1 Département de stomatologie, Faculté de médecine dentaire and 2 Centre de recherche en sciences neurologiques, Université de Montréal, Montréal, Québec, Canada, H3C 3J7; 3 Department of Neurology and Neurosurgery, Faculty of Medicine, 4 Faculty of Dentistry, and 5 Department of Anesthesiology, Faculty of Medicine, McGill University, Montréal, Québec, Canada; and 6 Université du Québec en Abitibi-Témiscamingue, Rouyn-Noranda, Québec, Canada; and 7 Department of Neurology and Neurosurgery, University Hospital, Gasthuisberg, Louvain, Belgium
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ABSTRACT |
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Duncan, Gary H., Ron C. Kupers, Serge Marchand, Jean-Guy Villemure, Jan M. Gybels, and M. Catherine Bushnell. Stimulation of human thalamus for pain relief: possible modulatory circuits revealed by positron emission tomography. J. Neurophysiol. 80: 3326-3330, 1998. Stimulation of the somatosensory thalamus was used for more than 2 decades to treat chronic pain in the human. However, despite clinical reports of successful results, little is known about the actual mechanisms mediating this form of stimulation-produced analgesia. To reveal possible neuronal pathways evoked by thalamic stimulation, we measured regional changes in cerebral blood flow (rCBF) in five patients who received successful long-term relief of chronic pain with somatosensory thalamic stimulation. Positron emission tomography during thalamic stimulation revealed significant activation of the thalamus in the region of the stimulating electrodes as well as activation of the insular cortex ipsilateral to the thalamic electrodes (contralateral to the patients' clinical pain). For these patients, thalamic stimulation also evoked paresthesiae that included thermal sensations in addition to tingling sensations. Results of this study indicate that in some cases somatosensory thalamic stimulation may activate a thalamocortical pain modulation circuit that involves thermal pathways. These results are consistent with other recent reports suggesting that activation of thermal pathways may contribute to modulation of nociceptive information.
The first reports of direct electrical stimulation of the somatosensory thalamus (ventroposterior lateral and medial; VPL/VPM) to treat chronic pain in the human appeared in the early 1970s (Hosobuchi et al. 1973 Participants in this study were five patients (4 females, 1 male; mean age: 58 yr, range: 43-78 yr), for whom electrical stimulation of the somatosensory thalamus produced satisfactory long-term relief from chronic neuropathic pain. Only subjects having pain relief for Pain relief and paresthesiae
Patient data are summarized in Table 1. All patients selected for the study reported satisfactory pain relief from thalamic stimulation for
Stimulation-related changes in rCBF
Table 3 describes response peaks observed in directed searches of thalamocortical somatosensory regions for subtractions of LATE-BEFORE and EARLY-BEFORE. The most evident change in rCBF related to thalamic stimulation was seen as a large, widespread activation in the region approximating the thalamic stimulation site itself (including VPL, internal capsule, and the lenticular nucleus) contralateral to the patient's clinical pain problem. This increase in blood flow was present at the time of the EARLY scans, taken 1 min after stimulation began, but was much stronger toward the end of stimulation, as shown in the comparison of LATE and BEFORE scans (Fig. 1B).
In this study, we observed that low frequency (<100 Hz) thalamic stimulation produces an increase in rCBF in and near the thalamus contralateral to the painful body site and in some cortical projection sites, with the effect being more prominent with continued stimulation. This increase in thalamic and cortical activity is similar to that observed by Katayama et al. (1986)
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
; Mazars et al. 1973
, 1974
). This procedure is most often employed for treating neuropathic pain and was used with varying success during the last 3 decades. Nevertheless, despite numerous clinical studies reporting pain relief, the success of thalamic stimulation for the treatment of chronic pain remains unpredictable (see Duncan et al. 1991
; Gybels and Kupers 1995
; Kumar et al. 1997
). Furthermore, evaluation of stimulation-produced pain relief is difficult because there can be a large placebo effect (Marchand et al. 1992
). Mazars originally stimulated the ventroposterior thalamus in patients suffering from deafferentation pain, based on the theory that such pain is caused by lack of proprioceptive stimuli reaching the thalamus (Head and Holmes 1911
). Stimulating the primary somatosensory pathway at this thalamic site was an effort to compensate for the lack of normal sensory input (Mazars et al. 1974
). The gate control theory (Melzack and Wall 1965
) further championed the idea that stimulation of low threshold somatosensory pathways inhibits pain; thus direct stimulation of this pathway at the thalamic level would be expected to reduce neuropathic pain, which is characterized by loss of such input after damage in the peripheral or CNS. Physiological studies in anesthetized animals confirmed that stimulation in VPL thalamus inhibits the activity of both spinothalamic nociceptive neurons in monkey (Gerhart et al. 1981
, 1983
) and thalamic parafascicular nociceptive neurons in rat (Benabid et al. 1983
). However, there is little behavioral evidence in animals confirming the predicted stimulation-produced analgesia, although Kupers and Gybels (1993)
found that VPL stimulation in rat reduces mechanical allodynia in a model of neuropathic pain.
).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
3 yr were studied to reduce the possibility of placebo effects contributing to the analgesia. The regions of pain involvement included the face, hand, low back, and leg. Before any testing, patients gave informed consent for their participation in this study, which was approved by the local ethics committee of the Montreal Neurological Institute.
). Subjects lay immobile in the scanner2 with eyes closed. Scans began 15 s postinjection, lasted for 60 s, and were separated by
12-15 min to allow the tracer to decay to background levels.
) and coregistered with each other by using automated methods of Collins et al. (1994)
. Statistical brain maps comparing the various experimental conditions were derived from normalized data averaged across the five patients (Worsley et al. 1992
). Directed searches of the subtracted brain volumes were subsequently performed assessing changes in rCBF within thalamus and in cortical regions that receive somatosensory thalamic projections in primates [S1, secondary somatosensory cortex (S2), insular cortex, and anterior cingulate cortex]. Subtractions of LATE-BEFORE and EARLY-BEFORE were performed to examine cerebral regions directly activated by therapeutic thalamic stimulation. The subtraction of AFTER-BEFORE was performed to reveal pain-related cerebral regions in which activity might be reduced as a result of thalamic stimulation. Threshold for statistical significance was set at P < 0.05, one-tailed, corrected for multiple comparisons.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
3 yr (mean duration: 4.5 yr). With normal regular use of the thalamic stimulators in their home environment, they reported a mean reduction in clinical pain of ~60%. However, this relief was not always immediately time locked to the onset of stimulation but rather reflects a global comparison of pain between periods of regular stimulator use and periods during which the stimulators were not used at all. During scanning sessions, three of five subjects had an immediate reduction in pain on onset of the thalamic stimulation, whereas two subjects did not. Nevertheless, both of these latter subjects reported substantial long-term relief with repeated stimulation. All participants reported paresthesiae during thalamic stimulation. A postexperiment questionnaire (a single-blind checklist allowing responses concerning a variety of possible sensations) mailed to the patients several months after the scans revealed that during regular home use thalamic stimulation produced sensations of prickling, tingling, hot, warm, or cold (based on the responses of 3 of 5 patients questioned; of the remaining 2, 1 died and 1 could not be reached; see Table 2).
View this table:
TABLE 1.
Study participants
View this table:
TABLE 2.
Temperature paresthesiae
View this table:
TABLE 3.
Thalamocortical activation sites
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FIG. 1.
Positron emission tomography (PET) data from LATE-BEFORE subtraction (color coded for statistical significance; t = +1.5 to + 5.0) are shown coregistered with an average magnetic resonance volume of 305 normal subjects, mapped into standardized stereotaxic space (Talairach and Tournoux 1988 ); horizontal slices are ordered from superior inferior. A: horizontal slice through maximum change in cerebral blood flow (
rCBF) observed in S1 (nonsignificant trend, t = +2.02). Inset: coronal and horizontal slices with PET data threshold set to t = +1.0, illustrating the specificity of this response ipsilateral to thalamic stimulation. B: horizontal and coronal (inset) slices centered on maximum rCBF change observed during thalamic stimulation in the region extending from thalamus to the lenticular nucleus (t = +4.88). C: horizontal and coronal (inset) slices illustrating maximum
rCBF observed within the insular cortex, ipsilateral to thalamic stimulation (t = +3.02).
29, 0 (t = 3.89); 12,
7, 7 (t = 2.9)].
View this table:
TABLE 4.
Comparison of activation sites for patients with (n = 3) and without (N = 2) immediate pain relief
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
, who used lower-resolution PET in patients receiving ventroposterior thalamic stimulation for pain control. We also observed a decrease in thalamic activity after stimulation compared with before, which could reflect a decrease in nociceptive sensory transmission that might underly the therapeutic effects of thalamic stimulation.
with lower resolution rCBF measures. Nevertheless, our data do not support the hypothesis that activation of tactile thalamocortical pathways is the sole mechanism underlying successful thalamic stimulation-produced analgesia.
; Coghill et al. 1994
; Craig et al. 1996a
; Derbyshire et al. 1994
; Rainville et al. 1997
) and neuropathic pain (Hsieh et al. 1995
), but in addition it is activated by both warm and cool innocuous temperatures applied to the skin (Craig et al. 1996a
). In monkeys, both nociceptive and thermoreceptive neurons were observed within the rostral insula (Dostrovsky and Craig 1996
), and this region receives a strong projection from the VMpo thalamic nucleus (Bushnell et al. 1995
), which is subjacent to VPM and contains both nociceptive and thermoreceptive neurons (Craig et al. 1994b
). VMpo was identified anatomically in humans (Craig et al. 1994b
), and stimulation in the region of human VMpo can evoke painful but more commonly thermal sensations (Davis 1996
; Dostrovsky et al. 1992
; Lenz et al. 1993
). On the basis of evidence that cold inhibits pain processing (Bini et al.,1984
; Osgood et al. 1990
; Schoenfeld et al. 1985
; Wahren et al. 1989
; Yarnitsky and Ochoa 1990
) and the probable involvement of temperature-related activation of the insular cortex in an illusion of pain produced by a combination of warm and cool skin stimulation (Craig and Bushnell 1994a
; Craig et al. 1996a
), Craig proposed that the temperature projection involving VMpo and anterior insula is an important pain-inhibitory pathway (Craig and Zhang 1996b
; Craig et al. 1996a
).
and Dostrovsky et al. (1992)
, indicates that the bipolar stimulating electodes used for pain relief could easily stimulate neurons within both the VMpo-insular and VPL/VPM-S1 pathways.
; Coghill et al. 1994
; Craig et al. 1996a
), whereas painful stimulation reliably activates it (Casey et al. 1996
; Coghill et al. 1994
; Craig et al. 1996a
; Derbyshire et al. 1994
; Hsieh et al. 1995
; Jones et al. 1991
; Rainville et al. 1997
; Talbot et al. 1991
). The possibility exists that the patients' recognition of the thalamic stimulation conditions triggered attention-related processes within the ACC that were observed to be distinct from those related to nociceptive processing (see Davis et al. 1997
).
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ACKNOWLEDGEMENTS |
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We express our appreciation to Dr. K. Kumar for help in identifying appropriate patients for this study, Medtronics Canada for financial support of patients' travel arrangements, and F. Bélanger and P. Rainville for assistance in preparing the manuscript and illustrations.
Supported by grants from the Medical Research Council of Canada. Positron emission tomography was performed at McConnel Brain Imaging Center, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
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FOOTNOTES |
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1 During surgical implantation, placement of the thalamic electrode is typically guided by the patient's report of paresthesiae, which are evoked by electrical stimulation as the electrode advances through the thalamus. Electrodes are normally targeted within thalamus so as to maximize these sensory paresthesiae projected to the site of clinical pain. This induction of stimulation-produced paresthesiae is frequently considered a prerequisite for pain relief with thalamic stimulation.
2
PET scans were obtained with the Scanditronix PC-2048 system, which provides 15 image slices 6.5 mm apart with a transverse image resolution of 4.6-6.4 mm and an axial resolution of 5.4-7.1 mm (Evans et al. 1989, 1991
). Data were collected in two sequential frames of 40 and 20 s; data presented here are derived from the 40-s frame, which yielded the better signal-to-noise ratio.
Address for reprint requests: G. H. Duncan, Center de recherche en sciences neurologiques, C. P. 6128, Succursale Centre-ville, Université de Montréal, Montréal, Québec, Canada, H3C 3J7.
Received 19 February 1998; accepted in final form 8 September 1998.
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REFERENCES |
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