Pain 101 (2003) 97–107

www.elsevier.com/locate/pain

Thalamic field potentials in chronic central pain treated by periventricular

gray stimulation – a series of eight cases
Dipankar Nandi a, Tipu Aziz a,b,*, Helen Carter b, John Stein a
a
University Laboratory of Physiology, Oxford University, Parks Road, Oxford OX1 3PT, UK
b
Department of Neurosurgery, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK
Received 13 March 2002; accepted 1 August 2002

Abstract
Chronic deep brain stimulation (DBS) of the periventricular gray (PVG) has been used for the treatment of chronic central pain for
decades. In recent years motor cortex stimulation (MCS) has largely supplanted DBS in the surgical management of intractable neuropathic
pain of central origin. However, MCS provides satisfactory pain relief in about 50–75% of cases, a range comparable to that reported for DBS
(none of the reports are in placebo-controlled studies and hence the further need for caution in evaluating and comparing these results). Our
experience also suggests that there is still a role for DBS in the control of central pain. Here we present a series of eight consecutive cases of
intractable chronic pain of central origin treated with PVG DBS with an average follow-up of 9 months.
In each case, two electrodes were implanted in the PVG and the ventroposterolateral thalamic nucleus, respectively, under guidance of
corneal topography/magnetic resonance imaging image fusion. The PVG was stimulated in the frequency range of 2–100 Hz in alert patients
while pain was assessed using the McGill-Melzack visual analogue scale. In addition, local field potentials (FPs) were recorded from the
sensory thalamus during PVG stimulation.
Maximum pain relief was obtained with 5–35 Hz stimulation while 50–100 Hz made the pain worse. This suggests that pain suppression
was frequency dependent. Interestingly, we detected low frequency thalamic FPs at 0.2–0.4 Hz closely associated with the pain. During 5–
35 Hz PVG stimulation the amplitude of this potential was significantly reduced and this was associated with marked pain relief. At the
higher frequencies (50–100 Hz), however, there was no reduction in the FPs and no pain suppression.
We have found an interesting and consistent correlation between thalamic electrical activity and chronic pain. This low frequency potential
may provide an objective index for quantifying chronic pain, and may hold further clues to the mechanism of action of PVG stimulation. It
may be possible to use the presence of these slow FPs and the effect of trial PVG DBS on both the clinical status and the FPs to predict the
probable success of future pain control in individual patients. q 2002 International Association for the Study of Pain. Published by Elsevier
Science B.V. All rights reserved.
Keywords: Central pain; Thalamic field potentials; Periventricular gray; Deep brain stimulation

1. Introduction nucleus (Young et al., 1992), periacquecductal and periven-

Medically intractable pain has been treated by chronic
stimulation of deep brain structures for nearly half a century
(Heath, 1954; Pool et al., 1956). Several deep brain struc-
tures have served as targets in the search for maximal and
consistent clinical effect. These include the septal region
(Heath, 1954), caudate (Ervin et al., 1966), ventropostero-
lateral nucleus (Mazars, 1975), several other thalamic nuclei
including the dorsal medial nucleus, the parafascicular
nucleus and the centromedian nucleus (Andy, 1987; Boivie
and Meyerson, 1982; Thoden et al., 1979), Kolliker-Fuse
* Corresponding author. Tel.: 144-1865-224605; fax: 144-1865-
224898.
E-mail address: tipu.aziz@physiol.ox.ac.uk (T. Aziz).
tricular gray matter (PAG and PVG) (Hosobuchi et al.,
1977; Meyerson et al., 1978; Plotkin, 1980; Richardson
and Akil, 1977; Young et al., 1985). In recent years motor
cortex stimulation (MCS) has largely supplanted deep brain
stimulation (DBS) in the surgical management of intractable
pain of central origin (Canavero and Bonicalzi, 2001;
Carroll et al., 2000; Katayama et al., 1998; Saitoh et al.,
2000; Smith et al., 2001; Tsubokawa et al., 1991; Yama-
moto et al., 1997). However, there is a wide range in the
reported efficacy of MCS in providing satisfactory pain
relief (50–75%) in patients with medically refractory central
pain (Canavero and Bonicalzi, 2002; Carroll et al., 2000;
Katayama et al., 1998; Nguyen et al., 2000; Smith et al.,
2001; Tsubokawa et al., 1991). This is comparable to the

0304-3959/02/$20.00 q 2002 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
doi:10.1016/S0 304-3959(02)00 277-4
98 D. Nandi et al. / Pain 101 (2003) 97–107
literature on DBS for the alleviation of central neuropathic
pain (Mundinger and Salomao, 1980; Tasker and Vilela
Filho, 1995; Young, 1990). It needs to be emphasized,
however, that none of the reports referred to are rando-
mized, double-blinded, placebo-controlled studies. Hence,
interpretation of this data for evaluating the efficacy of
either treatment modality against best medical treatment
or for assessing the relative efficacy of one method over
the other requires a considerable degree of caution. Based
on some of the literature and our experience (Carroll et al.,
2000) we believe there still is a definite role for DBS in
control of central pain. Here we present a series of eight
consecutive cases of intractable chronic pain of central
origin treated with PVG DBS.
The mechanism of PVG pain relief is believed to involve
the opioid pathways that contact serotoninergic neurones
that descend from the raphe nuclei to the dorsal horn of
the spinal cord (Hosobuchi et al., 1979; Young and Dawson,
1987; Young et al., 1993). However, there are very few
studies that have explored the ascending effect of PVG
stimulation on the activity of the sensory thalamus (Nashold
and Wilson, 1966; Parrent et al., 1992; Rinaldi et al., 1991).
In this report we describe local field potential recordings
(FPs) from the ventroposterolateral thalamic nucleus
(VPL) during PVG stimulation in eight patients with
chronic intractable central pain.
FPs are believed to reflect the superposition of synchro-
nized dendritic currents, averaged over a volume of tissue
extending a few millimeters from the tip of the recording
electrode (Mitzdorf, 1987). The FPs produced by a group of
cells also reflect in an indirect way the membrane potential
changes, that is, the synaptic and action potentials, which
the cells undergo in unison (Hubbard et al., 1969). A study
of such potentials therefore gives invaluable information
regarding the average activity of the cells in the group,
and is important for the understanding of the physiological
characteristics of any neural assembly (Hubbard et al.,
1969). In support of this argument, most studies agree that
FPs are dominated by the activity of nearby neurons (Bress-
ler et al., 1993; Eckhorn et al., 1988; Roelfsema et al.,
1997). The functional relevance of FPs has been demon-
strated in recent studies on anaesthetized monkeys that
involved comparing simultaneously recorded functional
magnetic resonance imaging (fMRI) and neuronal signals,
including FPs, single-unit activity (SUA) and multi-unit
activity (MUA), from the visual cortex. It was found that
FPs showed the strongest correlation with blood oxygen
level dependent (BOLD) fMRI signals; significantly greater
than that showed by MUA and SUA signals (Logothetis et
al., 2001). We have previously reported clinical studies
showing correlation of deep brain FPs with simultaneous
recording of abnormal electrical activity from related
peripheral tissue, i.e. electromyogram (EMG) from corre-
sponding dysfunctional muscle groups (Liu et al., 2000;
Nandi et al., 2002a,c). The use of macro-electrode FPs
recording offers other clinical advantages over microelec-
trode SUA and MUA monitoring more commonly
employed in functional stereotactic neurosurgical proce-
dures. It is very much less time consuming – a matter of
considerable importance in functional neurosurgery as this
often involves a conscious patient whose alert cooperation
may be vital to the final siting of the stimulating electrode.
(Operations involving microelectrode recordings can take
several hours) Also it requires fewer penetrations of the
brain, thereby decreasing the risk of complications like
intracerebral hemorrhage (Carrol et al., 1998; Palur et al.,
2002). In addition, the use of the stimulating macro-elec-
trode for FPs recording ensures avoidance of the siting error
possible when replacing microelectrodes with the stimulat-
ing macro-electrode. We have found that FPs recording has
improved our ability to target effective sites for chronic
DBS in various movement disorders (Liu et al., 2000;
Nandi et al., 2002a,c).
The inability to accurately predict the success of pain
relief in individual patients has been a major limiting factor
in the application of both DBS and MCS in routine clinical
practice (Carroll et al., 2000; Katayama et al., 1998; Nandi
et al., 2002d). We have explored the electrophysiological
correlations of PVG DBS in an attempt to better understand
the mechanism of action of such treatment and to try and
improve the prediction of satisfactory pain relief in indivi-
dual patients. We studied the effects of stimulation of the
PVG on the sensory thalamus in all the patients in this
series. We have previously reported our findings in two of
the cases in this series in a pilot study (Nandi et al., 2002b).
2. Methods
2.1. Patients
We report our findings in eight patients with intractable
neuropathic pain of central origin recruited consecutively
between March 1999 and October 2001. Clinical details
are described in Table 1. All patients described their pain
as burning and incapacitating. Five of the patients were
post-stroke and had hemi-body pain in the contralateral
side. One had Chiari malformation but did not have a syrinx
as seen on MRI. This patient had no symptoms attributable
to the Chiari malformation and was suffering from intract-
able burning pain and occasional paresthesia in the left arm
for 10 years prior to being referred to our unit. One patient
had suffered from left-sided trigeminal neuralgia for over 20
years. She underwent an unsuccessful gasserian ganglion
blockade followed by microvascular decompression,
which too was unable to control her trigeminal pain. She
then underwent a pontine tractotomy 5 years ago following
which she became hemi-paretic and the nature of her painful
syndrome changed. She developed a constant, burning and
severe pain involving both the left side of the face and her
left arm. One patient had multiple sclerosis. All patients had
been tried on extensive pharmacotherapy and had proved
 D. Nandi et al. / Pain 101 (2003) 97–107 99

Table 1
Clinical details of patients with chronic central pain treated with periventricular gray stimulation a

No. Age Sex Primary diagnosis (year Site/character of pain Surgical complications Current pain relief (in %
of onset of pain) reduction) and duration of
follow-up

1 52 F Multiple sclerosis (1985) Constant burning pain and heaviness in 46% at 30 months
L shoulder and calf
2 62 F Post stroke (aneurysmal R hemi-body pain, constant, burning, 42% at 12 months
SAH 1997) severe
3 61 F Trigeminal neuralgia L side of face and arm; constant, 33% during trial stimulation
(1pontine tractotomy) burning, very severe (IPG not implanted initially)
(1980)
4 47 M Post stroke (1995) L hemi-body constant, burning, severe Hematoma IPG site; resolved 41% at 9 months
5 53 M Post stroke (1997) R hemi-body pain, constant, burning, 5% during trial stimulation.
severe (IPG not implanted)
6 60 F Post stroke (1996) Constant, severe, burning pain in her L 32% at 6 months
arm and leg, occasionally face
7 70 M Post stroke (1997) R hemi-body pain, constant, heaviness 44% at 3 months
and burning, severe
8 34 F Chiari malformation (no Severe burning in L arm; occasional 32% at 3 months
syrinx) (1991) pins and needles
a
Assessment at last follow-up is included. IPG, implantable pulse generator.

resistant. The drugs included tricyclic and heterocyclic anti-
depressants, opioid analgesics including morphine, benzo-
diazepines, non-narcotic analgesics, lamotrigine,
carbamazepine and mexiletine. Apart from the patient
with trigeminal neuralgia, none of the other patients under-
went any surgical procedure, e.g. MCS, for relief from their
pain. All patients were evaluated in a designated pain clinic
either in the referring center and/or in our unit. They were
all independently assessed by a neurologist and a neuropsy-
chologist in our unit. Pain scores on a self-rated visual
analogue scale (VAS, McGill-Melzack) were recorded at
different times of the day over at least 7 days prior to surgery
on each patient.
2.2. Surgery
Informed consent was obtained from each patient. All
patients were offered both PVG and VPL stimulation simul-
taneously based on the literature (and our previous experi-
ence) of DBS for the relief of intractable central neuropathic
pain (Young and Rinaldi, 1997). It was explained to them
that only trial stimulation subsequent to electrode placement
would clarify which site (or a combination) would provide
satisfactory pain relief. All procedures were approved by the
Local Ethics Committee, Radcliffe Hospitals NHS Trust,
Oxford, UK. A CRW base ring was applied to the patients’
head under local anaesthesia. A stereotactic corneal topo-
graphy (CT) scan was then performed and using the Radio-
nics Image Fusionw and Stereoplanw (Radionics Inc.,
Burlington, MA, USA) program the coordinates for the
anterior and posterior commissures were calculated. After
washing the patient’s scalp with alcoholic chlorhexidine, a
parasaggital posterior frontal scalp incision 3.0 cm from the
midline, was made contralateral to the side of pain. The
VPL nucleus was implanted with a Medtronic 3387
(Medtronic Inc., Minneapolis, MN, USA) electrode where
stimulation induced paresthesia in the area of pain and the
PVG with a Medtronic 3389 (later 3387) electrode where
stimulation induced relief of pain or a sensation of warmth
in the area of pain. Both electrodes have four exposed
contacts, each 1.5 mm long, placed linearly. The Medtronic
3387 has a gap of 1.5 mm between contacts (span of
10.5 mm between the most proximal and the most distal
contacts) while the Medtronic 3389 has a gap of 0.5 mm
between contacts (span of 7.5 mm between the most prox-
imal and the most distal contacts). We used the 3389 elec-
trode initially (first two cases) in the PVG in anticipation
that the area of stimulation would be smaller compared to
that in the VPL. We found that this is not the case and hence
since then we have used the 3387 at both sites. The ranges of
the coordinates of the final targets with reference to the mid-
commissural point are listed in Table 2.
2.3. Trial stimulation and pain assessment
In all patients the electrodes were externalized for a
Table 2
This table details the ranges of the stereotactic coordinates of the periven-
tricular gray (PVG) and the ventroposterolateral thalamus (VPL) targets
used in the final placement of the DBS electrodes a
Target Axis
Anteroposterior Lateral Vertical
VPL 210 to 213 14–18 2 to 25
PVG 210 3–4 0
a
The coordinates are given in millimeters relative to the mid-commis-
sural point and refer to the position of the tip of the Medtronic electrode.
100 D. Nandi et al. / Pain 101 (2003) 97–107
week’s trial stimulation and recording of FPs to assess the
degree of pain relief. Pain was assessed after recovery from
surgery and during stimulation by VAS scores. Trial stimu-
lation was conducted after the patient reported the return of
pain to pre-operative levels. Each trial session was spread
over 90 min and a maximum of two sessions were
conducted in 1 day. Different frequencies of stimulation
were tried ranging from 5 to 100 Hz. Both the VPL and
the PVG were stimulated, individually and together, to
determine degree of pain relief or other wise. In each
patient, once the effective frequencies for pain relief were
recorded in the initial sessions, further trials concentrated on
these frequencies. Those frequencies that were ineffective or
actually worsened the pain were used briefly to record corre-
sponding FPs.
2.4. Field potential recording
FPs were recorded through the thalamic DBS leads in the
ward after the patient had recovered from the operation and
pain had returned to the pre-operative level. Recordings
were bipolar from adjacent exposed leads in the DBS elec-
trode. FPs were amplified 1000 £ (CED 1902, Cambridge,
UK), filtered between 0 and 100 Hz, digitized at 250 Hz and
continuously displayed on-line with an adjustable window.
Initially, recording was done from both the VPL and the
PVG, either off stimulation or when the other was being
stimulated. Later, after it was found that the PVG FPs
were independent of both the pain scores and the state of
stimulation of the VPL, records were obtained before,
during and after sessions of stimulation of the PVG leads
at different frequencies. Some recordings were made from
the VPL after stimulating it through the same DBS electrode
just prior to onset of recording. Voltage used ranged from
1.5 to 2.5 V and the pulse width was kept constant at 210 ms.
Off-line analysis was performed using Matlab software
Fig. 1. This figure shows the response of the self-assessed pain scores (VAS) (mean ^ SD, n ¼ 10) to trial periventricular gray (PVG) stimulation. Dark bars
represent scores before stimulation and light bars scores during stimulation. Each score was averaged over ten trials and comparisons were made using two-
tailed paired t-test.
(Mathworks Inc. Natick, MA, USA). Analysis of the signals
concentrated on windowed Fourier transform (WFT) to
display the FPs in terms of a power versus frequency distri-
bution. WFT assumes stationarity of the signals for the
windows selected for analysis. Further analysis was done
to aggregate the power spectra from effective low frequency
stimulation and ineffective high frequency stimulation
across different patients.
2.5. Pulse generator
Patients who reported satisfactory relief from pain
following trial PVG stimulation were then implanted with
a subcutaneous pulse generator (IPG, Synergyw, Medtronic
Inc, Minneapolis, MN, USA), placed in a pectoral pouch
under general anaesthesia.
3. Results
3.1. Clinical results
Six of the eight patients who had trial PVG stimulation
had satisfactory pain relief and opted to have the IPG
implanted in a second procedure. VPL stimulation tried
alone was able to provide a reasonable degree of pain
suppression in four of the patients. These were the ones
with multiple sclerosis, pontine tractotomy, post-SAH
stroke and Chiari malformation, respectively. However, in
the first two cases it caused an unacceptable degree of
persistent paresthesia and was not continued as a therapeutic
option. In the other two responders to VPL stimulation,
PVG stimulation alone was superior in its effectiveness.
Combined PVG and VPL stimulation were not found to
add to the degree of pain relief in any of the patients; it
made the side effects worse in two. Hence, none of the
 D. Nandi et al. / Pain 101 (2003) 97–107
patients were offered continued chronic VPL stimulation.
The VPL leads were, however, not removed, with the
patient’s consent, and it was hoped to be put to use in the
future if pain suppression failed to be sustained with PVG
stimulation alone. Details of the self-rated VAS scores and
the effect of trial PVG stimulation on each patient are given
in Fig. 1. Interestingly, one of the two patients who opted
not to proceed to full implantation despite a 35% reduction
in self-rated pain scores elected to have the DBS leads
implanted in the scalp to allow placement of the IPG if
she changed her mind later. She returned after 6 months
to have the IPG inserted.
Pain suppression was related to the frequency of stimula-
tion of the PVG. Maximum pain relief was obtained with 5–
35 Hz stimulation while 50 and 100 Hz made the pain
worse. However, each patient responded to a specific
narrow range of PVG stimulation frequencies, which though
in the low frequency range (,50 Hz) in all cases, was not
identical. Thus three patients had pain suppression at 25 Hz;
one patient each responded best to stimulation at 10 and
35 Hz, respectively, while another had maximum pain relief
with both 5 and 25 Hz PVG stimulation. There was a range
(few seconds to 12 h) in the time from beginning of PVG
stimulation to onset of pain relief. Thus, while three patients
reported decreased pain immediately following stimulation
during surgery, two others experienced pain relief few hours
after starting PVG stimulation. One other patient had appre-
ciable relief only after overnight continuous PVG stimula-
tion. However, during the sessions of trial stimulation, pain
relief was almost immediately felt after commencing stimu-
lation with the frequencies that were finally found to be
most effective.
3.2. Field potential recordings (Figs. 3–5)
We recorded bipolar FPs from the sensory thalamus
during PVG stimulation and from the PVG during VPL
stimulation. The PVG FPs did not correspond to the state
of VPL stimulation and also did not change with the concur-
rent pain scores. In two of the patients who responded to
Fig. 2. This figure illustrates the degree of reduction in pain scores during periventricular gray (PVG) stimulation. The dark bars represent the reduction during
the trial period while the light bars show the situation at the time of last follow-up. The number over each of the light bars is the length of follow-up in months.
101
VPL stimulation we tried recording the VPL FPs after stop-
ping stimulation; interestingly, we did not find the kind of
stable flattening of the slow waves as seen with PVG stimu-
lation. There were irregular, unsustained low amplitude
discharges over a wide range of frequencies. This was
followed by the return of the slow wave FPs within a few
(1–3) minutes. On the other hand, switching on the PVG
stimulation was followed immediately by change in the
thalamic potentials. However, the FPs did not revert to base-
line immediately on cessation of stimulation, but only after
a lag of 5–15 min depending on the duration of stimulation
(Fig. 8). The FPs consisted of a very low frequency poten-
tial, of 0.2–0.4 Hz, in the sensory thalamus; it’s amplitude
seemed to correlate with the intensity of pain perception. It
was much stronger off stimulation and with higher
frequency stimulation ($50 Hz) when there was no pain
suppression, than while stimulating the PVG at low frequen-
cies (5–35 Hz) with accompanying pain relief (Figs. 6 and
7A, B). This pattern was seen even in the patient who had a
33% reduction in her pain scores during trial stimulation,
although she chose, at the time, not to proceed with implan-
tation of the IPG. In the only patient who did not respond to
the trial stimulation of the PVG, there was no flattening in
the slow wave thalamic FPs across different frequencies of
PVG stimulation.
4. Discussion
We have found novel slow frequency FPs in the sensory
thalamus of eight consecutive patients suffering from
intractable neuropathic pain of central origin. This includes
the two patients who had unsatisfactory relief of pain
following trial PVG stimulation. The fact that these FPs
were seen in pain syndromes of different etiologies, namely
post-stroke pain, Chiari malformation, multiple sclerosis
and trigeminal neuralgia (this patient had onset of burning
dysesthetic pain only after undergoing pontine tractotomy
following a failed microvascular decompression for idio-
pathic trigeminal neuralgia), suggests that it is related
 102
D. Nandi et al. / Pain 101 (2003) 97–107
Figs. 3–5. These figures plot the thalamic field potentials (FPs) recorded in three different patients during trial stimulation of the periventricular gray (PVG) at varying frequencies. All the patients whose plots are
shown here responded favorably to low frequency (5–35 Hz) stimulation. It is clear from the traces that there is a decrease in the amplitude of the thalamic FPs at specific frequencies of PVG stimulation. The
corresponding VAS pain scores are given above each raw FP trace (top left). This decrease corresponded closely with the reduction in the pain scores recorded during stimulation.
 D. Nandi et al. / Pain 101 (2003) 97–107
Fig. 6. This figure plots the power spectrum of the FPs, the raw traces of which are shown in Fig. 4, in the frequency domain. There is clear reduction in power
in the 0.2–0.4 Hz range with 5 and 25 Hz stimulation of the PVG, compared with that obtained from traces off stimulation and with 50 and 100 Hz stimulation.
closely to the sensation of pain rather than to the mechan-
isms of origin of pain. This is further supported by the
correlation between pain suppression and the amplitude of
the FPs (Fig. 7A, B). On the other hand, it is generally
agreed that central pain, due to lesions at whatever level
of the neuraxis, is sustained by a common generator.
However, these two observations need not be contradictory.
It may well be that while a common mechanism supports the
origin of central pain, the thalamic FPs we have described
are actually independent of this mechanism and related
more to the processing of the sensation at the thalamic
level. Further exploration of different types of painful
syndrome, especially electrophysiological studies in cases
of peripheral neuropathic pain, is required to further clarify
this issue.
Though the effect of PVG stimulation on the thalamic FPs
was immediate at onset of stimulation, there was a lag
period in the decay of this effect after the cessation of stimu-
lation (Fig. 8). This was also found by Rinaldi from micro-
electrode recordings of VPL inhibition by PVG stimulation
(Rinaldi et al., 1991). The length of the recovery period
corresponded to the duration of stimulation. This delay
suggests that there is a combination of axonal and chemical,
e.g. opioid pathways at work; the former causes the immedi-
ate effect while the latter leads to a build up of opioids that
decay over time. Another, perhaps simpler, explanation for
this delay seen in the reappearance of the slow potentials
after stopping stimulation may be the effect of a GABA
propagating wave of inhibition. Depolarization activity
after such hyperpolarizing influence will take longer than
the normal baseline. This persistence of pain relieving effect
beyond the cessation of stimulation of the central gray
matter in central pain has also been commented upon by
Mundinger and Salomao (Mundinger and Salomao, 1980).
This is also consistent with the greater delay seen with
longer duration of continuous stimulation, as recruiting
103
sufficient number of neurones to elicit the FPs will depend
on the area of hyperpolarization.
This study brings into focus the importance of FPs in the
realm of functional clinical neuroscience. The superior
correlation of FPs to neuronal function (as derived from
interpretation of BOLD fMRI), compared to MUA and
SUA signals, has already been established in a recent semi-
nal study (Logothetis et al., 2001). It has also been recently
reported that it is possible that neuronal synchrony (and
hence FPs) could increase without a concomitant increase
in mean firing rate (Fries et al., 2001). This could explain the
inability of MUA or SUA to detect functionally significant
neuronal activity that can be recorded by changes in FPs.
The method of recording FPs is crucial – see review (Heeger
and Ress, 2002); our system that relies on two adjacent
intra-cerebral leads separated by 2 mm closely mimics the
cortical equivalent of ‘transcortical field potential’ that has
been shown to provide the best localization available with
FPs (Bressler et al., 1993; Roelfsema et al., 1997). We have
found that stimulation of the PVG induces changes in the
electrical activity recorded from the sensory thalamus. This
supports the work by other groups exploring ascending
modulation of somatosensory activity elicited by PVG
stimulation (Rinaldi et al., 1991). The fact that this change
is almost instantaneous with the onset of stimulation
suggests it is likely to be mediated through a fairly direct
neuronal circuit rather than as a consequence of descending
modification of the endogenous opioid pathway. There was
a strong correlation between the alleviation of pain sensa-
tion and the amplitude of the thalamic slow frequency FPs
(Fig. 7A, B). The PVG projects to the intralaminar nuclei.
Hence it may be speculated that its direct effects on the
thalamus have to be added to any effects on the opioid
projections to the raphe. It is known that both PVG/PAG
and ventrobasal thalamic stimulation activates the raphesp-
inal and the reticulospinal neurons which in turn influence
104 D. Nandi et al. / Pain 101 (2003) 97–107

Fig. 7. (A and B) These figures average the power spectrum derived from the VPL FPs recorded during different frequencies of PVG stimulation across all eight
patients. (A) Averages the power traces off stimulation and during stimulation that does not result in pain relief (mainly high frequency DBS – 50–100 Hz). (B)
Averages the power traces during stimulation that results in reduced pain scores (low frequency DBS – 5–35 Hz). The corresponding mean (and SD) of the
VAS pain scores of all the recording sessions in each category are also given. The averaged power traces are plotted with their respective 95% confidence
limits.

the activity of the dorsal horn cells via the dorsal funiculus
(Vilela Filho and Tasker, 1994). Perhaps the neural
substrate for the ascending effects we have seen lies in the
communication with the raphespinal and reticulospinal
neurons, which is shared by the PVG/PAG and the ventro-
basal thalamus. Ascending efferent projections from the
PVG/PAG to the midline and intralaminar thalamic nuclei,
the nucleus reticularis thalami and the nucleus medialis
dorsalis have been established (Mantyh, 1983; Meller and
Dennis, 1991). There is also some evidence of communica-
tion between the PVG/PAG and the nociceptive ventrobasal
thalamic neurons in a study conducted in lightly anaesthe-
tized rats (Kayser et al., 1983). The authors found a nalox-
one-reversible reduction in the responses of neurons in the
ventrobasal complex to microinjection of morphine in the
PAG. There is additional clinical electrophysiological
evidence of a link between the PVG and the VPL/VPM
(Rinaldi et al., 1991). These authors observed that electrical
stimulation of the PVG had a profound inhibitory effect on
spontaneous activity of both nociceptive and non-nocicep-
tive neurons in the VPL/VPM.
Six of the eight patients studied experienced relief from
chronic pain when the PVG was stimulated within a speci-
fic narrow frequency band. The exact range of frequency of
 D. Nandi et al. / Pain 101 (2003) 97–107 105

Fig. 8. This figure plots the real-time FPs recorded from the VPL (of patient number 7, raw traces in Fig. 4) during PVG stimulation at 25 Hz and its course after
stopping stimulation. There is a break in the x-axis (showing time) to accommodate the long delay in the reappearance of the slow waves. The VAS pain scores
at the beginning and end of the plot are given in the left and right top corners, respectively.

effective stimulation was not identical across cases.
However, in all patients, only low frequencies (,50 Hz)
were effective in providing pain relief. In fact, higher
frequency ($50 Hz) stimulation worsened the pain. This
is at variance with other reports of DBS in chronic central
pain (Young and Rinaldi, 1997). A viable and consistent
explanation of this apparent variation in the response to
PVG DBS in patients with central pain (Hosobuchi,
1986; Levy et al., 1987; Mundinger and Salomao, 1980;
Schvarcz, 1980; Tasker and Vilela Filho, 1995; Young,
1990) can only be arrived at by collecting far more elec-
trophysiological data from the many different neuropathic
pain syndromes.
It is interesting that while the analgesic effect of PVG
stimulation seemed to be linked to the modulation of the
FP activity (a combination of the synaptic, membrane and
action potential activity) in the region of the VPL, stimula-
tion of the latter did not achieve similar degree of pain relief.
One possible explanation that may be offered with the
evidence available, and this is speculative, is that PVG
stimulation does not result in pain relief by influencing the
sensory thalamus alone, if at all. As mentioned earlier, the
thalamic FPs we have described are perhaps independent of
the mechanism of pain relief and related more to the proces-
sing of the sensation at the thalamic level. Furthermore,
there is evidence suggesting that the mechanisms involved
in analgesia produced by central gray stimulation may be a
combination of opioid (Akil et al., 1978; Hosobuchi et al.,
1977; Hosobuchi et al., 1979) and non-opioid (Duncan et al.,
1991; Young, 1990) pathways. Even less is known about the
mechanisms of action of VPL/VPM stimulation (Benabid et
al., 1983; Gerhart et al., 1981; Tsubokawa et al., 1984).
Further neuroanatomical, neurochemical and electrophysio-
logical studies will be required to render clarity and also to
permit more accurate selection of targets for intervention in
specific pain syndromes.
Six of the eight patients with medically intractable
chronic central pain recruited consecutively in this series
had satisfactory pain suppression with PVG DBS. Of the
two patients who did not respond well enough to the trial
stimulation to choose to continue with full implantation, one
has since returned after 6 months and has had an IPG placed.
The other patient, the only one in this series to have shown
almost no pain suppression with PVG DBS, had borderline
scores in his neuropsychological evaluation and perhaps
represents poor patient selection. The results in this series
compare favorably with results reported with MCS (Cana-
vero and Bonicalzi, 2002; Carroll et al., 2000; Katayama et
al., 1994; Nandi et al., 2002d; Saitoh et al., 2000; Smith et
al., 2001; Tsubokawa et al., 1991). Other reports on the use
of DBS for the treatment of chronic central pain vary
considerably (from close to 0 to close to 100%) in the effi-
cacy of the technique both in the acute phase and after long
follow-up (Hosobuchi, 1986; Levy et al., 1987; Mundinger
and Salomao, 1980; Schvarcz, 1980; Tasker and Vilela
Filho, 1995; Young, 1990). Thus while Mundinger and
Salomao reported a reduction in pain of over 50% in half
the patients in a series of 32 with a follow-up of nearly 4
years (Mundinger and Salomao, 1980), Levy et al. reported
less effective pain relief lasting for a shorter duration (Levy
et al., 1987). As seen in Fig. 2, the pain suppression obtained
during trial stimulation is fairly robust and was maintained
over the average follow-up period of 9 months. In all but one
of the six patients with full implantation the degree of pain
suppression was greater at last follow-up than during initial
trials. The level of pain relief remained satisfactory in this
patient and DBS was continued. The use of a period of trial
stimulation with externalized leads helped in avoiding full
106 D. Nandi et al. / Pain 101 (2003) 97–107
implantation of a subcutaneous pulse generator in the two
cases where satisfactory pain relief was not achieved during
the trial. This provides an interim step during the procedure,
which has implications in improving economic cost–benefit
and complication rates.
There is clearly a need for better methods of patient selec-
tion to choose the appropriate modality of treatment in diffi-
cult refractory cases of central pain. Many groups have used
several pharmacological and electrophysiological tests to be
able to predict response to treatment more accurately (Cana-
vero and Bonicalzi, 1998; Katayama et al., 1998; Nguyen et
al., 1999; Yamamoto et al., 1997). Further study needs to be
conducted to try and establish the links between the neuro-
chemistry of central pain and the electrophysiological
observations obtained from sub-cortical electrodes in these
patients. This will lead to better understanding of the patho-
physiological mechanisms involved. Our study makes a
contribution to this effect.
5. Conclusions
Our findings suggest there might exist a frequency regu-
lated neural pathway for chronic central pain specific to the
origin and nature of the pain, which can be influenced by
PVG DBS to deliver satisfactory pain suppression. This
study also suggests a functional frequency-coded commu-
nication between the PVG and the ventrobasal thalamus in
central pain.
We have found an interesting and consistent correlation
between thalamic electrical activity and chronic central
pain. This curious low frequency potential may provide an
objective index for quantifying chronic pain, and may hold
further clues to the mechanism of action of PVG stimula-
tion. It may be possible to use the presence of these slow FPs
and the effect of trial PVG DBS on both the clinical status
and the FPs to predict the probable success of future pain
control in individual patients.
Acknowledgements
This work was supported by grants from the Norman
Collisson Foundation and Medical Research Council, UK.
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