Motor cortex stimulation in neuropathic pain. Correlations between analgesic effect and hemodynamic changes in the brain. A PET study

www.elsevier.com/locate/ynimg NeuroImage 34 (2007) 310 – 321

Motor cortex stimulation in neuropathic pain. Correlations between analgesic effect and hemodynamic changes in the brain. A PET study☆ Roland Peyron, a,b,d,e,⁎ Isabelle Faillenot, b,d Patrick Mertens, c,d Bernard Laurent, a,b,d and Luis Garcia-Larrea d,e a

Department of Neurology, CHU Saint-Etienne, France Department of Pain Center, CHU Saint-Etienne, France c Department of Neurosurgery, CHU Lyon, France d INSERM 342 F-69003 & F42000, UCB Lyon1 & UJM St-Etienne universities, France e CERMEP, Lyon, France b

Received 15 February 2006; revised 13 July 2006; accepted 23 August 2006 Available online 18 October 2006 To investigate brain mechanisms whereby electrical stimulation of the motor cortex (MCS) may induce pain relief in patients with neuropathic pain, cerebral blood flow (CBF) changes were studied using H2O PET in 19 consecutive patients treated with MCS for refractory neuropathic pain. Patients were studied in three conditions, (a) before MCS (Baseline, stimulator stopped 4 weeks before), (b) during a 35-min period of MCS and (c) during a 75-min period after MCS had been discontinued (OFF). Compared to Baseline, turning on the stimulator was associated with CBF increase in the contralateral (anterior) midcingulate cortex (aMCC, BA24 and 32) and in the dorso-lateral prefrontal (BA10) cortices. The most important changes of CBF were observed in the 75 min after discontinuation of MCS (OFF). This post-stimulation period was associated with CBF increases in a large set of cortical and subcortical regions (from posterior MCC (pMCC) to pregenual (pg) ACC, orbitofrontal cortex, putamen, thalami, posterior cingulate and prefrontal areas) and in the brainstem (mesencephalon/periaqueductal grey (PAG) and pons). CBF changes in the post-stimulation period correlated with pain relief. Functional connectivity analysis showed significant correlation between pgACC and PAG, basal ganglia, and lower pons activities, supporting the activation of descending ACC-to-PAG connections. MCS may act in part through descending (top-down) inhibitory controls that involve prefrontal, orbitofrontal and ACC as well as basal ganglia, thalamus and brainstem. These hemodynamic changes are lengthened and might therefore underlie the long-lasting clinical effects that largely outlast the actual stimulation periods. © 2006 Elsevier Inc. All rights reserved. Keywords: Neuropathic pain; Motor cortex stimulation; PET; ACC; PAG

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PET study of motor cortex stimulation. ⁎ Corresponding author. Departement de Neurologie, Hôpital de Bellevue, Bd Pasteur, 42055 Saint-Etienne, France. Fax: +33 477 120 543. E-mail address: [email protected] (R. Peyron). Available online on ScienceDirect (www.sciencedirect.com). 1053-8119/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2006.08.037

Introduction Motor cortex stimulation (MCS) is generally proposed as a “last chance therapy” for patients with chronic and medically refractory neuropathic pain. Since the first clinical reports (Tsubokawa et al., 1991, 1993), different groups have reported 50–75% success rates, thus making of this surgical procedure a promising therapy for patients with severe refractory pain (Meyerson et al., 1993; Carroll et al., 2000; Nguyen et al., 2000; Nuti et al., 2005). However, even in the best case series, MCS failed to improve chronic pain in up to one third of the patients (Tsubokawa et al., 1993; Nguyen et al., 2000; Nuti et al., 2005) and the rate of success of this technique has not significantly improved over the years. The absence of precise knowledge on how MCS may induce pain relief probably contributes to the absence of improvements in both technical upgrades and rates of success. Over the last decade, this has been clearly the main limitation to the development of this therapy, the real benefit of which is still a matter of debate in the absence of double-blind evaluations (Wallace et al., 2004). Several independent groups have investigated how MCS may help to control neuropathic pain. Direct evidence that MCS may act on thalamic pain processing was first obtained in a cat model of spinothalamic tractotomy where abnormal thalamic bursting was inhibited by motor cortex stimulation (Tsubokawa et al., 1991). A second series of findings was derived from human studies using positron emission tomography (PET) and showed that MCS was associated with increased blood flow in orbitofrontal, subgenual (sg)ACC, MCC and insular cortices, thalamus, and brainstem (Peyron et al., 1995; Garcia-Larrea et al., 1999). In these studies, it was also shown that most of the regions hemodynamically activated during MCS still remained so 30 min after the stimulator was turned off. These observations were reminiscent of clinical findings showing that the analgesic effect of MCS, if present, often extend over several hours, and even

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days or weeks (Tsubokawa et al., 1993; Nuti et al., 2005). It can be concluded that the neural mechanisms set up by MCS and responsible for long-term analgesia most probably occur (and are most readily observable) during the periods that follow actual MCS, rather than during neurostimulation itself. The present PET study was therefore designed to put special emphasis on processes occurring after MCS is discontinued. To this aim, we explored the post-stimulation period using an enlarged temporal window – as long as PET studies can allow – to identify brain regions possibly responsible for the MCS lengthened effects. Since the sample of patients was relatively large and included various levels of pain relief, it was also possible to investigate the relationships between regional cerebral blood flow (rCBF) changes induced by motor cortex stimulation and clinical pain relief. Finally, by applying functional correlation methods to the set of activated regions, it was possible to identify a brain network likely involved in the mechanisms of long-term analgesia set up by MCS. Material and methods Patients Nineteen consecutive patients undergoing MCS between September 1999 and June 2000 were elected for the study. All had chronic, medically refractory neuropathic pain, for the treatment of which they were proposed to enter a programme of MCS, together with extensive pre- and post-operative investigations including PET scan. After being informed of the procedure for neurosurgery, patients who provided written consent were operated upon and underwent the present PET study, the whole procedure of which was conducted in conformity with the Helsinki declaration and was approved by the local ethics committee (StEtienne University Hospital, France). All the patients presented here have details of their clinical status and neurosurgical procedure, including MCS parameters reported separately in a clinical follow-up study (see Tables 1 and 2, Nuti et al., 2005). Clinical characteristics of patients are summarized on Table 1. Briefly, they all suffered chronic neuropathic pain lasting for more than 1 year, with a proven and at least 2-year-old lesion, the latter criterion being introduced to exclude patients who might have spontaneous recovery. Localization of brain lesions was performed with 3D anatomical T1 MRI (SIEMENS® MPRage, voxel size 2 × 2 × 2 mm3) in each patient. Lesion susceptible to induce neuropathic pain was unique and had a small size. They were either frankly standardized (Wallenberg's syndrome, VPL ischemia), or relatively standardized (lenticular hematoma, spinal cord lesion) or not standardized for the cortical/subcortical localizations. Patients with psychiatric disorders were excluded from the study. To exclude any subjects in search of financial compensation and to uncover any psychiatric comorbidity, a psychiatric interview was systematically performed before implantation. Patients taking chronic classical or extended-release morphine or opioid therapies were also excluded from the study to avoid the possibility of confounding effects in the course of the study, consecutively to opioid doses adjustments and/or to opioid habituation. This option was also decided to exclude the possibility of CBF changes that could not be interpreted because of their localization in brain region with a high density of opioid receptors and the simultaneous consumption of exogenous opioid treatments. This position was supported also by previous findings showing that the main CBF

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changes induced by MCS were located in anterior cingulate cortex, thalamus and brainstem (Peyron et al., 1995; Garcia-Larrea et al., 1999), three brain structures precisely with maximal density of opioid receptors. Those under co-analgesic treatments (antiepileptics and/or anti-depressants) had their medications kept constant in the months between neurosurgery and the PET experiment. Other agents with rapid absorption and elimination (paracetamol, codein, dextropropoxyphen, NSAIDs, tramadol) were allowed as “emergency drugs” to treat pain crises. However, patients were instructed to refrain from tablet intake for the 12 h preceding the PET study. This goal was achieved for all the patients reported here. One (or two) 4-contact electrodes (Resume Medtronic®) were implanted over the primary motor cortex according to whether the pain affected one or two limbs. The central sulcus was localized both functionally and anatomically using somatosensory-evoked potentials (N20 phase-reversal), direct electrical stimulation of the motor cortex, and MRI-guided 3D neuronavigation. Then, the MCS electrodes were fixed immediately anterior to the central sulcus, over the precentral gyrus (primary motor cortex). After surgery, MCS parameters were set to a frequency of 35 Hz, 180-μs pulse width, 2.5 V peak amplitude, and cyclic operating mode (30 min ON and 2 h OFF). Pain assessment Short-term pain assessment After each 90-s PET acquisition, patients were asked to score their mean pain intensity using a verbal pain score. A score of 0/10 indicated no pain while a 10/10 score was defined as intolerable pain. Patients were also systematically questioned on the occurrence of spontaneous paroxysmal pain attacks, which, if present during the scan period, led to the exclusion of data from the analysis. Long-term pain assessment The overall benefit of MCS on the patients' pain was appreciated through a subjective score indicating the average pain relief (%PR) in the period of time between surgery and the PET experiment. This scale ranged from 0% (no improvement) to 100% (complete pain relief). It was deliberately an averaged score over several weeks to take into account the long time course of MCS effects (Nuti et al., 2005). PET data acquisition To ensure that pain was in a steady state, the PET study was performed after at least 3 months of chronic stimulation (4.2 ± 1.3 months on average, range: 3–7) without changing parameters, so as to maximize stability of pain relief (Nuti et al., 2005). In three of the 19 patients PET was delayed (7, 9 and 19 months) because of intercurrent diseases or therapies that made the recording of PET at the predicted period impossible. PET scan was performed with a HR+ (SIEMENS®) PET scanner generating 63 slices (2.4 mm thick) after injection of 9 mCi of 15O-labeled water in the antecubital vein on the nonpainful side. Spatial resolution was 7 mm. Thirteen PET scans were recorded for each patient. All scans were recorded with patients at rest, with eyes closed. External stimulations were minimized and no particular instructions were provided, except that of being calm and keep the eyes closed. Patient movements

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were constrained by fitting the head with a thermoplastic custommolded facial mask. MCS was turned off 4 weeks prior to the PET study, and the first four consecutive scans (Baseline condition) were recorded with the stimulator still inactive, and after verification (with the telemetry) that stimulator was indeed in a Off position for the preceding 4-week period. At any time of the study, patients were not informed of the status (on or off) of their MCS, and thus, in the absence of direct indicator of whether MCS was in an on or in an off position, they were blind of MCS status. Each baseline scan was separated from the previous one by 10-min rest. Then, MCS was turned on and the next 4 scans were acquired at 5, 15, 25 and 35 min after the onset of MCS (On condition). Finally, MCS was turned off again and 5 further scans were recorded at 15, 30, 45, 60

and 75 min after the stimulator had been stopped (Off condition). To keep the patients blind of MCS status, the telemetry was placed over the internal stimulator before each scan, to perform either effective or simulated adjustments of MCS so that all patients ignored whether and when MCS was turned on or turned off. In these occasions, it was checked that MCS was in the correct position (on or off according to the experimental design). Randomization of conditions was not possible because of the time necessary to obtain a clinical analgesic effect and the time needed for the analgesic effect to disappear (Tsubokawa et al., 1993; Peyron et al., 1995; Garcia-Larrea et al., 1997; Nuti et al., 2005). Possible confounding effects of time of acquisition were specifically addressed and excluded from the results by a specific post-processing of the data (see below).

Table 1 Clinical data

Abbreviations: B Pl, brachial plexus; sc, spinal cord; C, cervical; T, thoracic; W, Wallenberg's syndrome; VPL, ventro-postero-lateral nucleus of the thalamus; LT, lateral thalamus; PreF, pre-frontal; L, left; R, right; UL, upper limb; LL, lower limb; Hyp, clinical hypesthesia, A, allodynia; +, present, −, absent; SEPs, somatosensory-evoked potentials, N, normal; Im, impaired; ST, spino-thalamic assessment with QST (Quantitative Sensory Testing) and LEPs (laser evoked potentials), n.a. = non-available; Mot, motor function, N, normal, Im, impaired; Graph indicates the percent of pain relief declared by patients for the months between surgery and the PET study. # Refers to identification number of patient in the parallel clinical study (see Table 1, Nuti et al., 2005). * Refers to the average pain relief indicated in Table 2 (Nuti et al., 2005).

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Table 2 Regression analysis (On and Off covariates tested CBF changes vs. Baseline) BA

On covariate

BA

Ipsilateral

PF Cx OF Cx MCC

pgACC SMA PC Cx Putamen Thalamus Mesencephalon Hypothalamus Pons Cerebellum

Contralateral T

(Corrected p) (cluster)

26, 46, 0

5.11

0.006

Ipsilateral

Coordinates

T

(Corrected p) (cluster)

− 50, 42, 10

4.01

0.054

32 32/9

− 12, 22, 44 − 18, 40, 24

4.59 4.44

0.003 0.057

24 32

− 10, 34, − 2 − 18, 36, 14

3.23 3.86

0.057 0.057

46/10 10

Coordinates

Off covariate

10/46 10 11 32 32/9 32 24 6 31

Contralateral

Coordinates

T

(Corrected p) (cluster)

Coordinates

T

(Corrected p) (cluster)

30, 46, 14 26, 56, − 4

5.84 5.47

∞(0.000) ∞(0.000)

− 50, 42, 14

4.92

∞(0.000)

6.49

∞(0.000)

4 4.27 3.95 3.4

∞(0.000) ∞(0.000) ∞(0.000) ∞(0.000)

− 14, 48, −10

10, 18, 44 10, 40, 24 12, 14, 42 4, 24, 18

− 16, 44, 26

5.65

∞(0.000)

− 4, 36, 4

6.35

∞(0.000)

− 10, 28, 42

4.9

0, −38, 44 22, 2, − 8 12, − 16, 10

∞(0.000)

5.51 6.41 4

0.001 ∞(0.000) ∞(0.000)

5.29 6.41 5.42 5.75 4.24

12, − 44, −18

∞(0.000) ∞(0.000) ∞(0.000) ∞(0.000) ∞(0.000)

4.4

∞(0.000)

− 22, 2, 6 − 14, −28, 10 − 4, − 14, − 14 − 14, −4, − 8 − 8, − 32, − 28

PAG

Abbreviations: BA = Brodmann areas; Cx: cortex, MCC: midcingulate cortex, OF: orbitofrontal, PAG: periaqueductal grey, PC: posterior cingulate, PF: prefrontal, pgACC: pregenual anterior cingulate cortex. Results are shown with corrected probabilities at the cluster level (p ≤ 0.05 threshold). A more permissive (0.057) threshold was also used to sensitize activation detection for the On covariate (italic).

Statistical analysis Preparation of the data Images were first arranged in such a way that MCS referred to the right side of the brain (scans were x-flipped for patients stimulated on the left motor cortex). Then, they were analyzed using the SPM2 software (FIL, London, UK). Patients' movements between scans were corrected by a realignment procedure. Then, images were spatially normalized according to a stereotaxic space to allow inter-individual pooling onto the MNI (Montréal Neurological Institute, Canada) standard brain, and smoothed with a Gaussian filter (full-width half maximum, 12 mm) to account for anatomical–functional variability. The effect of global activity changes was removed by proportional scaling. Since the PET experiment extended over a relatively long time (150 min), a preliminary analysis estimated the possible confounding effect of acquisition time. The four scans in the Baseline condition were considered for this analysis since only time (or a time-dependant variable) could reasonably induce CBF changes in these scans. Time was set as a covariable with 0 value attributed to the first scan and the real time delay to each of the following scans. A statistical map was computed using a permissive threshold of uncorrected p = 0.001, describing the spatial distribution of brain regions whose activity covaried with acquisition time. This map was saved as a binary image to be used as an “exclusive mask” in all the following analyses to remove voxels where activity could have changed as a function of time. Correlation study In a first analysis considering the three conditions of the study, On and Off scans were compared successively to Baseline scans and provided On and Off contrasts maps, respectively. Then, a second (covariate) analysis considered the possible correlations between amplitude of CBF changes and magnitude

of long-term pain relief, as assessed on long-term subjective scores (percentage of pain relief (%PR)). To this aim, two covariates were defined. The first one (On covariate) described CBF correlations between long-term pain relief and amplitude of CBF changes in the On condition (relative to Baseline). The second one (Off covariate) described CBF correlations between long-term pain relief and amplitude of CBF changes in the Off condition (relative to Baseline). The aim of this analysis was therefore to determine the set of regions whose activity was, at the same time, increased relative to baseline, and correlated with long-term pain relief. Functional connectivity analysis The regions detected in the correlation study were then considered for a further specific analysis of functional connectivity. Functional connectivity is defined as the temporal correlation of neurophysiological events between distributed brain areas, and is meant to describe the direct or indirect influence of different brain regions on each other (Friston et al., 1996; Friston et al., 1997). The basis of the analysis is that brain regions with similar covarying rCBF patterns during a specific experimental paradigm are most likely in functional exchange with each other (Friston et al., 1996). To estimate such functional connectivity, the adjusted activity was extracted over all scans of all subjects in the voxels showing the highest Z-value (peaks) in the On and the Off (vs. baseline) contrasts. After mean correction, the values obtained for each voxel in these regions were then used as a userspecified covariate. This analysis was applied to the five key regions showing significant activation in these contrasts, namely ACC, midbrain, basal ganglia, orbitofrontal and prefrontal cortices. Statistical parametric maps were computed with an uncorrected threshold of p = 0.001 at the voxel-level but with a joint corrected probability (p ≤ 0.05) of peak height and clusters size (Poline et al., 1997). For the functional connectivity study, results were displayed

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with a corrected probability of p < 0.05 at the voxel level (statistics on cluster non-available). Localization of activations was performed with a stereotaxic atlas (Talairach and Tournoux, 1988). Cingulate activations were identified with respect to the classification proposed by Vogt (2005). Results Psychophysical data Short-term pain assessment At the beginning of the PET session, but also during the whole PET experiment, patients were not able to discriminate whether or not the MCS was effective. No significant change was observed in the mean pain intensities reported by the patients between Baseline, On and Off (post-stimulation) conditions (one-way ANOVA, p = 0.999). Therefore, the brain activations reported here could not be interpreted as resulting from acute changes in the intensity of neuropathic pain across conditions, but rather, as directly resulting from MCS, which was either turned on or turned off. Long-term pain assessment Scores of long-term pain relief declared by the patients during the PET session are presented on the graph in Table 1. Range of relief scores extended from 0 to 90% (mean 38%). Three patients reported no pain relief at all; analgesia was small or moderate (10–40%) in 8 patients, good (60%) in 6, and excellent (> 80%) in 2. These scores, declared early after surgery (here during the PET session) correlated (Pearson correlation 0.72, p = 0.01) with the long-term pain relief that was reported by the same patients in the follow-up study (Nuti et al., 2005) (see also Table 1). PET data On vs. baseline and off vs. Baseline analysis Only a limited activation of the pregenual ACC contralateral to MCS was found in the On vs. Baseline comparison. The large majority of activations were found in the Off vs. Baseline subtraction, in the ipsilateral premotor cortex, the contralateral pregenual ACC and midcingulate (MCC) and supplementary motor area (SMA), pallidum, putamen and periaqueductal grey (PAG, data are available in Supplementary Table 1). Most of these activations were also found to be correlated with the amount of pain relief (see below, the correlation study).

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Correlations between rCBF and pain relief A vast majority of correlations between rCBF changes and pain relief were detected using the Off covariate (see Table 2). This finding indicates that most of the rCBF changes that correlated with long-term pain relief occurred during the 75 min subsequent to MCS discontinuation (after 35 min of effective stimulation). Brain regions where CBF changes correlated positively with pain relief in the On (during MCS) and Off conditions (after MCS discontinuation) are shown in Table 2 and Figs. 1A–B. The On covariate showed a correlation between longterm pain relief and increased CBF in contralateral MCC (equivalence BA32/24) and in both prefrontal cortices (ipsilateral and contralateral BA s10). The Off covariate correlated with increased CBF in a larger set of areas including anterior (a) and posterior (p) MCC, and pgACC, bilaterally, contralateral orbitofrontal cortex and supplementary motor Area (SMA), ipsilateral cerebellum and posterior cingulate cortex, prefrontal cortices and basal ganglia bilaterally, upper mesencephalon, in a localization consistent with PAG, and lower pons. Conversely, the motor cortex below the electrode was not found to increase CBF or to correlate with pain scores at any time of the analysis, even by using more permissive thresholds. Functional connectivity analysis Responses that correlated with pain relief as MCS was in a On position (see above) were found to correlate also with CBF changes in other subdivisions of lateral prefrontal cortices, in contralateral orbitofrontal cortex, pgACC, anterior insula, putamen and lower pons. Responses that correlated with pain relief as MCS was in a Off position also correlated with CBF changes in a large cortical and subcortical network including basal ganglia, brainstem, posterior cingulate and different subdivisions of ACC including aMCC and pgACC. More precisely, significant covariations were found between pgACC and brainstem, pgACC and basal ganglia, pgACC and posterior cingulate. Basal ganglia covariated together bilaterally but also with posterior cingulate and with insular cortex. In a bottom-up direction, CBF in mesencephalon and lower pons covariated with basal ganglia and with pgACC (Table 3, Fig. 2). Discussion Post-stimulation hemodynamic effects In the present study, regional increases in CBF were predominant, both in terms of activity increase and of number of structures

Fig. 1. (A) Regions where regional CBF increased relative to baseline and correlated positively with long-term pain relief in the ON condition. Group analysis over the 19 patients. Stimulating electrode is placed over the right primary motor cortex. “On” covariate describes the On condition and takes into account the pain relief obtained by each patients over the period between surgery and PET session. CBF is compared to the rest condition (MCS discontinued 4 weeks before the PET session). Increased CBF was found in midcingulate cortex (MCC) and pregenual ACC, contralaterally to stimulation, and in prefrontal cortices, bilaterally. Note the linear correlation between pain relief and CBF increase: each red dot represents individual scans and each dark dot represents averaged scans for each subject. Plots indicate size of effects, comparatively in the On and the Off conditions. Note that the trend for the MCC was to be activated in the ON condition with a persisting activation in the Off condition while the pregenual ACC still showed increased activity in the Off condition. Images are displayed with a corrected p ≤ 0.06 at a cluster level and according to the Neurological convention (left side of the brain on the left side of the image). (B) Regions where regional CBF increased relative to baseline and correlated positively with long-term pain relief in the OFF condition, after discontinuation of MCS. “Off” covariate describes the Off condition compared to the rest condition and takes into account the average pain relief obtained by each patient over the period between surgery and PET session. Note the large ACC activation, extended from the pMCC and aMCC to the pregenual ACC, the extension to orbitofrontal area, to mesencephalon, in a localization consistent with PAG, in basal ganglia, hypothalamus, posterior cingulate and prefrontal cortices. Note that these activations were maximal in the Off condition and that they correlated to the average pain relief (each red dot represents scans and each dark dot represents averaged scans for each subject). See also Table 2. Results are displayed with a p < 0.05 threshold, corrected at the cluster level and according to the neurological convention (left side of the brain on the left side of the image).

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activated, during the period that followed discontinuation of MCS, relative to the period when the stimulator was “On”. This pattern of response reminds clinical findings in patients under motor cortex neurostimulation, in whom pain relief is not obtained immediately after MCS onset, but rather needs some time to appear, and then extends over several hours, and even days (Tsubokawa et al., 1993; Nuti et al., 2005). Our results indeed suggest that most of brain activities triggered by MCS are delayed with respect to the actual period of neurostimulation. They are therefore in line with the slow onset of analgesic MCS effects, and also with the persistence of such effects once the stimulator is stopped (Tsubokawa et al., 1993; Nuti et al., 2005). Although the time scale of the hemodynamic changes was shorter than common clinical delays to obtain pain relief, their relevance to clinical analgesia is supported by the positive correlations observed between a number of rCBF increases and long-term pain relief scores assessed independently before PET scan (see Materials and methods). The fact that the duration of clinical analgesia outlasts the neurostimulation periods is, more or less, a common finding with all stimulation procedures, both at spinal or cortical levels (Tsubokawa et al., 1993; Meyerson, 2003; Nuti et al., 2005). This has prompted many investigators to postulate that local rapid changes in synaptic activity give rise to long-lasting secondary neuro-humoral transmission (Cui et al., 1997). To the best of our knowledge, the present results are the first to provide direct evidence of persistent local hemodynamic changes that (a) develop after the end of actual MCS periods, (b) persist or are enhanced during the 2 h that follow stimulation offset, and (c) are significantly correlated with long-term pain relief. All these observations support the hypothesis of delayed mechanisms of action with long-lasting and tonic activations in definite brain regions. Functional connectivity The assessment of functional connectivity showed that most brain regions whose activity was modified by motor cortex stimulation were also functionally interrelated. An early activation (during MCS) is observed in the aMCC which is known to be anatomically connected to primary motor (MI) cortex (Leichnetz, 1986; Morecraft and Van Hoesen, 1992; Arikuni et al., 1994; Wang et al., 2001). Later on, in the OFF condition, an additional activation is found in the pgACC, a brain area which was previously shown to be activated with medial prefrontal cortices, in several conditions of pain control (see below). Since then, all the brain activations reported here, including thalamus, PAG and brainstem nuclei as well as various prefrontal, insular and parietal regions have known connections with the pgACC and orbitofrontal cortex (Hardy and Leichnetz, 1981; Mantyh, 1982; An et al., 1998). In particular, ACC and orbitofrontal cortices (Hardy and Leichnetz, 1981; Mantyh, 1982; An et al., 1998), as well as insula (Jasmin et al., 2003), are known to be strongly connected, both anatomically and functionally, with PAG and brainstem nuclei. The functional connectivity study confirms that these brain regions are indeed connected together, and achieve a network that may be influenced more or less directly by MCS. Correlation with pain relief Beyond the localization and dynamics of brain structures activated during or after a period of MCS stimulation, questions

remain on the functional significance of activations and the meaning of the functional network reported here. Activations in MCC and pgACC have been repeatedly reported as responses to experimental noxious pain (Peyron et al., 2000; Vogt, 2005). Clearly, the results reported here cannot be attributed to MCSrelated changes in pain intensity during the PET session. The first evidence was that there was not any trend in pain scores modifications during the experiment. The second argument was that other activations that are known to assume the function of encoding pain intensity (such as insular cortices and SII) were unchanged. The finding that cingulate activations in the present study were clearly located anteriorly to most of the activations reported in response to noxious stimuli (Vogt et al., 2003) is a third argument. It may seem paradoxical that a same structure – anterior cingulate cortex – can share both nociceptive and anti-nociceptive (i.e., opposite) functions, unless it is considered that a nociceptive sensation can induce a parallel (anti-nociceptive) defensive reaction. In that case, the more unpleasant the pain, the more efforts would do the system to control the pain. Our results and those of previous literature support such a duality of function since they are clearly supporting a functional distinction between MCC (including its posterior subdivision pMCC) being mainly involved in noxious processing and pgACC (activated in the present study) being mainly involved in pain control mechanisms. There is a series of converging arguments in the recent literature, showing that pharmacological and non-pharmacological procedures used in patients with clinical pain activated ACC regions, in the pregenual subdivision as well as its contiguous medial orbitofrontal area (see Fig. 3). The pattern of post-MCS rCBF changes in the present study was similar to that reported in other procedures aiming at controlling pain including peripheral anesthetic blocks (Hsieh et al., 1995), acupuncture (Wu et al., 2002), opioid analgesia (Firestone et al., 1996; Casey et al., 2000), Gasserian, thalamic and motor cortex stimulations (Peyron et al., 1995; Duncan et al., 1998; Garcia-Larrea et al., 1999; Davis et al., 2000; Kupers et al., 2000; Willoch et al., 2003; Saitoh et al., 2004). Most interestingly, cognitive tasks which lessen pain by manipulating attention and distraction have also shown activity increases with almost identical ACC/orbitofrontal localization (Frankenstein et al., 2001; Valet et al., 2004), as well as placebo manipulation (Petrovic et al., 2002; Wager et al., 2004). The latter studies may bring about the question whether MCS pain-relieving benefit could be mediated through a placebo effect, and this possibility cannot be definitely ruled out in the absence of a double-blind placebo-controlled trial. However, long-term clinical follow-up in large populations of patients has provided arguments against a placebo effect being the main result of MCS (Nguyen et al., 1998; Franzini et al., 2003; Nuti et al., 2005). So did case reports of patients who reported progressive suppression of MCS analgesic effects following technical MCS malfunction they were unaware of (Nguyen et al., 1998; Franzini et al., 2003; Nuti et al., 2005). So did also the present correlation study in which patients were kept ignorant of whether and when MCS was turned on. Thus, rather than considering MCS as a placebo procedure, current evidence points to the notion that both opioid and placebo analgesia (and according to our results also MCS) may share as a final step the activation of a common network of cortical and subcortical structures involved in both pain suppression and reward mechanisms, and which include the rostral and

Table 3 Functional connectivity analysis

R. Peyron et al. / NeuroImage 34 (2007) 310–321 Abbreviations: BA = Brodmann area, p is corrected probability at the voxel level; Cx: cortex; MCC: midcingulate cortex; LN: lenticular nucleus; NA: amygdala; OF: orbitofrontal; PAG: periaqueductal grey; PC: posterior cingulate. PF: prefrontal; pgACC: pregenual anterior cingulate cortex; PP: posterior parietal; M: motor; preM: premotor; SMA: supplementary motor area; T: temporal. PHG: para-hippocampal gyrus; Th: thalamus; MD: medial dorsal; VL: ventral lateral; VPL: ventro-postero-lateral. Left column: to test the functional connectivity, two activations obtained in the On vs. Baseline comparisons were considered (boxes). Middle and right columns: to test the functional connectivity, four activations obtained in the Off vs. Baseline comparison were considered (boxes).

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Fig. 2. Functional connectivity analysis. On the left column of the figure, are shown brain activations that were considered for extraction of adjusted activity over all scans of all subjects in the Off (vs. baseline) contrasts: (A) midcingulate cortex (MCC, BA32); (B) pregenual ACC (BA24); (C) orbitofrontal cortex (BA11); (D) brainstem. After mean correction, the values obtained for each voxel in these regions were then used as a user-specified covariate. The main functional connectivity was found between pregenual ACC and mesencephalon, basal ganglia, right insula, and posterior cingulate. Mesencephalic activities covariated with pregenual ACC, the latter covariating also with thalami and striatum, bilaterally. Results are displayed with a corrected threshold at the voxel level, p < 0.05.

pregenual ACC, the orbitofrontal region, the medial thalamus, the PAG and probably also the ventral striatum. Opioid analgesia has been the most thoroughly studied of these procedures. Functional imaging studies of both healthy controls and patients in pain converge to point out the rostral and pregenual ACC and the PAG as major areas for opioid-mediated pain control in humans (Firestone et al., 1996; Adler et al., 1997; Casey et al., 2000; Petrovic et al., 2002). Consistent with this, patients with chronic refractory neuropathic pain have been recently shown to have a deficit in opioid receptor binding in ACC, thalamus and PAG (Jones et al., 2004; Willoch et al., 2004; Maarrawi et al., 2006). More interestingly, opioid receptor binding is decreased in MCC and PAG after MCS compared to before MCS, in correlation with the amount of pain relief (Maarrawi et al., 2005, personal communication), suggesting that at least one part of the MCSrelated activations may be supported by a release of endogenous opioids. A particular aspect of the present study was that MCC and pgACC activities did not correlated with current pain relief but rather correlated with the amount of pain relief that was obtained after several cycles of MCS. CBF changes in the poststimulation period correlated positively with pain relief after 3 months of MCS, and, for the first time, correlations were attempted with the steady, long-lasting pain relief in these patients (not with punctual estimations during the PET scan session). Results suggested that activity changes in pgACC, aMCC, orbitofrontal and prefrontal cortices, but also striatum,

thalamus and PAG may be involved in mediating long-term relief of neuropathic pain. Although functional imaging does not permit to distinguish between activatory or inhibitory processes, the present study pointed out, without a priori hypothesis, the brain structures that are – or that have been – the target of neurosurgical procedures for pain relief: cingulotomy has been performed with more or less success for alleviating pain (for review, see Boivie, 1994; Nandi et al., 2002). The finding that both activation of a structure, and its destruction, could induce pain relief may seem paradoxical, but this is also observed at the thalamic level, where either destruction (thalamotomy) or electrical stimulation has been proposed. At a lower level, PAG stimulation have also been proposed to control neuropathic pain (review in Brown and Barbaro, 2003). Thus the present connectivity study provided an interesting parallel between CBF changes during MCS and brain targets of neurosurgical procedures, including neurostimulations and lesional models. In a number of functional imaging studies investigating pain controls, the PAG in the upper mesencephalon was also activated, either alone when it was the only region investigated (Tracey et al., 2002) or in conjunction with the pregenual ACC (Valet et al., 2004). Using correlation analyses, these latter authors demonstrated, as we did in the present study, functional interactions between ACC, oribitofrontal and PAG structures, which was specific to the conditions when pain was attenuated, and suggested top-down influences of cingulo-frontal cortex on the PAG and thalamus to gate pain inputs. In our patients, functional connectivity analysis

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Other aspects – consistency with previous reports – effects of the lesions

Fig. 3. Stereotaxic projections of peaks of activation in various conditions resulting in pain relief: -in normal subjects during experimental pain. •. Pl: placebo effect: 1: (Casey et al., 2000); 2: (Wager et al., 2004); 3: (Petrovic et al., 2002); 4: (Bingel et al., 2004). •. O: opioid effect: 1: (Adler et al., 1997); 2: (Firestone et al., 1996); 3: (Petrovic et al., 2002). •. Green letters: physiological modulations of pain: D: distraction: D: (Bantick et al., 2002); Dv: (Valet et al., 2004); C: controllability: (Salomons et al., 2004). –and in patients during clinical pain, including neuropathic pain. •. A: anesthetic blocks: (Hsieh et al., 1995). •. Th: thalamic stimulation for pain relief: (Kupers et al., 2000); Th: (Davis et al., 2000). •. M: motor cortex stimulation for pain relief: 1: (Garcia-Larrea et al., 1997); 2: (Saitoh et al., 2004); 3: present study. •. V: trigeminal stimulation for pain relief: (Willoch et al., 2003).

clearly showed functional interactions among the pregenual ACC, orbitofrontal cortex and PAG (Fig. 2). In particular, the pregenual part of ACC showed activity covariation with structures located below in brainstem, including PAG, which were themselves coactivated together with thalami and striatum. The hypothesis of descending modulatory influences triggered by motor cortex stimulation is also supported by experimental studies in animals. Inhibition of dorsal horn sensory neurons by stimulation of pyramidal axons in rodents was shown as early as 1957 by Lindblom and Ottosson (1957), and has been recently demonstrated after direct motor cortex stimulation mimicking that applied to humans (Senapati et al., 2005a) as well as after anterior cingulate stimulation (Senapati et al., 2005b). Descending pathways have also been identified between Pf nucleus of the thalamus and PAG (Sakata et al., 1988). We have previously shown that the amplitude of nociceptive spinal flexion reflexes can be significantly attenuated by MCS (Peyron et al., 1995; Garcia-Larrea et al., 1999), again supporting the view that MCS triggers non-specific descending controls to brainstem and spinal cord. We hypothesize that these mechanisms may be initiated in pregenual ACC in response to various experimental conditions – including physiology – and therapies. Finally, it has been previously shown that patients with neuropathic pain have decreased CBF in the pgACC during allodynic pain (Peyron et al., 1998) suggesting that MCSinduced activations could take place progressively over weeks in a structure with a possibly impaired function.

The present study confirmed that the electrical epidural stimulation over the motor cortex was not associated to CBF changes (even with more permissive statistical thresholds), neither in the primary motor, nor in the adjacent primary somatosensory cortices. Models of electrical stimulation of the cortex have concluded that axons rather than cell bodies are activated primarily (Nowak and Bullier, 1998a,b; Hanajima et al., 2002), in particular if the cathode is placed over the motor cortex (Manola et al., 2005), as it is the case in our patients. Extrapolation of these findings to human MCS would indeed predict that changes in regional synaptic activity, and thus of rCBF, would not concern the sensorimotor strip itself but rather projection sites of efferent axons, such as the thalamus, ACC and brainstem (Leichnetz, 1986; Arikuni et al., 1994; Wang et al., 2001). Previous studies by our group suggested that the lateral thalamic area would represent an important entry point of MCS distant activation (through corticofugal projections) that would in turn entail increased synaptic activity in ACC, orbitofrontal cortex, insula and brainstem (Peyron et al., 1995; Garcia-Larrea et al., 1999). Even though the present study confirms and extends most of our previous findings, it failed to demonstrate significant thalamic rCBF increase, except in the functional connectivity analysis. Neither technical nor population differences with previous studies seem to be at the origin of this discrepancy, as spatial resolution in this new study was improved (7 mm instead of 12 mm previously) and the proportion of thalamic and juxta-thalamic lesions remained almost identical. The same applies to the clinical response to MCS, the success rate of which was overall the same in previous and present studies. Conversely, the overall design of the present work most probably affected its ability to disclose thalamic activation. By using long “On” and “Off” periods, the present study emphasized activities with long time constant, as in ACC and upper brainstem, to the detriment of activities with rapid onset and offset such as those previously observed in lateral thalamus (see e.g. Fig. 5 in GarciaLarrea et al., 1999). These findings suggest that MCS-related thalamic activation is phasic and short lasting, and may be averaged out when 35 min of electrical stimulation are lumped together and analyzed as a whole. Because of its position as first synaptic relay of corticofugal excitation, thalamic activity may be of importance as a trigger for other cortical and subcortical activations, but was uncorrelated with pain relief (Garcia-Larrea et al., 1999). A last issue is the participation of the lesion in both clinical outcome (pain relief) and in CBF changes. A first argument against this hypothesis is the lack of correlation between lesion localization and pain relief in a larger population of patients than in the present study (Tsubokawa et al., 1993; Nuti et al., 2005). Since our analysis mainly investigated CBF changes that correlated to pain relief, it seems therefore unlikely that brain damage may interfere with PET findings. As a second argument, an interference between lesion and PET findings – that correlated with pain relief – would imply that pain relief is not uniformly distributed in subgroups of patients with different lesions. This is indeed not the case since each subgroup of patient, according to lesion localization, includes very different levels of pain relief, ranging from poor to excellent results (see Table 1). Finally, patients with similar lesions of the nervous system were equally distributed in number in the different subgroups, making unlikely the possibility that one particular lesion on the nervous system interfered with the PET findings.

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In conclusion, although the mechanisms by which MCS may relieve refractory neuropathic pain are far from being elucidated, the present work add two relevant results to our knowledge: first, the activity in a network involving the pregenual ACC and MCC, orbitofrontal cortex, striatum and PAG showed both functional interconnectivity and a positive correlation with pain relief, in accordance with recruitment of descending inhibitory controls. Second, this network became activated only after MCS was discontinued, and remained so for more than 1 h after the end of the stimulation period, providing for the first time a link between lengthened brain activities and late onset clinical benefit from MCS. Besides justifying the choice of stimulation runs shorter that “off” periods, these results may help to disclose other potential sites of neurostimulation by which neuropathic pain could be alleviated. Acknowledgments This work was supported in part by Projet Hospitalier de Recherche Clinique (PHRC, appels d'offre 1996–1999) and Fondation pour le Recherche Médicale (FRM, Appel d'offre 2005). Special thanks to Mr. M. Michel Magnin (INSERM EMI342) for reviewing the manuscript and to M. A. Richard (Equation®) for computer and network assistance.

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