Roland Peyron

Electrical stimulation of motor cortex for pain control: a combined PET-scan and electrophysiological study☆

Although electrical stimulation of the precentral gyrus (MCS) is emerging as a promising technique for pain control, its mechanisms of action remain obscure, and its application largely empirical. Using positron emission tomography (PET) we studied regional changes in cerebral flood flow (rCBF) in 10 patients undergoing motor cortex stimulation for pain control, seven of whom also underwent somatosensory evoked potentials and nociceptive spinal reflex recordings. The most significant MCS-related increase in rCBF concerned the ventral-lateral thalamus, probably reflecting cortico-thalamic connections from motor areas. CBF increases were also observed in medial thalamus, anterior cingulate/orbitofrontal cortex, anterior insula and upper brainstem; conversely, no significant CBF changes appeared in motor areas beneath the stimulating electrode. Somatosensory evoked potentials from SI remained stable during MCS, and no rCBF changes were observed in somatosensory cortex during the procedure. Our results suggest that descending axons, rather than apical dendrites, are primarily activated by MCS, and highlight the thalamus as the key structure mediating functional MCS effects. A model of MCS action is proposed, whereby activation of thalamic nuclei directly connected with motor and premotor cortices would entail a cascade of synaptic events in pain-related structures receiving afferents from these nuclei, including the medial thalamus, anterior cingulate and upper brainstem. MCS could influence the affective-emotional component of chronic pain by way of cingulate/orbitofrontal activation, and lead to descending inhibition of pain impulses by activation of the brainstem, also suggested by attenuation of spinal flexion reflexes. In contrast, the hypothesis of somatosensory cortex activation by MCS could not be confirmed by our results.

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

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.

Motor cortex stimulation for refractory neuropathic pain: four year outcome and predictors of efficacy.

&NA; Thirty‐one patients with medically refractory neuropathic pain were included in a prospective evaluation of motor cortex stimulation. The long‐term outcome was evaluated using five variables: (a) rate (percentage) of pain relief, (b) pain scores as assessed on VAS, (c) postoperative decrease in VAS scores, (d) reduction in analgesic drug intake, (e) a dichotomic (yes/no) response to the question whether the patient would accept, under similar circumstances, to be operated on again. Pain relief was rated as excellent (>70 % pain relief) in 10 % of cases, good (40‐69 %) in 42 %, poor (10‐39 %) in 35 % and negligible (0‐9 %) in 13 %. Intake of analgesic drugs was decreased in 52 % of patients and unchanged in 45 % (unavailable data in 3 %), with complete withdrawal of analgesic drugs in 36 % of patients. Twenty‐one patients (70 %) declared themselves favourable to re‐intervention if the same beneficial outcome could be guaranteed. Neither preoperative motor status, pain characteristics, type or localisation of lesions, quantitative sensory testing, Somatosensory Evoked Potentials, nor the interval between pain and surgery were found to predict the efficacy of MCS. The level of pain relief, as evaluated in the first month following implantation was a strong predictor of long‐term relief (regression analysis, R=0.744; p<0.0001). These results confirm that MCS can be a satisfactory and durable alternative to medical treatments in patients with refractory pain, and suggest that the efficacy of MCS may be predicted in the first month of therapy.

Precentral Cortex Stimulation for the Treatment of Central Neuropathic Pain

The authors report a series of 23 patients with central neuropathic pain who were treated with the recently developed technique of precentral cortex stimulation (PCS). Of the 20 patients with a follow-up of more than 1 year (mean of 23 months) 25% had an excellent, 35% a good and 15% a fair relief of pain. In 25% the method failed. On the basis of these findings and the literature data (127 reported cases), the authors advocate PCS in patients with severe and medically refractory poststroke pain.

Functional imaging and neurophysiological assessment of spinal and brain therapeutic modulation in humans.

We summarize here our experience in the neurophysiological and neuroimaging assessment of spinal and brain neuromodulation for pain relief. Techniques reviewed include somatosensory evoked potentials (SEPs), nociceptive spinal (RIII) reflexes, and positron emission tomography (PET), which have been applied both to investigate the mechanisms and to optimize the application of neurostimulation procedures. SEPs are especially useful in the preoperative assessment of patients with neuropathic pain, as they allow the establishment of the functional state of the dorsal column system. Patients with strongly abnormal SEPs due to ganglionic or preganglionic pathology are not likely to benefit from spinal (SCS) or peripheral (TENS) neurostimulation, because ascending fibers disconnected from their soma will undergo rapid degeneration and not be excitable. In the postoperative period, nociceptive spinal reflexes yield objective data concerning the effects of neurostimulation on spinal circuitry. In our experience, the best clinical results are achieved in patients with preserved preoperative SEPs, in whom neurostimulation entails profound attenuation of nociceptive reflexes.PET-scan imaging techniques have recently been used to demonstrate changes in cerebral blood flow during new neuromodulation schemes such as motor cortex stimulation for pain control (MCS). PET studies highlight the thalamus as the key structure mediating functional MCS effects. Thalamic activation would trigger a cascade of synaptic events influencing activity in other pain-related structures including the anterior cingulate gyrus, insula, and upper brainstem. The combination of clinical electrophysiology and functional neuroimaging provides insight into the mechanisms of action of neuromodulation procedures, guides clinical decision, and contributes to optimize patient selection.

Organic Background of Restrictive-Type Anorexia Nervosa Suggested by Increased Serotonin1A Receptor Binding in Right Frontotemporal Cortex of Both Lean and Recovered Patients: [18F]MPPF PET Scan Study

BACKGROUND Serotonin (5-HT) pathway abnormalities were demonstrated in anorexia nervosa (AN). Brain imaging studies on 5-HT receptors support this evidence. 4-(2-methoxyphenyl)-1-[2-(N-2-pyridinyl)-p-fluorobenzamido]-ethylpiperazine ([(18)F]MPPF) is a selective 5-HT(1A) receptor antagonist with an affinity close to that of endogenous 5-HT. METHODS In 24 subjects including 8 lean restrictive-type AN patients, 9 recovered from restrictive-type AN subjects and 7 age-matched control subjects, we assessed in vivo brain [(18)F]MPPF binding by positron emission tomography and eating-related psychopathological traits. Inter-groups differences in [(18)F]MPPF binding were evaluated by voxel-based analyses. RESULTS Restrictive AN patients presented increased [(18)F]MPPF binding in a selective area of the right cortex including part of the superior temporal gyrus, inferior frontal gyrus, parietal operculum, and temporoparietal junction. Striking regional similarities of increased [(18)F]MPPF binding were found in recovered from AN subjects. Most of the psychiatric scores were increased in restrictive AN patients, and elevated perfectionism and interpersonal distrust scores were noticed in subjects recovered from AN. CONCLUSIONS The persistent increased 5-HT(1A) receptor binding in frontotemporal region of recovered AN concomitantly with specific psychopathological traits support the hypothesis of an organic dysfunction of this area and corroborates with previous literature reports of AN cases induced by temporal lesions.

Brain opioid receptor density predicts motor cortex stimulation efficacy for chronic pain.

Summary Brain 11C‐diprenorphine positron emission tomography scans help clinicians to select the best candidates for motor cortex stimulation among patients with severe refractory neuropathic pain. Abstract The clinical effects of motor cortex stimulation (MCS) for neuropathic pain (NP) is thought to be mediated primarily by the secretion of endogenous opioids in humans and in animal models. Because opioid receptor density is itself decreased in patients with NP, we investigated whether the magnitude and distribution of the remaining opioid receptors in patients with NP could be biological predictors of the pain‐relieving effects of MCS. Using 11C‐diprenorphine positron emission tomography scans, opioid receptor availability was assessed in 15 patients suffering refractory NP, who subsequently received chronically implanted MCS. All patients underwent 2 preoperative baseline scans at 2‐wk intervals and were clinically assessed after 7 mo of chronic MCS. The levels of preoperative opioid‐binding in the insula, thalamus, periaqueductal gray, anterior cingulate, and orbitofrontal cortex were significantly and positively correlated with postoperative pain relief at 7 mo. Patients with receptor density values below the lower limits in age‐matched controls in the thalamus, periaqueductal gray and contralateral insula were the least likely to benefit from MCS. Opioid‐receptor availability as shown in preoperative positron emission tomography scans appears to be related to the efficacy of MCS in NP and may help clinicians to select the candidates most likely to benefit from this procedure.

Effects of GABAA receptors activation on brain glucose metabolism in normal subjects and temporal lobe epilepsy (TLE) patients. A positron emission tomography (PET) study Part I: Brain glucose metabolism is increased after GABAA receptors activation

Though gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the human central nervous system, the metabolic response to GABA system activation remains imperfectly known. We studied in vivo with positron emission tomography (PET) the variations of glucose metabolism in the human brain after stimulation of the GABAA receptors by systemic administration of the specific GABAA agonist, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). These investigations were performed in three normal volunteers and as part of presurgical evaluation for temporal lobe epilepsy in six patients. While clinical and electroencephalographic (EEG) monitoring showed a sedative effect and sleepiness after THIP administration, glucose metabolism was paradoxically increased in grey matter structures, which are known to have a high density of GABAA receptors. These findings suggest that the pharmacological activation of GABA pathways, although inhibitory and producing a decrease of vigilance, increases the energetic demand at least during a phase of GABA agonist action, probably at the synaptic or at the glial cell level.

In-patient versus out-patient withdrawal programmes for medication overuse headache: A 2-year randomized trial

Background: Medication-overuse headache (MOH) management usually includes a medication withdrawal. The choice of withdrawal modalities remains a matter of debate. Methods: We compared the efficacy of in-patient versus out-patient withdrawal programmes in 82 consecutive patients with MOH in an open-label prospective randomized trial. The main outcome measure was the reduction in number of headache days after 2 months and after 2 years. The responders were defined as patients who had reverted to episodic headaches and to an intake of acute treatments for headache less than 10 days per month. Results: Seventy-one patients had a complete drug withdrawal (n = 36 in the out-patient group; n = 35 in the in-patient group). The reduction of headache frequency and subjective improvement did not differ between groups. The long-term responder rate was similar in the out- and in- patient groups (44% and 44%; p = 0.810). The only predictive factor of a bad outcome 2 years after withdrawal was an initial consumption of more than 150 units of acute treatments for headache per month (OR = 3.1; 95% confidence interval 1.1–9.3; p = 0.044). Conclusion: Given that we did not observe any difference in efficacy between the in- and out-patient withdrawals, we would recommend out-patient withdrawal in the first instance for patients with uncomplicated MOH.

De novo artistic activity following insular–SII ischemia

&NA; We report here the case of a female patient who developed the following behavioural changes after a brain lesion involving the left posterior insula and SII cortices. She discovered de novo artistic capabilities for painting, with an episodic and compulsive need to paint (“hyperpainting”), but also exhibited changes in her ability to feel emotions. In addition, she had a typical neuropathic pain syndrome, including provoked pain and spontaneous pain, whose intensity was worsened when she painted with cold colours. This case‐report suggests some kind of synaesthesiae, which has previously been reported for other sensory modalities. These findings suggest that a cross‐talk between emotional, thermosensory, pain, and motivational functions may take place during recovery, at the level of the left insular–SII cortices.