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1Department of Neurosurgery, Sungkyunkwan University, Seoul, South Korea; 2Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, Maryland; and 3Department of Anesthesiology, M.D. Anderson Medical Center, Houston, Texas
Submitted 4 April 2005; accepted in final form 17 May 2005
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Lenz et al. 1988b). These responses can be understood in terms of the glutamatergic inputs from afferent fibers to monkey thalamo-cortical projection neurons (Beggs et al. 2003; Dougherty et al. 1996, 1998; Ralston and Ralston 1992, 1994). These same studies demonstrate that afferent fibers activate inhibitory interneurons and glomeruli, both of which produce inhibitory GABAergic feedback to projection neurons (Beggs et al. 2003; Ralston and Ralston 1994). Collaterals of the axons of projection neurons synapse in the thalamic nucleus reticularis, again resulting in GABAergic inhibitory feedback to the projection neurons (Deschenes et al. 1985).
Inhibitory events may contribute to the bursts of action potentials that have been identified in the spontaneous firing of projection neurons in Vc studied in patients with chronic pain or movement disorders (Jeanmonod et al. 1996; Lenz et al. 1994c, 1998; Radhakrishnan et al. 1999; Zirh et al. 1997). These high-frequency action potential bursts crown a voltage-dependent calcium conductance that is de-inactivated by prolonged inhibition (low-threshold spike, LTS) (Jahnsen and Llinas 1984; Steriade et al. 1990).
We now address the hypothesis that the stimulus-evoked activity of neurons in Vc is characterized by inhibitory events leading to LTS bursting. This hypothesis has been tested by studying the response of single neurons in human Vc to nonpainful and painful stimuli of the mechanical, heat, and cold submodalities during awake surgical procedures in patients with movement disorders. The results demonstrate that, although all neuron types have stimulus-evoked LTS bursting, those neurons responding to cold have the highest burst rates. This paper describes analysis of bursting in a group of Vc neurons previously characterized by their firing rates in response to the same stimuli (Lee et al. 1999).
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METHODS |
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). The subjects carried diagnoses of essential tremor (15 patients), Parkinson's tremor (5), intention tremor (2), and dystonia (2) (Watts and Koller 1998). All subjects were taken off medications for the treatment of movement disorders for 24 h prior to the procedure. No patient had either abnormal somatic sensory function as assessed by standard sensory testing (Lenz et al. 1993) or an abnormal MRI.
Thalamic exploration was performed as a stereotactic procedure using the Leksell frame (Lenz et al. 1988a). First, the three-dimensional frame coordinates of the anterior (AC) and posterior commissures (PC) were measured by CT/MRI scan. Physiological corroboration of anatomical loci was then performed under local anesthesia, i.e., subject fully conscious, by using both single-neuron recording and microstimulation as previously described (Lee et al. 1999; Lenz et al. 1988a). Both recording and stimulation results were used to generate a map (Fig. 1) that was fitted to the sagittal sections of a standard atlas (Schaltenbrand and Bailey 1959).
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The protocol for these studies was identical to that for the prior report of responses to somatic stimuli (Lee et al. 1999) and was reviewed and approved annually by the Hopkins Institutional Review Board. All subjects signed an informed consent for these studies. Initial sensory testing included determination of mechanical and thermal thresholds for face and arm. Subjects described these stimuli with verbal descriptors, which were chosen from a questionnaire of ideal descriptors (Lenz et al. 1994a; Torgerson et al. 1988). Painful sensations were also described by a visual analog scale (VAS) pain rating anchored by the verbal statement that "0 is no pain and 10 is the most intense sensation imaginable" (Gracely et al. 1978, 1979; Lenz et al. 1994a).
As in the previous report of the same raw data (Fig. 1 in Lee et al. 1999), sensory stimuli included brushing the skin with a camel-hair brush, separate application to a fold of skin of a large arterial clip [painful in 40% of subjects, with a pain VAS of 1.9/10 averaged over all patients (Lee et al. 1999)], a medium clip (painful in 75% with VAS of 3.3/10), and a small clip (painful in 90% with VAS of 8.2/10) arterial clip (Chung et al. 1986; Guilbaud et al. 1987; Surmeier et al. 1988). Additionally, mechanical stimulation was carried out with a nonpenetrating towel clip with two parallel 4 x 5-mm serrated surfaces that could be approximated by 10 reproducible steps on a ratchet.
Thermal stimuli were applied by using a Peltier device (LTS-3, 1-in square head, Thermal Devices, Golden Valley, MN), which delivered a series of thermal stimuli from an adapting temperature of 33 to 6°C (painful in 30% with VAS of 1.2/10), 12°C (painful in 5% with VAS of 5/10), 18°C (painful in 0%), and 24°C (painful in 2% with VAS of 1.3/10), 42°C (painful in 21% with VAS of 1.8/10), 45°C (painful in 42% with VAS of 3.6/10), and 48°C (painful in 78% with VAS of 5.3/10) (Lee et al. 1999).
Study of thalamic activity
As the electrode was advanced, we applied search stimuli, which included gentle stroking, brisk tapping, and manual pinching on the contralateral face and hand and in the projected field for threshold microstimulation. Neurons that responded to manual pinching were selected for application of quantitative stimuli more often than for those that responded to stroking or tapping (Lee et al. 1999).
When a neuron was isolated, spontaneous activity was first recorded for a period of 30–60 s. The center and boundaries of the receptive field were then defined by nonpainful, mechanical stimuli. Thereafter, all stimuli applied during preoperative sensory testing were applied. The timing of the stimulus was indicated by the output of the Peltier for thermal stimuli (duration: heat 10 s individual temperature, cold 20 s) and by a foot pedal for mechanical stimuli (duration: 10 s/individual clip setting). These clip or manual mechanical stimuli are standard for studies of nociception in primates (Bushnell et al. 1993; Casey and Morrow 1983; Lenz et al. 2004; Pollin and Albe-Fessard 1979; Willis 1985; Willis et al. 1973). The application of a clip to a fold of skin takes 
1 s; therefore the time of onset is judged subjectively by the examiner and signaled by use of a foot pedal.
All stimuli were applied as close as possible to the center of the receptive field while minimizing the overlap between the areas stimulated by the different modalities. The site where the mechanical stimuli were applied varied from stimulus to stimulus but always included the center of the receptive field (Lee et al. 1999). The location of the thermal stimuli from the Peltier always included the center of the receptive field, and the Peltier was moved between the cold and the hot series of stimuli. All recording and stimulation results were recorded manually and on tape (Model 4000, Vetter, Reberburg PA) for postoperative analysis.
Analysis of thalamic activity
The neuronal response to somatic stimuli was categorized by the response to mechanical and thermal stimuli as previously described (Lee et al. 1999). Low threshold (LT) neurons responded only to nonpainful stimuli. Multiple receptive (MR) neurons responded significantly to both brushing and compressive stimuli but were not graded with intensity into the painful range. Multiple receptive neurons included MR for neurons responding only to mechanical stimuli, MRC for neurons also responding to cold, and MRH for neurons also responding to heat. Wide dynamic range neurons (WDR) responded to brushing and compressive stimuli in a graded fashion to stimuli across the intensive continuum from the nonpainful into the painful range (Lee et al. 1999). These neurons included: WDR for neurons responding only to mechanical stimuli, WDRC for those also responding to cold, and WDRH for those also responding to heat. Thus there were a total of seven neuronal categories: LT, MR, MRC, MRH, WDR, WDRC, and WDRH.
Neurons were also classified by two separate dimensions of their response to somatic stimuli. The first was the presence of either graded (e.g., WDR) or nongraded responses (e.g., MR) to stimuli across the intensive continuum into the painful range (neuronal response). The second was by the presence of a response to mechanical stimuli only or to cold or hot stimuli (stimulus response). Therefore our classification included seven neuronal categories, which were subdivided by two neuronal responses and three stimulus responses not including the LT category.
Postoperative analysis focused on rate indices, e.g., burst rates, and inhibitory indices, e.g., preburst interval. All stimuli of a submodality were combined for the analysis so that all cold stimuli were combined for analysis, for example. LTS bursts were identified by criteria identical to criteria used in studies of awake monkeys and based on intracellular confirmation (Ramcharan et al. 2000a,b). Criteria (50-6-16) to select bursts were as follows: the inter-spike interval (ISI) preceding the first action potential in the burst had a duration >50 ms, the ISI after the first action potential in the burst had a duration of <6 ms, and all following action potentials were considered as part of the burst if their ISI increased by no more than 2 ms for each succeeding action potential, up to maximum ISI of 16 ms. Bursts of two action potentials were included, consistent with all studies of awake animals (Domich et al. 1986; Glenn and Steriade 1982; Jeanmonod et al. 1996; Lenz et al. 1994c; Radhakrishnan et al. 1999; Ramcharan et al. 2000b).
We also calculated the primary event rate, a well-established measure of the firing rate between bursts (Cox and Lewis 1966; Lenz et al. 1994c; McCarley et al. 1983; Reinagel et al. 1999). The primary event rate included all single spikes plus the first spike in each burst. The ratio of burst rate/primary event rate was calculated to determine whether the burst rate was dependent on background firing. If the difference in burst rates between two neuronal categories was lost when this ratio is calculated, then the difference in bursting was considered to be dependent on the primary event rate.
All firing rate indices were calculated by subtracting the baseline firing value and expressed in units of s–1 (see Spontaneous bursting and inhibitory events). Ratios of rates were calculated without subtracting the baseline value because they are the result of a nonlinear transformation. In some cases, differences among the seven neuronal categories (LT, MR, MRC, MRH, WDR, WDRC, and WDRH) were compared by a one-way ANOVA. Post hoc testing was carried out by Tukey's honestly significant difference test (HSD).
Rate indices were also analyzed by a two-way ANOVA by on the neuron type classified by two axes: the presence of graded or nongraded responses to stimuli of different intensity (neuronal response) and the response to mechanical, cold, or hot stimuli (stimulus response). Post hoc testing of the main effects of neuronal response, stimulus response, and interaction was then carried out (Tukey's HSD test).
Inhibitory events were also analyzed to confirm that selected bursts were associated with LTS because LTS bursts must be preceded by a prolonged inhibition. We first tested whether mean preburst ISIs were significantly different from 100 ms, which is the inhibitory interval consistent with the maximal LTS (Jahnsen and Llinas 1984). The mean for a neuronal category was judged to be different from 100 ms if 100 ms was outside the 95% confidence intervals for the distribution of preburst ISIs (2.7 SE, Bonferroni corrected experiment-wise estimate of error).
Interpretation of the preburst ISI is not entirely straightforward because a preburst ISI >50 ms in the selection criteria may be the result either of an inhibitory event or of a primary event rate of <20 s–1. We identified the presence of preburst inhibition by normalizing the preburst inhibition to the primary event rate, a standard measure of firing rates between bursts (ratio of the preburst ISI/inverse of the primary event rate) (Cox and Lewis 1966; Lenz et al. 1994c; McCarley et al. 1983; Reinagel et al. 1999). The mean for a neuronal category was judged to be >1 if the 95% confidence interval for the distribution of this ratio was >1 (2.7 SE, Bonferroni corrected experiment-wise estimate of error). A ratio of significantly greater than one was taken to indicate a preburst inhibition. As in the case of rate indices preburst ISI and the ratio were tested by a one-way ANOVA by neuronal category and a two-way ANOVA by neuronal response and stimulus response. All tests were considered significant for P < 0.05.
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RESULTS |
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). There were 15 neurons with graded neuronal responses classified as WDR (6 neurons), WDRC (3 neurons), and WDRH (6 neurons). There were 25 neurons with nongraded neuronal responses classified as MR (17 neurons), MRC (5 neurons), and MRH (3 neurons). On average, these neurons had their largest response to brushing and a smaller response to mechanical stimuli. There were nine neurons in the LT category that had a response to brush but not to other mechanical stimuli. In addition, four neurons responded to manual compression and four neurons to tapping (n = 4) but not to the quantitative stimuli used in this study.
Figure 2 shows an example of the firing of a neuron responding to cold and mechanical stimuli (MRC neuron: 05055) (see also Figs. 2, 4, and 6 in Lee et al. 1999). This neuron fires in bursts of action potentials during the response to most stimuli. However, there is a good deal of variability in bursting during spontaneous or prestimulus activity and during the response a single sub-modality of stimulation e.g., 18 and 24°C. Some stimuli, such as heat (42 and 45°C), had very low burst rates, suggesting that some stimuli might fail to evoke bursts consistently. Therefore we examined all stimulus epochs for the presence of bursting.
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Bursting occurred during the majority of stimulation epochs (30–120 s, see Study of thalamic activity) for all neuronal categories during the response to mechanical, cold, and heat stimuli (Table 1). The cold stimuli evoked bursting in a higher proportion of epochs for LT (P = 0.008) and MR (P = 0.007) than for WDR neurons. There were no other significant differences in the proportions of such epochs. Because bursting was present in the response of all neuronal categories to all stimuli, we next looked for quantitative differences in bursting as a function of neuron classification and stimulus submodality. Burst rates were not related to stimulus intensity for any submodality of stimulation. Therefore subsequent analyses combined all intensities of stimulation within each submodality.
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STIMULI OVERALL. The primary event rate, the burst rate, and the burst rate/primary event rate were first analyzed by the response to all stimuli combined (stimuli overall) in a two-way ANOVA by neuronal response and stimulus response (see Analysis of thalamic activity). The primary event rates in response to stimuli overall were significantly related to stimulus response due to higher rates for neurons responding to cold than heat or to mechanical stimuli only (Fig. 3 C, left). There was significant interaction due to MRC neurons having higher primary event rates than WDRC neurons. The primary event rate, the burst rate, and the burst rate/primary event rate varied significantly with stimulus response but did not vary significantly with neuronal response.
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To determine whether the burst rate was dependent on background firing, the ratio of burst rate/primary event rate was calculated (see Analysis of thalamic activity). The burst rate/primary event rate in response to overall stimuli showed a significant main effect of stimulus response due to a higher ratio for neurons responding to cold than for those responding to heat or only to mechanical stimuli. Neither the neuronal response nor interaction was significant. Thus the burst rate was significantly higher among neurons responding to cold independent of the primary event rate.
These results suggest that bursting was preferentially related to neural elements subserving cold. Those neural elements might have been the fibers transmitting cold to the thalamus, or the inhibitory connections of neurons responding to cold. To test whether the afferent fiber was a critical determinant of bursting, we next analyzed the response of neurons to their optimal stimulus, e.g., cold for MRC neurons.
OPTIMAL STIMULUS RESPONSE.
The optimal stimulus was defined as brushing for LT neurons and as nonpainful and painful intensities of heat for MRH and WDRH neuronal categories, cold for MRC and WDRC neuronal categories, or mechanical stimuli only for MR and WDR neuronal categories (Lee et al. 1999). The primary event rate in response to optimal stimuli was significantly related to stimulus response due to a significantly higher rate for neurons responding to cold than for those responding to heat stimuli or to mechanical stimuli only. Neither the main effect for neuronal response (Fig. 4, left top) nor to interaction was significant.
Burst rate in response to optimal stimuli was significantly related to stimulus response due to rates for neurons responding to cold being higher than for those responding to mechanical stimuli only (Fig. 4B, middle). Neither the neuronal response (Fig. 4, middle, bottom) nor the interaction term was significant (not shown).
The burst rate/primary event rate in response to optimal stimuli was significantly related to stimulus response due to a higher ratio that was higher for neurons responding to cold than for those responding to heat or to mechanical stimuli only (Fig. 4B, right). Neither the main effect of neuronal response (Fig. 4, right, top) nor to the interaction term was significant. Therefore burst indices for the optimal stimulus and stimuli overall were significantly related to stimulus response independent of the primary event rate. This effect was due to higher burst indices among cells responding to cold, which is consistent with a mechanism involving afferent fibers subserving cold. To test this mechanism, we next analyzed bursting in response to all stimuli except the optimal stimulus so that the effect of the afferent fiber on the stimulus response is eliminated.
RESPONSE TO ALL STIMULI EXCEPT THE OPTIMAL STIMULUS. For all stimuli except the optimal stimulus, the primary event rate was significantly related to stimulus response (F = 12.3, df = 2, P < 0.001) but not to neuronal response (F = 3.7, df = 1, P = 0.057) with significant interaction (F = 9.3, df = 2, P < 0.001). Post hoc tests showed that MRC neurons (24.4/s) had a significantly higher primary event rate than MR (7.9/s) and MRH neurons (3.7/s, P < 0.001). WDRH neurons (14.1/s) had a significantly higher primary event rate than WDR neurons (–3.4/s, P < 0.001).
The burst rate for all stimuli except optimal was significantly related to the interaction term (F = 4.4, P = 0.01) but not to the stimulus response (F = 1.6, P = 0.20) or neuronal response (F = 0.1, P = 0.72). The burst rates were as follows: MRC, 0.34/s; MR, 0.34; WDRH, 0.29; WDRC, 0.23; WDR, 0.14; and MRH, –0.12). The burst rate for MRC neurons was significantly higher than for MRH neurons (P = 0.02).
Burst/primary event rate was significantly related to stimulus response (F = 7.6. P < 0.001) but to neither neuronal response (F = 3.5, P = 0.064) nor the interaction term (F = 1.4, P = 0.248). Post hoc testing for stimulus type showed that the burst/primary event rate was significantly higher for neurons responding to cold (0.06, P = 0.003) or mechanical stimuli only (0.05, P = 0.018) than for those responding to heat (0.03). Therefore, the higher burst rates that were observed among cells responding to cold persisted even if the optimal response was excluded from stimuli overall. This suggests that the bursting behavior of neurons responding to cold is not due to the afferent fiber transmitting cold stimuli but rather due to the inhibitory connections of these neurons.
Inhibitory events
RATIO OF PREBURST ISI/INVERSE OF THE PRIMARY EVENT RATE.
The presumed LTS bursting activity described in the preceding text assumes the presence of a preburst inhibition (Jahnsen and Llinas 1984). We attempted to distinguish prolonged preburst ISIs due to a pause/inhibition before the burst from prolonged preburst ISIs reflecting a slow firing rate, i.e., all interburst ISIs are prolonged. The interburst ISI is the inverse of the primary event rate (see Analysis of thalamic activity). Therefore if we calculate the ratio of the preburst ISI/inverse of the primary event rate, then a preburst pause/inhibition will result in a ratio of >1. In Fig. 5 A, the error bars of mean ±2.7 SE indicate the 95% confidence limits for the ratio (Bonferroni corrected experiment-wise estimate of error). The ratio for stimuli overall of all neuronal categories was significantly >1, as indicated by error bars above the dashed horizontal line. Therefore all neuronal categories had significant preburst inhibition in response to stimuli overall (Fig. 5A. left). In the case of the optimal response (Fig. 5A, right), all neuronal categories had significant preburst inhibition except MRH neurons.
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The two-way ANOVA for preburst interval of stimuli overall showed significance by interaction but not by stimulus response or neuronal response. Post hoc analysis (Fig. 5B, left) revealed that the ratio for WDRH neurons was significantly higher than for the MRH neurons. The two-way ANOVA for optimal stimuli showed no significant main effects but significant interaction (Fig. 5B, right). The post hoc testing on interaction found that MR neurons had significantly (P = 0.017) higher ratios than WDR neurons consistent with the one-way ANOVA. WDRH had a significantly higher ratio than WDR neurons (P = 0.040). Therefore WDR neurons consistently had the least pronounced preburst inhibition.
PREBURST ISI.
Maximal LTS burst amplitude occurs with the duration of preburst inhibition of 100 ms (Jahnsen and Llinas 1984). The preburst ISIs were not significantly <100 ms in the case of any neuronal category for stimuli overall, since the error bars overlap or are above the 100 ms horizontal dashed line in that panel (see preceding text and Analysis of thalamic activity). Preburst ISIs were >50 ms because error bars were above the lowest dashed horizontal line for all neuronal categories except MRH. Therefore optimal stimuli preburst ISIs were not significantly <100 ms but were significantly >50 ms in the case of all categories except the MRH neurons.
The preburst ISIs were not significantly different among different neuronal categories (1-way ANOVA) for either stimuli overall (Fig. 6 A, left) or optimal stimuli (Fig. 6A, right).
The two-way ANOVA for stimuli overall showed significant effects only by neuronal response. Post hoc testing revealed that preburst ISIs were significantly longer for the graded response type than nongraded response type (Fig. 6B, left). The two-way ANOVA for optimal stimuli showed no significant effects.
By many measures, WDR neurons the weakest preburst inhibition, i.e., smallest ratio, and the longest preburst ISI, suggesting that their firing is dominated slow primary event rates and by burst rates that were consistently less than for neurons responding to cold.
For stimuli overall and optimal stimuli, the different neuronal categories had significant preburst inhibition and preburst ISIs that were not significantly <100 ms. The only exception is in the optimal response for the MRH, which might be explained by the high variance and small sample size (see Fig. 6A). These results demonstrate that the preburst ISI is not likely an artifact of the burst selection criteria (preburst ISI: >50 ms) but is consistent with a maximal LTS (Jahnsen and Llinas 1984).
Spontaneous bursting and inhibitory events
Spontaneous firing was studied as a measure of the baseline firing pattern which commonly displayed bursts for these neurons (Table 1). The two-way ANOVAs for primary event rate or burst rate showed no significance. The burst/primary event rates during spontaneous period showed significance by stimulus response (F = 3.6, P = 0.037) but not to neuronal response (F = 0.4, P = 0.544) or interaction (F = 1.9, P = 0.165). The post hoc test for stimulus response showed that neurons responding to cold had significantly higher burst/primary event rates (0.06) than those responding to heat (0.02, P = 0.048). Thus spontaneous bursting in neurons responding to cold was higher than those responding to heat, suggesting that the burst rate of neurons responding to heat, but not those responding to cold, was dependent on the primary event rate.
The ratio of preburst ISI/inverse of primary event rates for spontaneous activity was significantly >1 for all neuron types, indicating significant spontaneous preburst inhibition. Preburst ISIs during spontaneous period were not significantly <100 ms for any neuronal category. For spontaneous activity, the two-way ANOVA showed no significant effects by either the ratio of preburst ISI/inverse of the primary event rate or preburst ISI.
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DISCUSSION |
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Methodological considerations
Different criteria have been used to identify LTS bursts in thalamic "relay" nuclei in both different species (Domich et al. 1986; Guido et al. 1992; Lu et al. 1992; Ramcharan et al. 2000b), and awake humans with neurological disorders (Jeanmonod et al. 1996; Lenz et al. 1994c, 1998; Radhakrishnan et al. 1999; Zirh et al. 1997). Except in the case of humans, all of the criteria mentioned in the preceding text have been validated by intracellular confirmation (Deschenes et al. 1984; Domich et al. 1986; Guido et al. 1992; Lu et al. 1992; Ramcharan et al. 2000b). We have adopted selection criteria that have been validated by intracellular recordings and applied in studies of awake Old World primates (Ramcharan et al. 2000a,b). The ability of these criteria to select LTS bursts in humans demonstrated by the presence of significant preburst inhibition of a duration (100 ms) that is consistent with maximal LTS (see Figs. 5 and 6).
Afferent mechanisms mediating thalamic bursting evoked by somatic stimuli
The present study demonstrates that neurons responding to cold stimuli have higher rates of stimulus-evoked LTS bursting (Figs. 3 and 4). The higher stimulus-evoked burst rates among neurons responding to cold was independent of the background firing rate because they persisted after burst rates were normalized to the primary event rate. Another possibility is that bursting among thalamic neurons responding to cold is the result of cold-evoked bursting in the periphery that is transmitted to the thalamus.
Thalamic neuronal responses to cool, heat, and painful stimuli may originate in A
cool fibers, A- or C-mechano-heat fibers and be transmitted to spinothalamic tract (STT) neurons in the dorsal horn (Apkarian and Hodge 1989a,b; Craig 1990; Craig et al. 1994; Dostrovsky and Craig 1996; Ferrington et al. 1987; Kumazawa et al. 1975). The axons of these neurons project to ventral posterior nucleus (Apkarian and Hodge 1989b; Ferrington et al. 1987; Mehler 1962) and, perhaps, to the posterior part of ventral medial nucleus, i.e.VMpo (Craig et al. 1994; Dostrovsky and Craig 1996; cf. Graziano and Jones 2004; Lenz et al. 2004; Willis et al. 2001). Another possibility is that Vc neurons responding to cold might receive inputs from type 1 slowly adapting mechanoreceptors that are activated by cold (Burton et al. 1972; Duclaux and Kenshalo 1972; Hensel and Zotterman 1951; Iggo and Muir 1969). The activity of these fibers is transmitted through the dorsal column nuclei to the ventral posterior thalamus (Burton et al. 1970; Willis and Coggeshall 1991).
The present report of bursting activity in thalamic neurons responding to cold stimuli is reminiscent of the response of cold receptors to cold stimuli (Iggo 1969; Kenshalo and Duclaux 1977). Cool responsive neurons in the ventral posterior nucleus also respond to bursting activity at high frequency (ISIs of 2–4 ms) during the cooling phase after a heat stimulus (Martin and Manning 1971). However, transmission of thalamic bursting from the periphery is in doubt because STT neurons responding to cold do not show the bursting, unlike the primary afferents and the thalamic neurons (Iggo and Ramsey 1976; Poulos 1975). The activity of these STT neurons may reflect their response to multiple primary afferents firing out of phase. Therefore it seems unlikely that thalamic bursting is the result of transmission of bursting activity from the periphery. The present evidence for stimulus-evoked LTS bursting in Vc argues for a mechanism based on thalamic circuitry rather than transmission of bursting activity to the thalamus via afferent pathways.
Thalamic circuitry related to stimulus-evoked inhibitory events
In primate species, afferent axons terminate on excitatory amino acid (EAA) receptors based on both anatomic and electrophysiologic criteria (Dougherty et al. 1996; Jones 1983; Sherman and Guillery 2001). Axons in the monkey dorsal column pathway form triadic structures in the ventral posterior nucleus by terminating separately on the dendrite of a GABAergic interneuron and the dendrite of a thalamic projection neuron (Ralston and Ralston 1994). That GABAergic dendrite then forms an inhibitory synapse on the same projection neuron. Therefore the afferent-evoked excitatory postsynaptic potential (EPSP) in the projection neuron is immediately followed by an inhibitory postsynaptic potential (IPSP) produced by input from the GABAergic interneuron (Ralston and Ralston 1994). This arrangement shortens the afferent evoked EPSP and so provides short-latency inhibitory feedback to excitatory somatic sensory input. Conversely, STT terminals commonly end in simple axo-dendritic terminations (Ralston and Ralston 1994), which are clustered together on individual dendrites.
Thalamic projection neurons also receive inhibitory GABAergic nontriadic synapses, arising from thalamic nucleus reticularis and intrinsic inhibitory interneurons. Cortico-thalamic axons commonly send a branch to neurons of the thalamic reticular nucleus that project back to thalamic projection neurons, either directly or indirectly (Bourassa et al. 1995; Darian-Smith et al. 1999; Deschenes et al. 1994). Therefore there are many possible explanations of inhibitory events and the associated LTS bursting evoked by somatic sensory pathways afferent to the thalamus.
In comparison to other neuron types, those responding to cold have higher rates of stimulus-evoked LTS bursts, regardless of the stimuli analyzed. Therefore it seems unlikely that burst firing is related directly to the afferent fiber transmitting cold. It is more likely that the increased bursting is the result of the properties and inhibitory connections of neurons responding to cold. These stimulus-evoked inhibitory events may result from afferent connections to the inhibitory circuitry described in the preceding text (Jones 1985; Sherman and Guillery 2001; Steriade et al. 1997).
Although neurons responding to cold have more stimulus-evoked LTS bursts, all neuronal categories had preburst ISIs not less than 100 ms and preburst inhibition, regardless of the stimuli analyzed. Therefore increased bursting in neurons responding to cold may be the result of differences in the numbers of afferent-activated inhibitory events, the size of which is similar across neuronal categories in Vc.
Whatever the mechanism of this stimulus-related LTS bursting, the resulting spike trains include long pauses followed by brief, intense bursts of action potentials that cannot be described by a linear model (Bendat and Piersol 1976). Previous studies have documented the presence of bursting, nonlinear, transformations of sensory signals in the forebrain visual system (Guido et al. 1995; Livingstone et al. 1996; Martinez-Conde et al. 2002). In addition, descending control of eye movements related to visual stimulation can transform sensory input by evoking LTS bursts (Martinez-Conde et al. 2002; Ramcharan et al. 2001). In the present data, the spike trains of WDR neurons, transmitting sensory aspect of pain (Price et al. 2003; Price and Dubner 1977), have the smallest preburst inhibition. This suggests that preburst ISIs are strongly influenced by interburst firing rates.
It is not clear how bursting in the present data relates to the assumption of linearity of thalamic pain and temperature transmission that is explicit in primate thalamic stimulus-response functions (Bushnell et al. 1993; Kenshalo et al. 1980; Lee et al. 1999). The same assumption is implicit in the graded mechanical stimulus-response function that defines WDR neurons in the dorsal horn (Kumazawa and Perl 1978; Maixner et al. 1986; Willis et al. 1973), thalamus (Bushnell and Duncan 1987; Lenz et al. 1994b; Morrow and Casey 1992), and cortex (Kenshalo and Isensee 1983; Price et al. 2003). Stimulus-evoked LTS bursting may be related to nonlinear, binary processes in the primate thalamus and cortex (Bornhovd et al. 2002; Coghill et al. 1999; Lenz et al. 2004) that contribute to attentional or cognitive aspects of pain (Becker et al. 1993; Bornhovd et al. 2002; Zaslansky et al. 1995).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: F. A. Lenz, Dept. of Neurosurgery, Meyer Bldg. 8-181, Johns Hopkins Hospital, 600 N. Wolfe St, Baltimore, MD 21287-7713 (E-mail: flenz1{at}jhmi.edu)
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REFERENCES |
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) than other neuron types (
) in the post hoc analysis. Those categories without an arrow are not significantly different from any other category. Left: the results of analysis of the ratio of preburst ISI/inverse of the primary event rate for stimuli overall showed significant differences between neuronal categories (F = 6.2, df = 6, P < 0.001). Right: the ratio for optimal stimuli was significantly dependent on neuronal category (A, right, 1-way ANOVA, F = 3.6, df = 6, P = 0.003). B: the 2-way ANOVA for stimuli overall (left) showed a significant interaction but no significant main effects as follows: stimulus response (F = 1.7, df = 2, P < 0.0.187), neuronal response (F = 0.1, df = 1, P < 0.715), and interaction (F = 12.2, df = 2, P < 0.001). The 2-way ANOVA for optimal stimuli (right) showed significant interaction (B, right: F = 5.3, df = 2, P = 0.006) but no significant effects.