Prrrn, 45 (1991) 49-59 R 1991 Elsevier Science Publishers A DONIS 0304395991001032
49 B.V. 0304-3959/91/$03.50
PAIN 01768
Basic Section Review A rticle Deep brain stimulation: Gary
H. Duncan
a review of basic research and clinical studies a,‘, M. Catherine
Bushnell
a,b and
Serge
Marchand
a
u Cenire de Recherche en Sciences Neurologiques and h Far&P de Mt!decine Deniaire, Universitk de Montr&al, Montreal, Quebec (Canada) (Accepted
5 October
1990)
Deep brain stimulation for pain control in humans was first used almost 30 years ago and has Summary continued to receive considerable attention. Despite the large number of clinical reports describing pain relief, numerous studies have indicated that the results of these procedures vary considerably. In addition, many neurosurgeons find the procedures unpredictable, and considerable disagreement still exists regarding important issues related to the technique itself. This review gives an historical overview of the relevant basic and clinical literature and provides a critical examination of the clinical efficacy, choice of stimulation sites, parameters of stimulation, and effects on experimental pain. Finally, we give suggestions for future research that could more definitively determine the usefulness of deep brain stimulation for pain control. Key words: Deep brain
stimulation;
Thalamus;
(Pain)
Introduction The use of ‘deep brain stimulation’ for pain control began almost 30 years ago, when Mazars first implanted electrodes in the somatosensory thalamus of patients suffering from deafferentation pain [76,77]. The use of more medial sites was later prompted by Reynolds who [92] published the first evidence that electrical stimulation of the grey matter surrounding the sylvian aqueduct (PAG) could produce sufficient analgesia to permit abdominal surgery in rats. Today deep brain stimulation is an accepted clinical technique for the relief of chronic intractable pain resulting from a variety of pathological conditions. Despite the large number of clinical studies describing pain relief by deep brain stimulation, several recent reviews of the clinical literature suggest that the results of these procedures vary considerably among different studies [42], that many neurosurgeons find the procedure unpredictable [Sl], that no major progress has been made recently to im-
-Correspondence to: Gary H. Duncan, D.D.S., Ph.D., Dtpartement de Stomatologie, Facultk de Mtdecine Dentaire, UniversitC de Montrkal, C.P. 6128, Succ. A, Montreal, Que. H3C 357, Canada.
prove its efficacy and reliability [81], and that considerable disagreement still exists regarding important issues related to the technique itself [51]. The present paper reviews both the basic and clinical literature relevant to these issues in the hope that a more critical evaluation of previous efforts can lead toward a unified approach in answering a number of major questions: (1) Is the rationale for deep brain stimulation based on known physiological mechanisms? (2) What is the effectiveness of deep brain stimulation in reducing clinical pain? (3) Is the effectiveness of certain deep brain stimulation sites specific to certain pain syndromes? (4) Are some parameters of stimulation more effective than others? (5) Does deep brain stimulation diminish the perception of experimental noxious stimuli?
Rationale and historical background The most commonly used deep brain stimulation sites in humans for the treatment of intractable pain are located: (1) in somatosensory areas of the ventrobasal thalamus which include ventroposterior lateral (VPL)
and ventroposterior medial (VPM) nuclei [46]: (2) in caudal medial thalamic areas around the third ventricle. including the periventricular grey matter (PVG) and adjacent nuclei, centralis medialis (CM) and parafascicularis (Pf): and (3) near the junction of the third ventricle and the syivian aqueduct (rostrai ventral PAG/caudai ventral PVG).
The original rationale for the clinical use of medial mesen-/diencephaiic stimulation arose from experimental findings in rats indicating that electrical stimulation of the PAG produced profound analgesia {74.75,92,93]. Although the most consistent early results in animal studies had been produced by PAG stimulation, initial trials in humans at this site frequently resulted in unpleasant side effects, including feelings of impending doom [9SJ. On the other hand, stimulation of the posterior thalamic PVG appeared to be clinicaily effective in reducing intractable pain without producing such side effects ]52,95,96]. Results of animal studies have also confirmed the analgesic effects of PVG stimulation [59,74,86,93]. More recently, the CM and Pf nuclei in medial thaiamus 1461, adjacent to the PVG, have been implicated in pain modulation in humans [8,9,91,96,108], monkeys [36.85.86,100] and rats [3]. Sakata et al. [99] showed that Pf stimulation in rats excites PAG neurons. thus suggesting the possibility of common analgesic mechanisms activated by stimulation of these different sites. The exact nature of these analgesic mechanisms remains controversial. Most animal studies have indicated that PAG stimulation-produced analgesia is at least partially mediated by opioid mechanisms. Injection of opioids into the PAG produces behavioral analgesia similar to that of electrical stimulation f67,117]. Likewise, morphine microinjected into the PVG and along the ventromediai borders of CM and Pf results in a dose-dependent analgesia that is completely reversed by nnioxone [86]. Naloxone has also been shown to reduce the behavioral analgesia produced by stimuiatioI1 of PAG in rats [5]. Finally, the effects of both opiate and stimulation-produced analgesia associated with the PAG are blocked by lesions of the descending pathways of the dorsoiateral spinal cord [14,84]. By contrast. aithough Carstens et al. [23] showed that PVG stimulation inhibited dorsal horn heat-evoked responses, this inhibition was not reversed by naloxone. For a review of descending analgesic pathways. see recent discussions of endogenous pain control systems [ 15,32,89]. in man, Adams [l] and Hosobuchi et al. [52] showed that naioxone reverses PAG/PVG stimulation-produced analgesia, and Akil et ai. 161 and Hosobuchi et al. [54] reported increases in ventricular ’ beta-endorphinlike’ activity after PVG stimulation. Nevertheless. two subsequent reports showed that these increased beta-en-
dorphin levels may have been due to cross-reactivity 04 the immunoassay to metrizamide, injected as a v,entr’icn lar contrast medium. rather than to endorphins released by the PVG stimulatit~n [27,3i]. Further. Young and his associates [I 18,119] found that PVG and PAG .stimuiatinn does not show cross-tolerance with opioids. nor is it reversed by naioxone admit~istrati~~n. It may bc that the inconsistencies in the human studies are related III differences in electrode placement; Cannon et al. 121 j showed in rats that analgesia induced by ventral. but not dorsal. PAG xtimuiation ix opioid mediated. Thus. one might expect in humans that tjnlv some PA< i electrode placements would he reversed hv nalox~~~.
The pain suppressing effects of stimulating more lateral (somatosensory) ventrobasal areas of the thalamus were reported clinically before animal studies wcw performed [53,76.79]. Mazars indicated that his implantation of VPL stimulating electrodes (as early as 1961) in patients suffering from deafferentation pain was based on the theory that pain is caused by lack of proprioceptive stimuli reaching the thaiamus. Thus. stimulation of the primary somatosensory pathway at this thalamic site was intended to relieve pain in these patients by compensating for the lack of normal sensory input f76.775. During the 1970s. the rationale for stimulating the somatosensory thalamus was probably based on the clinical experiences with dorsal column stimulation. which in turn. had been prompted by the Gate Control Theory ]80] of large fiber inhibition of small fiber pain pathways. Acute physiological studies in anesthetized preparations have shown that stimulation of the somatosensory thalamus does inhibit the activity of both spinothalamic nociceptive neurons in monkey [34,35] and thalamic parafascicuiar nociceptive neurons in rat 1161. It has also been demonstrated in cats and monkeys that VPL stimulation excites neurons in the raphe magnus [ I1 1,114]. a brain-stem nucleus associated with drscending pain inhibitory pathways (151. In addition. Aiko et aI. have demonstrated that sensory thalamic stimulation in rats alters cerebral glucose utilization in the substantia nigra 131. a finding consistent with evidence that the dopaminergic nigrostriatal system exerts a potential influence on pain inhibition [11,68,111]. Thus. although VPL stimulation has been reported to have tzo effect on beta-endorphin levels in humans [60], the animal data involving stimulation of somatosensory thaiamus suggest the possibility of descending pain inhibit~~ry pathways activated by VPL stimuiation, which are nonopioid in nature. This suggestion is supported bv WIdence that administratio1~ of nlon~)~~rnine precursors prevents the development of tolerance to VPL, stimulation in humans [ill]; however. this uncontrolled studv lacks sufficient data to draw substantive conclusions.
51
An interesting paradox exists in the literature concerning stimulation of the somatosensory thalamus. Although several studies in anesthetized animals have reported data suggesting neurophysiological substrates for the analgesia produced by stimulation of VPL/VPM. as indicated above [16,34,35,111,114], there are to date, no behavioral data in awake animals to confirm the clinical analgesia described in humans. In contrast to the positive results observed in behavioral studies of medial thalamic or PAG stimulation [3-5,10,36,59, 74,75,85,86,93,100], studies involving stimulation of VPL and VPM (in both rat and monkey) have shown no behavioral evidence indicative of stimulation-produced analgesia [3,74,100]. This lack of behavioral results for ventrobasal stimulation may be related to the use of tests (tail flick and pinch [3], tail flick and electric shock/jump [74], tail shock [loo]) that are not sufficiently sensitive to reveal subtle analgesic effects or changes in sensory discriminative aspects of nociceptron. In addition, since somatosensory thalamic stimulation in humans has been generally reported to be more effective for the relief of neurogenic pain, antinociceptive tests like tail flick may be considered inappropriate models for evaluating such analgesia. In summary, the theoretical rationale for using deep brain stimulation in humans is still not clearly delineated. A number of behavioral studies in animals support the clinical findings of analgesia produced by stimulation of medial areas, but not by stimulation of VPL/VPM. On the other hand, neurophysiological studies in animals have shown some evidence for activation of pain-inhibiting pathways by stimulation of VPL/VPM. In neither area does there appear to be a clear dependence on endogenous opioid pathways for the analgesia.
Clinical efficacy Regardless of whether or not the basic neurophysiological mechanisms underlying deep brain stimulation are clearly understood, questions regarding the clinical efficacy of this surgical procedure should be a primary concern to health professionals. There is now an abundance of published reports on thalamic stimulation (see Table I), and most of these reports indicate that deep brain stimulation can be a valuable tool for relieving chronic pain that is intractable to other available techniques. Before the availability of electrical stimulation for pain control, ablative surgery was the most common alternative when pharmacological treatments proved to be ineffective or inappropriate. Deep brain stimulation now provides a less invasive treatment that appears to have good clinical results in many cases. Nevertheless, the majority of the clinical reports are case histories rather than well controlled studies. The pain measures
described usually involve imprecise questions about pain relief that do not allow a rigorous statistical evaluation (see Table I). The patient studies are rarely conducted in a double-blind fashion, in which the experimenter and patient are unaware of the parameters and location of stimulation, and data from placebo-controlled experiments are seldom included (see Table I). The potential for at least a short-term placebo response is substantial, considering the elaborate nature of the surgical procedure, the mysterious electronic technology involved and the close interpersonal relationship that develops between the pain patient and the attending clinician. The 42 clinical studies of thalamic stimulation listed in Table I are representative of the majority of reports appearing in respected journals over the last two decades. Of these only two studies include sham stimulation as a control [52,96], and none provide a statistical analysis of the clinical pain changes. One additional report [116], which appeared only in abstract form, found that patients’ pain ratings following stimulation of the VPM were not statistically different from that of sham stimulation. Thus, in spite of the large number of published reports ranging from 14% [24] to 100% [8] success, the absence of well controlled studies and statistically significant results prohibits an objective appraisal of the clinical efficacy of deep brain stimulation.
Choice of stimulation
sites
Assuming that thalamic stimulation is clinically effective, another unresolved issue involves the appropriate choice of stimulation sites. Hosobuchi and others have championed the idea that somatogenic pain, caused by tissue-damaging stimulation of peripheral nerves or surrounding structures, is responsive to PVG/PAG stimulation, while neurogenic pain, arising from deafferentation or central nervous system destruction, is more likely to respond to stimulation of the somatosensory thalamus [48,66,78,121]. Numerous clinical observations indeed support this relationship [17,47,49,53,66,82,88,95,103,112,119-1211. However, there are a number of reports of the converse relationship - somatogenic pain responsive to stimulation of VPL/VPM [77,109-1111 and neurogenic pain responsive to PVG stimulation [1,8,9,26,91,96,101] (see Table I). As emphasized above, the vast majority of these, whether supporting one view or the other, is simply the presentation of cases attesting to the efficacy of stimulating a particular thalamic site. Thus, although the specificity of PVG/PAG and somatosensory thalamic sites for somatogenic and neurogenic pain syndromes, respectively, is suggested by most of the clinical reports, the relative usefulness of the different stimulation sites
52 TABLE
I
CLINIC.4L
STUDIES
OF MEDIAL
AND
LATERAL
N = neurogenic; S = somatogenic; IC = int. capsule; * = insufficient data; EP = evoked potential. Authors
Pat
Adams [I] Adams et al. [Z]
1 21 I1 19
.Akil et al. [6]
x
Andy 181 Andy [9] Boivie and Meyerson [17] Cosyn and Gybels [24] Gybels et al. [41] Gybels [44] Dieckmann and Witzmann [26] Gybels et al. [43]
4 5 5 7
26 20 19 3
Hoaobuchi Hosobuchi
[47] [48]
Hosobuchi et al. [53] Hosobuchi and Wemmer 1551 Hoaobuchi et al. 1521
Hoaohuchi
1491
40 11 5 6 6
65
Kumar
[50]
et al. [58]
17
44 13 48 12
]951
and Akil
s N
2x 5 5 8
STIMULATION
outcome:
0 = negative
outcome:
pain
verbal report 3 categories
S.Th. = somatosen.
Experimental
Sham
Stat test no 170
out-
Evaluation
+ r
no
~+
report report report questionnaire
verbal report
f
i
I -t
0
no
+
no no no no heat paun ischemia electric no
+
i-
clec. diff. threshold no no
no no
N *
verbal report 0- 10 scale
no no
-t
0- 10 scale. analgesic use. life style analgesic use. verbal report verbal report
no
i
no
i
no
in
no
V4S. McGill
170
no
stimulation use and verbal report
no
t t t
verbal report
no
t 0
N. S N. S S
+
+
no no pinprick, Hardy-WolfGoodell dolor no
L
N S
Sham
c
verbal verbal verbal VAS. VAS
_
no
no
N
s
0 +
S
S
N S S N
N. S * N. S S
verbal report
no
0
no
_
no
_ _
~+
*
“o
+ +
VAS. self-adm questionnaire O-10 scale
no
+
no
no
+
no
+
* v,erbal report verbal report self report, rating scale
no no no
t
no
+
+ +
no pinprick pinprick pinprick radiant heat &hernia exacerbation of clinic pain
= not applicable:
pam
no
analgesic use verbal report
*
thal.;
come
N N. S
N
93
[961 Richardson
N
S.Th. STh. S.Th. PAG/ PVC PVC S.Th. CM-Pf PVC PAG/ PVG, Pf PVG
84
Ray and Burton [91] Richardson [94] Richardson and Akil
N N
K
S
22
Plotkin [gg]
PVC S.Th. S.Th. CM-Pf S.Th. PAG + S.Th. S.Th. PVC
N N N. S *
S.Th.
Mazara et al. [78]
et al. [R2]
N
17
35 57
Meyerson
Evaluation
67
7
Levy et al. [66]
Mazars [77]
Clinical
S N S
4
lvlazars et al. [76]
Pain
PVC IC S.Th. PVC; PVC CM-Pf CM-Pf PVC PAG,’ PVC
PAG/ PVG
+ = positive
type
PAl..
tr>
5’; (1YXh) 1091
1103.
s
Andy,
O.J..
intractable
Parafascicular-certter
physiol.. 43 (19X0) Y Andy. 0.J..
IO Balagura.
‘Thalamtc stimulation S. and
stimulation 60 (1973) Baraai.
Appl. Neuro-
for chronic pain. Zppt.
Nw~vr-
116. 123. Ralph.
‘I..
The
of the diencephalnn
analgew
effect
of elcctrxxl
and mesencephalon.
BraIn Rcs..
36Y- 37’3.
S.. Responses
stimulation. 12 Barbara.
nuclei stlrnul~~iol~ for-
133Sl44.
physiol.. 46 (1983)
II
median
pain and diskinesia (painful-Jiskincsia).
N.M..
m humans.
of \uhatantia
Brain Reh., 171 (1979) Studies of PAG/PVG
In: H.L.
Brain Research,
Fields and J.M.
Elsevier, Amsterdam.
13 Barber. J. and Mayer. rncchansm
nigru neuronc‘s 10 nw.~ou~ 121-130.
D.. Evaluation
of a hypnotic
analgesia
stirnul~ti~~n for pain relwl Besson (Eds.),
Progress 111
1988. pp. 165-173. of the efficaq procedure
arrd ncur:sl
in expcrim~I~t~l
2nd clinical dental pain, Pain, 4 (1977) 41--4X. 14 Basbaum,
A.I..
Clanton.
stimulus-pr[xiuccd lospinal pathway.
C’.H.
analgesia:
and
Fields.
functional
H.L..
Opiate
anatomy
Proc. Nat. Acad. Sci. (U.S.4.).
and
of .t mcdu-
73 (1976) 46X5
4688. 1s Basbaum,
A.I.
;md Fields.
terns: brainstem Rev. Neurosci.. 16 Benabid. fxx%xlaris pathway.
7 (1984)
A.L..
Thalamic
H.L.,
spinal pathways
Endogcnous
pawn control
and endorphm
cwcuitr~.
309. 33X.
Henrikaen.
S.J., McGinty,
J.1:. and Bloom.
nucleus ventro-postercl-lateralis response
to noxious
Brain Rec.. 280 (lYX3)
17 B&vie. J. and Meyerson. ctudy of pain
?\i\-
.Annu.
stimuli
nucleus pora-
through
a non-qwid
217-231.
A.. A correlative
suppression
F..l-..
inhibits
anatomical
by deep brain
and clinical
htimulaticm.
iJ
Pain.
(19X2) 113..126. 1x Bushnell, M.C. and Duncan. G.H., Sensory and affectlrc aspects of pain perception: is medial thaiamw restricted to emotional
Acknowledgements
We would like to thank Dr. James Lund for his critical comments on this manuscript. This research was supported by the Medical Research Council of Canada. Mr. Marchand was supported by the QuCbec ‘Fonds pour la formation de chercheurs et l’aide B la recherche.’
issues’?. Exp. Brain Rea., 7X (19X9) 415-41X. 19 Bushnell. M.C.. Duncan. G.H., Dubner, R. and He, L.F.. Acti\ity of trig~t~~inoth~larnic neurons in medullary dorsal horn of awake
monkeys
Neurophysiol..
cutaneous heat detection
1 Adams,
J.E., Naloxone
stimulation
reversal of analgesia produced
in the human. Pain, 2 (1976)
161~-166.
by brain
170-
20 Bushnell, M.C., Duncan, Maixner. W., Att~ntion~~ (1985) 1103-1110. 21 Cannon. J.T.. Prietto. opioid and non-opioid
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61 LeBars. D.. Dickenson, A.H. and Besson, J.M.. Diffuse noxious inhibitory controls (DNIC). 1. Effects on dorsal horn convergent neurones in the rat. Pain. 6 (1979) 2X3-304. 62 Lee. M.H.M., Zarestsky, H.H.. Ernst, M. Dworkin. B. and Jonas. R.. The analgesic effects of aspirin and placebo on experimentally induced tooth pulp pain, J. Med.. 16 (1985) 417-42X. 63 Lenz. F.A., Dostrovsky, J.O.. Kwan. H.C.. Tasker. R.R., Yamashiro. K. and Murphy, J.T.. Methods for microstimulati(~n and recording of single neurons and evoked potentials in the human central nervous system, J. Neurosurg., 68 (1988) 630-634. 64 Lena. F.A.. Dostrovsky, J.O.. Tasker. R.R.. Yamashiro. K.. Kwan. H.C. and Murphy. J.T.. Single-unit analysis of the human ventral thalamic nuclear group: somatosensnry responses, J. Neurophgstoi.. 59 (1988) 299-316. 65 Lenz.. F.A.. Kwan, H.C.. Dostrovsky, J.O. and Tasker. R.R.. Characteristics of the bursting pattern of action potentials that occur in the thalamus of patients wnith central pain. Brain Res.. 496 (1989) 357-360. 66 Levy. R.M.. Lamb, S. and Adams. J.E.. Treatment of chronic pain by deep brain stimulation: long term follow-up and review of the literature, Neurosurgery. 21 (19X7) 885-893. 67 Lewis. V.A. and Gebhart. G.F., Morphine-induced and stimulation-produced analgesias at coincident periaqueductal central gray loci: evaluation of analgesic congruence. tolerance, and cross-tolerance. Exp. Neural.. 57 (1977) 934-955. 6X Lin. M.T.. Wu. J.J.. Chandra. A. and Tsay, B.L.. Activation of striatal dopamine receptors induces pain inhibiti(~n in rats. J. Neural Transm.. 51 (1981) 213-222. 69 Maixnrr. W., Duhner, R.. Kenshalo. Jr., D.R.. Bushnell, M.C. and Oliveras. J.-L.. Responses of monkey medullary dorsal horn neurons during the detection of noxious heat stimuli, J. Neurophysiol.. 62 (1989) 437-449. 70 Marchand, S., Bushnell, M.C. and Duncan, G.H.. Effects of high frequency TENS on thermal pain. Can./Am. Pain Sot. Joint Mtg. Ahst. (1988) SS-2f. 71 Marchand. S.. Bushnell. M.C. and Duncan, G.H.. Effects of high frequency TENS on heat pain discrimination, Sot. Neurosci. Abstr.. 15 (1989) X.50. 72 Marchand. S., Duncan. G.H.. Bushnell. M.C. and Molina-Negro. P., The effects of dorsal column stimulation on experimental pain measures in man, Pain, Suppi. 5 (1990) S85. 73 Marchand. S.. Trudeau. N.. Bushnell. M.C. and Duncan. G.H.. A primate model for the study of tonic pain. pain tolerance and diffuse noxious inhibitory controls. Brain Rea.. 487 (1989) 3X8391. 74 Mayer, D.J. and Liebeskind. J.C., Pain reduction by focal electrical stimulation of the brain: an anatomical and behavioral analysts, Brain Res.. 68 (t974) 73-93. 75 Mayer, D.J., Wolfle, T.L., Akil. H., Carder. B. and Liebeskind, J.C.. Analgesia from electrical stimulation in the brain-stem of the rat, Science. 174 (1971) 1351-1354. 76 Mazars. G., Merienne, L. and Cioloca. C., Treatment de certain5 types de douleurs par des stimulateurs thalamiques implantables. Nemo-Chirurgie, 2 (1974) 117-124. 77 Mazars. G.J.. lnterm~ttent stimulati~~tl of nucleus ventralis pasterolateralis for intractable pain. Surg. Neurol., 4 (1975) 93-95. 7X Marars, G.J., Merienne. L. and Cioloca, C., Comparative study of electrical stimulation of posterior thalamic nuclei, periaqueductal gray, and other midline mesencephalic structures in man. 11~: J.J. Bonica, J.C. Liebeskind and D.G. Albe-Fessard (Eds.), Advances in Pain Research and Therapy, Vol. 3. Raven Press. 1979, pp. 541-54s. 7Y Mazars, G.J., Merienne. L. and Ciolocca. C.. Stinlulations thalamiques intermittentes antalgiques. Note preliminaire, Rev. Neural., 128 (1973) 273-279. 80 Melzack, R. and Wall, P.D.. Pain mechanisms: a new theory. Science. 150 (1965) 971-979.
B.A.. Problems and controversies in l'Vi)r\ thalamic stimulation as treatment for pain. 111. H.L. Fields and J.M. Besson (Eds.). Progress tn Brain Research. Vol. 77, Ilscv~er ,Amsterdam. 198X. pp. 175.. 187. X2 Meyerson. B.A.. Boethms. .I. and C‘arlsson. AM.. Allcv~atio~~ (>I malignant pain by electrical stimulation in the periventriculai-periaqueductal region: pain relief as related to sti~?~ulat~(~~~site. In: J.J. Bonica. J.(‘. Lieheskind and D.G. ,Alhe-Fessard (Ed\.). Advances in Pain Research and Therapy. Vol 3. Raven Prcsh. New York, 1979. pp. 525-533. X3 Miron. D.. Duncan. G.H. and Bushnell, M.C ., Effects ot attention on the intensity and unpleasantness of thermal pain. Pain. iY ( 19X9) 345 -352. X4 Murfin, R.. Bennett, G.J. and Mayer. D.J.. i‘hr effects of dorso lateral spinal cord (DL.F) lesions on anaigesta from morphtnc mtcroinjected into the periaqueductat gray matter (PA(;) of the rat, Sot. Neurosci. Ahst.. 2 (1976) 946. X5 Oleson. T.D.. Kirkpatrick, D.B. and Goodman. S.J.. l~levation 01 pain threshold to tooth shock hy brain stimulation in primate\. Brain Res.. 194 (19X0) 79.-95. X6 Pert. A. and Yaksh, T.. Sites of morphine rnduced anaigesia in the primate brain: relation to pain pathwav-s. Brain Re\.. %I (1974) 135-140. X7 Pertovaara. A.. Experimental pain and tranacutaneous electrical nerve stimulation at high frequency, Appl. Neurophystol.. 4.3 ( 19X0) 2YO- 297. XX Plotkin, R.. Results in 60 cases of deep hrum stimulatron f;>r chronic intractable pain. Appl. Neurophysiol.. 45 (1982) 173 17X. X9 Price. D.D.. Psych&gicat and Neural Mechanisms c>f Patit. Raven Press. New York, 19xX. 90 Price. D.D.. McGrath. P., Rafii, A. and Buckingham. B.. I‘hc validation of visual nnalogue scales as ratio scale measure, for chronic and expertmental pain. Pain. 17 ( 19X3) 45 56. Yl Ray. C.D. and Burton. C.V.. Deep brain stirnLilati[in for severs. chronic pain. Acta Neurochir. (Wien), 30 (1980) 2X9- 293. 92 Revnolds, D.V.. Surgcr\ in the rat during electrical anaigesra ind~uced hy focal brain stimulation. Science. 164 (1969) 444..445. 93 Rhodes. D.L. and Liebeskind. J.C., Analgesta from rostra1 brainstem stimulation in the rat. Brain Res.. 143 (1Y78) 521.532. 94 Richardson, D.E., Analgesia produced by stimulation of various sites in the human beta-~ndorphin system, .Appt_ Nrurophysioi.. 45 (19X2) 116-122. Y5 Richardson. D.E. and Akil, H.. Pain reduction by electrtcal brain
49 B.V. 0304-3959/91/$03.50
PAIN 01768
Basic Section Review A rticle Deep brain stimulation: Gary
H. Duncan
a review of basic research and clinical studies a,‘, M. Catherine
Bushnell
a,b and
Serge
Marchand
a
u Cenire de Recherche en Sciences Neurologiques and h Far&P de Mt!decine Deniaire, Universitk de Montr&al, Montreal, Quebec (Canada) (Accepted
5 October
1990)
Deep brain stimulation for pain control in humans was first used almost 30 years ago and has Summary continued to receive considerable attention. Despite the large number of clinical reports describing pain relief, numerous studies have indicated that the results of these procedures vary considerably. In addition, many neurosurgeons find the procedures unpredictable, and considerable disagreement still exists regarding important issues related to the technique itself. This review gives an historical overview of the relevant basic and clinical literature and provides a critical examination of the clinical efficacy, choice of stimulation sites, parameters of stimulation, and effects on experimental pain. Finally, we give suggestions for future research that could more definitively determine the usefulness of deep brain stimulation for pain control. Key words: Deep brain
stimulation;
Thalamus;
(Pain)
Introduction The use of ‘deep brain stimulation’ for pain control began almost 30 years ago, when Mazars first implanted electrodes in the somatosensory thalamus of patients suffering from deafferentation pain [76,77]. The use of more medial sites was later prompted by Reynolds who [92] published the first evidence that electrical stimulation of the grey matter surrounding the sylvian aqueduct (PAG) could produce sufficient analgesia to permit abdominal surgery in rats. Today deep brain stimulation is an accepted clinical technique for the relief of chronic intractable pain resulting from a variety of pathological conditions. Despite the large number of clinical studies describing pain relief by deep brain stimulation, several recent reviews of the clinical literature suggest that the results of these procedures vary considerably among different studies [42], that many neurosurgeons find the procedure unpredictable [Sl], that no major progress has been made recently to im-
-Correspondence to: Gary H. Duncan, D.D.S., Ph.D., Dtpartement de Stomatologie, Facultk de Mtdecine Dentaire, UniversitC de Montrkal, C.P. 6128, Succ. A, Montreal, Que. H3C 357, Canada.
prove its efficacy and reliability [81], and that considerable disagreement still exists regarding important issues related to the technique itself [51]. The present paper reviews both the basic and clinical literature relevant to these issues in the hope that a more critical evaluation of previous efforts can lead toward a unified approach in answering a number of major questions: (1) Is the rationale for deep brain stimulation based on known physiological mechanisms? (2) What is the effectiveness of deep brain stimulation in reducing clinical pain? (3) Is the effectiveness of certain deep brain stimulation sites specific to certain pain syndromes? (4) Are some parameters of stimulation more effective than others? (5) Does deep brain stimulation diminish the perception of experimental noxious stimuli?
Rationale and historical background The most commonly used deep brain stimulation sites in humans for the treatment of intractable pain are located: (1) in somatosensory areas of the ventrobasal thalamus which include ventroposterior lateral (VPL)
and ventroposterior medial (VPM) nuclei [46]: (2) in caudal medial thalamic areas around the third ventricle. including the periventricular grey matter (PVG) and adjacent nuclei, centralis medialis (CM) and parafascicularis (Pf): and (3) near the junction of the third ventricle and the syivian aqueduct (rostrai ventral PAG/caudai ventral PVG).
The original rationale for the clinical use of medial mesen-/diencephaiic stimulation arose from experimental findings in rats indicating that electrical stimulation of the PAG produced profound analgesia {74.75,92,93]. Although the most consistent early results in animal studies had been produced by PAG stimulation, initial trials in humans at this site frequently resulted in unpleasant side effects, including feelings of impending doom [9SJ. On the other hand, stimulation of the posterior thalamic PVG appeared to be clinicaily effective in reducing intractable pain without producing such side effects ]52,95,96]. Results of animal studies have also confirmed the analgesic effects of PVG stimulation [59,74,86,93]. More recently, the CM and Pf nuclei in medial thaiamus 1461, adjacent to the PVG, have been implicated in pain modulation in humans [8,9,91,96,108], monkeys [36.85.86,100] and rats [3]. Sakata et al. [99] showed that Pf stimulation in rats excites PAG neurons. thus suggesting the possibility of common analgesic mechanisms activated by stimulation of these different sites. The exact nature of these analgesic mechanisms remains controversial. Most animal studies have indicated that PAG stimulation-produced analgesia is at least partially mediated by opioid mechanisms. Injection of opioids into the PAG produces behavioral analgesia similar to that of electrical stimulation f67,117]. Likewise, morphine microinjected into the PVG and along the ventromediai borders of CM and Pf results in a dose-dependent analgesia that is completely reversed by nnioxone [86]. Naloxone has also been shown to reduce the behavioral analgesia produced by stimuiatioI1 of PAG in rats [5]. Finally, the effects of both opiate and stimulation-produced analgesia associated with the PAG are blocked by lesions of the descending pathways of the dorsoiateral spinal cord [14,84]. By contrast. aithough Carstens et al. [23] showed that PVG stimulation inhibited dorsal horn heat-evoked responses, this inhibition was not reversed by naloxone. For a review of descending analgesic pathways. see recent discussions of endogenous pain control systems [ 15,32,89]. in man, Adams [l] and Hosobuchi et al. [52] showed that naioxone reverses PAG/PVG stimulation-produced analgesia, and Akil et ai. 161 and Hosobuchi et al. [54] reported increases in ventricular ’ beta-endorphinlike’ activity after PVG stimulation. Nevertheless. two subsequent reports showed that these increased beta-en-
dorphin levels may have been due to cross-reactivity 04 the immunoassay to metrizamide, injected as a v,entr’icn lar contrast medium. rather than to endorphins released by the PVG stimulatit~n [27,3i]. Further. Young and his associates [I 18,119] found that PVG and PAG .stimuiatinn does not show cross-tolerance with opioids. nor is it reversed by naioxone admit~istrati~~n. It may bc that the inconsistencies in the human studies are related III differences in electrode placement; Cannon et al. 121 j showed in rats that analgesia induced by ventral. but not dorsal. PAG xtimuiation ix opioid mediated. Thus. one might expect in humans that tjnlv some PA< i electrode placements would he reversed hv nalox~~~.
The pain suppressing effects of stimulating more lateral (somatosensory) ventrobasal areas of the thalamus were reported clinically before animal studies wcw performed [53,76.79]. Mazars indicated that his implantation of VPL stimulating electrodes (as early as 1961) in patients suffering from deafferentation pain was based on the theory that pain is caused by lack of proprioceptive stimuli reaching the thaiamus. Thus. stimulation of the primary somatosensory pathway at this thalamic site was intended to relieve pain in these patients by compensating for the lack of normal sensory input f76.775. During the 1970s. the rationale for stimulating the somatosensory thalamus was probably based on the clinical experiences with dorsal column stimulation. which in turn. had been prompted by the Gate Control Theory ]80] of large fiber inhibition of small fiber pain pathways. Acute physiological studies in anesthetized preparations have shown that stimulation of the somatosensory thalamus does inhibit the activity of both spinothalamic nociceptive neurons in monkey [34,35] and thalamic parafascicuiar nociceptive neurons in rat 1161. It has also been demonstrated in cats and monkeys that VPL stimulation excites neurons in the raphe magnus [ I1 1,114]. a brain-stem nucleus associated with drscending pain inhibitory pathways (151. In addition. Aiko et aI. have demonstrated that sensory thalamic stimulation in rats alters cerebral glucose utilization in the substantia nigra 131. a finding consistent with evidence that the dopaminergic nigrostriatal system exerts a potential influence on pain inhibition [11,68,111]. Thus. although VPL stimulation has been reported to have tzo effect on beta-endorphin levels in humans [60], the animal data involving stimulation of somatosensory thaiamus suggest the possibility of descending pain inhibit~~ry pathways activated by VPL stimuiation, which are nonopioid in nature. This suggestion is supported bv WIdence that administratio1~ of nlon~)~~rnine precursors prevents the development of tolerance to VPL, stimulation in humans [ill]; however. this uncontrolled studv lacks sufficient data to draw substantive conclusions.
51
An interesting paradox exists in the literature concerning stimulation of the somatosensory thalamus. Although several studies in anesthetized animals have reported data suggesting neurophysiological substrates for the analgesia produced by stimulation of VPL/VPM. as indicated above [16,34,35,111,114], there are to date, no behavioral data in awake animals to confirm the clinical analgesia described in humans. In contrast to the positive results observed in behavioral studies of medial thalamic or PAG stimulation [3-5,10,36,59, 74,75,85,86,93,100], studies involving stimulation of VPL and VPM (in both rat and monkey) have shown no behavioral evidence indicative of stimulation-produced analgesia [3,74,100]. This lack of behavioral results for ventrobasal stimulation may be related to the use of tests (tail flick and pinch [3], tail flick and electric shock/jump [74], tail shock [loo]) that are not sufficiently sensitive to reveal subtle analgesic effects or changes in sensory discriminative aspects of nociceptron. In addition, since somatosensory thalamic stimulation in humans has been generally reported to be more effective for the relief of neurogenic pain, antinociceptive tests like tail flick may be considered inappropriate models for evaluating such analgesia. In summary, the theoretical rationale for using deep brain stimulation in humans is still not clearly delineated. A number of behavioral studies in animals support the clinical findings of analgesia produced by stimulation of medial areas, but not by stimulation of VPL/VPM. On the other hand, neurophysiological studies in animals have shown some evidence for activation of pain-inhibiting pathways by stimulation of VPL/VPM. In neither area does there appear to be a clear dependence on endogenous opioid pathways for the analgesia.
Clinical efficacy Regardless of whether or not the basic neurophysiological mechanisms underlying deep brain stimulation are clearly understood, questions regarding the clinical efficacy of this surgical procedure should be a primary concern to health professionals. There is now an abundance of published reports on thalamic stimulation (see Table I), and most of these reports indicate that deep brain stimulation can be a valuable tool for relieving chronic pain that is intractable to other available techniques. Before the availability of electrical stimulation for pain control, ablative surgery was the most common alternative when pharmacological treatments proved to be ineffective or inappropriate. Deep brain stimulation now provides a less invasive treatment that appears to have good clinical results in many cases. Nevertheless, the majority of the clinical reports are case histories rather than well controlled studies. The pain measures
described usually involve imprecise questions about pain relief that do not allow a rigorous statistical evaluation (see Table I). The patient studies are rarely conducted in a double-blind fashion, in which the experimenter and patient are unaware of the parameters and location of stimulation, and data from placebo-controlled experiments are seldom included (see Table I). The potential for at least a short-term placebo response is substantial, considering the elaborate nature of the surgical procedure, the mysterious electronic technology involved and the close interpersonal relationship that develops between the pain patient and the attending clinician. The 42 clinical studies of thalamic stimulation listed in Table I are representative of the majority of reports appearing in respected journals over the last two decades. Of these only two studies include sham stimulation as a control [52,96], and none provide a statistical analysis of the clinical pain changes. One additional report [116], which appeared only in abstract form, found that patients’ pain ratings following stimulation of the VPM were not statistically different from that of sham stimulation. Thus, in spite of the large number of published reports ranging from 14% [24] to 100% [8] success, the absence of well controlled studies and statistically significant results prohibits an objective appraisal of the clinical efficacy of deep brain stimulation.
Choice of stimulation
sites
Assuming that thalamic stimulation is clinically effective, another unresolved issue involves the appropriate choice of stimulation sites. Hosobuchi and others have championed the idea that somatogenic pain, caused by tissue-damaging stimulation of peripheral nerves or surrounding structures, is responsive to PVG/PAG stimulation, while neurogenic pain, arising from deafferentation or central nervous system destruction, is more likely to respond to stimulation of the somatosensory thalamus [48,66,78,121]. Numerous clinical observations indeed support this relationship [17,47,49,53,66,82,88,95,103,112,119-1211. However, there are a number of reports of the converse relationship - somatogenic pain responsive to stimulation of VPL/VPM [77,109-1111 and neurogenic pain responsive to PVG stimulation [1,8,9,26,91,96,101] (see Table I). As emphasized above, the vast majority of these, whether supporting one view or the other, is simply the presentation of cases attesting to the efficacy of stimulating a particular thalamic site. Thus, although the specificity of PVG/PAG and somatosensory thalamic sites for somatogenic and neurogenic pain syndromes, respectively, is suggested by most of the clinical reports, the relative usefulness of the different stimulation sites
52 TABLE
I
CLINIC.4L
STUDIES
OF MEDIAL
AND
LATERAL
N = neurogenic; S = somatogenic; IC = int. capsule; * = insufficient data; EP = evoked potential. Authors
Pat
Adams [I] Adams et al. [Z]
1 21 I1 19
.Akil et al. [6]
x
Andy 181 Andy [9] Boivie and Meyerson [17] Cosyn and Gybels [24] Gybels et al. [41] Gybels [44] Dieckmann and Witzmann [26] Gybels et al. [43]
4 5 5 7
26 20 19 3
Hoaobuchi Hosobuchi
[47] [48]
Hosobuchi et al. [53] Hosobuchi and Wemmer 1551 Hoaobuchi et al. 1521
Hoaohuchi
1491
40 11 5 6 6
65
Kumar
[50]
et al. [58]
17
44 13 48 12
]951
and Akil
s N
2x 5 5 8
STIMULATION
outcome:
0 = negative
outcome:
pain
verbal report 3 categories
S.Th. = somatosen.
Experimental
Sham
Stat test no 170
out-
Evaluation
+ r
no
~+
report report report questionnaire
verbal report
f
i
I -t
0
no
+
no no no no heat paun ischemia electric no
+
i-
clec. diff. threshold no no
no no
N *
verbal report 0- 10 scale
no no
-t
0- 10 scale. analgesic use. life style analgesic use. verbal report verbal report
no
i
no
i
no
in
no
V4S. McGill
170
no
stimulation use and verbal report
no
t t t
verbal report
no
t 0
N. S N. S S
+
+
no no pinprick, Hardy-WolfGoodell dolor no
L
N S
Sham
c
verbal verbal verbal VAS. VAS
_
no
no
N
s
0 +
S
S
N S S N
N. S * N. S S
verbal report
no
0
no
_
no
_ _
~+
*
“o
+ +
VAS. self-adm questionnaire O-10 scale
no
+
no
no
+
no
+
* v,erbal report verbal report self report, rating scale
no no no
t
no
+
+ +
no pinprick pinprick pinprick radiant heat &hernia exacerbation of clinic pain
= not applicable:
pam
no
analgesic use verbal report
*
thal.;
come
N N. S
N
93
[961 Richardson
N
S.Th. STh. S.Th. PAG/ PVC PVC S.Th. CM-Pf PVC PAG/ PVG, Pf PVG
84
Ray and Burton [91] Richardson [94] Richardson and Akil
N N
K
S
22
Plotkin [gg]
PVC S.Th. S.Th. CM-Pf S.Th. PAG + S.Th. S.Th. PVC
N N N. S *
S.Th.
Mazara et al. [78]
et al. [R2]
N
17
35 57
Meyerson
Evaluation
67
7
Levy et al. [66]
Mazars [77]
Clinical
S N S
4
lvlazars et al. [76]
Pain
PVC IC S.Th. PVC; PVC CM-Pf CM-Pf PVC PAG,’ PVC
PAG/ PVG
+ = positive
type
PAl..
tr>
5’; (1YXh) 1091
1103.
s
Andy,
O.J..
intractable
Parafascicular-certter
physiol.. 43 (19X0) Y Andy. 0.J..
IO Balagura.
‘Thalamtc stimulation S. and
stimulation 60 (1973) Baraai.
Appl. Neuro-
for chronic pain. Zppt.
Nw~vr-
116. 123. Ralph.
‘I..
The
of the diencephalnn
analgew
effect
of elcctrxxl
and mesencephalon.
BraIn Rcs..
36Y- 37’3.
S.. Responses
stimulation. 12 Barbara.
nuclei stlrnul~~iol~ for-
133Sl44.
physiol.. 46 (1983)
II
median
pain and diskinesia (painful-Jiskincsia).
N.M..
m humans.
of \uhatantia
Brain Reh., 171 (1979) Studies of PAG/PVG
In: H.L.
Brain Research,
Fields and J.M.
Elsevier, Amsterdam.
13 Barber. J. and Mayer. rncchansm
nigru neuronc‘s 10 nw.~ou~ 121-130.
D.. Evaluation
of a hypnotic
analgesia
stirnul~ti~~n for pain relwl Besson (Eds.),
Progress 111
1988. pp. 165-173. of the efficaq procedure
arrd ncur:sl
in expcrim~I~t~l
2nd clinical dental pain, Pain, 4 (1977) 41--4X. 14 Basbaum,
A.I..
Clanton.
stimulus-pr[xiuccd lospinal pathway.
C’.H.
analgesia:
and
Fields.
functional
H.L..
Opiate
anatomy
Proc. Nat. Acad. Sci. (U.S.4.).
and
of .t mcdu-
73 (1976) 46X5
4688. 1s Basbaum,
A.I.
;md Fields.
terns: brainstem Rev. Neurosci.. 16 Benabid. fxx%xlaris pathway.
7 (1984)
A.L..
Thalamic
H.L.,
spinal pathways
Endogcnous
pawn control
and endorphm
cwcuitr~.
309. 33X.
Henrikaen.
S.J., McGinty,
J.1:. and Bloom.
nucleus ventro-postercl-lateralis response
to noxious
Brain Rec.. 280 (lYX3)
17 B&vie. J. and Meyerson. ctudy of pain
?\i\-
.Annu.
stimuli
nucleus pora-
through
a non-qwid
217-231.
A.. A correlative
suppression
F..l-..
inhibits
anatomical
by deep brain
and clinical
htimulaticm.
iJ
Pain.
(19X2) 113..126. 1x Bushnell, M.C. and Duncan. G.H., Sensory and affectlrc aspects of pain perception: is medial thaiamw restricted to emotional
Acknowledgements
We would like to thank Dr. James Lund for his critical comments on this manuscript. This research was supported by the Medical Research Council of Canada. Mr. Marchand was supported by the QuCbec ‘Fonds pour la formation de chercheurs et l’aide B la recherche.’
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