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Behavioural evidence for vestibular stimulation

as a treatment for post-stroke pain

Article in Journal of neurology, neurosurgery, and psychiatry · July 2008

DOI: 10.1136/jnnp.2008.146738 · Source: PubMed

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Behavioural evidence for vestibular stimulation as

a treatment for central post-stroke pain
P D McGeoch, L E Williams, R R Lee and V S Ramachandran

J. Neurol. Neurosurg. Psychiatry 2008;79;1298-1301; originally published online

11 Jun 2008;
doi:10.1136/jnnp.2008.146738

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Short report

Behavioural evidence for vestibular stimulation as a

treatment for central post-stroke pain
P D McGeoch,1 L E Williams,1 R R Lee,2,3 V S Ramachandran1

c Additional data ABSTRACT The basis of the thermosensory disinhibition

(supplementary figs 1–3, Background: Central post-stroke pain (CPSP) is often hypothesis is that central pain is a thermoregula-
supplementary table 1 and
appendices 1–3) are published
resistant to treatment. We have previously proposed that tory disorder that occurs from the loss of the
online only at http://jnnp.bmj. caloric vestibular stimulation might alleviate it. central inhibition of pain by cooling.4 5 This
com/content/vol79/issue11 Methods: We conducted a single blind placebo happens because non-painful cold temperatures
1
Center for Brain and Cognition, controlled investigational study of caloric vestibular below 25uC actually activate both cold thermo-
University of California, San stimulation (CVS) in nine patients with CPSP. Participants receptors (Ad fibres) and also C nociceptors. These
Diego, California, USA; rated their pain levels before and after the procedure on a inputs pass together in the lamina I layer to the
2
Department of Radiology, 10 point scale. thalamus, where the C fibre input travels via the
University of California, San
Diego, California, USA; Results: We found a significant immediate treatment ventral caudal part of the medial dorsal nucleus of
3
Veterans Affairs San Diego effect of the cold water caloric stimulation with an the thalamus to the anterior cingulate cortex
Healthcare System, San Diego, average pain reduction of 2.58 points (SEM 0.52) for the (ACC) and the Ad fibre input passes via the
California, USA experimental condition compared with 0.54 points (SEM posterior part of the ventromedial nucleus (VMpo)
Correspondence to: 0.49) for the placebo conditions. in the lateral thalamus to dpIns (supplementary
Dr P D McGeoch, University of Conclusions: Participants who responded best to CVS fig 1, available online).
California, San Diego, Centre for had suffered strokes that spared and permitted activation It is thought, from functional imaging, that it is
Brain and Cognition, Mandler
Hall, 9500 Gilman Drive, Mail
of the dominant parieto-insular vestibular cortex (PIVC), the ACC which is selectively associated with the
Code 0109, La Jolla, CA 92093- which is known to be located in the non-dominant motivation to take corrective action that charac-
0109, USA; hemisphere. These findings tie in closely with the terises thermoregulatory distress.6 9 10 Normally,
[email protected] thermosensory disinhibition hypothesis for central pain, when Ad fibres activate the dpIns it acts (via the
which leads us to propose that vestibular stimulation may parabrachial nucleus (PB) and periaqueductal grey
Received 9 February 2008
Revised 17 March 2008
alleviate CPSP from cross activation between the PIVC (PAG)) to suppress the perception of pain at the
Accepted 19 March 2008 and the thermosensory cortex in the adjacent dorsal ACC. However, when the temperature falls below
Published Online First posterior insula. Alternatively, if one views vestibular 15uC, the C activity predominates over the Ad
11 June 2008 function and thermoregulation as part of a larger activity.6 Therefore, the ACC is no longer sup-
interoceptive system that exists to maintain homeostasis, pressed and potentially harmful cold temperatures
then it is possible they share a common integrative are perceived as pain with a motivation to take
mechanism in the brainstem, which may act to reset the corrective action.
balance in central pain. Consequently, lesions of the lamina I spinotha-
lamocortical pathway terminating in dpIns can
disinhibit a thermosensory network, including the
Central post-stroke pain (CPSP) is often treatment PB, PAG and ACC.4–6 Clearly, hemispheric imbal-
refractory.1 We have suggested that caloric vestib- ance also plays a role as CPSP rarely develops with
ular stimulation (CVS) may bring relief to indivi- bilateral thermosensory impairment.5 11 The ther-
duals with this condition.2 3 Here we present a mosensory disinhibition hypothesis proposes that
placebo controlled single blind study of CVS in lesions of the lamina I pathway can cause an
nine patients with CPSP. Our findings are best imbalance in the bilateral integration of thermo-
interpreted within the framework of the thermo- sensation in the brainstem by the PB and PAG and
sensory disinhibition hypothesis for central pain.4 5 the development of CPSP.6

Interoception and the thermosensory disinhibition The parieto-insular vestibular cortex

hypothesis Functional imaging during CVS demonstrates
CPSP can develop from a lesion affecting any part activation of the parietal and posterior insular
of the lamina I layer of the spinothalamic tract or cortices.12 13 This area, the parieto-insular vestibular
its projection via the lateral thalamus to the dorsal cortex (PIVC), is dominant in the hemisphere that
posterior insula (dpIns).5–8 The lamina I layer is non-dominant for language.14 Intriguingly, it has
carries the interoceptive senses (eg, itch, tickle been reported that CPSP is twice as likely after
and thermosensation) to the interoceptive cortex non-dominant hemisphere strokes.15 The major
in the posterior insula and parietal operculum, vestibular outflow from the thalamus to PIVC
which includes the thermosensory cortex in was obscure,16 but was recently located in primates
dpIns.6 8 The role of these senses is to monitor (AD Craig, personal communication, 2007) as lying
the body’s physiological condition and maintain in the posterolateral thalamus between VMpo and
homeostasis. They do so by conferring both a the magnocellular part of the medial geniculate
sensation and, when necessary, a motivation to body (see supplementary fig 2, available online).
take corrective action. Craig found it to be about 4 mm posterior to the

1298 J Neurol Neurosurg Psychiatry 2008;79:1298–1301. doi:10.1136/jnnp.2008.146738

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Short report

Table 1 Pain ratings pre and post procedures

Subject Condition Pre Post Change Radiology

A (0 days) Left tepid 8.5 8.5 0 Lacunar infarct lateral nuclei right thalamus. Posterior pole of right
Left cold 8.5 5 23.5 thalamus spared. Also lacune right caudate (1.5 T)
Ice pack 7 7 0
Right cold 8 5 23
B (1 day) Left tepid1 8.5 7.5 1 AVM. Infarct involving entire right posterolateral thalamus and right
Left cold1 8.5 8.5 0 PCA territory (3 T)
Ice pack2 8.5 7 21.5
Right cold2 7 5 22
C (1 day) Right tepid1 6 4 22 Lacunar infarct lateral nuclei right thalamus. Posterior pole of right
Left cold1 7.5 4 23.5 thalamus spared. Hypertensive periventricular white matter
changes and lacune right putamen (1.5 T)
Ice pack2 3 3 0
Right cold2 3 1 22
D (1 day) Right tepid1 7.5 2.5 25 Left posterior insula infarct with involvement of left parietal lobe
Right cold1 5.5 5 20.5 and operculum (1.5 T)
Left cold2 6.5 5 21.5
Left tepid2 7 6 21
E (0 days) Right tepid 8 8 0 Haemorrhage right sub-insular white matter. Insula and thalamus
Left cold 8 1 27 both spared (1.5 T)
Ice pack 1 1 0
Right cold 1 0 21
F (1 day) Right tepid1 10 9 21 SAH. Infarction left posterior insula and temporal pole. Tiny lacune
Left cold1 9 5 24 left thalamus (region VMpo). Parietal operculum spared. (CT)
Ice pack2 10 10 0
Right cold2 10 8 22
G (20 days) Right tepid1 7 6 21 SAH. Right insula, frontal operculum and temporal pole infarcted.
Right cold1 6 3 23 Parietal operculum spared (CT)
Ice pack2 4 4 0
Left cold2 4 2.5 21.5
H (1 and 6 Left cold1 7 4 23 Very large left internal carotid artery infarct. Complete infarction
days) Left tepid2 7 7 0 frontal lobe, except ACC. Involves ventrolateral thalamus, entire
insula, internal capsule, caudate, putamen, parietal operculum and
Right cold2 7 3 24
superior parietal lobe. Left medial thalamus and temporal
Ice pack3 4.5 4.5 0 operculum spared (CT)
I (1 day) Right tepid1 7.5 6 21.5 Lacune right thalamus (1.5 T)
Right cold1 7 4.5 22.5
Ice pack2 5.5 5 20.5
Left tepid2 5.5 4.5 21
Left cold2 5.5 3 22.5
Number in parentheses indicates intersession interval and superscript indicates in which session the procedure was carried out.
Imaging reported by RRL. We could not obtain a copy of patient I’s scan. Imaging modality is in brackets.
ACC, anterior cingulate cortex; AVM, arteriovenous malformation; PCA, posterior cerebral artery; SAH, subarachnoid haemorrhage;
VMpo, ventromedial nucleus.

part of VMpo that relays cool specific activity to the posterior taken as their post-procedure rating. They rated their overall
insula. pain level and the pain in their face, arm/hand and leg/foot (see
appendix 1, available online).
METHODS
The institutional review board of the University of California, RESULTS
San Diego, granted ethics approval for the study. Nine patients Patient responses
with CPSP gave signed informed consent to participate and The age range of the patients was 36–88 years, with three males
were run in two experimental sessions, separated by at least and six females, and the duration post-stroke was 30–
1 day (except patients A and E who were seen in 1 day for 180 months (see supplementary table 1, available online).
logistical reasons). During each session, participants were Seven of the patients were right-handed and two left-handed.
administered one experimental cold water irrigation and one All but one (patient H) had pain in their non-dominant side.
placebo intervention, either a body temperature irrigation or Five of the strokes were ischaemic, one haemorrhagic, two
application of an ice pack to the pinna. Patients were blind to subarachnoid haemorrhages (SAH) and one iatrogenic from
the experimental procedure. Before and after each procedure embolisation of an arteriovenous malformation.
participants rated their pain on a numerical rating scale from 0, All participants described the cold CVS and ice pack control
for no pain, to 10, for the worst imaginable. as unpleasant procedures. CVS produced vertigo and nystagmus
Patients gave ratings every 10 min for 30 min after the in all. Clinically, the response to CVS split the population into
procedure. If by then their pain level had not plateaued, we three groups (table 1). The first group (patients A, E, G and H)
continued to measure it at 10 minute intervals until an hour had an excellent response; their pain was reduced immediately
after the procedure. Whatever level their pain plateaued at was and stayed reduced for several days. The second group (patients

J Neurol Neurosurg Psychiatry 2008;79:1298–1301. doi:10.1136/jnnp.2008.146738 1299

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Short report

F, C and I) reported some reduction in their pain score but either Patient F
this was not sustained (patients F and I) or the procedure was Patient F was a 49-year-old left-handed man who had a left
not tolerated (patient C). The third group (patients B and D) middle cerebral artery SAH in 2002. His pain did respond to
did not respond (see appendix 2, available online). CVS, with greater relief in his face and hand than foot, but rose
again within a few hours.
Patient A
Patient A was an 87-year-old right-handed man who had a right Patient G
thalamic infarct in 1992 (fig 1A) centred on the right VMpo Patient A was a 49-year-old right-handed woman who had a
(supplementary fig 2, available online). The posterolateral right middle cerebral artery SAH in 2000. Her baseline was 7.
thalamus, where the vestibular outflow lies, was spared. His She responded to CVS. This response was greater in her hand
baseline rating was 8 throughout. He responded to CVS, with than foot. She has continued with CVS and reports a month of
greater relief in his face (0) and hand (1) than foot (7). The pain relief after bilateral stimulations.
was replaced by numbness, similar to immediately post-stroke.
He now describes 2 weeks of relief post-bilateral stimulations. Patient H
Patient H was a 69-year-old right-handed woman who in 1992
Patient B had a left internal carotid artery occlusion, rendering her
hemiplegic and expressively aphasic. Her baseline was 7. She
Patient B was a 59-year-old right-handed woman who had a
responded to CVS with greater relief in her face (2) and hand (3)
right posterior cerebral artery infarct in 1999. She described
than foot (5). It remained reduced for several weeks.
significant ongoing disequilibrium. She did not respond to CVS.
Imaging (fig 1B) showed infarction of the posterolateral right
thalamus with evident involvement of both the VMpo and the Patient I
vestibular outflow. Patient I was a 60-year-old right-handed man who had a right
thalamic infarct in 2003. His pain only transiently responded to
CVS.
Patient C
Patient C was a 78-year-old right-handed woman with a right
thalamic infarct from 1993. Her pain fell following CVS and
Statistical analysis
An ANOVA analysis (appendix 3, available online) found a
was replaced by numbness. However, she found CVS excruciat-
significant treatment effect of the cold CVS, with an average
ing and has not continued.
pain reduction of 2.58 points (SEM 0.52) for the experimental
condition compared with 0.54 points (SEM 0.49) for the placebo
Patient D conditions (supplementary fig 3, available online). There was no
Patient D was a 36-year-old left-handed woman with a left significant difference between the left and right stimulations.
posterior insula and parietal lobe infarct from 2004. She
described ongoing disequilibrium and did not respond to CVS. DISCUSSION
Several aspects suggest that CVS alleviates CPSP by a distinct
Patient E biological mechanism. These include: the duration of relief;
Patient E was a 55-year-old right-handed woman who had a differentially greater response in the face and hand compared
right sub-insular haemorrhage in 2002. After bilateral CVS she with the foot, which corresponds with a map of these areas in
was pain free. Her pain was replaced by numbness. Although the ACC17; that the pain is replaced by numbness; and the
the pain in her foot returned after 24 h, the pain in her face (0.5 statistical analysis. It seems that patients with CPSP who gain
vs 2.5) and hand (2 vs 5) were reduced 3 weeks afterwards. relief from CVS are those in whom it is possible to activate the

Figure 1 (A) 1.5 T MRI of patient A.

Posterior pole of right thalamus spared by
stroke. (B) 3 T MRI of patient B. Stroke
involves the posterolateral pole of the
right thalamus.

1300 J Neurol Neurosurg Psychiatry 2008;79:1298–1301. doi:10.1136/jnnp.2008.146738

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Short report

dominant PIVC, which is in the non-dominant hemisphere.14 Ethics approval: The institutional review board of University of California, San Diego,
The two patients who failed to respond (patients B and D) gave granted ethics approval for the study.
a history of marked post-stroke disequilibrium. In fig 1B, the
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