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Changes in brain anatomy in focal hand dystonia.

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Changes in Brain Anatomy
in Focal Hand Dystonia
Gaëtan Garraux, MD, PhD,1,2 Andrew Bauer,1
Takashi Hanakawa, MD, PhD,1 Tao Wu, MD,1
Kenji Kansaku, MD, PhD,1 and Mark Hallett, MD1
No consistent cerebral anatomical abnormality has ever
been reported in primary focal hand dystonia (FHD). The
present voxel-based morphometry study showed a significant bilateral increase in gray matter in the hand representation area of primary somatosensory and, to a lesser extent, primary motor cortices in 36 patients with unilateral
FHD compared with 36 controls. The presence of anatomical changes in the perirolandic cortex for the unaffected
hand as well as that for the affected hand suggests that
these disturbances may be, at least in part, primary.
Ann Neurol 2004;55:736 –739
Focal hand dystonia (FHD) is a primary dystonia produced by excessive cocontraction of antagonist pairs of
hand and forearm muscles.1,2 In many cases, the abnormal movement is unilateral and task specific, occurring during a skilled motor task such as writing or
playing a musical instrument. It is a common clinical
observation that FHD patients have a long history of
repetitive, stereotyped hand movements before the onset of dystonia.
Many aspects of the pathophysiology of primary dystonia remain unclear, and both the site and nature of
initial dysfunction are still unknown. There is increasing evidence to suggest that disturbances in the sensory
system play an important pathogenic role.3–5 In FHD,
a disorganized homonculus representation of the hand
in the primary sensorimotor cortex (S1M1) has been
described by many physiological studies.4,6 – 8 Interestingly, bilateral abnormalities were sometimes reported.4
In addition, basal ganglia dysfunction has been frequently incriminated in dystonia.9
In contrast with most previous brain mapping stud-
From the 1Human Motor Control Section, Medical Neurology
Branch, National Institute of Neurological Disorders and Stroke,
National Institutes of Health, Bethesda, MD; and 2Cyclotron Research Center and Department of Neurology, University of Liège,
Sart Tilman, Liège, Belgium.
Received Oct 7, 2003; and in revised form Mar 3, 2004. Accepted
for publication Mar 4, 2004.
Published online Apr 26, 2004, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.20113
Address correspondence to Dr Hallett, Human Motor Control Section, NINDS, NIH, Building 10, Room 5N226, 10 Center Drive,
MSC 1428, Bethesda, MD 20892-1428.
E-mail: hallettm@ninds.nih.gov
736
ies, this study focuses on anatomical rather than functional changes. To the best of our knowledge, no neuropathological data have ever been reported in FHD,
and conventional magnetic resonance imaging (MRI)
does not show any anatomical abnormality. Taking
into account the robustness of changes in the functional organization of both left and right perirolandic
cortices and/or lenticular nuclei described in multiple
studies, we predicted that those regions might be structurally impaired in FHD. To test that hypothesis, we
took advantage of voxel-based morphometry (VBM)10
to process and analyze high-resolution anatomical
MRIs prospectively collected in a relatively large group
of patients and controls.
Subjects and Methods
Informed verbal and written consent for this research protocol, which was approved by the National Institute of Neurological Disorders and Stroke (NINDS) Institutional Review Board, were obtained from all patients and controls.
Demographic and clinical data are summarized in Table 1.
Subjects with prior head trauma with loss of consciousness,
epilepsy, brain surgery, systemic illness, or excessive drug or
alcohol misuse were not included.
The diagnosis of primary FHD was made by medical history and the NINDS standard neurological examination.
The chief complaint was difficulty writing and playing a musical instrument in 31 and 5 cases, respectively. One patient
also had spasmodic dysphonia. All subjects were scanned on
the same 3T GE Signa system (General Electric, Milwaukee,
WI) using a unique standard head coil (IGC Medical Advances, Milwaukee, WI). A three-dimensional structural
MRI scan of the brain was acquired using a T1-weighted
inversion recovery fast spoiled gradient recall (FSPGR) sequence designed to optimize the tissue contrast between gray
and white matter (TR, 8.2 milliseconds; TE, 3.3 milliseconds; TI, 725 milliseconds; flip angle, 6 degrees; matrix size,
256 ⫻ 256, yielding 124 contiguous axial slices with a thickness of 1.3 mm and in-plane resolution of 0.97 ⫻ 0.97
mm).
Data were processed and analyzed using the statistical
parametric mapping software (SPM2, http://www.fil.ion.ucl.ac.uk/spm). VBM refers to a fully automated, unbiased,
validated11 whole-brain morphometric technique in which
MRIs are processed and analyzed to test for regional structural differences on a voxel-wise basis between groups of subjects.10 An optimized version of the VBM protocol was followed to refine spatial normalization of the data by using a
customized, population-specific, symmetric gray matter template.12 To test for group differences in gray matter volume
(GMV), we modulated data by the Jacobian determinants
from deformation parameters used for spatial normalization.10 The spatially normalized and modulated gray matter
partitions were smoothed using an 8 mm full-width at halfmaximum Gaussian kernel. Finally, images from the four patients whose affected hand was on the left were left-right
flipped so that the hemisphere contralateral to the affected
hand was on the left for all patients.
Processed images of gray matter were analyzed in the
© 2004 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
Table 1. Demographic and Clinical Data
Characteristic
Patients
Controls
p
No. of subjects
36
36
—
15/21
15/21
—
Sex (F/M)a
Mean age (years) ⫾ SD 53 ⫾ 9.7 52 ⫾ 9.6
NS
Handedness (L/R)
3/33
2/34
NS
Estimated duration of
13 ⫾ 7
—
—
illness (yr) ⫾ SD
Affected hand (L/R)
4/32
—
—
Disability scoreb (%) ⫾ 53 ⫾ 21
—
—
SD
131 ⫾ 40 84 ⫾ 13 ⬍0.0001
Writing timed testc
(seconds) ⫾ SD
a
The sex prevalence in our focal hand dystonia sample is similar to
that reported in epidemiological studies.1
b
Patients were tested according to the Fahn dystonia disability scale
as previously described.5 A score of 100% corresponds to a lack of
awareness of any disability; patients with simple writer’s cramp1
have a score of 75% or above.
c
Twenty-six patients and all controls wrote a standard paragraph,
and the time in seconds for completion was recorded. Five patients
could not complete the task because of the dystonia, and data from
patients with musician’s cramp (N ⫽ 5) were discarded. Both the
disability scale and written timed sentence were administered on the
day of the magnetic resonance imaging study.
SD ⫽ standard deviation; NS ⫽ not significant.
framework of the general linear model. In addition to the
regressors modeling the main effect of the groups, age, and
gender, total GMV also was incorporated in the design matrix (analysis of covariance) to improve the normality of the
residuals and to examine regional differences between groups
beyond those occurring due to a difference in total GMV.10
Indeed, the mean total GMV calculated from nonnormalized
segmented images was significantly greater in the group of
patients (0.734 ⫾ 0.056 liters) than in the controls (0.706 ⫾
0.052 liters; two-tailed t test, p ⫽ 0.04).
Group differences in regional GMV were assessed statistically using a two-tailed contrast, namely, testing for an increase or a decrease probability of a particular voxel representing gray matter. Significance level was set at p value less
than 0.05 after family-wise error correction for multiple
comparisons in the entire volume of analysis. The correction
was limited to a spherical volume (small volume correction
[SVC]) around regions where an effect was hypothesized,
namely, S1M1 and lenticular nuclei.
Results
The most significant result is a relative increase in
GMV in the hand representation area13 of perirolandic
cortices in the patients (Fig; Table 2). We also tentatively report an increase in GMV in left S1 area 1, left
and right dorsolateral premotor and inferior parietal areas, left dorsolateral prefrontal cortex, and right cerebellum ( p ⬍ 0.001, uncorrected), but those results are
not discussed because they did not reach the level of
significance specified a priori. There is no significant
group difference in GMV in either lenticular nucleus
even for lowered statistical threshold and SVC accord-
ing to our prior hypothesis. There are no regions showing a significant decrease in GMV in FHD relative to
controls.
Discussion
This study is the first to our knowledge to demonstrate
that there are robust disturbances in gray matter in the
hand representation area of S1 and possibly M1 when
FHD patients are compared with controls. The anatomical change identified here corresponds to an increase in GMV. This finding is consistent with disorganized cortical representation of the hand in S1M1
suggested by functional studies.4,6 – 8 The anatomical
nature of the changes identified here strongly emphasizes the critical role of these regions in the pathophysiology of FHD.
The most significant abnormality detected by VBM
is located in a region most probably corresponding to
the hand representation13 of S1 areas 3b and 2, bilaterally.14,15 The topography of those findings is consistent with subtle sensory disturbances reported in both
hands in FHD patients.16 An increase in GMV in the
adjacent M1 area 413 cannot be excluded. There is an
inherent spatial ambiguity introduced by the curved
path of the central sulcus and neighboring gyri in that
region. This combined with spatial averaging and blurring of MRI data inherent to VBM makes it very difficult to separate hand areas 4 and 3b. Nevertheless, if
anatomical disturbances in gray matter in the hand
representation area of M1 exist in FHD patients, these
results suggest that they are much less widespread than
those in S1.
There are no other regions showing a significant
group difference. The absence of detectable abnormality in basal ganglia is in contradiction with most9
but not all17 clinicoanatomic correlation studies in
secondary dystonia. The discrepancy with a region of
interest–based MRI study that showed a 10% increase
in putamen volume in patients with primary dystonia18 might be related to several methodological factors among which the type of patients studied and the
methods used for data analysis are the most important.
How relevant are structural changes in S1M1 in the
pathogenesis of FHD? A first interpretation is that they
may be related to nonspecific plastic changes. This is
unlikely and the strongest evidence against this is the
high specificity of their topography (ie, hand area). Another explanation is that they are secondary to overuse
and/or maladaptative plasticity. However, if those
mechanisms were predominant, one also would predict
that changes would be proportionally more pronounced in M1 than S1, the opposite pattern of what
is found here. Furthermore, FHD patients usually
avoid practicing the task that triggers the dystonia and
because dystonia was on average present for 13 years at
Garraux et al: Brain Anatomy in Hand Dystonia
737
Fig. Areas of increased gray matter in focal hand dystonia. The SPM{t} is thresholded at T ⬎ 3.22 (peak) and of 290 voxels (spatial extent). Results are superimposed on axial (A) and sagittal (B, C) slices through the mean magnetic resonance image (MRI) in
standard stereotaxic space from all 72 study subjects. Sagittal slices are shown from the hemisphere contralateral (B) and ipsilateral
(C) to the affected hand. Values in the upper right corner of each image indicate the distance (in mm) of the image from the axial
plane through the anterior and posterior commissures (A) and from the parasagittal plane through the midline (B, C). Note the
position of the statistical peaks in relation to that of the hand area defined as an omega-shaped formation in the central sulcus in
the axial plane and a hook-like folding of the cortical mantle in the sagittal plane.13 According to probabilistic atlases in humans,
area 3b is located in the posterior wall of the central sulcus, whereas area 1 sits in the crown, and area 2 sits in the posterior bank
of the postcentral gyrus, respectively.14,15 By convention in this study, the hemisphere contralateral to the dystonic hand corresponds
to the left hemisphere (L).
Table 2. Relative Increase in Gray Matter Volume in Focal Hand Dystonia
MNI Coordinatesa
Brodmann’s Area
x
Hemisphere contralateral to the affected hand (left)
S1/M1
3b/4
⫺38
S1
3b
⫺33
S1
2
⫺38
S1
2
⫺45
Hemisphere ipsilateral to the affected hand (right)
S1/M1
3b/4
38
S1
3b
45
S1
2
41
y
z
Z-score
p
(SVC)b
⫺24
⫺31
⫺31
⫺25
58
60
65
51
3.77
3.24
3.68
3.18
0.009
0.042
0.012
0.049
⫺21
⫺15
⫺29
59
57
64
3.90
3.81
3.72
0.006
0.008
0.01
a
Coordinates (in mm) of peak group differences in MNI space (Montreal Neurological Institute, http://www.bic.mni.mcgill.ca) are given for
information. Anatomical localization of voxel-based morphometry detected peak differences was assessed on the average spatially normalized
magnetic resonance image from all 72 subjects (see Fig) rather than on coordinates in stereotaxic space. This approach is appropriate because
it takes into account the variance of brain structures between subjects under investigation. Moreover, individual images of gray matter were
spatially normalized on a customized template that was specific for the data under investigation and thus that did not perfectly match the
canonical template image in MNI space (see Subjects and Methods).
b
p values are given after family-wise error correction for multiple comparisons in a 10 mm radius spherical volume.
738
Annals of Neurology
Vol 55
No 5
May 2004
the time of the MRI, it is questionable to explain an
increased GMV in S1M1 by overuse and/or maladaptative plasticity only. Finally, one would expect secondary changes restricted to or more pronounced in the
hemisphere contralateral to the affected hand, which
does not agree with our results. Indeed, the magnitude
of the increase in GMV in hand area in the hemisphere
contralateral to the dystonic hand is similar to that in
the hand area of the opposite hemisphere (see Table 2)
despite the fact that MRI data were processed in a way
that the hemisphere contralateral to the affected limb
was on the same side (left) in all patients regardless of
the laterality of the dystonic hand. Although direct evidence is still missing, bilateral disturbances in S1M1
of patients clinically diagnosed with unilateral primary
FHD described in this and previous studies4 supports
the notion that both hemispheres might be originally
affected by genetic and/or epigenetic factors rendering
dystonia patients more vulnerable to environmental
factors, such as repetitive, stereotyped motions. Future
studies should directly test this hypothesis.
11. Maguire EA, Gadian DG, Johnsrude IS, et al. Navigationrelated structural change in the hippocampi of taxi drivers. Proc
Natl Acad Sci USA 2000;47:4398 – 4403.
12. Good CD, Johnsrude I, Ashburner J, et al. A voxel-based morphometric study of ageing in 465 normal adult human brain.
Neuroimage 2001;14:21–36.
13. Yousry TA, Schmid UD, Alkadhi H, et al. Localization of the
motor hand area to a knob on the precentral gyrus. A new
landmark. Brain 1997;120:141–157.
14. Geyer S, Schormann T, Mohlberg H, et al. Areas 3a, 3b, and 1
of human primary somatosensory cortex. Part 2. Spatial normalization to standard anatomical space. Neuroimage 2000;11:
684 – 696.
15. Grefkes C, Geyer S, Schormann T, et al. Human somatosensory area 2: observer-independent cytoarchitectonic mapping,
interindividual variability, and population map. Neuroimage
2001;14:617– 631.
16. Molloy FM, Carr TD, Zeuner KE, et al. Abnormalities of spatial discrimination in focal and generalized dystonia. Brain
2003;126:2175–2182.
17. Burguera JA, Bataller L, Valero C. Action hand dystonia after
cortical parietal infarction. Mov Disord 2001;16:1183–1185.
18. Black KJ, Ongur D, Perlmutter JS. Putamen volume in idiopathic focal dystonia. Neurology 1998;51:819 – 824.
This study was supported by grants from the Horlais-Daspens
Foundation (G.G.), the Belgian American Educational Foundation
(G.G.), North Atlantic Treaty Organization (NATO) (G.G.), and
the NIH (National Institute of Neurological Disorders and Stroke
G.G.). G.G. is a postdoctoral researcher at the Belgian National
Fund for Scientific Research.
We thank E. Considine, for her help in recruiting patients and D.
Schoenberg, for skillful manuscript editing.
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Garraux et al: Brain Anatomy in Hand Dystonia
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