1Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland 21287-7713; and 2Graduate Program in Physical Therapy, School of Medicine, University of California, San Francisco, California
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ABSTRACT |
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Lenz, Fred A. and Nancy N. Byl. Reorganization in the Cutaneous Core of the Human Thalamic Principal Somatic Sensory Nucleus (Ventral Caudal) in Patients With Dystonia. J. Neurophysiol. 82: 3204-3212, 1999. A wide range of observations suggest that sensory inputs play a significant role in dystonia. For example, the map of the hand representation in the primary sensory cortex (area 3b) is altered in monkeys with dystonia-like movements resulting from overtraining in a gripping task. We investigated whether similar reorganization occurs in the somatic sensory thalamus of patients with dystonia (dystonia patients). We studied recordings of neuronal activity and microstimulation-evoked responses from the cutaneous core of the human principal somatic sensory nucleus (ventral caudal, Vc) of 11 dystonia patients who underwent stereotactic thalamotomy. Fifteen patients with essential tremor who underwent similar procedures were used as controls. The cutaneous core of Vc was defined as the part of the cellular thalamic region where the majority of cells had receptive fields (RFs) to innocuous cutaneous stimuli. The proportion of RFs including multiple parts of the body was greater in dystonia patients (29%) than in patients with essential tremor (11%). Similarly, the percentage of projected fields (PFs) including multiple body parts was higher in dystonia patients (71%) than in patients with essential tremor (41%). A match at a thalamic site was said to occur if the RF and PF at that site included a body part in common. Such matches were significantly less prevalent in dystonia patients (33%) than in patients with essential tremor (58%). The average length of the trajectory where the PF included a consistent, cutaneous RF was significantly longer in patients with dystonia than in control patients with essential tremor. The findings of sensory reorganization in Vc thalamus are congruent with those reported in the somatic sensory cortex of monkeys with dystonia-like movements resulting from overtraining in a gripping task.
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INTRODUCTION |
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Dystonia is a movement disorder characterized by
sustained muscle contractions that lead to twisting movements and
abnormal postures (Fahn 1988). Many observations suggest
that dystonia is characterized by abnormal processing of sensory
information (reviewed by Hallett 1995
). Abnormal sensory activity, in
fact, has been found in the CNS of patients with dystonia (dystonia patients) studied by positron emission tomography (Tempel and Perlmutter 1995
). Monkeys with dystonia-like movements after
overtraining in a gripping task showed somatic sensory degradation
characterized by large receptive fields (RFs), RFs from multiple body
parts located along a single cortical penetration, and RFs overlapping adjacent digits (Byl et al. 1996b
). In dystonia
patients, however, the activity of neurons in a representation of
cutaneous sensory structures within the human CNS has not previously
been reported.
Medically intractable dystonia can be treated by thalamotomy
(Andrew et al. 1983; Cardoso et al. 1995
;
Cooper 1976
; Tasker et al. 1988
). During
such operations, the location of the target is first defined by
radiological studies (Bertrand and Lenz 1995
; Vitek and Lenz 1997
). Thereafter, microelectrode
recordings may be used to confirm the target predicted by the
radiological studies. These physiological studies provide a unique
opportunity to examine thalamic neuronal activity in dystonia patients.
We now report changes in the representation of cutaneous structures in
the core of the principal somatic sensory nucleus of the thalamus
(ventral caudal, Vc) in dystonia patients.
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METHODS |
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Twenty-six patients were studied during the physiological
exploration that precedes stereotactic thalamotomy for treatment of
dystonia or essential tremor. The somatic sensory thalamus was explored
in these patients to determine the anterior and inferior borders of Vc,
which predict the borders of the thalamic nucleus ventral intermediate
(Vim) and the thalamic nucleus ventral oral posterior (Vop), which are
the nuclei to be lesioned during thalamotomy for dystonia or tremor
(Bertrand and Lenz 1995; Hua et al.
1998
; Lenz et al. 1994b
; Zirh et al.
1999
). Therefore, Vc was thoroughly examined in both patient
groups. Analysis was restricted to the cutaneous core of Vc, defined as
the region where the majority of cells respond to innocuous, cutaneous,
mechanical stimuli. This region probably corresponds to Vc and thalamic
ventral caudal parvocellular nucleus (Vcpc) (Lenz et al.
1988b
, 1993b
). The previously described
operative, physiological, and analytic methods are outlined briefly
here (Lenz et al.1993
, 1994b
). The protocol used
in these studies conforms to the principles stated in the Declaration
of Helsinki regarding the use of human subjects and is reviewed and approved annually by the Johns Hopkins University Joint Committee on
Clinical Investigation.
Operative procedures
The stereotactic coordinates of the anterior
commissure-posterior commissure line were determined by computerized
tomography or magnetic resonance imaging. The target region was
explored with a microelectrode that was advanced along trajectories
made through a burrhole located 1.5 cm lateral to the midline at the level of the coronal suture (Lenz et al.1988a). The
first trajectory was toward Vc, the most reliable landmark for the
exploration. Next, the regions anterior to Vc
presumed Vim and
presumed Vop
were explored to identify the optimal lesion site.
Physiological exploration with the microelectrode involved both
recording of neuronal activity and stimulation at microampere current
levels (Lenz et al. 1994b
).
During recordings, we examined two aspects of neuronal activity in particular: spontaneous firing pattern and neuronal activity during somatic sensory stimulation. The somatic sensory examination included stimulation of both cutaneous structures and structures deep to the skin. Cutaneous sensory cells responded to touch or pressure applied to the skin. Deep sensory cells responded to joint movement and/or squeezing of muscles or tendons but did not respond to stimulation of the skin deformed by these stimuli.
Microstimulation was delivered through the microelectrode in trains of
approximately 1 s duration at 300 Hz by means of a biphasic pulse
consisting of a 0.2 ms anodal pulse followed 0.1 ms later by a 0.2 ms
cathodal pulse of the same magnitude. The effect of the stimulation on
dystonia was assessed with the patient's arm elevated. Additionally,
during stimulation, patients were asked if they felt anything. If any
effect was observed, the current was first decreased in a series and
then increased in a series until a threshold for the effect was
established (threshold microstimulation; see Lenz et
al.1993). The quality and location of the evoked sensation (projected field, PF) was then determined.
The lesion site in dystonia patients was chosen at sites anterior to Vc where cells displayed activity related to the dystonia and had deep RFs, and where stimulation evoked changes in the patient's dystonia. One or more lesions were made at sites with these properties. Lesions were made by introducing a radiofrequency lesioning electrode (outside diameter 1.1 mm, exposed length 3 mm) with a thermistor at the tip to monitor temperature (TM electrode, Radionics Inc., Burlington, MA). To make each lesion, the temperature of the electrode was held at 70° and then at 80° centigrade for 1 min for each temperature. Neurological examinations stressing pyramidal tract, sensory, speech, and cerebellar functions were carried out before, during, and after each lesion.
Data analysis
In this study, Vc in patients with essential tremor was compared
with that in patients with generalized dystonia. Somatotopic organization was assessed by the number of different body parts included in PFs or in RFs, the match between RF and PF at one site, and
the length of the trajectories with consistent RFs or PFs. A
multiple-part RF for a single neuron is defined by the presence of two
or more separate cutaneous parts of the body and a multiple-part PF is
defined by the presence of two or more separate cutaneous parts of the
body. In identifying parts of the body, we followed the conventions
used in previous studies (Byl et al. 1996b; Lenz
et al. 1988b
). Specifically, separate parts of the body
included separate digits, thenar eminence, hypothenar eminence, palm,
forearm, upper arm, lip, chin, outer surface of the cheek, inner
surface of the cheek, nose, forehead, tongue, gums, ear, thigh, lower
leg, foot (excluding toes), and toes. When the RF and the PF were
limited to the same part of the body, they were said to form a match.
When the RF and PF included both the same part of the body and other
separate body parts, they were said to have a partial match. When the
RF and PF did not overlap, they were said to form a mismatch.
Two sites were said to have a consistent RF if the RF of both sites
included the same part of the body. The length of a trajectory with
consistent RFs is the distance along the trajectory where each RF
continues to include the same part of the body. The part of the body
chosen for any trajectory length was the part that maximized the length
of the trajectory with a consistent RF. The same convention was applied
to PFs. Human thalamic somatotopy in Vc is a function of the
mediolateral plane and rows of trajectories were aligned in
parasagittal planes (Lenz et al. 1988b). The maximal distance along a trajectory over which the RF or the PF stays consistent is longer for body parts with larger representations (Lenz
et al. l994a). This technique of estimating the size of representations
is arbitrary, but it conforms to our previous studies in humans
(Lenz et al. 1994a
, 1998b
). The same
conventions were applied to all patients studied.
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RESULTS |
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These data describe the results of cellular recordings at 382 sites along 45 microelectrode trajectories for 15 patients with essential tremor and at 388 sites along 49 microelectrode trajectories through the cutaneous core of Vc in 11 dystonia patients (Table 1). Figure 1 is a map of RFs and PFs in the region of Vc for a patient with essential tremor; sites 77-97 constitute the cutaneous core of Vc. This map shows the representation of the digits and lip. As is common in patients with tremor (tremor patients), no neurons had multiple-part RFs in the cutaneous core of Vc. Multiple-part PFs occurred at 5 of 8 stimulation sites (63%). The RF representation of the third digit (sites 77-81) was 0.95 mm long and the second digit (sites 82 and 83) was 0.31 mm long. The PF representation of the third digit (sites 77-80) was 0.5 mm long and the second digit (sites 83-92) was 2.8 mm long. Examples of mismatches are seen at sites 85 and 92.
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A map for a patient with dystonia is shown in Fig.
2. The trajectory traversed the
representation of cutaneous structures in the hand in the core of Vc
(sites 14-22). In this patient, 5 of 9 cells (55%) in the cutaneous
core of Vc had multiple-part RFs (thenar or hypothenar and palm,
fourth/fifth and thumb/second digit). This patient had multiple-part
PFs at 7 of 8 sites (88%) in the cutaneous core of Vc. Obviously,
multiple-part RFs and PFs were more common in this dystonia patient
(Fig. 2) than in the tremor patient (Fig. 1). In both patients,
multiple-part PFs were more common than multiple-part RFs. In the
patient shown in Fig. 2, the RF representation of the fifth digit was
1.6 mm long whereas the PF distribution of the fifth finger (sites
14-20) was 3.1 mm long. These are large distributions
considering that the RF representation of the fifth digit is normally
the smallest of all the digits (Lenz et al. 1994a).
Examples of mismatches are seen at sites 17 and 22.
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Evidence of somatotopic reorganization: multiple-part RFs
The differences in the presence of multiple-part RFs and PFs for patients with essential tremor and those with dystonia are summarized in Table 2. Significantly more neurons with multiple-part RFs (chi square, P < 0.00001) and significantly more stimulation sites with multiple-part PFs occurred in dystonia patients than in tremor patients (chi square, P < 0.0002). Thus PFs and RFs involving more than one part of the body were significantly more common in dystonia patients than in tremor patients.
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Length of trajectories with RFs or PFs
Figure 3 provides a visual representation of the length and distribution of the trajectories with consistent neuronal RFs for the controls and the dystonia patients. The trajectories with consistent PF were significantly longer [Fig. 3B, P < 0.05, Kruskal Wallis analysis of variance (ANOVA) by ranks] for dystonia patients than for controls with essential tremor. Lengths of trajectories with consistent RFs did not differ significantly (Fig. 3A, P > 0.05, Kruskal Wallis ANOVA by ranks) between these two patient groups.
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Match between RFs and PFs
Each of the neuronal RFs and the PFs at a site was coded according to body parts (Fig. 4, inset), and all were plotted against each other (Fig. 4). For this section of the analysis, all digits together (labeled "multiple digits" in the inset) and the hand excluding digits (labeled "palm/hand" in the inset) were considered as separate parts of the body. The PF of a stimulation site where a cell was not recorded was paired with the RF of the closest recorded cell. For example, in Fig. 1, stimulation at site 88 was paired with the RF for the cell recorded at site 89. For any RF/PF pair, we plotted the part of the body to which the RF of the recorded cell was closest against the part of the body involved in the PF (Fig. 4A, essential tremor; Fig. 4B, dystonia). Thus points on the 45°-angle line indicate thalamic sites where the RF and PF matched or partially matched. The number of such sites was significantly higher (chi square, P < 0.002) in patients with essential tremor (36 of 62 or 58%) than in patients with dystonia (33 of 103 or 32%).
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Effects of duration and age of onset of dystonia on reorganization
The effect of duration and age of onset of dystonia on reorganization in the cutaneous core of Vc was examined. The population of patients with duration of dystonia <5 yr (n = 2) was compared with that with duration of >5 yr (n = 9). The patients with the longer duration of dystonia had a significantly greater (chi square, P < 0.001) percentage of cells with multiple RFs (35.7%) than did patients with the shorter duration of dystonia (7.4%). Differences between these two groups in mismatch of RFs and PFs and in numbers of trajectories with constant RF length >1 mm were not significant.
The population of patients with onset at age <10 yr (n = 8) was compared with the population with age of onset >33 yr (n = 3). The patients with the younger age of onset had a significantly greater (chi square, P < 0.001) percentage of cells with multiple RFs (29.7%) than did the patients with later onset (6.7%). Differences between these two groups in mismatches of RFs and PFs and in numbers of trajectories with constant RF length >1 mm were not significant.
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DISCUSSION |
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The findings from this study suggest that significant somatotopic
reorganization of Vc occurs in patients with dystonia. Given the input
from Vc to the primary sensory cortex (Jones 1985), this
finding is consistent with reports of somatic sensory reorganization in
cortical area 3b in monkeys with focal dystonia caused by overtraining for a gripping task (Byl et al. 1996a
,b
, l997). These
results thus lend support to the suggestion that somatic sensory
reorganization occurs in thalamocortical circuits as a result of, and
perhaps as a cause of, dystonia.
Methodologic considerations
Time constraints in the operating room greatly limit mapping the
human thalamus as compared with mapping the monkey cortex. To obtain
enough data to draw conclusions about sensory reorganization, we
collected data from a relatively large number of patients
(n = 26). However, the total number of neuronal RFs and
PFs for each patient was limited. Therefore, interindividual
differences may significantly influence the results. For patients with
essential tremor, there are no known neurological abnormalities other
than tremor and the population is relatively homogeneous (Watts
and Koller 1998). Maps of the thalamic location of RFs
(Lenz et al. 1988a
) and PFs (Lenz et al.
1993
) are similar in essential tremor and many other disorders,
but we have no way of knowing how such maps would compare with those of
normal controls. An earlier detailed analysis of motor thalamus in the
dystonia patients reported here suggested that characteristics of
dystonia and sensory properties of neurons were relatively constant in
this population (Lenz et al. 1999
). Thus the major
features of sensory organization may be similar among patients
within each of the two groups. Finally, because our conclusions depend
on comparisons of the two populations, the statistical techniques
should account for the variability within each population.
The location of the core of Vc rests entirely on the
physiological criteria. The region where the majority of cells respond to innocuous cutaneous stimuli probably corresponds to Vc and Vcpc
(Lenz et al. 1988b, 1993
); this is our
inference based on comparisons with monkey studies employing
histological confirmation of recording sites (Jones
1985
, Kaas 1991
). Of course, we have no way of
anatomically confirming the location of the region described in this report.
Somatic sensory activity: somatotopic reorganization
Interruption of somatic sensory inputs leads to reorganization of
somatotopic maps in the principal sensory nucleus of the thalamus in
monkeys and humans. Monkey or raccoon ventral posterior lateral pars
caudalis, corresponding to human Vc (Jones 1985), has
been studied after adult nerve injury or digit amputation (Garraghty and Kaas 1991
; Rasmusson
1996
). Increased representation of the stump of an
amputated digit was found with large RFs that included both
the stump and adjacent digits. In humans, major reorganization of
inputs to Vc occurs in patients with chronic pain after spinal
transection (Lenz et al. 1994a
) or amputation (Davis et al. 1998
; Lenz et al.
1998
). Representations of the part of the body next to
the area of sensory loss are increased and PFs are poorly matched to
RFs. Thus changes in human thalamic organization are consistent with
those found in animals after interruption of somatic sensory inputs.
The present results suggest that thalamic sensory organization is
plastic and thus can be altered by dystonia, as it can be by
deafferentiation. In this study involving sampling of cells from Vc,
the cellular RFs were more likely to have multiple body segments
represented in each RF in dystonia patients than in tremor patients. In
addition, there was a poorer match between RFs and PFs at any site.
Similar alterations in sensory organization in Vim in many of these
same dystonia patients have been briefly described (Lenz et al.
1999). To our knowledge, that study and the present one are the
only reports of thalamic plasticity in the presence of alterations in
motor behavior.
Neural plasticity in response to interruption of sensory input and
motor behavior is better established in the cortex where it may arise,
in part, as a result of thalamic reorganization. It is well known that
cortex, specifically area 3b, adapts to interruption of sensory input
after peripheral nerve transections (Merzenich et al. 1983a,b
,
1987
; Wall et al. 1986
), dorsal
rhizotomies (Pons et al. 1991
), surgical amputation
(Kelahan and Doetsch l984; Merzenich et al. l984; Rassmusson l982),
surgical syndactyly (Clark et al. l988), and nerve crush with skin
reinnervation (Wall et al. 1983
).
Training in different behavioral paradigms has been observed to change
the representation of the body in the primate sensory cortex.
Behavioral training at a constant skin locus (e.g., tip of one digit,
Recanzone et al. 1992) and behavioral training in which stimuli move
across the skin (Jenkins et al. l990) produced changes in the cortical
representation of the body. Cortical plasticity induced by behavior can
be characterized by an increased differentiation of the representation
of the body part, including unusually small RFs, and by an increased
area of somatic sensory representation of the body part that is
involved in the behavioral paradigm (Jenkins et al. l990; Recanzone et
al. 1992
). Alternatively, dedifferentiation of the representation of
the body can occur and is characterized by unusually large RFs and a
decreased area of somatic sensory representation (Merzenich et
al. 1983b
; Wang et al. 1995
).
Reorganization of the motor cortical representation can also result
from learned repetitive motor tasks (Nudo et al.1992
,
1996
). It is also likely that somatic sensory disorganization
is a potential outcome of excessive use, chronic pain, or nearly
coincident repetitive inputs (Byl et al. 1996b
; 1997
;
Elbert et al. l995; Flor et al. 1997
; Wang et al.
1995
). The effect of these behavioral manipulations appears to
depend on the age of onset and the duration of the motor behavior
(Kaas 1991
), as in the present data.
Thalamocortical plasticity in dystonia
In monkeys, sensory cortex has been studied in dystonia-like
movements induced by repetition of a motor task involving rapid opening
and closing of a manipulandum (Byl et al. 1996b, 1997
). These monkeys developed hand cramps characterized by disordered motor
coordination and posturing reminiscent of dystonia (Byl et al.
1996b
; Hallett 1995
). In these animals,
representations of the hand surface are remodeled in the primary
sensory cortex, area 3b (Byl et al. l996b, l997). The cutaneous RFs
extend across multiple digits and the whole hand. This somatotopic
reorganization is strikingly different from the normal representation
of the hand of the adult monkey, which is defined by small, distinct, orderly, topographical RFs (Kaas 1991
; Merzenich
et al. l987). The present results demonstrate that similar
changes in the thalamic cutaneous representation occur in dystonia patients.
The learning hypothesis for focal hand dystonia suggests that
repetitive, nearly simultaneous sensory inputs lead to a degradation of
the somatic sensory representation of the hand. This mechanism may
apply in patients who perform repetitive jobs (e.g., data entry clerks,
musicians) under conditions of high cognitive drive (Byl et al.
1996a,b
). A similar mechanism could apply to patients with
generalized dystonia if the dystonic movements lead to nearly simultaneous stimulation of the afferents from different cutaneous structures or from different muscle groups. It is unclear, however, if
the observed changes are merely a consequence of dystonia. Recent
studies of reorganized areas of Vim demonstrate that thalamic activity
leads and might drive EMG activity in dystonia, that stimulation in
these areas can increase dystonia, and that lesions of these areas can
decrease dystonia (Lenz et al. 1999
). These findings
make it unlikely that cortical changes are responsible for the
alteration in thalamic activity. Thus reorganization of thalamic
structures such as that reported here might contribute to dystonia.
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ACKNOWLEDGMENTS |
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We thank L. H. Rowland for excellent technical assistance. We also thank F. Baker, M. DeLong, J. O. Dostrovsky, R. L. Martin, R. T. Richardson, R. R. Tasker, and J. L. Vitek for assistance during various stages of this project.
This research was supported by grants from the Eli Lilly Corporation and National Institute of Neurological Disorders and Stroke Grants NS-28598, K08-NS-1384, and P01 NS-32386, Project 1, to F. A. Lenz.
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FOOTNOTES |
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Address for reprint requests: F. A. Lenz, Dept. of Neurosurgery, Meyer Building 7-113, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287-7713.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 22 February 1999; accepted in final form 31 August 1999.
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REFERENCES |
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