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Intrathalamic non-propagating generators of high-frequency (1000 Hz) somatosensory evoked potential (SEP) bursts recorded subcortically in man
clinical Neurophysiology 113 (2002) 1001–1005 www.elsevier.com/locate/clinph
Intrathalamic non-propagating generators of high-frequency (1000 Hz) somatosensory evoked potential (SEP) bursts recorded subcortically in man Fabian Klostermann a,*, Rene´ Gobbele b, Helmut Buchner b, Gabriel Curio a a
Department of Neurology, Neurophysics Group, Klinikum Benjamin Franklin, Freie Universitaet, Hindenburgdamm 30, 12200 Berlin, Germany b Department of Neurology, RWTH Aachen, Germany Accepted 15 April 2002
Abstract Objectives: Recently, bursts of high-frequency (1000 Hz) median nerve somatosensory evoked potential (SEP) wavelets were recorded subcortically near and inside the thalamus from deep brain electrodes implanted for tremor therapy. This study aimed to clarify whether these subcortical SEP bursts reflect evoked axonal volleys running in the thalamocortical radiation or a locally restricted intrathalamic response. Methods: During deep brain electrode implantation, median nerve SEP were recorded in 7 patients sequentially along the subcortical stereotactic trajectory at sites 120 and 110 mm above the respective target nucleus (ventral intermediate thalamus or nucleus subthalamicus). Low- and high-frequency SEP components (corner frequency 430 Hz) were analyzed separately with respect to peak latency and amplitude as they changed along the recording trajectory. Results: Individual wavelets of the subcortical 1000 Hz SEP burst showed fixed peak latencies independent from the depth of the electrode penetration; they increased markedly in amplitude with decreasing distance to the thalamus. In contrast, the amplitude gradient between the two recording sites was shallower for the low-frequency SEP component, which peaked earlier at the lower recording site. Conclusions: Subcortically recorded 1000 Hz SEP wavelet bursts predominantly reflect locally restricted near-field activity, presumably generated in the somatosensory relay nucleus. In contrast, the variable peak latency of the subcortical low-frequency component could reflect postsynaptic potentials sequentially evoked during passage of the lemniscal afferences curving through the thalamus and contributions from the thalamocortical radiation. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Median nerve somatosensory evoked potentials; 1000 Hz burst; Somatosensory thalamus; Thalamocortical radiation
1. Introduction Neurosurgical interventions allow for intracerebral nearfield recordings of somatosensory evoked potentials (SEP) from the deep lemniscal and thalamocortical system. Such studies on subcortically recorded SEP helped to establish concepts on the generators of the earliest SEP components which can be picked up in part as far-field micropotentials on the scalp (Abbruzzese et al., 1978; Allison and Hume, 1981; Suzuki and Mayanagi, 1984; Tsuji et al., 1984; Albe-Fessard et al., 1986; Katayama and Tsubokawa, 1987; Morioka et al., 1989; Yamashiro et al., 1989; Vanderzant et al., 1991): corresponding to the scalp responses peaking at about 9, 11, 13 and 14 ms after median nerve stimulation, a successive activation of the lemniscal system at the spinal entry zone of the periph* Corresponding author. Tel.: 149-30-8445-4703; fax: 149-30-84454264. E-mail address: [email protected] (F. Klostermann).
eral nerve, the dorsal column, the cuneate nucleus and the medial lemniscus was demonstrated (Allison and Hume, 1981; Suzuki and Mayanagi, 1984). For the component peaking at about 16 ms poststimulus (P16), which exhibits a duration of several milliseconds in subcortical recordings, a local postsynaptic generation in the somatosensory thalamic relay nucleus was proposed (Mauguiere et al., 1983; Hashimoto, 1984; Tsuji et al., 1984; Vanderzant et al., 1991). Recent subcortical recordings showed that this slow component was superimposed by a burst of high-frequency (about 1000 Hz) low-amplitude wavelets, extending from 14 to 22 ms post-stimulus (Klostermann et al., 1999). When SEP are recorded non-invasively at the scalp (Emerson et al., 1988; Yamada et al., 1988), electroencephalogram (EEG) mapping analyses of burst SEP (spectral energy maximum around 600 Hz) suggested early (around 16 ms) deep generators, presumably being located in the near-thalamic thalamocortical radiation, as well as later
1388-2457/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1388-245 7(02)00119-0
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(around 20 ms) superficial cortical generators (Gobbele et al., 1998; Gobbele et al., 1999). The radiation fiber model is consistent with the spike-like character of the burst wavelets, pointing to fast axonal generators rather than to slower postsynaptic responses (cf. Allison and Hume, 1981; Katayama and Tsubokawa, 1987). The more superficial burst components are superimposed on the primary cortical N20 component of median nerve SEP and could be interpreted at least partially as the presynaptic arrival of thalamic activity at the primary somatosensory (S-I) cortex. Notably, additional burst components generated intracortically are likely to contribute (Curio et al., 1994, 1997; Curio, 2000), with a recent emphasis on cortical interneurons discharging synchroneously at 600 Hz (Hashimoto et al., 1996; Swadlow et al., 1998; Jones et al., 2000). A still unresolved, critical issue is the difference in intraburst frequencies recorded subcortically (,1000 Hz) and at the scalp (,600 Hz). Specifically, with regard to the 1000 Hz burst components which can be recorded at the thalamus in patients the question needs to be addressed how to discriminate intrathalamic stationary sources from generators propagating in suprathalamic white matter. To this end, SEP were recorded here at different brain depths when stereotactically advancing the electrode towards the respective thalamic targets, in order to assess possible latency and amplitude shifts along the recording trajectory.
2. Methods In 7 patients with movement disorders (6 Parkinson disease, one essential tremor; 6 male, one female; 67.4 ^ 7.8 years, range: 58–78 years), SEPs were recorded intraoperatively from the electrode implant for deep brain stimulation. None of the patients suffered from a somatosensory impairment; all patients gave informed consent under a study protocol approved by the local Ethics Committee. When driving the electrode from a frontal burrhole towards the thalamic target site, recordings were performed during two momentary stops 120 and 110 mm above the calculated target positions, i.e. the subthalamic nucleus (STN) in 6 patients and the ventral intermediate nucleus in one patient. The electrode (Medtronic 3389) consists of a shaft with four ring contacts spaced at distances of 0.5 mm and with a width of 1.5 mm, each. The basal contact was referenced against the cranial cathode, covering a distance of 4.5 mm. Additionally, a frontoparietal scalp SEP (C3 0 versus F3) and a peripheral compound action potential (CAP) were recorded; the CAP was derived mediolaterally at the ipsilateral upper arm to control the somatosensory input. The median nerve contralateral to the intrathalamic and scalp electrodes was stimulated at 2 £ motor threshold. Electrical stimuli were applied at 8.1 Hz (constant current squarewave pulses of 0.1 ms width) and 2000 single sweeps were averaged per SEP. A wide bandpass (5–1500 Hz) was
used for data acquisition (sampling rate 10 kHz). Offline digital highpass and lowpass filters (corner frequency: 430 Hz; 24 dB/octave) were applied to separate high- from lowfrequency responses which, thereby, could be analyzed independently. Amplitudes of the low-frequency subcortical SEPcomponents were determined baseline-to-peak in the 5– 428 Hz bandpass. Latencies of high-frequency burst peaks were determined in the 428–1500 Hz bandpass. The mean burst amplitude was determined as a root-mean-square (rms) value over the burst time window, ranging from about 14 to 22 ms, and corrected for noise contributions as estimated in a burst-free time interval from 30 to 45 ms (cf. Klostermann et al., 1998). Statistical analyses were performed on the basis of nonparametrical Wilcoxon tests (two-sided matched pairs signed rank test). Results were considered statistically significant at P-levels , 0.05.
3. Results In all patients between 4 and 7 burst peaks (mean ^ SD ¼ 5.4 ^ 1.2), were identified reliably at both subcortical recording sites, occurring between 13.7 and 24.7 ms poststimulus. When the successive burst peaks of each subject were paired according to their intra-burst positions between recordings from the two electrode sites, no significant peak latency shifts were observed (Fig. 1). As the high-frequency burst duration differed between subjects, peaks 1 to 4 could be compared between both recording sites in all 7 subjects and peak 5 in 6 subjects; for the late peaks 6 (two subjects) and 7 (one subject) no statistical analysis could be performed due to their rare occurrence, but – as for the earlier peaks – no latency shifts were observed. Statistically (peaks 1–5), all peak latencies were reproduced at nearly identical latencies at the upper and lower recording position (range of inter-site peak latency differences: Dt ¼ 0–0.03 ms), and none of the observed latency shifts was significant in this group of subjects. In contrast, the peak latency of the underlying low-frequency response was consistently later at the more superficial recording site (19.33 ^ 1.5 ms) compared to the lower recording site (18.8 ^ 1.41 ms), with the inter-site latency difference (0.53 ^ 0.35 ms) being significantly different from zero (P ¼ 0:02; n ¼ 7). Additional recordings were performed in two patients at subcortical locations even more superficial than the standard upper recording site: at 140 mm above the target area the subcortical low-frequency component was found prolonged by 0.8 ms and reduced by 50% in amplitude (19.5 ms/0.5 mV) in comparison to the deeper 120 mm site (18.7 ms/1 mV); in a second patient (at 130 mm) it was found similarly prolonged and reduced (20 ms/0.6 mV) in comparison to the deeper 120 mm site (19.6 ms/1.3 mV). Subcortical burst activity could not be identified in these additional records, more distant from the thalamic target area.
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Fig. 1. Characteristic example of subcortical SEP recordings at two depths along the sterotactic electrode trajectory, 120 (position 1) and 110 mm (position 2) above the STN. At 120 mm a small high frequency signal becomes discernible which replicates at 110 mm with nearly identical peak latencies but with significantly higher peak amplitudes. In contrast, a latency shift is obtained in the underlying low-frequency component.
N20 values were available in four patients, since three frontoparietal scalp recordings dropped out due to interfering artifacts in the operating room. Comparing the subcortical and N20 latencies in these four subjects, a difference of 3.15 ^ 0.24 ms (19.13 ^ 1.67 ms at the lower recording position versus 22.28 ^ 1.44 ms for the N20) was obtained, consistent with the conductance time from a recording position slightly above thalamus to cortex. The amplitude analysis of burst and low-frequency peaks showed different response patterns, as well. The burst rmsamplitude decreased from the lower recording site (0.12 ^ 0.04 mV) to the more superficial one (0.05 ^ 0.02 mV); the low-frequency component decreased from 1.78 ^ 0.83 to 1.33 ^ 0.31 mV. Accordingly, the voltage ratio between lower and higher recording site was 2.4 ^ 1.44 for the burst and 1.3 ^ 0.59 for the P19, their difference being significant (P ¼ 0:02). The peripheral CAP was found unchanged during recordings at both subcortical sites.
4. Discussion The present study provided two main results. First, the peak latencies of high-frequency (1000 Hz) wavelets in subcortical SEP bursts were found stable across two recording sites spaced 10 mm apart in depth, contrasting with a latency increase of subcortical low-frequency SEP between lower and more superficial recording sites. Second, a marked amplitude decrease of the 1000 Hz wavelet burst was observed with increasing distance from the thalamus, unlike the shallower amplitude gradient of the lowfrequency component. As this pattern was obtained in patients with different pathological conditions, i.e. Parkinson’s disease and essential tremor, it is unlikely that the results reflect disease specific alterations of thalamocortical activation only. With respect to possible burst generator sites, the fixed
wavelet peak latencies along with the steep burst voltage gradients are characteristic for near-field recordings and hence indicate intrathalamic non-propagating generators for the 1000 Hz SEP burst, possibly reflecting population spike responses from neurons in the neighboring thalamic relay nucleus and from lemniscal terminal arborizations. A remarkable feature of high-frequency signals common to both thalamic and scalp recordings is their pronounced short-term variability which occurs uncorrelated to the weaker fluctuations of the respective locally underlying low-frequency components (Klostermann et al., 1999, 2001). Accordingly, low-frequency SEP might reflect the more stable ‘hard-wired’ mandatory part of somatosensory input processing, linked to the physical aspects of stimulation, whereas the momentary degree of local burst activity reflects a more fluctuating modulation of this input, e.g. by attention or the level of vigilance (Gobbele et al., 2000). Indeed, multiple populations of thalamic neurons exert their modulatory functions on the basis of high frequency burst discharges. For example thalamocortical cells with intraburst frequencies up to 1000 Hz were identified in the intralaminar centrolateral nucleus (Steriade et al., 1993); this discharge mode was postulated to be involved in the generation of fast EEG rhythms during arousal reactions and operates on the basis of low threshold calcium spiking (LTS), but a relation to the somatosensory system has not yet been demonstrated. In contrast, LTS-based bursting of up to 500 Hz was observed in sensory relay cells, capable of switching between a single spiking and a bursting mode (McCormick and Feeser, 1990), presumably related to filtering of afferent information. Moreover, relay cells of thalamic sensory nuclei are surrounded by local and reticular interneurons featuring intraburst frequencies of up to 200 Hz (Amzica et al., 1992; Zhu et al., 1999): while local interneurons are supposed to sharpen thalamocortical signal transmission (Zhu and Heggelund, 2001), reticular interneurons reduce the thalamocortical throughput of information, as they are driven by the output from thalamic relay
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neurons which in turn receive an inhibitory feed-back projection from the reticular cell (Sherman and Koch, 1986; Cox et al., 1998). Thus, a superimposition of different intrathalamic bursting cell populations could explain the high-frequency content of subcortically recorded SEP. In previous multi-channel scalp EEG recordings multiple dipole sources of high-frequency SEP bursts were reconstructed, at the primary somatosensory cortex (S-I) as well as subcortically near the thalamus. The cortical burst was attributed partially to the presynaptic arrival of rapidly repeating 600 Hz thalamocortical population spikes (Gobbele et al., 1998). The present data suggest to exclude the subcortically recorded 1000 Hz burst from the set of possible scalp burst generators because it reflects localised non-propagating thalamic activity. This concept of independent 1000 and 600 Hz burst generators fits well with earlier results demonstrating their differential reactivity to experimental interventions, such as double pulse stimulation and propofol narcosis (Klostermann et al., 2000a,b). Concerning possible generators of the subcortical lowfrequency component, two concepts will be briefly reviewed: on the one hand, slow SEP components are assumed to represent excitatory or inhibitory postsynaptic potentials instead of fast action potentials (Allison et al., 1991), and as the time course of the low-frequency component is significantly slower than the burst dynamics it might reflect postsynaptic potentials evoked intrathalamically by lemniscal afferences. Its variable peak latency, as recorded along the one-dimensional electrode track through the three-dimensional potential distribution in the suprathalamic white matter, might then reflect simply an asynchronous activation of thalamic sources with different 3D-orientations; such source configuration generates overlapping potential distributions which sum to a rotating pattern characteristically showing systematically varying latencies of peak activities along any onedimensional subset of recording sites. On the other hand, a peak latency varying across different white matter recording sites is compatible also with a source propagating in the somatosensory thalamocortical radiation. While the present data set can neither exclude nor prove contributions from propagating population spikes to the low-frequency component, these appear less likely to dominate the recordings because (a) its time course is untypically broad for axonal activity (several milliseconds); and (b) additional recordings in two patients at more superficial white matter sites revealed a clear amplitude decrease with increasing distance from the thalamus, thus favoring a deep generator site for the lowfrequency component. In conclusion, the present data suggest that the subcortically recorded high-frequency (1000 Hz) SEP bursts reflect a local intrathalamic response.
Acknowledgements Supported by DFG grants KI 1276/1-1 and Ma 1782/1-4.
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Intrathalamic non-propagating generators of high-frequency (1000 Hz) somatosensory evoked potential (SEP) bursts recorded subcortically in man Fabian Klostermann a,*, Rene´ Gobbele b, Helmut Buchner b, Gabriel Curio a a
Department of Neurology, Neurophysics Group, Klinikum Benjamin Franklin, Freie Universitaet, Hindenburgdamm 30, 12200 Berlin, Germany b Department of Neurology, RWTH Aachen, Germany Accepted 15 April 2002
Abstract Objectives: Recently, bursts of high-frequency (1000 Hz) median nerve somatosensory evoked potential (SEP) wavelets were recorded subcortically near and inside the thalamus from deep brain electrodes implanted for tremor therapy. This study aimed to clarify whether these subcortical SEP bursts reflect evoked axonal volleys running in the thalamocortical radiation or a locally restricted intrathalamic response. Methods: During deep brain electrode implantation, median nerve SEP were recorded in 7 patients sequentially along the subcortical stereotactic trajectory at sites 120 and 110 mm above the respective target nucleus (ventral intermediate thalamus or nucleus subthalamicus). Low- and high-frequency SEP components (corner frequency 430 Hz) were analyzed separately with respect to peak latency and amplitude as they changed along the recording trajectory. Results: Individual wavelets of the subcortical 1000 Hz SEP burst showed fixed peak latencies independent from the depth of the electrode penetration; they increased markedly in amplitude with decreasing distance to the thalamus. In contrast, the amplitude gradient between the two recording sites was shallower for the low-frequency SEP component, which peaked earlier at the lower recording site. Conclusions: Subcortically recorded 1000 Hz SEP wavelet bursts predominantly reflect locally restricted near-field activity, presumably generated in the somatosensory relay nucleus. In contrast, the variable peak latency of the subcortical low-frequency component could reflect postsynaptic potentials sequentially evoked during passage of the lemniscal afferences curving through the thalamus and contributions from the thalamocortical radiation. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Median nerve somatosensory evoked potentials; 1000 Hz burst; Somatosensory thalamus; Thalamocortical radiation
1. Introduction Neurosurgical interventions allow for intracerebral nearfield recordings of somatosensory evoked potentials (SEP) from the deep lemniscal and thalamocortical system. Such studies on subcortically recorded SEP helped to establish concepts on the generators of the earliest SEP components which can be picked up in part as far-field micropotentials on the scalp (Abbruzzese et al., 1978; Allison and Hume, 1981; Suzuki and Mayanagi, 1984; Tsuji et al., 1984; Albe-Fessard et al., 1986; Katayama and Tsubokawa, 1987; Morioka et al., 1989; Yamashiro et al., 1989; Vanderzant et al., 1991): corresponding to the scalp responses peaking at about 9, 11, 13 and 14 ms after median nerve stimulation, a successive activation of the lemniscal system at the spinal entry zone of the periph* Corresponding author. Tel.: 149-30-8445-4703; fax: 149-30-84454264. E-mail address: [email protected] (F. Klostermann).
eral nerve, the dorsal column, the cuneate nucleus and the medial lemniscus was demonstrated (Allison and Hume, 1981; Suzuki and Mayanagi, 1984). For the component peaking at about 16 ms poststimulus (P16), which exhibits a duration of several milliseconds in subcortical recordings, a local postsynaptic generation in the somatosensory thalamic relay nucleus was proposed (Mauguiere et al., 1983; Hashimoto, 1984; Tsuji et al., 1984; Vanderzant et al., 1991). Recent subcortical recordings showed that this slow component was superimposed by a burst of high-frequency (about 1000 Hz) low-amplitude wavelets, extending from 14 to 22 ms post-stimulus (Klostermann et al., 1999). When SEP are recorded non-invasively at the scalp (Emerson et al., 1988; Yamada et al., 1988), electroencephalogram (EEG) mapping analyses of burst SEP (spectral energy maximum around 600 Hz) suggested early (around 16 ms) deep generators, presumably being located in the near-thalamic thalamocortical radiation, as well as later
1388-2457/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1388-245 7(02)00119-0
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F. Klostermann et al. / clinical Neurophysiology 113 (2002) 1001–1005
(around 20 ms) superficial cortical generators (Gobbele et al., 1998; Gobbele et al., 1999). The radiation fiber model is consistent with the spike-like character of the burst wavelets, pointing to fast axonal generators rather than to slower postsynaptic responses (cf. Allison and Hume, 1981; Katayama and Tsubokawa, 1987). The more superficial burst components are superimposed on the primary cortical N20 component of median nerve SEP and could be interpreted at least partially as the presynaptic arrival of thalamic activity at the primary somatosensory (S-I) cortex. Notably, additional burst components generated intracortically are likely to contribute (Curio et al., 1994, 1997; Curio, 2000), with a recent emphasis on cortical interneurons discharging synchroneously at 600 Hz (Hashimoto et al., 1996; Swadlow et al., 1998; Jones et al., 2000). A still unresolved, critical issue is the difference in intraburst frequencies recorded subcortically (,1000 Hz) and at the scalp (,600 Hz). Specifically, with regard to the 1000 Hz burst components which can be recorded at the thalamus in patients the question needs to be addressed how to discriminate intrathalamic stationary sources from generators propagating in suprathalamic white matter. To this end, SEP were recorded here at different brain depths when stereotactically advancing the electrode towards the respective thalamic targets, in order to assess possible latency and amplitude shifts along the recording trajectory.
2. Methods In 7 patients with movement disorders (6 Parkinson disease, one essential tremor; 6 male, one female; 67.4 ^ 7.8 years, range: 58–78 years), SEPs were recorded intraoperatively from the electrode implant for deep brain stimulation. None of the patients suffered from a somatosensory impairment; all patients gave informed consent under a study protocol approved by the local Ethics Committee. When driving the electrode from a frontal burrhole towards the thalamic target site, recordings were performed during two momentary stops 120 and 110 mm above the calculated target positions, i.e. the subthalamic nucleus (STN) in 6 patients and the ventral intermediate nucleus in one patient. The electrode (Medtronic 3389) consists of a shaft with four ring contacts spaced at distances of 0.5 mm and with a width of 1.5 mm, each. The basal contact was referenced against the cranial cathode, covering a distance of 4.5 mm. Additionally, a frontoparietal scalp SEP (C3 0 versus F3) and a peripheral compound action potential (CAP) were recorded; the CAP was derived mediolaterally at the ipsilateral upper arm to control the somatosensory input. The median nerve contralateral to the intrathalamic and scalp electrodes was stimulated at 2 £ motor threshold. Electrical stimuli were applied at 8.1 Hz (constant current squarewave pulses of 0.1 ms width) and 2000 single sweeps were averaged per SEP. A wide bandpass (5–1500 Hz) was
used for data acquisition (sampling rate 10 kHz). Offline digital highpass and lowpass filters (corner frequency: 430 Hz; 24 dB/octave) were applied to separate high- from lowfrequency responses which, thereby, could be analyzed independently. Amplitudes of the low-frequency subcortical SEPcomponents were determined baseline-to-peak in the 5– 428 Hz bandpass. Latencies of high-frequency burst peaks were determined in the 428–1500 Hz bandpass. The mean burst amplitude was determined as a root-mean-square (rms) value over the burst time window, ranging from about 14 to 22 ms, and corrected for noise contributions as estimated in a burst-free time interval from 30 to 45 ms (cf. Klostermann et al., 1998). Statistical analyses were performed on the basis of nonparametrical Wilcoxon tests (two-sided matched pairs signed rank test). Results were considered statistically significant at P-levels , 0.05.
3. Results In all patients between 4 and 7 burst peaks (mean ^ SD ¼ 5.4 ^ 1.2), were identified reliably at both subcortical recording sites, occurring between 13.7 and 24.7 ms poststimulus. When the successive burst peaks of each subject were paired according to their intra-burst positions between recordings from the two electrode sites, no significant peak latency shifts were observed (Fig. 1). As the high-frequency burst duration differed between subjects, peaks 1 to 4 could be compared between both recording sites in all 7 subjects and peak 5 in 6 subjects; for the late peaks 6 (two subjects) and 7 (one subject) no statistical analysis could be performed due to their rare occurrence, but – as for the earlier peaks – no latency shifts were observed. Statistically (peaks 1–5), all peak latencies were reproduced at nearly identical latencies at the upper and lower recording position (range of inter-site peak latency differences: Dt ¼ 0–0.03 ms), and none of the observed latency shifts was significant in this group of subjects. In contrast, the peak latency of the underlying low-frequency response was consistently later at the more superficial recording site (19.33 ^ 1.5 ms) compared to the lower recording site (18.8 ^ 1.41 ms), with the inter-site latency difference (0.53 ^ 0.35 ms) being significantly different from zero (P ¼ 0:02; n ¼ 7). Additional recordings were performed in two patients at subcortical locations even more superficial than the standard upper recording site: at 140 mm above the target area the subcortical low-frequency component was found prolonged by 0.8 ms and reduced by 50% in amplitude (19.5 ms/0.5 mV) in comparison to the deeper 120 mm site (18.7 ms/1 mV); in a second patient (at 130 mm) it was found similarly prolonged and reduced (20 ms/0.6 mV) in comparison to the deeper 120 mm site (19.6 ms/1.3 mV). Subcortical burst activity could not be identified in these additional records, more distant from the thalamic target area.
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Fig. 1. Characteristic example of subcortical SEP recordings at two depths along the sterotactic electrode trajectory, 120 (position 1) and 110 mm (position 2) above the STN. At 120 mm a small high frequency signal becomes discernible which replicates at 110 mm with nearly identical peak latencies but with significantly higher peak amplitudes. In contrast, a latency shift is obtained in the underlying low-frequency component.
N20 values were available in four patients, since three frontoparietal scalp recordings dropped out due to interfering artifacts in the operating room. Comparing the subcortical and N20 latencies in these four subjects, a difference of 3.15 ^ 0.24 ms (19.13 ^ 1.67 ms at the lower recording position versus 22.28 ^ 1.44 ms for the N20) was obtained, consistent with the conductance time from a recording position slightly above thalamus to cortex. The amplitude analysis of burst and low-frequency peaks showed different response patterns, as well. The burst rmsamplitude decreased from the lower recording site (0.12 ^ 0.04 mV) to the more superficial one (0.05 ^ 0.02 mV); the low-frequency component decreased from 1.78 ^ 0.83 to 1.33 ^ 0.31 mV. Accordingly, the voltage ratio between lower and higher recording site was 2.4 ^ 1.44 for the burst and 1.3 ^ 0.59 for the P19, their difference being significant (P ¼ 0:02). The peripheral CAP was found unchanged during recordings at both subcortical sites.
4. Discussion The present study provided two main results. First, the peak latencies of high-frequency (1000 Hz) wavelets in subcortical SEP bursts were found stable across two recording sites spaced 10 mm apart in depth, contrasting with a latency increase of subcortical low-frequency SEP between lower and more superficial recording sites. Second, a marked amplitude decrease of the 1000 Hz wavelet burst was observed with increasing distance from the thalamus, unlike the shallower amplitude gradient of the lowfrequency component. As this pattern was obtained in patients with different pathological conditions, i.e. Parkinson’s disease and essential tremor, it is unlikely that the results reflect disease specific alterations of thalamocortical activation only. With respect to possible burst generator sites, the fixed
wavelet peak latencies along with the steep burst voltage gradients are characteristic for near-field recordings and hence indicate intrathalamic non-propagating generators for the 1000 Hz SEP burst, possibly reflecting population spike responses from neurons in the neighboring thalamic relay nucleus and from lemniscal terminal arborizations. A remarkable feature of high-frequency signals common to both thalamic and scalp recordings is their pronounced short-term variability which occurs uncorrelated to the weaker fluctuations of the respective locally underlying low-frequency components (Klostermann et al., 1999, 2001). Accordingly, low-frequency SEP might reflect the more stable ‘hard-wired’ mandatory part of somatosensory input processing, linked to the physical aspects of stimulation, whereas the momentary degree of local burst activity reflects a more fluctuating modulation of this input, e.g. by attention or the level of vigilance (Gobbele et al., 2000). Indeed, multiple populations of thalamic neurons exert their modulatory functions on the basis of high frequency burst discharges. For example thalamocortical cells with intraburst frequencies up to 1000 Hz were identified in the intralaminar centrolateral nucleus (Steriade et al., 1993); this discharge mode was postulated to be involved in the generation of fast EEG rhythms during arousal reactions and operates on the basis of low threshold calcium spiking (LTS), but a relation to the somatosensory system has not yet been demonstrated. In contrast, LTS-based bursting of up to 500 Hz was observed in sensory relay cells, capable of switching between a single spiking and a bursting mode (McCormick and Feeser, 1990), presumably related to filtering of afferent information. Moreover, relay cells of thalamic sensory nuclei are surrounded by local and reticular interneurons featuring intraburst frequencies of up to 200 Hz (Amzica et al., 1992; Zhu et al., 1999): while local interneurons are supposed to sharpen thalamocortical signal transmission (Zhu and Heggelund, 2001), reticular interneurons reduce the thalamocortical throughput of information, as they are driven by the output from thalamic relay
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neurons which in turn receive an inhibitory feed-back projection from the reticular cell (Sherman and Koch, 1986; Cox et al., 1998). Thus, a superimposition of different intrathalamic bursting cell populations could explain the high-frequency content of subcortically recorded SEP. In previous multi-channel scalp EEG recordings multiple dipole sources of high-frequency SEP bursts were reconstructed, at the primary somatosensory cortex (S-I) as well as subcortically near the thalamus. The cortical burst was attributed partially to the presynaptic arrival of rapidly repeating 600 Hz thalamocortical population spikes (Gobbele et al., 1998). The present data suggest to exclude the subcortically recorded 1000 Hz burst from the set of possible scalp burst generators because it reflects localised non-propagating thalamic activity. This concept of independent 1000 and 600 Hz burst generators fits well with earlier results demonstrating their differential reactivity to experimental interventions, such as double pulse stimulation and propofol narcosis (Klostermann et al., 2000a,b). Concerning possible generators of the subcortical lowfrequency component, two concepts will be briefly reviewed: on the one hand, slow SEP components are assumed to represent excitatory or inhibitory postsynaptic potentials instead of fast action potentials (Allison et al., 1991), and as the time course of the low-frequency component is significantly slower than the burst dynamics it might reflect postsynaptic potentials evoked intrathalamically by lemniscal afferences. Its variable peak latency, as recorded along the one-dimensional electrode track through the three-dimensional potential distribution in the suprathalamic white matter, might then reflect simply an asynchronous activation of thalamic sources with different 3D-orientations; such source configuration generates overlapping potential distributions which sum to a rotating pattern characteristically showing systematically varying latencies of peak activities along any onedimensional subset of recording sites. On the other hand, a peak latency varying across different white matter recording sites is compatible also with a source propagating in the somatosensory thalamocortical radiation. While the present data set can neither exclude nor prove contributions from propagating population spikes to the low-frequency component, these appear less likely to dominate the recordings because (a) its time course is untypically broad for axonal activity (several milliseconds); and (b) additional recordings in two patients at more superficial white matter sites revealed a clear amplitude decrease with increasing distance from the thalamus, thus favoring a deep generator site for the lowfrequency component. In conclusion, the present data suggest that the subcortically recorded high-frequency (1000 Hz) SEP bursts reflect a local intrathalamic response.
Acknowledgements Supported by DFG grants KI 1276/1-1 and Ma 1782/1-4.
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