Departments of 1Neurosurgery and 2Neurology, Johns Hopkins Hospital, Baltimore, Maryland, 21287-7713; and 3Department of Neurology, Emory University, Atlanta, Georgia 30322
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ABSTRACT |
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Lenz, F. A., C. J. Jaeger, M. S. Seike, Y. C. Lin, S. G. Reich, M. R. DeLong, and J. L. Vitek. Thalamic Single Neuron Activity in Patients With Dystonia: Dystonia-Related Activity and Somatic Sensory Reorganization. J. Neurophysiol. 82: 2372-2392, 1999. Indirect evidence suggests that the thalamus contributes to abnormal movements occurring in patients with dystonia (dystonia patients). The present study tested the hypothesis that thalamic activity contributes to the dystonic movements that occur in such patients. During these movements, spectral analysis of electromyographic (EMG) signals in flexor and extensor muscles of the wrist and elbow exhibited peak EMG power in the lowest frequency band [0-0.78 Hz (mean: 0.39 Hz) dystonia frequency] for 60-85% of epochs studied during a pointing task. Normal controls showed low-frequency peaks for <16% of epochs during pointing. Among dystonia patients, simultaneous contraction of antagonistic muscles (cocontraction) at dystonia frequency during pointing was observed for muscles acting about the wrist (63% of epochs) and elbow (39%), but cocontraction was not observed among normal controls during pointing. Thalamic neuronal signals were recorded during thalamotomy for treatment of dystonia and were compared with those of control patients without motor abnormality who were undergoing thalamic procedures for treatment of chronic pain. Presumed nuclear boundaries of a human thalamic cerebellar relay nucleus (ventral intermediate, Vim) and a pallidal relay nucleus (ventral oral posterior, Vop) were estimated by aligning the anterior border of the principal sensory nucleus (ventral caudal, Vc) with the region where the majority of cells have cutaneous receptive fields (RFs). The ratio of power at dystonia frequency to average spectral power was >2 (P < 0.001) for cells in presumed Vop often for dystonia patients (81%) but never for control patients. The percentage of such cells in presumed Vim of dystonia patients (32%) was not significantly different from that of controls (31%). Many cells in presumed Vop exhibited dystonia frequency activity that was correlated with and phase-advanced on EMG activity during dystonia, suggesting that this activity was related to dystonia. Thalamic somatic sensory activity also differed between dystonia patients and controls. The percentage of cells responding to passive joint movement or to manipulation of subcutaneous structures (deep sensory cells) in presumed Vim was significantly greater in patients with dystonia than in control patients undergoing surgery for treatment of pain or tremor. Dystonia patients had a significantly higher proportion of deep sensory cells responding to movement of more than one joint (26%, 13/52) than did "control" patients (8%, 4/49). Deep sensory cells in patients with dystonia were located in thalamic maps that demonstrated increased representations of parts of the body affected by dystonia. Thus dystonia patients showed increased receptive fields and an increased thalamic representation of dystonic body parts. The motor activity of an individual sensory cell was related to the sensory activity of that cell by identification of the muscle apparently involved in the cell's receptive field. Specifically, we defined the effector muscle as the muscle that, by contraction, produced the joint movement associated with a thalamic neuronal sensory discharge, when the examiner passively moved the joint. Spike X EMG correlation functions during dystonia indicated that thalamic cellular activity less often was related to EMG in effector muscles (52%) than in other muscles (86%). Thus there is a mismatch between the effector muscle for a thalamic cell and the muscles with EMG correlated with activity of that cell during dystonia. This mismatch may result from the reorganization of sensory maps and may contribute to the simultaneous activation of multiple muscles observed in dystonia. Microstimulation in presumed Vim in dystonia patients produced simultaneous contraction of multiple forearm muscles, similar to the simultaneous muscle contractions observed in dystonia. These observations are consistent with a model in which sensory input to Vim in dystonia is transmitted through altered sensory maps to activate multiple muscles in the periphery, producing the overflow of muscle activation that is characteristic of dystonia.
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INTRODUCTION |
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Dystonia is a movement disorder characterized by sustained muscle
contractions leading to twisting movements and abnormal postures
(Fahn 1988). There is indirect evidence that neuronal activity in a cerebellar relay nucleus of the human thalamus (ventral intermediate, Vim) and in a pallidal relay nucleus (ventral oral posterior, Vop) is related to dystonic movements. Lesions in Vim and
Vop can relieve dystonia (Andrew et al. 1983
;
Cardoso et al. 1995
; Cooper 1976
;
Gros et al. 1976
; Laitinen 1970
;
Tasker et al. 1988
), and stimulation of Vim and Vop can
increase (Tasker et al. 1982
) or decrease dystonic
movements (Benabid et al. 1996
). The effects of thalamic
lesioning and stimulation may be related to abnormalities in sensory
processing observed in the CNS (Reilly et al. 1992
;
Tempel and Perlmutter 1990
, 1995
). These results suggest
that thalamic activity is related to dystonic movements.
The characteristics of dystonic movements have not previously been
studied quantitatively, but descriptive studies show slow variation of
electromyographic (EMG) activity and cocontraction of antagonists
around a joint during spontaneous or movement-evoked dystonia
(Marsden and Rothwell 1987; Yanagisawa and Goto
1971
; Yanagisawa et al. 1972
). Rapid phasic
bursts also are reported in individual muscles or in both agonists and
antagonists together (Cohen and Hallett 1988
;
Rothwell et al. 1983
; Yanagisawa and Goto
1971
). Because EMG activity in dystonia is variable, thalamic neuronal and EMG activity must be studied together to understand the
relationship of neuronal activity to dystonia.
The purpose of the present study was to test the hypothesis that
thalamic activity contributes to dystonic movements. We investigated thalamic neuronal signals and EMG activity recorded during surgical procedures for the treatment of dystonia. We found altered spontaneous activity in Vop and somatic sensory reorganization in Vim of dystonia patients, findings that suggest a model for the mechanism of dystonia. A preliminary report has been published (Zirh et al.
1998).
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METHODS |
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The operative, physiological, and analytic procedures are
outlined briefly because they have been described in previous
publications (Lenz et al. 1988a-c
, 1990
, 1993
).
Operative procedures
Observations were made during the physiological exploration
preceding either stereotactic thalamotomy for treatment of dystonia or
tremor or the implantation of deep brain stimulating electrodes for
treatment of chronic pain. During the first stage, the Leksell stereotactic frame was applied and the coordinates of the anterior commissure-posterior commissure (AC-PC) line were determined. Neuronal
activity in the thalamus was recorded with a high-impedance microelectrode (Lenz et al. 1988a,b
). The first
electrode trajectory was directed toward the principal somatic sensory
nucleus (ventral caudal, Vc), the most reliable landmark for the
exploration. Subsequently the region anterior to Vc was mapped by
analysis of both single neuron activity and effects of microstimulation
(Lenz et al. 1988a
).
During neuronal recordings, we examined the spontaneous firing pattern, the relationship of spontaneous activity to dystonia, and the neuronal activity during somatic sensory stimulation and active movement. Cutaneous sensory cells responded to touch or pressure to the skin. Deep sensory cells responded to joint movement and/or squeezing of muscles or tendons in the absence of any response to stimulation of skin deformed by these stimuli. Care was taken to isolate movements to single joints.
Microstimulation was delivered in trains of ~1-s duration at 300 Hz
by using biphasic pulses consisting of a 0.2-ms anodal pulse followed
in 0.1 ms by a 0.2-ms cathodal pulse of the same magnitude. At each
stimulation site, the patient was asked to elevate his/her arm, and the
effect of the stimulation on dystonia was assessed. Additionally,
patients were asked to describe stimulation-evoked sensations using a
standard protocol (Lenz et al. 1993, 1994a
). If any
effect was observed, then a threshold was determined for the effect
(threshold microstimulation, TMIS) (Lenz et al. 1993
).
The lesion site in patients with dystonia was located anterior to the principal sensory nucleus (Vc) where the majority of cells responded to cutaneous stimulation. Lesion sites were chosen in regions where cells displayed activity related to dystonic movements and where microstimulation evoked changes in the dystonic movements. Lesions were made by using a radiofrequency lesioning electrode with an outside diameter of 1.1 mm and an exposed length of 3 mm (TM electrode, Radionics, Burlington, MA). A neurological examination to evaluate pyramidal tract function, cutaneous sensation, speech, and cerebellar function was carried out before, during, and after each stage of lesion making. Lesions were made in two stages, with the temperature of the electrode held at 70°C for 1 min and then at 80°C for 1 min.
An egg white test was carried out to estimate the size of the lesion
made by this technique (Cosman and Cosman 1985). The electrode was suspended in egg white maintained at 37°C, and a lesion
was made as described in the preceding text. The resulting coagulum was
measured with calipers. The coagulum approximated a cylinder with a
diameter of 3 mm [2.8 ± 0.1 (SD) mm,
n = 5] and a length of 5 mm (4.9 ± 0.1)
(Lenz et al. 1995
). Lesions of this size compare
favorably with those measured by others using a similar electrode
(Cosman and Cosman 1985
).
Movement paradigm and assessment
Dystonic movements occurred spontaneously in the upper limb in all patients and increased when the patients elevated the arm. Patients were seated in a reclining position with the back tilted 20° above the horizontal. Patients then were asked to point toward the ceiling (arm elevated). This action flexed (45°) and abducted the shoulder (45°) and extended the elbow, wrist, metacarpophalangeal, and interphalangeal joints (~160°). Neuronal activity was assessed for 20-60 s with the arm in this position. The activity of a subpopulation of cells (15 cells in 3 patients) was assessed with the arm in two separate positions, elevated and at rest. Throughout the analysis differences in these two positions were compared statistically for this subpopulation.
Thalamic neuronal activity was recorded as previously described
(Lenz et al. 1988b). Standard techniques were used to
record EMG activity in wrist flexors, wrist extensors, biceps, and
triceps (Lenz et al. 1988c
). EMG activity in deltoid was
not monitored because dystonia, either at rest or during pointing,
always involved elbow and wrist more than shoulder. Neuronal and EMG
signals were recorded on a multiple channel tape recorder (Model 4000, Vetter, Rebersburg, PA). An audio channel recorded a description of the procedure, and another channel recorded the signal from a foot pedal,
indicating the duration of somatic sensory stimuli.
Analytic procedures
Tape-recorded neuronal and EMG activities were examined
postoperatively. The present report focuses on single neuron activity recorded in the region where cells exhibited activity related to active
or passive movements of the upper extremity (Lenz et al.
1990). Action potentials were discriminated by amplitude
(D-DISI, Bak Electronics, Rockville, MD) and confirmed to arise from a single cell. The confirmation criterion was constant shape of the
action potential as verified by displaying the shape on a storage
oscilloscope. Times of occurrence of discriminated action potentials
were stored at a clock rate of 1,000 Hz. EMG signals were digitized at
a rate of 200 Hz on a digital computer (11/73, Digital Equipment). The
data were analyzed on a workstation (DECstation 3100, Digital
Equipment) with SAS, version 6.
Figure 1 shows an example of
simultaneously recorded thalamic and EMG activity in a patient with
dystonia. Both thalamic and EMG signals varied slowly at about the same
frequency and increased at 4 s and possibly at 6 and 7.5 s.
Visual examination of the spike and EMG signals, however, is inadequate
to assess either the composition of or the correlation between the
spike and EMG signals. Therefore thalamic and EMG signals were analyzed
in the frequency domain. The spike train was converted into an
equivalent analog signal by use of the French-Holden algorithm
(French and Holden 1971; French et al.
1972
; Glaser and Ruchkin 1976
; Lenz et
al. 1988c
). The EMG signal first was processed to eliminate movement artifact by band-pass filtering (
6 dB below 20 Hz and above
120 Hz). The envelope of EMG activity then was produced by full-wave
rectification and filtering (
6 dB above 20 Hz). The 10% cosine rule
then was applied to eliminate low-frequency components generated by
finite sampling of the signals (Glaser and Ruchkin
1976
).
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Standard techniques used to take the spectrum of these two
signals resulted in 256 estimates of the spectrum between 0 and 25 Hz
(Bendat and Piersol 1976; Glaser and Ruchkin
1976
; Lenz et al. 1988c
; Oppenheim and
Schafer 1975
). Cross-correlation spectral analysis (Fig. 1,
B-D) was carried out to determine whether the two signals
were correlated. The raw power spectra are shown in Fig. 1,
B and C, left (resolution, 0.1 Hz). In Fig. 1,
B and C, right, eight contiguous, nonoverlapping
spectral estimates are averaged to produce smoothed spectral estimates
(resolution, 0.78 Hz). Smoothed spectra give a more statistically
reliable estimate but at a cost of decreased resolution (Glaser
and Ruchkin 1976
).
The coherence function was evaluated as a measure of the
probability that two signals were related linearly. The coherence had a
value of 0 if the spike and EMG signals were not linearly related and a
value of 1 if the two had a perfect linear relationship (Bendat
and Piersol 1976; Glaser and Ruchkin 1976
;
Lenz et al. 1988c
; Oppenheim and Schafer
1975
). A coherence of >0.42 at a given frequency indicated
that the two signals were likely (P < 0.05) to be
related linearly at that frequency (Benignus 1969
). The
signals in Fig. 1 were coherent in the lowest frequency band as
indicated by a coherence of 0.5. Phase was calculated by standard techniques (Bendat and Piersol 1976
; Glaser and
Ruchkin 1976
; Lenz et al. 1988c
;
Oppenheim and Schafer 1975
) so that a negative phase for
the cross-correlation function spike X EMG indicated that the spike
signal was phase advanced on the EMG signal. The phase of the spike X
EMG function at the frequency of dystonia in Fig. 1 was
100°, which
indicated that the spike train was phase advanced on the EMG signal.
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RESULTS |
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The patient population included 10 patients with dystonia
undergoing thalamotomy for treatment of the disorder (see Table 1). In accord with accepted definitions,
dystonia was classified as either primary and secondary (Fahn
1988). Primary dystonia was either familial or sporadic and was
characterized by the absence of an identifiable underlying cause.
Secondary dystonia was caused by a specific disease or lesion.
Secondary dystonia affecting the upper and lower extremity on the same
side was termed hemidystonia. All patients selected for surgery had
disabling distal upper extremity dystonia, characterized by twisting
movements rather than sustained postures.
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For studies of thalamic dystonia-related activity the control population consisted of five patients (referred to as "controls with pain") undergoing implantation of deep brain stimulating electrodes in the thalamus for treatment of deafferentation pain. Four of these patients had a complete and one an incomplete thoracic spinal cord transection. None had motor or sensory abnormalities involving the upper extremity. For the study of EMG activity, the four control subjects (referred to as "normal controls") were normal by neurological history and examination.
Comparisons between dystonia patients and controls are of interest, although they are constrained by limitations of human intraoperative studies. In dystonia patients, all cells were studied during pointing, and a subpopulation of cells was studied during pointing and with the arm at rest. In this subpopulation, spike data were similar during pointing and with the arm at rest. In controls with pain, cells were studied with the arm at rest. Spike data in dystonia patients (83 cells, 19 electrode trajectories) were compared with that in controls with pain (59 cells, 11 electrode trajectories).
EMG signal
CHARACTERISTICS OF EMG POWER IN DYSTONIA.
Studies of EMG signals in dystonia focused on spectral composition of
these signals and the degree to which different EMG channels were
cross-correlated. A linear relationship between two signals was
explained most easily if the two signals had a similar spectral
composition (Bendat and Piersol 1976; Glaser and
Ruchkin 1976
; Lenz et al. 1988c
;
Oppenheim and Schafer 1975
). Therefore the spectral
composition of EMG activity first was studied as a basis for
interpreting the spectral composition of thalamic signals. Because
thalamic activity was to be analyzed relative to multiple EMG channels,
we analyzed the degree to which different EMG channels were
cross-correlated with each other. After studies of spectral composition
and cross-correlation of EMG channels, we analyzed the relationship
between thalamic and EMG signals.
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ANALYSIS OF SIMULTANEOUS CONTRACTION.
To assess the degree to which muscles were contracting simultaneously,
we performed cross-correlation analysis between pairs of muscles
throughout the upper extremity (Fig. 4).
Simultaneous contraction of muscle pairs was defined by EMG peaks at
dystonia frequency with coherence >0.42 and phase difference less than |30°|. Simultaneous contraction of antagonistic muscles
(cocontraction) occurred in 63% (42/67) of epochs for antagonists
about the wrist and 39% (26/67) of epochs for antagonists about the
elbow. Differences between patients in the proportions of epochs
showing simultaneous contraction were not significant for antagonists
about the elbow (P > 0.09, 2)
or wrist (P > 0.3,
2), a
finding that suggests cocontraction was not a function of the etiology
of dystonia (Table 1).
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Thalamic spike signal
NEURONAL LOCATION.
Because neuronal properties may vary between nuclei, neuronal location
was considered before details of neuronal activity were studied. In
human studies mapping this area, the anterior border of Vc usually is
estimated from the most anterior cell in the region where the majority
of cells respond to either deep or cutaneous stimulation (Lenz
et al. 1990, 1994c
). This distinguishes Vc from Vim, where deep
sensory cells are less common. This border was poorly defined in
dystonia patients because of the high density of deep sensory cells in
presumed Vim in many of these patients (Figs.
5 and 7). For this
reason, the physiological map was shifted along the AC-PC line until
the most anterior cell responding to cutaneous stimulation was at the
anterior border of Vc. The borders of presumed Vim and presumed Vop
were determined from this transformed map.
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MEAN INTERSPIKE INTERVALS IN PATIENTS WITH DYSTONIA AND IN CONTROLS WITH PAIN. We first compared basic properties of the spike train among patients with dystonia. Differences in mean interspike intervals (ISIs) among these patients were not significant (1-way ANOVA, F = 2.38, df = 3, P > 0.07), suggesting that the firing rate of spontaneous activity during dystonia was not related to etiology. In dystonia patients, spontaneous neuronal activity during pointing was recorded for all cells; some cells were studied both during pointing and at rest, but no significant difference (1-way ANOVA F = 0.50, df = 1, P > 0.4) in the mean ISI was found between the two positions. Thalamic firing rates in patients with dystonia were thus independent of arm position and could be compared with those of the control population with the arm at rest. Table 2 lists mean ISIs for thalamic neurons in dystonia patients and in control patients with pain. Populations of neurons also were grouped by nuclear location (row A) and the presence of sensory input (row B).
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CHARACTERISTICS OF SPIKE POWER.
In dystonia patients, the peak spike activity usually occurred at
dystonia frequency (Fig. 6). The
proportion of neurons with peak activity at dystonia frequency was
significantly higher (P < 0.005, 2) in patients with dystonia than the
proportion in controls with pain. For the subpopulation of cells
studied during pointing and with the arm at rest in dystonia patients,
the average frequency of peak spike power did not vary significantly
(F = 0.68, df = 1, P > 0.4)
between the two positions. Therefore with the arm elevated or at rest,
peak activity at dystonia frequency was much more common in dystonia
patients than in controls with pain.
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POPULATIONS OF CELLS WITH POWER CONCENTRATED IN THE LOWEST
FREQUENCY BAND.
Table 3 shows populations of cells having
peak spectral power at dystonia frequency and a ratio of power at
dystonia frequency to total spectral power (signal-to-noise ratioSNR)
greater than two. The proportion of cells with a dystonia frequency
peak of SNR
2 was significantly higher (P < 0.05,
2) for patients with dystonia (37/83, 44.6%)
than for control patients with pain (15/59, 25.4%). The proportion of
nonsensory cells with a dystonia frequency peak of SNR
2 was
significantly higher in patients with dystonia than in controls
(P < 0.01,
2). The proportion
of sensory cells with these characteristics did not differ
significantly (P > 0.05,
2)
between these two populations.
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Spike X EMG function in patients with dystonia
The spike X EMG coherence did not vary significantly between muscles (1-way ANOVA, F = 0.92, df = 3, P > 0.4) nor did spike X EMG functions differ substantially between a single cell and each of the four muscles studied. Eleven cells had significant spike X EMG coherence at dystonia frequency for two of the muscles studied. Three cells had significant spike X EMG coherence for three muscles, and two cells had significant spike X EMG coherence for all four of the muscles studied. For 81% (13/16) of these cells, maximal differences in spike X EMG coherence between different EMG channels coherent with the spike train were <0.1. For 75% (12/16) of these cells, maximal differences in spike X EMG phase were <60°. Therefore EMG channels correlated with a single thalamic cell often had correlation functions with similar phase and coherence, perhaps because of the degree of simultaneous contraction in dystonia (see ANALYSIS OF SIMULTANEOUS CONTRACTION). Because no single channel could be identified as the one best related to EMG activity in dystonia, spike X EMG functions were studied for all channels.
One possible explanation of the correlation between channels was they were studied during pointing, a movement that involves all muscles studied. This explanation seemed unlikely because different EMG channels were uncorrelated during pointing in normal controls. Nevertheless to assess this possibility, we analyzed coherence in the subpopulation of cells studied during pointing and with the arm at rest. There was no significant difference by arm position and muscle group in the spike X EMG coherence (2-way ANOVA, F = 0.60, df = 7, P > 0.75). The difference in phase could not be statistically tested because of the small number of cells with interpretable phase (i.e., spike X EMG coherence >0.42). These results suggested that thalamic activity, EMG activity, and the relationship between them were independent of arm position in patients with dystonia.
Spike X EMG as a function of location in presumed Vim or presumed Vop
The spike X EMG function at dystonia frequency was examined for
both presumed Vim and presumed Vop. This analysis showed no significant
difference (P > 0.05, 2) in
the percentage of cells having spike X EMG coherence >0.42 between
presumed Vim (range for the 4 EMG channels: 28-46%) and presumed Vop
(range: 13-23%) for any of the four EMG channels, perhaps due to the
small sample. Thus there was no significant difference between presumed
Vim and presumed Vop in the proportion of cells correlated with EMG activity.
The number of spike X EMG pairs showing negative phase was examined
separately for each EMG channel. The proportion of cells with a
negative phase for any EMG channel was the same (P > 0.05, 2) in presumed Vim (range of percentages
for the 4 EMG channels: 50-83%) and presumed Vop (range: 66-100%).
Thus spike activity was phase advanced on EMG activity in dystonia for
most spike X EMG functions in both presumed Vim and presumed Vop.
Differences between EMG channels were not significant.
Thalamic somatic sensory activity
For studies of somatic sensory activity, the control group was
enlarged to allow statistical comparisons. This group (referred to as
"controls with pain or tremor") consisted of patients undergoing thalamotomy for the treatment of essential tremor (2 patients), cerebellar tremor (4 patients), and tremor in Parkinson's disease (3 patients), in addition to the five patients with chronic pain. The
patients with Parkinson's disease had the tremor predominant variant,
with tremor and cogwheel rigidity but no dystonia and minimal
bradykinesia (Paulson and Stern 1997).
A total of 38 electrode trajectories were made in the dystonia patients
and 43 in the controls with pain or tremor. All electrode trajectories
in a patient were separated by 2 mm. Neuronal recordings were made
from 483 cells in the region of presumed Vim and presumed Vop of
patients with dystonia and from 412 cells in the controls. The target
for the surgery was Vc in patients with pain (Hosobuchi 1986
), Vim in patients with tremor (Lenz et al.
1995
), and Vim/Vop in patients with dystonia (Bertrand
and Lenz 1995
). Therefore the exploration in controls with pain
or tremor was biased toward Vc and Vim, whereas the exploration in
dystonia patients was biased toward Vop and Vim. To correct for the
differences in sampling of Vc, presumed Vim, and presumed Vop by
patient population, neuronal results are reported by nucleus.
Somatic sensory activity
ANATOMIC DISTRIBUTION. Figure 5 shows a dystonia patient's map of the thalamus with nuclear location shifted to align the anterior border of Vc with the location of the most anterior cutaneous sensory cell. Numerous cells in the region anterior to Vc were classified as deep sensory cells. This figure illustrates the large area in which cells respond to movements of the wrist (P5, 116-121, and P4, 72-78). Many of these cells (site numbers 79, 111, 114, 120, 122, and 123) responded to movements of more than one joint. The number of deep sensory cells responding to movement of more than one joint was significantly higher in patients with dystonia (26%, 13/52) than in control patients (8%, 4/49; Fisher exact, P < 0.05).
In Fig. 7, the locations of cells from different patients are displayed relative to presumed Vim and presumed Vop (transformed as earlier described in NUCLEAR LOCATION) for control patients with pain or tremor (left, n = 8) and for patients with dystonia (right, n = 10). Deep sensory cells are present in presumed Vim and presumed Vop of both groups of patients. This finding is consistent with several recent studies in the corresponding nuclei, ventral posterior lateral pars oralis (VPLo) and ventral lateral pars oralis (VLo) (Hirai and Jones 1989a
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THALAMIC REORGANIZATION IN DYSTONIA.
In addition to the increased percentages of deep sensory cells, there
was an apparent increase in the size of the representation of
individual joints in presumed Vim of patients with dystonia. For
example, passive wrist movements were represented over a distance of
3.2 mm in electrode trajectory P4 of patient C (see Fig. 5, sites 72-78). Detailed mapping of the two- or three-dimensional extent
of the representation of deep structures could not be justified clinically, although it is the standard in monkey studies. For this
reason, the maximum size of the representation of a part of the body
was estimated from the lengths of single electrode trajectories along
which all RFs included a single joint as in a previous study
(Lenz et al. 1994b). We restricted our analysis to the
wrist or elbow representation to target the thalamic area in which
these joints are represented (Lenz et al. 1988b
, 1990
). The bias toward this representation is indicated by the incidence of
RFs, which included the wrist or elbow joint for 79% of all deep RFs
in dystonia patients.
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Spike X EMG functions for sensory and nonsensory cells
The correlation between thalamic and EMG activity was
studied to examine the mechanism by which sensory cells influenced
dystonia. At dystonia frequency, the proportion of cells with coherence >0.42 for one spike X EMG function did not differ significantly (P > 0.05, 2) between
nonsensory cells (range for EMG channels 1-4: 25-32%; n = 58 cells) and sensory cells (range: 0-60%;
n = 25) for any EMG channel. Differences between the
number of sensory and nonsensory cells showing phase <0 were assessed
for each EMG channel separately. This analysis showed no significant
difference (P > 0.05, Fisher exact test) in the
percentage of sensory cells having spike X EMG phase <0 (range for the
4 EMG channels: 0-100%) and the percentage of nonsensory cells
(range: 40-100%) for any of the four EMG channels. Overall, sensory
and nonsensory cells were equally likely to be correlated with and to
lead EMG activity.
Spike X EMG functions of individual sensory cells
We next examined the spike X EMG function for the EMG channel appropriate to the neuronal RF for sensory cells in Vim and Vop. As a first approximation, the effector muscle of a thalamic neuron was defined as the muscle that, by contraction, caused a joint movement that produced a sensory discharge when the joint was passively moved by the examiner. For example, biceps would be the effector muscle for a cell that discharged when the examiner flexed the elbow. In the present study, noneffector muscles were either antagonists or synergists. Because EMG activity in the effector muscle would produce the movement that caused a sensory response, thalamic activity might be expected to have a phase lag with respect to EMG activity in that muscle during dystonia (positive phase of the spike X EMG function). Results of this analysis are compiled in Table 5. Studies were limited to cells with RFs involving the wrist or elbow joint because EMG was studied only for muscles acting across these joints. A negative spike X EMG phase for the effector muscle was more common (73%, 8/11) than expected (P < 0.0005, Fisher exact) because thalamic activity would be expected to lag EMG in these muscles. This result suggested that sensory input to this cell might produce dystonia frequency activity that causes dystonia by transmission of that activity to the periphery.
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This analysis of the spike X EMG function for the effector muscle
also revealed that thalamic cells often were correlated with and
phase-advanced relative to muscles other than the effector muscle. The
proportion of cells with activity correlated with the effector muscle
and with noneffector muscles is shown in Table 6. The results of this analysis
demonstrate that thalamic cells commonly were correlated with and
phase-advanced relative to EMG activity in noneffector muscles (86%,
18/21). Contrary to expectation, cells more often were correlated with
the noneffector muscles than with the effector muscles (52%, 11/21,
P < 0.02, Fisher exact; these 11 cells are listed in
Table 5). Cells were as likely to be correlated with and phase advanced
on noneffector muscles (52%, 11/21, P > 0.25, Fisher
exact) as with effector muscles (38%, 8/21, these 8 cells are starred
in Table 5). In dystonia patients, therefore, sensory input to thalamic
cells was as likely to occur in advance of EMG activity in noneffector
muscles as in the effector muscle (Butler et al. 1992a;
Lenz et al. 1990
).
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Responses to microstimulation
Stimulation in presumed Vim often produced EMG activity in patients with dystonia, for example patient E (Fig. 9). At times when microstimulation was applied, there was a simultaneous increase in EMG activity in all muscles studied, similar to the simultaneous contraction of multiple muscles that is observed in dystonia (Fig. 4). In Fig. 9B the record of a burst of microstimulation is shown on an expanded time base; note the long latency of the evoked contraction.
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Increases in dystonia were observed at 24 sites, whereas decreases in dystonia were found at only 2 sites. Increases in dystonia resulted from stimulation in 6 of 10 patients: 2 of 4 patients with primary dystonia and 4 of 6 with secondary dystonia. Of the six patients in whom stimulation increased dystonia, three had marked decrease in dystonia after lesioning, whereas lesioning had no effect on the other three patients. Stimulation had no effect on dystonia in three patients, of whom two had no benefit from the lesion, whereas the third patient had a good long-term result. A decrease in dystonia after lesioning was not significantly (P > 0.05, Fisher exact) more likely among patients in whom stimulation increased dystonia (3/6, 50%) than among those for whom stimulation decreased dystonia or had no effect (1/4, 25%).
Figure 10 shows the sites where stimulation influenced dystonia. In the 13.5-mm lateral plane, these sites were observed in presumed Vim, ventral Vc, and the adjacent white matter. In the 15.0-mm lateral plane, these sites were observed within presumed Vim, presumed Vop (one site), and ventral caudal parvocellular (Vcpc). In the 16.5-mm plane, one site was observed within, and one site above, presumed Vim. Most of the sites where stimulation influenced dystonia (15/24, 63%) were in presumed Vim. Simultaneous contraction of multiple muscles was evoked by stimulation more frequently in Vim (20%, 15/75) than in Vop (2%, 1/53; P < 0.0001, Fisher exact).
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Thalamic lesions in patients with dystonia
Lesioning at a single site was sometimes associated with an immediate decrease in dystonia. The amount of spontaneous dystonia was reduced dramatically (Fig. 11) after the lesion at the estimated location shown in Fig. 12A (patient B, Table 1). The map of stimulation and recording sites (Fig. 12A) was aligned with the nuclear map by shifting the map of recording sites along the AC-PC line so that the most anterior cutaneous sensory cell was at the anterior border of Vc. Note that the estimated location (see METHODS) was centered in presumed Vop but involved part of presumed Vim. The lesion was located in a region containing deep sensory cells and/or cells with dystonia-related activity defined by SNR > 2 and coherence >0.42 (see METHODS).
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A dramatic effect similar to that shown in Fig. 11 resulted from the lesion in patient H (Fig. 12B). This lesion was estimated to be located in presumed Vop and included cells showing activity correlated with dystonia. These results suggested that lesions decreasing dystonia involved presumed Vim or presumed Vop or both (see Somatic Sensory Activity).
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DISCUSSION |
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The present results are the first report of thalamic neuronal activity in dystonia and suggest that different abnormalities occur in thalamic nuclei Vop and Vim. The activity of cells in presumed Vop, but not presumed Vim, is dominated by power at dystonia frequency (Table 3), and this activity often is correlated with and phase-advanced on EMG activity. The prevalence of dystonia frequency activity suggests that Vop may be involved in the mechanism of dystonia. Cells in presumed Vim in dystonia patients show changes in somatic sensory organization (Table 7). The thalamic representation of individual joints and the percentage of deep sensory cells in presumed Vim was significantly greater in patients with dystonia than in controls. During dystonia, thalamic activity often was correlated with and phase-advanced on EMG activity in muscles other than the muscle producing the movement that caused cellular firing. Stimulation in Vim often increased simultaneous muscular contraction, similar to dystonia.
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These results suggest that sensory input might drive the activity of
cells in Vim to produce dystonia by transmission of that activity
through altered somatic sensory maps to multiple muscles. This model
could explain the cocontraction and overflow of muscular activation
that are characteristic of dystonia (Hallett 1993; Rothwell et al. 1983
).
Dystonia-related activity in the basal ganglia
The present study showed that power was concentrated at dystonia
frequency for cells in presumed Vop (Table 3) and that lesions of this
nucleus (Fig. 12B) can relieve dystonia. These results suggest that Vop plays a significant role in the mechanism of dystonia.
Vop corresponds to monkey nucleus (Hirai and Jones
1989a) ventral lateral oral (VLo) (see references Hirai
and Jones 1989a
,b
), the main termination of pallidal efferents
(DeVito and Anderson 1982
; Hendry et al.
1979
; Jones 1985
; Kim et al.
1976
; Kuo and Carpenter 1973
). VLo, in turn,
projects predominantly to the motor cortex in the depths of the central
sulcus (Holsapple et al. 1991
) and to supplementary
motor cortex (Holsapple et al. 1991
; Jones 1985
; Schell and Strick 1984
). Neuronal activity
at dystonia frequency dominates in presumed Vop and both correlates
with and leads EMG activity. The high incidence of dystonia frequency
activity in presumed Vop may reflect altered pallidal activity in
dystonia patients, which is patterned in dystonia as grouped discharges at low frequency (Lenz et al. 1998b
; Vitek et al.
1998
). Because lesions of GPi (Vitek and Lenz
1998
) and presumed Vop (see Figs. 11 and
12B) can relieve dystonia, these results suggest that
patterned neuronal activity in Vop may be important in the mechanism of dystonia.
The mechanism of dystonia is usually explained in terms of the two
broad categories of movement disorders: hypokinetic and hyperkinetic
(Albin et al. 1989; DeLong 1990
). Recent
studies in monkeys rendered parkinsonian after treatment with
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; "MPTP monkeys")
(Burns et al. 1983
) suggest that thalamic spontaneous
activity should be decreased in hypokinetic disorders like parkinsonism
(Albin et al. 1989
; DeLong 1990
).
Activity in VLo and VPLo of MPTP monkeys, corresponding to Vop and Vim,
is characterized by decreased firing rates (Vitek et al.
1994b
) and increased responsiveness to somatic stimuli
(Vitek et al. 1990
). Consistent with dystonia's being a
hypokinetic disorder, like Parkinson's disease, the present study
documents decreased thalamic firing rates (see Table 2) and increased
thalamic responses to somatic sensory stimuli (Fig. 7). If dystonia is
a hypokinetic disorder, then thalamic lesions may be effective
(Andrew et al. 1983
; Cardoso et al. 1995
;
Cooper 1976
; Gros et al. 1976
;
Laitinen 1970
; Tasker et al. 1988
) by
interrupting abnormally patterned thalamic activity during dystonia
(see Table 7). On the other hand, dystonia has been called a
hyperkinetic disorder based on studies of MPTP monkeys rendered
dystonic after treatment with levodopa (Mitchell et al.
1992
). Dystonia may fit neither the hypokinetic nor the
hyperkinetic model.
It also has been suggested that dystonia is characterized by
disinhibition of the indirect pathway from striatum to pallidum (Perlmutter et al. 1997), which may lead to loss of
surround inhibition in the pallidum and motor system (Mink
1996
). Surround inhibition is proposed to allow isolated
movements to occur by inhibiting unwanted associated movements
(Mink 1996
). Loss of surround inhibition might explain
the mismatch between effector muscles and muscles with EMG activity
correlated with neuronal activity (Table 6). This mismatch is
consistent with the cocontraction and overflow of muscular activation
that are characteristic of dystonia (Hallett 1993
;
Rothwell et al. 1983
).
Methodologic considerations
Because cellular location cannot be determined precisely in human
studies, we estimated nuclear location from both radiological and
physiological data. In previous human studies, the anterior border of
Vc was estimated from the position of the most anterior cell in the
region where the majority of cells had either deep or cutaneous RFs
(Lenz et al. 1990, 1994c
). In the present study, the
region where most cells have a deep RF clearly extended far anterior to
the anterodorsal shell of Vc (Figs. 5 and 7) (see also Figs. 1 and 2 in
Hirai and Jones 1989b
). For this reason, the anterior
border of the region where cells had cutaneous RFs was assumed to be
the anterior border of Vc, as a first approximation of nuclear location.
The location of deep sensory cells in presumed Vim of the present study
(Fig. 5), corresponding to monkey VPLo (Hirai and Jones
1989a), may raise the concern that presumed Vim is actually an
enlarged anterodorsal shell of Vc (Friedman and Jones
1981
; Jones et al. 1982
). However, recent
studies of awake monkeys establish the presence of large numbers of
cells with deep somatic sensory RFs in VPLo and VLo (Anderson
and Turner 1991
; Butler et al. 1992
; Vitek et al. 1994a
), corresponding to human Vim and Vop
(Hirai and Jones 1989a
). These studies suggest that the
region containing cells with deep RFs includes the anterodorsal shell
of Vc as well as presumed Vim and presumed Vop.
Another concern of this study was the effect of arm position (pointing vs. at rest) on thalamic and EMG activity. To explore this question, we examined the frequency of peak EMG activity, mean ISI, peak spike activity, frequency of peak spike activity, and spike X EMG coherence as a function of position. Differences between the arm pointing and at rest were not significant for any of these variables. This finding suggests that comparisons with control patients were valid regardless of arm position.
The control group for thalamic activity (patients with pain) had
significant neurological pathology so that spontaneous activity in Vim
and Vop might have been abnormal. To address this concern, we compared
the mean ISI duration to that in the corresponding nuclei of normal
waking monkeys. Average ISIs in Vim of controls with pain (0.076 s)
were similar to those recorded in the corresponding monkey nucleus
(VPLo) of African Green monkeys (0.046 s) (Vitek et al.
1994a) and cynomolgus monkeys during the hold period before a
cue to movement (0.050 s) (Anderson and Turner 1991
).
Average ISIs in Vop of controls with pain (0.059 s) were similar to
those recorded in the corresponding nucleus (VLo) of African Green
monkeys (0.053 s) and cynomolgus monkeys (0.075 s). These results
suggested that thalamic firing rates in control patients with pain were similar to that recorded in other primates and higher than those recorded in patients with dystonia (Table 2).
Differences among dystonia patients might constitute a flaw in this study. However, such differences were not significant in terms of concentration of EMG activity in the lowest frequency band, probability of cocontraction, mean thalamic neuronal ISI, or concentration of spike activity in the lowest frequency range. Stimulation evoked simultaneous contractions of many muscles in similar proportions of patients with primary or secondary dystonia. Thalamotomy achieved good results in two of four patients with primary and two of six patients with secondary dystonias (Table 1). Thus studies of EMG activity, thalamic activity, responses to thalamic stimulation, and responses to lesions suggest that upper extremity dystonia in these patients was similar, regardless of etiology.
Somatic sensory activity
RESPONSES OF CELLS IN VIM AND VOP.
The number of deep sensory cells in presumed Vim was higher in patients
with dystonia than in the controls with pain and tremor (Fig. 7 and
Table 4). Although we controlled for methodologic differences by
correcting for nuclear location, we cannot exclude differences in the
explorations of these patients as an explanation of the results. The
number of cells in presumed Vim and presumed Vop responding to somatic
sensory inputs in both the dystonia and control groups is similar to
the results of early studies (Horne and Porter 1980;
MacPherson et al. 1980
; Strick 1976
) but not recent studies in alert monkeys (Anderson and Turner
1991
; Butler et al. 1992
; Vitek et al.
1994a
). These latter studies in monkeys reveal responses to
passive movements for 71-90% of cells in VPLo (Anderson and
Turner 1991
; Butler et al. 1992
; Vitek et
al. 1994b
), the nucleus corresponding to human Vim
(Hirai and Jones 1989a
). Responses to passive movement
are found in 40-60% of cells in monkey VLo (Anderson and
Turner 1991
; Butler et al. 1992
; Vitek et
al. 1994a
), which corresponds to human Vop (Hirai and
Jones 1989a
).
ORIGIN OF SENSORY INPUTS TO VIM AND VOP.
The origin of sensory inputs to the cerebellar and pallidal relay
nuclei is uncertain. Studies in monkeys show that cells in VPLo
projecting to the motor cortex (Horne and Tracey 1979; Lemon and van der Burg 1979
; Wiesendanger and
Miles 1982
) respond at short latency to peripheral stimulation
(Asanuma et al. 1980
; Horne and Tracey
1979
; Vitek et al. 1994a
). These somatic sensory responses may involve transmission of somatic sensory signals through
the dorsal column or spinothalamic tracts (Berkley 1983
; Greenan and Strick 1986
; Jones 1985
;
Lenz et al. 1990
; Tracey et al. 1980
;
Wiesendanger and Miles 1982
). However, the spinothalamic tract may not terminate in the part of VPLo that projects to motor cortex (Greenan and Strick 1986
), and dorsal column
nuclei may (Berkley 1983
) or may not (Tracey et
al. 1980
) project to VPLo in monkeys. Finally, sensory inputs
to the thalamic cerebellar relay nucleus might involve transmission of
sensory input through cortex either directly through corticothalamic
projections (Berkley 1983
; Greenan and Strick
1986
; Jones 1985
; Lenz et al.
1990
; Tracey et al. 1980
; Wiesendanger
and Miles 1982
) or via cerebellum to thalamus (Brooks
and Thach 1981
).
REFLEX FUNCTION IN PATIENTS WITH DYSTONIA.
There is considerable evidence of abnormal reflex function in dystonia.
For example, vibration of the palm is reported to evoke dystonic
postures in patients with writer's cramp, a form of focal dystonia,
but not in controls (Kaji et al. 1995). Writer's cramp
is reduced markedly by intramuscular injection of local anesthetic to
block tendon reflexes but not muscle contractions evoked by peripheral
nerve stimulation. As another example, contraction of muscles shortened
by passive joint rotation, the Westphal phenomenon, is elicited "with
ease" in cases of dystonia (Rothwell et al. 1983
;
Yanagisawa and Goto 1971
). This phenomenon may be
related to the loss, in dystonia, of reciprocal inhibition by which 1A afferents from forearm extensors inhibit forearm flexors
(Deuschl et al. 1992
; Marsden and Rothwell
1987
; Pannizza et al. 1990
). This effect could
involve CNS processing of afferent signals and may explain the
phenomenon of antagonist co-contraction (Cohen and Hallett
1988
; Yanagisawa and Goto 1971
).
Thalamic microstimulation and lesions in patients with dystonia
The effects of thalamic stimulation and lesions on dystonia
suggest that the cellular abnormalities observed in presumed Vim and
presumed Vop are involved in the mechanism of dystonia.
Microstimulation in presumed Vim evokes EMG activity in dystonia
patients, a result that might be attributed to stimulation of the
adjacent internal capsule (Schaltenbrand and Bailey
1959) except that stimulation in Vim of patients with chronic
pain (Lenz et al. 1998a
) does not produce motor effects.
The sites where stimulation evokes EMG activity in patients with
dystonia are found largely in presumed Vim. Alterations in dystonia by
microstimulation in Vim may be related to the muscle twitches evoked by
microstimulation in VPLo of monkeys (Buford et al. 1996
;
Strick 1976
; Vitek et al. 1996
), which
corresponds to human Vim (Hirai and Jones 1989a
). Recent studies report that muscle twitches occur in response to stimulation in
the cerebellar relay nuclei (including VPLo) but not the pallidal relay
nuclei of thalamus (Buford et al. 1996
; Vitek et
al. 1996
). One of these studies reports physiological
confirmation of the relay nuclei by thalamic responses to stimulation
of the cerebellar nuclei or GPi (Buford et al. 1996
). In
patients with dystonia, the stimulation-evoked activity shows
simultaneous contraction of multiple muscle groups (Fig. 9)
characteristic of dystonic movements (Figs. 1 and 4). The present
results thus suggest that activation of Vim by microstimulation can
drive dystonia.
The effect of lesions in Vim and Vop on dystonia is well described
(Cardoso et al. 1995; Gros et al. 1976
;
Narabayashi 1982
; Tasker et al. 1988
). In
all reports, dystonia is decreased in a proportion of patients,
although the improvement may be delayed (Cardoso et al.
1995
) and the dystonia sometimes returns with time
(Cardoso et al. 1995
; Gros et al. 1976
;
Tasker et al. 1988
). The present results indicate that a
small lesion (~30 mm3) involving presumed Vop
and presumed Vim can produce an immediate decrease in dystonia (Figs.
11 and 12). Therefore stimulation in Vim can drive movements with
cocontraction-like dystonia, and lesions in Vim and Vop can decrease
dystonia. These observations strongly suggest that abnormal neuronal
activity in these nuclei is involved in the generation of dystonia.
Somatic sensory activity: role of thalamic nuclei in the mechanism of dystonia
The present results reveal an increased representation of
deep structures in Vim in the effected extremity in dystonia patients. Lengths of electrode trajectories along which cells had RFs for a
single joint (Lenz et al. 1994b), either wrist or elbow,
were longer in patients with dystonia than in control patients. Because all of the patients studied had upper extremity dystonia (Table 1),
this result suggests an increased representation of parts of the body
with dystonia. Similar increases in the size of representations of
joints are found in monkey motor cortex after repetitive movements involving those same joints (Nudo et al. 1996
).
Sensorimotor cortical areas in which magnetic stimulation evokes
forearm movement are increased in patients with dystonia (M. Hallett,
personal communication). In sensory cortex, increases in
representations of cutaneous structures in the hand, as well as
increases in receptive field sizes, are found after training to a
repetitive gripping task that produces abnormalities of posture and
movement similar to dystonia (Byl et al. 1996
). The
present study showed significant increases both in the representation
of wrist and elbow (Fig. 8) and in RF size, as indicated by increases
in multijoint RFs (Fig. 5).
Changes in sensory organization of Vim may contribute to the
development of dystonia or may be an epiphenomenonthe passive result
of dystonic movements. The correlation and phase lead of neuronal
activity in presumed Vim with dystonic movements, in addition to the
effects of thalamic microstimulation and lesions (see previous
section), suggest that activity in Vim drives dystonia. In total, the
present data argue forcefully that sensory reorganization of Vim
contributes to the development of dystonia.
The present data and previous studies suggest the mechanism by which
reorganization may contribute to dystonia. Specifically, the mismatch
between effector muscles and muscles correlated with dystonia (see
Table 6) is reminiscent of findings in patients with spinal transection
(Lenz et al. 1994b) or amputation (Lenz et al.
1998c
). In both of these groups of patients, the reorganization of the thalamic map of RFs leads to a mismatch between RFs (input) and
the part of the body where thalamic microstimulation evokes sensation
(projected field, output) (Lenz et al. 1994b
, 1998c
). These patients have somatotopic reorganization of RF (input) maps but
have less complete reorganization of the projected field map (output)
(Lenz et al. 1998c
). In dystonia, there may be a similar failure of the muscles correlated with thalamic spike activity to
reflect the changes in the RF produced by shifts in the sensory map.
This mismatch between muscles in the RF and those correlated with
dystonia may cause somatic sensory input to be transmitted to multiple
muscles other than the effector muscle (Table 6). This mismatch might
produce the cocontraction and the overflow of muscle activation that
are characteristic of dystonia (Hallett 1993;
Rothwell et al. 1983
). A model of such a condition may
be the stump jerks that occur in some patients with amputation
(Marion et al. 1989
). Stump jerks have features of
dystonia (W. Olson, personal communication) and affect a population
with demonstrated reorganization of thalamic maps (Lenz et al.
1998c
). This type of reorganization also may produce focal
dystonias that occur in patients whose occupations (e.g., musicians)
include repetitive motor tasks performed under high cognitive drive
(Byl et al. 1996
; Hochberg et al. 1983
).
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ACKNOWLEDGMENTS |
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We thank L. Rowland for expert technical assistance, R. Cutler for computing assistance, and Drs. F. H. Baker, J. O. Dostrovsky, H. C. Kwan, R. L. Martin, R. T. Richardson, and R. R. Tasker for assistance with various phases of these studies. We thank the editors and reviewers for making a substantial contribution to this manuscript.
This work was supported by grants from the Eli Lilly Corporation and from the National Institutes of Health (NS-28598, K08-NS-1384, P01 NS-32386-Proj. 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 Bldg. 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 3 January 1997; accepted in final form 28 June 1999.
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REFERENCES |
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