one hand enable studying gender differ-
ences and on the other hand improve the quality of
the correlation analysis, because for both objectives
our sample size is rather small.
 This longitudinal study shows that deprivation of
the sensorimotor network by immobilization of the
right arm causes specific neuroanatomical changes in
the cortical gray and white matter architecture. We
found these changes primarily in regions responsible for
the sensorimotor control of the upper extremity. The
findings highlight the capacity of the human brain to
adapt rapidly to changing demands. In addition, the
morphologic changes in gray and white matter shed fur-
ther light on the potential biologic consequences of sen-
sorimotor deprivation. Because deprivation of a limb is
often used in rehabilitation therapy, these results should
be considered in clinical practice.
AUTHOR CONTRIBUTIONS
N. Langer: study concept/design, data acquisition, statistical analysis and
interpretation, wrote the manuscript. Dr. Hänggi: data acquisition, statis-
tical analysis and interpretation, revising of the manuscript. Dr. Müller:
patient recruitment, data acquisition, revising of the manuscript. Dr. Sim-
men: patient recruitment, revising of the manuscript, advice as clinical
expert in trauma surgery. Dr. Jäncke: study concept/design, statistical
analysis, revising of the manuscript, study supervision and coordination.
DISCLOSURE
N. Langer, Dr. Hänggi, Dr. Müller, and Prof. Simmen report no disclo-
sures. Prof. Jäncke serves on editorial advisory boards for Laterality, Neu-
roReport, Zeitschrift für Neuropsychologie (Herausgeber), Brain and
Language, Swiss Journal of Psychology, Psychological Science, European Jour-
nal of Developmental Sciences, Frontiers in Neurosciences, Psychological Re-
search, Quarterly Journal of Psychological Research, and Restorative
Neurology; has received publishing royalties for Macht Musik schlau? (Hu-
ber Verlag Göttingen, 2008) and Einführung in bildgebende Verfahren
(Kohlhammer Verlag, 2005); and has received research support from the
Swiss (SNF) and German Science (DFG) foundations and from the Euro-
pean Commission.
Received June 6, 2011. Accepted in final form September 7, 2011.
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188 Neurology 78 January 17, 2012

 Effects of limb immobilization on brain plasticity
N. Langer, J. Hänggi, N.A. Müller, et al.
Neurology 2012;78;182-188
DOI 10.1212/WNL.0b013e31823fcd9c

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