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Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland
Submitted 19 May 2004; accepted in final form 16 August 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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; Louis et al. 1998). It is a bilateral, symmetric, postural, and/or action tremor that is often familial and is attenuated by alcohol (Elble and Koller 1990). Although ET appears to be a mono-symptomatic illness, its etiology and pathophysiology have been elusive. In humans, surgical lesions or deep brain stimulation (DBS) of a cerebellar recipient thalamic nucleus, Vim, abolish ET (Goldman et al. 1992; Jankovic et al. 1995; Schuurman et al. 2000; Zirh et al. 1999). Additionally recent PET and fMRI studies have demonstrated increased metabolic activation of the cerebellum, thalamus, red nucleus, and sensorimotor cortex in patients with ET (Boecker et al. 1996; Boecker and Brooks 1998; Bucher et al. 1997; Jenkins et al. 1993; Perlmutter et al. 2002; Wills et al. 1994). These findings suggest that the cerebellum and the cerebellar thalamus are involved in the mechanism of ET.
The olivo-cerebellar system in ET is predicted to display oscillatory activity during tremor and at rest in part because functional imaging studies in patients with ET have demonstrated abnormally increased, bilateral cerebellar activity at rest (Boecker et al. 1996; Colebatch et al. 1990; Jenkins et al. 1993; Wills et al. 1995). Ipsilateral cerebellar activity is increased an additional 5% during unilateral postural tremor (Bucher et al. 1997; Jenkins et al. 1993; Wills et al. 1994). If this abnormal cerebellar activity during rest results from abnormal olivary oscillations, then the cerebellum and cerebellar efferent structures such as Vim should display oscillatory activity during rest and during postural tremor.
It has been suggested that oscillations originating in the inferior olive (IO) and transmitted through the cerebellum are responsible for ET (the olivary model) (Lamarre 1995). Electrotonic coupling predisposes IO neurons to synchronous activity (Llinas et al. 1974; Llinas and Yarom 1981). Furthermore, the 
-carboline drug harmaline produces both continuous olivary oscillations and a fine, generalized 8- to 12-Hz tremor during rest and movement that has been compared with ET (Elble and Koller 1990; Wilms et al. 1999). If the two are comparable, then abnormal oscillatory activity in ET should be present in the olive, cerebellum, and efferent structures during rest as well as posture and action, consistent with the imaging studies (Wilms et al. 1999).
We now provide a detailed analysis of human neuronal activity in ET. Specifically we demonstrate that thalamic activity exhibited oscillatory activity only during postural tremor and not at rest. Thalamic tremor activity was strongest among cells related to voluntary movement as compared with other functional classes and was highest in Vim as compared with pallidal recipient, Vop, and the principal sensory nucleus, Vc. These results demonstrate that human thalamic activity in ET is different from that predicted by the olivary model of ET and by recent functional imaging studies.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The data were recorded during physiologic exploration of ventral thalamus preceding stereotactic thalamotomy for the treatment of ET. During these procedures, the stereotactic coordinates of the anterior commissure-posterior commissure (AC-PC) line were determined by magnetic resonance imaging. A coronal burr hole was fashioned; the dura and arachnoid were coagulated and cut. A microelectrode was then used to locate the principal somatosensory nucleus of thalamus, Vc, and to explore the region anterior to it, including nuclei Vim and Vop (Lenz et al. 1988a). Standard techniques were used to record electromyographic (EMG) activity in the contralateral wrist flexors, wrist extensors, biceps, and triceps (Lenz et al. 1988b). The microelectrode and EMG signals were recorded on a multiple-channel tape recorder (Model 4000, Vetter, Rebersburg PA) along with an audio channel describing procedures and a foot pedal signaling the onset and duration of somatosensory stimuli.
Physiologic techniques
Physiologic exploration with the microelectrode involved both recording of neuronal activity and stimulation at microampere current levels (microstimulation) (Lenz et al. 1988a). During recordings, several aspects of neuronal activity were examined including: the spontaneous firing pattern, the relationship of spontaneous activity to tremor, and neuronal activity during somatic sensory stimulation and during active movement. The somatic sensory examination included stimulation of both cutaneous structures (Fig. 1C, neurons at sites 22–24) and structures deep to the skin (Fig. 1C, neurons at sites 10, 14, 21). Cutaneous sensory neurons responded to touch or pressure to skin, whereas deep sensory neurons responded to joint movement and squeezing of muscles or tendons in absence of any response to stimulation of skin deformed by these stimuli. Cells not responding to sensory stimulation were a separate category, i.e., nonsensory cells. Voluntary neurons were identified by activity during active movements such as making a fist, flexing or extending the wrist, elbow, or shoulder (Fig. 1C, neuron at site 47). Cells not responding during active movement were also a separate category, i.e., nonvoluntary cells. In the case of voluntary neurons with sensory (deep) receptive fields (combined neurons), voluntary neurons were defined by activity preceding the onset of active movement as indicated by EMG activity (Fig. 1C, neuron at site 46) (Lenz et al. 1990). Therefore the neuronal response during active movement could not be the result of afferent activity generated by the movement.
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1-s duration at 300 Hz using a biphasic pulse consisting of a 0.2-ms anodal pulse followed in 0.1 ms by a 0.2-ms cathodal pulse of the same magnitude. Patients were asked during stimulation if they felt anything. If any sensory effects were observed, then the current was lowered in a series then raised in a series until a threshold for the effect was established-threshold microstimulation, TMS (Lenz et al. 1993). The nature of the effect and the location of the projection field (PF) were determined at threshold.
Initially, the activity of some neurons (n = 52) was measured with the arm at rest by the patient's side as they reclined. Thereafter, tremor was produced by asking patients to elevate the arm. Patients were seated in a reclining position with the back at 20° above the floor and were asked to point to the corner of the room. In this position, the shoulder was flexed to 45° with the elbow, wrist, metacarpophalangeal, and interphalangeal joints all extended to <180°. Tremor was provoked by this maneuver, and the neuronal activity related to tremor was assessed for a period of between 10 and 30 s. During this interval, we attempted to judge whether neuronal activity was related to the tremor.
Estimate of nuclear location
In human studies, the borders of thalamic nuclei must be defined physiologically because radiologic estimates are not reliable. The monkey cerebellar relay nucleus can be defined physiologically by the occurrence of microstimulation evoked muscle contractions (Buford et al. 1996; Vitek et al. 1996). In humans, microstimulation evokes changes in the ongoing movement disorder (Lenz et al. 1988b, 1994) but does not evoke muscle twitches (Lenz et al. 1993; Tasker et al. 1982). These latter changes are not common enough to define the borders of Vim reliably. The borders of Vc can be defined physiologically and used to extrapolate locations of other nuclei from atlas maps (Lenz et al. 1990, 1994).
Previous studies in humans indicate that cutaneous and deep sensory neurons form the majority of neurons in Vc but are in the minority in Vim and Vop (Lenz et al. 1990, 1994; Vitek et al. 1996). Therefore the physiologic anterior border of Vc was defined as the most anterior neuron along a length of trajectory (see Fig. 1) in which more than half the neurons located posteriorly were sensory neurons, either deep or cutaneous. The physiologic map of each patient was shifted along the AC-PC line so that the anterior border on the physiologic map coincided with the anterior border of Vc on the atlas map (Lenz et al. 1990, 1994). The borders of presumed Vim and Vop were determined from this transformed physiologic map.
For example, along P4 in Fig. 1 all the neurons posterior to neuron 21 until the neuron at site 24 were sensory neurons. Therefore neuron 21 was the physiologic anterior border of Vc. The physiologic map (Fig. 1B) was then moved along the AC-PC line until site 21 was located at the anterior border of Vc in the atlas map (Fig. 1A). The borders of Vim and Vop are determined from the map in Fig. 1A.
Analytic techniques
Postoperatively, the tapes made during the operative procedure were examined. Neurons analyzed in the present report were located in the region where neurons exhibited activity related to tremor, sensory stimulation, or movements of the upper extremity (Lenz et al. 1990). Action potentials were discriminated by a window discriminator (DDIS-I, BAK Electronics, Rockville, MD) and confirmed to arise from a single neuron by the criterion of constant shape of the action potential, as verified by displaying the shape of the action potential on an oscilloscope. Times of occurrence of action potentials were digitized at a clock rate of 1,000 Hz, and EMG signals were digitized at a rate of 200 Hz and processed as previously described (Lenz et al. 2002).
To analyze the thalamic and EMG signals, we chose to work in the frequency domain. For all neurons, simultaneous EMG signals for wrist flexors and extensors plus elbow flexors and extensors were digitized and analyzed. 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. 1988b). The EMG signal was band-pass filtered to minus 6 dB at 20 and 120 Hz to eliminate movement artifact. The signal was then full wave rectified and filtered to minus 6 dB at 20 Hz to produce a signal known as the demodulated EMG, which yields the tremor frequency component of the EMG signal, e.g., Fig. 3A, EMG signals.
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) were then used to take the raw spectral estimate of these two signals (Bendat and Piersol 1976; Glaser and Ruchkin 1976; Lenz et al. 1988b; Oppenheim and Schafer 1975). This estimate is unreliable because it has a high degree of variability that can be decreased by averaging the spectral estimate across time or frequency windows. In this study, eight contiguous, nonoverlapping, raw spectral estimates were averaged together to produce one smoothed spectral estimate, thus decreasing the variablity. The autopower of a signal is the square of the magnitude of the signal at some frequency and indicates the amount of activity occurring at that frequency in the signal. The signal-to-noise ratio (SNR) for a particular frequency was defined as the autopower at that frequency divided by the mean autopower throughout the spectrum and indicates the extent to which power is concentrated at tremor frequency. A SNR of greater than two indicates that power is concentrated at that frequency to a statistically significant degree (Jenkins and Watts 1968; Lenz et al. 1988b; Oppenheim and Schafer 1975).
The cross-spectrum of the two signals is composed of the magnitude (cross-power) and phase spectra. The cross-power squared is often divided by product of the averages of the two autospectra to produce the coherence. The coherence is used to estimate the probability that the two signals are linearly related, which is to say that one signal could be described as a linear function of the other (Lenz et al. 1988b). The coherence has a value of 0 if the two signals are not linearly related and 1 if there is a perfect linear relationship between the signals at a particular frequency. By the technique used in the present study, coherence >0.42 indicates that two signals are linearly related at the level of P < 0.05 (Benignus 1969), and SNR >2 indicates a significant concentration of power at a particular frequency (Jenkins and Watts 1968; Lenz et al. 1988b).
The phase was calculated as the arc-tan of the negative value of the average real component of the cross-spectrum divided by the average imaginary component (Oppenheim and Schafer 1975). A given phase angle (e.g., 60°) may equally be the value which is 360° (or 720°, 1,080°, etc) out of phase with that given angle (e.g., 60° and –300°/+420°/etc.) (Bendat and Piersol 1976). In this study, we have arbitrarily identified the phase angle with the smallest absolute value as the phase. If the phase for the spike x EMG cross-spectrum is negative, then the spike train leads the EMG signal. In Fig. 3K, the spike x EMG 1 phase angle is –144° (or +216°), indicating that the spike signal leads the EMG signal at tremor frequency, according to our assumption. Because the tremor frequency is 5.8 Hz and the period of one oscillation (360°) is 170 ms, i.e., the EMG leads the spike signal by 69 ms.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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; Findley and Koller 1995). All patients failed treatment with mysoline, propranolol, and clonazepam, both alone and in combination. Table 1 provides a description of the patients and shows that the age of the patients ranged from 35 to 75 yr (mean: 52). Five patients (5, 6, 14, 25, and 148) displayed primarily synchronous contraction of forearm antagonists during intraoperative recording of tremor (i.e., 0° phase difference), and two patients exhibited reciprocal contraction of antagonists (i.e., 180° phase difference). Both synchronous and reciprocal varieties have been reported in ET (Deuschl et al. 1987; Shahani and Young 1976).
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). In this rating scale, a score of 0 represents normal function, whereas a score of 4 represents total disability for that task. On average patients improved 1.3 points after surgery (Table 1). Examples of the digitized spike trains for neurons exhibiting tremor-related activity are shown in Fig. 2. When patients held elevated the arm contralateral to the recording site, rhythmic patterns in the spike train were obvious for many of the tracings, as shown in Fig. 2A. There was marked variability of rhythmic activity during tremor ranging from distinct periodic "bursts" (e.g., Fig. 2A, lines 2 and 3) to continuous modulation without distinct bursts (e.g., Figure 2A, lines 4 and 5). When the arm was at rest, without EMG evidence of tremor, each neuron exhibited an aperiodic firing pattern, shown in the line of Fig. 2B corresponding to that in Fig. 2A, e.g., the same cell is represented in the third line from the top in A and B. The rest condition resembled Vim thalamic spike trains recorded in patients without movement disorders undergoing sensory thalamic procedures for treatment of pain (Fig. 2C).
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Figure 3, E and F, shows the cross power spectrum for spike x EMG 1 and spike x EMG 2 signals, and H and I show the corresponding coherence spectra. Both cross power spectra and both coherence spectra demonstrated distinct peaks at tremor frequency, i.e., 5.8 Hz. Additionally, the spike x EMG 1 coherence at tremor frequency was 0.71, whereas the spike x EMG 2 coherence at tremor frequency was 0.90. These findings demonstrate that the spike train was linearly related to both EMG signals to a significant degree. Furthermore, the spike signal demonstrated a negative phase with respect to both EMG signals at tremor frequency as shown in Fig. 3, K and L, suggesting that the spike train had a phase lead on both EMG signals.
Previously, the periodic firing of a neuron was judged to be significant if the SNR was >2 in the spike autopower spectrum (Jenkins and Watts 1968; Lemstra et al. 1999; Lenz et al. 1988b) and to be linearly related to the EMG to a significant degree if the coherence between the two signals was >0.42 (Benignus 1969). A neuron meeting both of these criteria at tremor frequency was said to show tremor-related activity. Thus the neuron shown in Fig. 3 was tremor related as were 78 (51%) of the 152 neurons studied.
Tremor activity related to functional class and nuclear location
As described under METHODS, neuronal responses to sensory stimulation and that preceding voluntary movement were determined. Responsiveness to sensory stimulation was not mutually exclusive of responsiveness to voluntary movements, i.e., the two categories were independent. Therefore each neuron was classified as either sensory or nonsensory and also as either voluntary or nonvoluntary. Cells could also be classified as combined, i.e., sensory and voluntary, or no response, i.e., neither sensory nor voluntary. Table 2 shows the distribution of neurons among three functional classes (sensory, nonsensory, and voluntary) and according to coherence, phase, SNR, and percentage of tremor relatedness. Voluntary neurons had the largest proportion of tremor-related neurons (75%, 15/20) as well as the largest percentage of neurons with significant coherence with EMG (95%, 19/20). Voluntary classification included 40% (8/20) sensory or combined and 60% (12/20) nonsensory neurons. The group of voluntary neurons had a significantly higher proportion of tremor-related neurons (75%, 15/20) than did the group of nonvoluntary neurons (48%, 63/132) (P = 0.03, 2-tailed Fisher exact test).
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Combined neurons exhibited tremor-related activity (75%, 6/8) as often as neurons other than combined neurons (noncombined neurons: 50%, 72/144, P = 0.3, Fisher's exact test) (Lenz et al. 1990). Furthermore, the average coherence of combined neurons (0.71 ± 0.07) was not significantly different from that of noncombined neurons (0.55 ± 0.02, P = 0.07, 2-tailed t-test assuming unequal variances).
The location of each neuron in specific thalamic nuclei was estimated as described under METHODS. This analysis identified that most of the neurons (61%, 92/152) were located in Vim, followed by Vc (18%, 27/152) and Vop (12%, 19/152). Fourteen neurons were located outside these three nuclei. Of the three nuclei, Vim had the highest percentage of tremor-related neurons (64%, 59/92) followed by Vc (41%, 11/27) and Vop (16%, 3/19). There were significant differences in the number of tremor neurons among the three nuclei (P = 0.0002, Fisher's exact test). Vim had significantly more tremor-related neurons than Vc (P = 0.04, 2-tailed Fisher's exact test) and Vop (P = 0.0002, 2-tailed Fisher's exact test). The number of tremor-related neurons did not differ significantly between Vc and Vop (P = 0.1, 2-tailed Fisher's exact test). The finding that cerebellar recipient thalamus, Vim, demonstrated the highest proportion of tremor neurons supports the hypothesis that ET is related to cerebellar efferent activity.
Thalamic activity at rest and during tremor
Abnormal cerebellar activity has been demonstrated during rest and tremor in functional imaging studies of ET (Boecker et al. 1996; Colebatch et al. 1990; Jenkins et al. 1993; Wills et al. 1995) and in the harmaline model of ET (Milner et al. 1995; Wilms et al. 1999). These results predict abnormal thalamic oscillatory activity in ET during both rest and tremor. Fifty-two neurons were studied with the contralateral arm at rest without tremor and during posture with tremor (Fig. 2). The mean firing rate increased significantly from rest (21.9 ± 5.0 spikes/s) to postural arm tremor (26.8 ± 5.3 spikes/s, P = 0.00001, pairwise 2-tailed t-test). Thirty-nine of the 52 (75%) neurons increased their firing rates when moving from a rest condition to tremor.
Spectral analysis of thalamic tremor neurons revealed very different frequency profiles between rest and tremor conditions. Of the 52 neurons studied at rest and during tremor, 16 were tremor-related neurons. The averaged normalized autopower spectrum in these 16 tremor neurons, shown in Fig. 4, demonstrated that tremor neuron autopower was distributed evenly among the frequencies at rest. In contrast, during postural arm tremor, there was a concentration of power 5 Hz. This finding demonstrated that thalamic neurons did not exhibit rhythmic activity during rest as predicted by functional imaging studies and by the harmaline model of tremor. Instead, thalamic neurons switched to a rhythmic firing pattern at tremor frequency during postural tremor.
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During spectral analysis, a single peak in the frequency domain represents a sinusoidal signal in the time domain with a single frequency. Multiple peaks in the frequency domain represent either concurrent signals at different frequencies or a signal with a nonsinusoidal waveform. We examined the coherence spectrum for significant peaks in the 8- to 25-Hz range. We identified 20 neurons with activity in the 8- to 25-Hz range that was related to EMG in that range as defined by spike SNR >2.0 and coherence >0.42 at the frequency of the peak in the 8- to 25-Hz range. Nineteen of these 20 neurons were tremor-related (i.e., tremor frequency activity), and in 18 of these 19 the 8- to 25-Hz peak occurred at multiples (harmonics) of tremor frequency. These cells were more commonly found in Vim (n = 14), than in Vc (n = 4) or Vop (n = 1), or regions outside these three nuclei (n = 1).
For each of these neurons, we constructed an autocorrelogram of the spike train, i.e., a histogram of interspike intervals (ISIs) between every pair of spikes in the spike train. A composite auto-correlogram for all 20 neurons was constructed by normalizing each individual auto-correlogram by the total number of ISIs for each neuron and averaging each bin across 20 neurons (Fig. 5). Figure 5 shows that there was a paucity of ISIs in the 83 ms to 125-ms range, i.e., the range corresponding to 8- to 25-Hz oscillatory activity. In contrast, there was a peak in the 200-ms range, which corresponded to 5-Hz tremor frequency activity. The distribution of ISIs demonstrated that the 8- to 25-Hz coherence peaks did not result from 8- to 25-Hz signals carried concurrently in the spike train. Instead, neurons with 8- to 25-Hz harmonic peaks had nonsinusoidal spike trains during tremor, i.e., spike trains were more square wave or burst-like than sinusoidal.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Mechanism of ET
Mechanical studies suggest that ET results primarily from a central oscillator (Elble 1996; Elble and Koller 1990). The identity of the central oscillator has been elusive, although the inferior olive is the leading candidate. Recent imaging studies have attempted to delineate the location of the central oscillator in ET. In patients with ET, PET scanning at rest without tremor using [18F]fluoro-2-de-oxyglucose to measure regional resting glucose metabolism demonstrated increased activity in the thalamus and medulla, perhaps in the olive (Hallett and Dubinsky 1993). Furthermore, PET scanning at rest using H215O and C15O2 to measure regional blood flow demonstrated increased activity in the cerebellar vermis and hemispheres, red nuclei, and thalamus bilaterally in patients with ET (Boecker et al. 1996; Colebatch et al. 1990; Jenkins et al. 1993; Wills et al. 1995). Unilateral postural tremor was associated with an additional 5% increase in blood flow in the same areas bilaterally as well as in the contralateral sensorimotor cortex (Bucher et al. 1997; Jenkins et al. 1993; Wills et al. 1994). Although this constellation of results does not identify a specific neuronal network as the central oscillator, these results do indicate that an altered neuronal substrate is present bilaterally in the cerebellum and in its connections with the red nucleus and thalamus, both at rest and during tremor.
The olivary model of ET is also suggested by harmaline tremor that has been proposed to mimic ET and that occurs during rest, posture, and action (Elble 1998; Lamarre 1995; Wilms et al. 1999). Harmaline induces continuous oscillatory activity in the inferior olive (Llinas and Yarom 1986), which suggests that similar activity occurs in ET. This activity may descend through bulbospinal pathways en route to spinal motor neurons in cats (Lamarre 1984; Weiss 1982). In monkeys, the olivary and cerebellar activity may be transmitted through a pathway involving cerebellum, thalamus, cortex, and corticospinal tract (Lamarre 1995).
If ET originates from continuous olivary cerebellar oscillations as predicted by functional imaging studies, oscillatory activity should be present in cerebellar efferent structures during rest and tremor. However, in the present study, we did not find evidence for oscillatory behavior at rest in Vim. Instead we found a dramatic change in the pattern of Vim activity from nonoscillatory activity at rest to tremor frequency oscillations during arm tremor. Although the single-unit techniques used in this study do not detect the presence of subthreshold potentials, local field potentials (LFPs) may detect membrane potentials. Marsden et al. (2000) have demonstrated the presence of LFPs in the thalamus that are coherent with EMG only during isometric contraction but not during rest in one patient with ET. The absence of thalamic oscillations during rest is in contrast to the significant resting cerebellar activity seen in functional imaging studies (Bucher et al. 1997; Jenkins et al. 1993; Milner et al. 1995; Wills et al. 1994).
For the present results to comply with an olivary model of tremor and with functional imaging studies, olivary activity should switch from an nonoscillatory pattern during rest to an oscillatory pattern during tremor (Welsh and Llinas 1997; Welsh et al. 1995). Mechanisms for such a switch in the context of tremor have not been proposed, and direct evidence for oscillatory activity in the olivary cerebellar system during normal movement has been difficult to demonstrate (Keating and Thach 1995, 1997).
Alternately, the switching could occur in the thalamus. The present results demonstrate that 50% of neurons in Vim or Vop are not activated either during sensory stimulation or during a range of active movements, yet many of these cells have tremor-related activity. A similar group of tremor-related cells have been described in patients with parkinsonian tremor (Lenz et al. 1990, 1994). The determinants of the activity of these neurons are unclear. It may be that the powerful cortical inputs not phase locked to voluntary movement can depolarize thalamic neurons. These "energizing" inputs (Jasper and Bertrand 1966) might not produce activity related to active movement but might elevate subthreshold tremor-related inputs from the deep cerebellar nuclei above threshold so enable the thalamic tremor-related activity (Butler et al. 1998; Sherman and Guillery 2001).
Another hypothesis for the generation of posture-dependent thalamic oscillations involves the activation of reverberating cerebellar thalamic cortical circuits during posture (Deuschl and Bergman 2002; Elble 1998). Recurrent premotor circuits involving the cerebellum, thalamus, cerebral cortex, and pons have been proposed to carry an efference copy and to mediate motor learning (Horne and Butler 1995; Houk and Wise 1995; Hua and Houk 1997). This and other recurrent feedback connections with the cerebellar nuclei are thought to exhibit reverberatory premotor activity that is modulated by Purkinje cell inhibition of the cerebellar nuclei (Allen and Tsukahara 1974; Houk et al. 1993). Activation of these recurrent premotor circuits during movement in the context of abnormal cerebellar cortical activity may lead to the generation of tremor activity during posture and movement but not at rest. This hypothesis is supported by the clinical findings that lacunar strokes in the cerebellum as well as the pons (both part of the cortico-cerebellar circuit) have been reported to eliminate essential tremor (Dupuis et al. 1989; Nagaratnam and Kalasabail 1997). Our finding that voluntary neurons in the thalamus have the highest proportion of tremor activity supports the involvement of premotor circuits in the mechanism of ET.
Sensory entrainment of the central oscillator
Although the exact location of the central oscillator in ET is still in debate, mechanical studies suggest that the oscillator in ET is of a nonlinear limit cycle variety (Elble and Koller 1990). Limb-perturbation studies have shown that the amplitude and phase of ET can be reset with large limb perturbations at particular frequencies (Elble et al. 1992; Lee and Stein 1981). Thus the central oscillator may be influenced by peripheral inputs, perhaps through a stretch-reflex arc (Lenz et al. 1983a, 1994). Although we found that voluntary neurons had the highest proportion of tremor activity, we also found a subset of proprioceptive neurons that exhibited high coherence with tremor and nonsinusoidal, burst-like, tremor-related activity. The burst-like activity of these sensory neurons may result in harmonic frequencies in the coherence spectrum. These sensory tremor neurons with harmonic coherence peaks may allow peripheral inputs to modulate the central oscillator in ET.
The presence of harmonics in the tremor-related activity of sensory cells means that their activity is not purely sinusoidal. The nonsinusoidal pattern may reflect the transformation of the tremor-related EMG signal either by coupling of EMG to muscle or of muscle to movement or by the sensory receptor which transduces the tremor sensory signal (Johnson et al. 2000; Mathews 1981). Alternately, this pattern may reflect the nature of essential tremor, the EMG of which can have harmonics (see Fig. 3, B and C). Whatever the mechanism, these results suggest that both voluntary activity and sensory feedback, both tremor and harmonic related, may play important roles in the generation of ET.
Comparison of ET with Parkinson's Disease
While ET and parkinsonian tremor are both treated effectively by thalamic lesions or DBS, they are believed to have different mechanisms. The most obvious difference is that ET is primarily a postural tremor, whereas parkinsonian tremor is primarily a resting tremor. The postural component of ET may arise from tremor-related inputs to thalamus that are enabled by active movement, whereas the best evidence indicates that tremor in PD is the result of reflex mechanisms. Studies using the present techniques demonstrate that thalamic neurons in PD exhibit strong tremor-related activity with the arm at rest (Lenz et al. 1988b) in contrast to the present findings in ET (Fig. 4) and intention tremor (Lenz et al. 2002). Furthermore, sensory neurons in PD had significantly higher proportions of tremor-related activity than neurons without sensory inputs (Lenz et al. 1994). There was also no difference in the proportion of tremor neurons between cerebellar recipient Vim and pallidal recipient Vop thalamus. Compared with the present findings in ET, these studies suggest that the role of the thalamus in PD tremor is different from in ET. The thalamus in PD may be involved in a sensory feedback mechanism of tremor, perhaps through long loop reflex arcs (Cheney and Fetz 1984; Desmedt 1978; Lenz et al. 1983b).
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. E. Hua, Dept. of Neurosurgery, Meyer Bldg. 8-161, Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287 (E-mail: shua{at}jhmi.edu)
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
|---|
Bendat JS and Piersol AG. Random Data. New York: Wiley, 1976.
Benignus V. Estimation of coherence spectrum and its confidence interval using fast fourier transform. IEEE Trans Audio Electroacoust 17: 145–150, 1969.[CrossRef]
Boecker H and Brooks DJ. Functional imaging of tremor. Mov Disord 13, Suppl 3: 64–72, 1998.
Boecker H, Wills AJ, Ceballos-Baumann A, Samuel M, Thompson PD, Findley LJ, and Brooks DJ. The effect of ethanol on alcohol-responsive essential tremor: a positron emission tomography study. Ann Neurol 39: 650–658, 1996.[CrossRef][ISI][Medline]
Brin MF and Koller W. Epidemiology and genetics of essential tremor. Mov Disord 13, Suppl 3: 55–63, 1998.
Bucher SF, Seelos KC, Dodel RC, Reiser M, and Oertel WH. Activation mapping in essential tremor with functional magnetic resonance imaging. Ann Neurol 41: 32–40, 1997.[CrossRef][ISI][Medline]
Buford JA, Inase M, and Anderson ME. Contrasting locations of pallidal-receiving neurons and microexcitable zones in primate thalamus. J Neurophysiol 75: 1105–1116, 1996.
Butler EG, Harvey MC, Finkelstein DI, and Horne MK. Neuronal activity in the monkey ventrolateral thalamus following perturbations of voluntary wrist movements. Exp Brain Res 118: 393–407, 1998.[CrossRef][ISI][Medline]
Cheney PD and Fetz EE. Corticomotoneuronal cells contribute to long-latency stretch reflexes in the rhesus monkey. J Physiol 349: 249–272, 1984.
Colebatch JG, Findley LJ, Frackowiak RS, Marsden CD, and Brooks DJ. Preliminary report: activation of the cerebellum in essential tremor. Lancet 336: 1028–1030, 1990.[CrossRef][ISI][Medline]
Desmedt JE. Cerebral Motor Control in Man: Long Loop Mechanisms. Basel: Karger, 1978.
Deuschl G, Bain P, and Brin M. Consensus statement of the Movement Disorder Society on tremor. Mov Disord 13: 2–23, 1998.[CrossRef][ISI][Medline]
Deuschl G and Bergman H. Pathophysiology of nonparkinsonian tremors. Mov Disord 17: S41–S48, 2002.
Deuschl G, Lucking CH, and Schenck E. Essential tremor: electrophysiological and pharmacological evidence for a subdivision. J Neurol Neurosurg Psych 50: 1435–1441, 1987.
Dupuis MJ, Delwaide PJ, Boucquey D, and Gonsette RE. Homolateral disappearance of essential tremor after cerebellar stroke. Mov Disord 4: 183–187, 1989.[CrossRef][ISI][Medline]
Elble RJ. Central mechanisms of tremor. J Clin Neurophysiol 13: 133–144, 1996.[ISI][Medline]
Elble RJ. Animal models of action tremor. Mov Disord 13 Suppl 3: 35–39, 1998.[Medline]
Elble RJ, Higgins C, and Hughes L. Phase resetting and frequency entrainment of essential tremor. Exp Neurol 116: 355–361, 1992.[CrossRef][ISI][Medline]
Elble RJ and Koller W. Tremor. Baltimore, MD: Johns Hopkins University Press, 1990.
Fahn S, Tolosa E, and Marin C. Clinical rating scale for tremor. In: Parkinson's Disease and Movement Disorders, edited by Jankovic J and Tolosa E. Baltimore, MD: Urban and Schwartzenberg. 1988, p. 225–234.
Findley LJ and Koller WC. Definition and behavioral classifications. In: Handbook of Tremor Disorders, edited by Findley LJ and Koller WC. New York: Dekker, 1995, p. 1–5.
French AS and Holden AV. Frequency domain analysis of neurophysiologic data. Comp Prog Biomed 1: 219–234, 1971.
French AS, Holden AV, and Stein RB. The estimation of the frequency response function of a mechanoreceptor. Kybernetik 11: 15–23, 1972.[CrossRef][ISI][Medline]
Glaser EM and Ruchkin DS. Principles of Neurobiological Signal Analysis. New York: Academic, 1976.
Goldman MS, Ahlskog JE, and Kelly PJ. The symptomatic and functional outcome of stereotactic thalamotomy for medically intractable essential tremor. J Neurosurg 76: 924–928, 1992.[ISI][Medline]
Hallett M and Dubinsky RM. Glucose metabolism in the brain of patients with essential tremor. J Neurol Sci 114: 45–48, 1993.[CrossRef][ISI][Medline]
Horne MK and Butler EG. The role of the cerebello-thalamo-cortical pathway in skilled movement. Prog Neurobiol 46: 199–213, 1995.[CrossRef][ISI][Medline]
Houk JC, Keifer J, and Barto AG. Distributed motor commands in the limb premotor network. Trends Neurosci 16: 27–33, 1993.[CrossRef][ISI][Medline]
Houk JC and Wise SP. Distributed modular architectures linking basal ganglia, cerebellum, and cerebral cortex: their role in planning and controlling action. Cereb Cortex 5: 95–110, 1995.
Hua SE and Houk JC. Cerebellar guidance of premotor network development and sensorimotor learning. Learn Mem 4: 63–76, 1997.
Jankovic J, Cardoso F, Grossman RG, and Hamilton WJ. Outcome after stereotactic thalamotomy for parkinsonian, essential, and other types of tremor. Neurosurgery 37: 680–686, 1995.[ISI][Medline]
Jasper HH and Bertrand G. Thalamic units involved in somatic sensation and voluntary and involuntary movements in man. In: The Thalamus, edited by Purpura DP and Yahr MD. New York: Columbia Univ. Press, 1966, p. 365–390.
Jenkins GW and Watts DG. Spectral Analysis. San Francisco, CA: Holden-Day, 1968.
Jenkins IH, Bain PG, Colebatch JG, Thompson PD, Findley LJ, Frackowiak RS, Marsden CD, and Brooks DJ. A positron emission tomography study of essential tremor: evidence for overactivity of cerebellar connections. Ann Neurol 34: 82–90, 1993.[CrossRef][ISI][Medline]
Johnson KO, Yoshioka T, and Vega-Bermudez F. Tactile functions of mechanoreceptive afferents innervating the hand. J Clin Neurophysiol 17: 539–558, 2000.[ISI][Medline]
Keating JG and Thach WT. Nonclock behavior of inferior olive neurons: interspike interval of Purkinje cell complex spike discharge in the awake behaving monkey is random. J Neurophysiol 73: 1329–1340, 1995.
Keating JG and Thach WT. No clock signal in the discharge of neurons in the deep cerebellar nuclei. J Neurophysiol 77: 2232–2234, 1997.
Lamarre Y. Animal models of physiological, essential, and parkinsonian-like tremors. In: Movement Disorders: Tremor, edited by Findley LJ and Capildeo R. New York: Oxford Univ. Press, 1984, p. 183–194.
Lamarre Y. Central mechanisms of experimental tremor and their clinical relevance. In: Handbook of Tremor Disorders, edited by Findley LJ and Capildeo R. New York: Dekker, 1995, p. 103–118.
Lee RG and Stein RB. Resetting of tremor by mechanical perturbations: a comparison of essential tremor and parkinsonian tremor. Ann Neurol 10: 523–531, 1981.[CrossRef][ISI][Medline]
Lemstra AW, Verhagen Metman L, Lee J-I, Dougherty PM, and Lenz FA. Tremor-frequency (3-6Hz) activity in the sensorimotor arm representation of the internal segement of the globus pallidus in patients with parkinson's disease. Neurosci Lett 267: 129–132, 1999.[CrossRef][ISI][Medline]
Lenz FA, Dostrovsky JO, Kwan HC, Tasker RR, Yamashiro K, and Murphy JT. Methods for microstimulation and recording of single neurons and evoked potentials in the human central nervous system. J Neurosurg 68: 630–634, 1988a.[ISI][Medline]
Lenz FA, Jaeger CJ, Seike MS, Lin YC, and Reich SG. Single-neuron analysis of human thalamus in patients with intention tremor and other clinical signs of cerebellar disease. J Neurophysiol 87: 2084–2094, 2002.
Lenz FA, Kwan HC, Dostrovsky JO, Tasker RR, Murphy JT, and Lenz YE. Single-unit analysis of the human ventral thalamic nuclear group. Activity correlated with movement. Brain 113: 1795–1821, 1990.
Lenz FA, Kwan HC, Martin RL, Tasker RR, Dostrovsky JO, and Lenz YE. Single-unit analysis of the human ventral thalamic nuclear group. Tremor-related activity in functionally identified cells. Brain 117: 531–543, 1994.
Lenz FA, Seike M, Lin YC, Baker FH, Richardson RT, and Gracely RH. Thermal and pain sensations evoked by microstimulation in the area of the human ventrocaudal nucleus (Vc). J Neurophysiol 70: 200–212, 1993.
Lenz FA, Tasker RR, Kwan HC, Schnider S, Kwong R, Murayama Y, Dostrovsky JO, and Murphy JT. Single-unit analysis of the human ventral thalamic nuclear group: correlation of thalamic "tremor cells" with the 3–6 Hz component of parkinsonian tremor. J Neurosci 8: 754–764, 1988b.[Abstract]
Lenz FA, Tatton WG, and Tasker RR. Electro-myographic response to displacement of different forelimb joints in the squirrel-monkey. J Neurosci 3: 783–794, 1983a.[Abstract]
Lenz FA, Tatton WG, and Tasker RR. The effect of cortical-lesions on the electro-myographic response to joint displacement in the squirrel-monkey forelimb. J Neurosci 3: 795–805, 1983b.[Abstract]
Llinas R, Baker R, and Sotelo C. Electronic coupling between neurons in cat inferior olive. J Neurophysiol 37: 560–571, 1974.
Llinas R and Yarom Y. Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances. J Physiol 315: 549–567, 1981.
Llinas R and Yarom Y. Oscillatory properties of guinea pig inferior olivary neurones and their pharmacological modulation: an in vitro study. J Physiol 376: 163–182, 1986.
Louis ED, Ottman R, and Hauser WA. How common is the most common adult movement disorder? estimates of the prevalence of essential tremor throughout the world. Mov Disord 13: 5–10, 1998.[CrossRef][ISI][Medline]
Marsden JF, Ashby P, Limousin-Dowsey P, Rothwell JC, and Brown P. Coherence between cerebellar thalamus, cortex and muscle in man: cerebellar thalamus interactions. Brain 123: 1459–1470, 2000.
Mathews PBC. Muscle spindles. In: Handbook of Physiology. The Nervous System. Motor Control. Rockville MD, APS Press. 1981, sect. 1, vol. II, part 1, p. 189–228.
Milner TE, Cadoret G, Lessard L, and Smith AM. EMG analysis of harmaline-induced tremor in normal and 3 strains of mutant mice with Purkinje-cell degeneration and the role of the inferior olive. J Neurophysiol 73: 2568–2577, 1995.
Nagaratnam N and Kalasabail G. Contralateral abolition of essential tremor following a pontine stroke. J Neurol Sci 149: 195–196, 1997.[CrossRef][ISI][Medline]
Oppenheim AV and Schafer RW. Digital Signal Processing. Englewood Heights, NJ: Prentice-Hall, 1975.
Perlmutter JS, Mink JW, Bastian AJ, Zackowski K, Hershey T, Miyawaki E, Koller W, and Videen TO. Blood flow responses to deep brain stimulation of thalamus. Neurology 58: 1388–1394, 2002.
Schuurman PR, Bosch DA, Bossuyt PM, Bonsel GJ, van Someren EJ, de Bie RM, Merkus MP, and Speelman JD. A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor [see comments]. N Engl J Med 342: 461–468, 2000.
Shahani BT and Young RR. Physiological and pharmacological aids in the differential diagnosis of tremor. J Neurol Neurosurg Psych 39: 772–783, 1976.
Sherman SM and Guillery RW. Exploring the Thalamus. San Diego, CA: Academic, 2001.
Tasker RR, Organ LW, and Hawrylyshyn P. The Thalamus and Midbrain in Man: A Physiologic Atlas Using Electrical Stimulation. Springfield, IL: Thomas, 1982.
Vitek JL, Ashe J, DeLong MR, and Kaneoke Y. Microstimulation of primate motor thalamus: somatotopic organization and differential distribution of evoked motor responses among subnuclei. J Neurophysiol 75: 2486–2495, 1996.
Weiss M. Rhythmic activity of spinal interneurons in harmaline-treated cats. A model for olivo-cerebellar influence at the spinal level. J Neurol Sci 54: 341–348, 1982.
, the frequency at which the maximum spectral component in the tremor frequency range (4–10 Hz in this study) (see also Deuschl et al. 1998
) and postural tremor conditions (
; n = 16, 2 patients). For each neuron, the averaged autopower spectrum for spike activity was normalized by scaling the maximum value to 1. Then these 16 normalized spectra were averaged. The means ± SE are plotted.
