Michel Magnin

Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients.

Microelectrode-guided stereotactic operations performed in 29 parkinsonian patients allowed the recording of 86 cells located in the globus pallidus and 563 in thalamic nuclei. In the globus pallidus, the average firing rate was significantly higher in the internal (91+/-52 Hz) than in the external (60+/-21 Hz) subdivision. This difference was further accentuated when the average firing rate in the external subdivision was compared with that of the internal part of the internal subdivision (114+/-30 Hz). A rhythmic modulation in globus pallidus activities was observed in 19.7% of the cells, and this only during rest tremor episodes. In these cases, modulation frequency of unit activities was not statistically different from the rest tremor frequency (average: 4.6+/-0.5 vs 4. 4+/-0.4 Hz, respectively). In the medial thalamus, four types of unit activities could be defined. A sporadic type was mainly found in the parvocellular division of the mediodorsal nucleus (96.8% of the cells recorded) and in the centre median-parafascicular complex (74.2%). Two other types of activities characterized by random or rhythmic bursts fulfilling the extracellular criteria of low-threshold calcium spike bursts were concentrated in the central lateral nucleus (62.3%) and the paralamellar division of the mediodorsal nucleus (34.1%). These activities could be recorded independently of the presence of a rest tremor. When a tremor episode occurred, the rhythmic low-threshold calcium spike bursts had an interburst frequency similar to rest tremor frequency, although they were not synchronized with it. The fourth type, the so-called tremor locked, was also characterized by rhythmic bursts which, however, did not display low-threshold calcium spike burst properties. These bursts occurred only when a rest tremor was present and was in-phase with the electromyographic bursts. All tremor-locked cells were located in the centre median-parafascicular complex. In the lateral thalamus, cells exhibiting random or rhythmic low-threshold calcium spike bursts were found preponderantly in the ventral anterior nucleus (53.4%) and in the ventral lateral anterior nucleus (52.7%). Tremor-locked units were confined to the ventral division of the ventral lateral posterior nucleus (35.4%). None of the random or rhythmic low-threshold calcium spike bursting units responded to somatosensory stimuli or voluntary movements, either in the medial or in the lateral thalamus. The presence of low-threshold calcium spike bursts at the thalamic level, together with the paucity (8%) of responses to voluntary movements compared to what is found in normal non-human primates, demonstrate a pathological state of inhibition due to the overactivity of the internal subdivision of the globus pallidus units. Activities of the thalamic cells producing low-threshold calcium spike bursts are not synchronized with each other or with the tremor. However, this does not exclude a causal role of these activities in the generation of tremor. Indeed, it has been demonstrated that even random electrical stimulations of the rolandic cortex in parkinsonian patients induce tremor episodes, probably due to the triggering of rhythmic, low-threshold calcium spike-dependent, thalamocortical activities. Similarly, low-threshold calcium spike bursts could be at the origin of rigidity and dystonia through an activation of the supplementary motor area and of akinesia when reaching the pre-supplementary motor area. We conclude that the intrinsic oscillatory properties of individual neurons, combined with the dynamic properties of the thalamocortical circuitry, are responsible for the three cardinal parkinsonian symptoms.

Thalamus and neurogenic pain: physiological, anatomical and clinical data

Microelectrode recordings in the medial thalamus of 45 neurogenic pain patients undergoing medial thalamotomy revealed that most units (316/318) did not respond to somatosensory stimuli, and that half exhibited low-threshold calcium spike bursts. After medial thalamotomy, 67% of the patients reached a 50 to 100% pain relief, without somatosensory deficits. Colocalization of bursting activities and of the most efficient therapeutic lesions in the central lateral nucleus suggests a key role of this structure in neurogenic pain. We propose that neurogenic pain is due to an imbalance between central lateral and ventroposterior nuclei, resulting in an overinhibition of both by the thalamic reticular nucleus.

Differential brain opioid receptor availability in central and peripheral neuropathic pain

Abstract This study used positron emission tomography (PET) and [11C]diprenorphine to compare the in vivo distribution abnormalities of brain opioid receptors (OR) in patients with peripheral (n = 7) and central post‐stroke pain (CPSP, n = 8), matched for intensity and duration. Compared with age‐ and sex‐matched controls, peripheral neuropathic pain (NP) patients showed bilateral and symmetrical OR binding decrease, while in CPSP binding decrease predominated in the hemisphere contralateral to pain. In CPSP patients, interhemispheric comparison demonstrated a significant decrease in opioid binding in posterior midbrain, medial thalamus and the insular, temporal and prefrontal cortices contralateral to the painful side. Peripheral NP patients did not show any lateralised decrease in opioid binding. Direct comparison between the central and peripheral groups confirmed a significant OR decrease in CPSP, contralateral to pain. While bilateral binding decrease in both NP groups may reflect endogenous opioid release secondary to chronic pain, the more important and lateralised decrease specific to CPSP suggests opioid receptor loss or inactivation in receptor‐bearing neurons. Opioid binding decrease was much more extensive than brain anatomical lesions, and was not co‐localised with them; metabolic depression (diaschisis) and/or degeneration of OR neurons‐bearing secondary to central lesions appears therefore as a likely mechanism. Central and peripheral forms of NP may differ in distribution of brain opioid system changes and this in turn might underlie their different sensitivity to opiates.

Parallel Processing of Nociceptive A-δ Inputs in SII and Midcingulate Cortex in Humans

The cingulate cortex (CC) as a part of the “medial” pain subsystem is generally assumed to be involved in the affective and/or cognitive dimensions of pain processing, which are viewed as relatively slow processes compared with the sensory-discriminative pain coding by the lateral second somatosensory area (SII)–insular cortex. The present study aimed at characterizing the location and timing of the CC evoked responses during the 1 s period after a painful laser stimulus, by exploring the whole rostrocaudal extent of this cortical area using intracortical recordings in humans. Only a restricted area in the median CC region responded to painful stimulation, namely the posterior midcingulate cortex (pMCC), the location of which is consistent with the so-called “motor CC” in monkeys. Cingulate pain responses showed two components, of which the earliest peaked at latencies similar to those obtained in SII. These data provide direct evidence that activations underlying the processing of nociceptive information can occur simultaneously in the “medial” and “lateral” subsystems. The existence of short-latency pMCC responses to pain further indicates that the “medial pain system” is not devoted exclusively to the processing of emotional information, but is also involved in fast attentional orienting and motor withdrawal responses to pain inputs. These functions are, not surprisingly, conducted in parallel with pain intensity coding and stimulus localization specifically subserved by the sensory-discriminative “lateral” pain system.

Thalamic deactivation at sleep onset precedes that of the cerebral cortex in humans

Thalamic and cortical activities are assumed to be time-locked throughout all vigilance states. Using simultaneous intracortical and intrathalamic recordings, we demonstrate here that the thalamic deactivation occurring at sleep onset most often precedes that of the cortex by several minutes, whereas reactivation of both structures during awakening is synchronized. Delays between thalamus and cortex deactivations can vary from one subject to another when a similar cortical region is considered. In addition, heterogeneity in activity levels throughout the cortical mantle is larger than previously thought during the descent into sleep. Thus, asynchronous thalamo-cortical deactivation while falling asleep probably explains the production of hypnagogic hallucinations by a still-activated cortex and the common self-overestimation of the time needed to fall asleep.

Does the insula tell our brain that we are in pain

&NA; Current knowledge on pain‐related cerebral networks has relied so far on stimulus‐induced brain responses, but not on the analysis of brain activity during spontaneous pain attacks. In this case report, correlation between intracerebral field potentials and online sensations during spontaneously painful epileptic seizures suggests a crucial role of the insula in the development of subjective pain. Attacks originated from a very limited dysplasia located in the posterior third of the right insula and propagated to other areas of the pain matrix, including the parietal operculum and the midcingulate gyrus. Concomitant painful symptoms started on the left hand or the left foot and extended in a few seconds to the whole left side of the body, sparing the head. Continuous during the first seconds of the attack, the painful feeling evolved to throbbing and remained so until it progressively vanished, together with the spike discharge. Stimulation of the insula, but not of other pain matrix regions, induced pain identical to that of seizures. After thermocoagulation of the insular epileptic focus, a short, transient exacerbation of seizures with same painful features but different location was observed before a long‐lasting and complete remission of the attacks. Although these preliminary data need to be confirmed, they strongly suggest that if the full pain experience involves the pain matrix network, the posterior insula seems to play a leading role in the triggering of this network and the resulting emergence of subjective pain experience. Evidence from intracerebral EEG recordings of epileptic painful seizures reveals that the posterior insula seems to play a leading role in the triggering of the so called pain matrix cortical network and the resulting emergence of subjective pain experience.

Corollary discharge: Its possible implications in visual and oculomotor interactions

Abstract Data concerning the possible role of a corollary discharge mechanism in the regulation of visual-oculomotor interactions are reviewed. Several modes of action for such a mechanism on the processing of visual information are discussed. Mere suppression of visual input during saccades is considered mostly as a peripheral mechanism. It is proposed that corollary discharge could either produce an active cancellation of the effects of eye movements on vision, or contribute to the evaluation that a given visual change is provoked by a saccade. Cancellation could occur at subcortical levels of visual processing although evaluation could occur at the cortical level.

On the importance of placebo timing in rTMS studies for pain relief.

&NA; The efficacy of repetitive transcranial magnetic stimulation (rTMS) of the motor cortex for neuropathic pain relief is founded on double‐blind studies versus placebo. In these studies, however, the analgesic effect of active interventions remained modest compared with the placebo effect. This observation led us to re‐evaluate the intrinsic placebo action on pain relief according to the relative timing of active and sham rTMS interventions. In a randomized controlled study including 45 patients, we compared the analgesic effect of sham rTMS that either preceded or followed an active rTMS, which could be itself either successful or unsuccessful. Placebo analgesia differed significantly when the sham rTMS session followed a successful or an unsuccessful active rTMS. Placebo sessions induced significant analgesia when they followed a successful rTMS (mean pain decrease of 11%), whereas they tended to worsen pain when following an unsuccessful rTMS (pain increase of 6%). Only when the sham intervention was applied before any active rTMS were placebo scores unchanged from the baseline. These results probably reflect an unconscious conditioned learning. The timing of placebo relative to active interventions should be taken into account in rTMS studies for pain relief, and possibly in other conditions too. The fact that placebo effects could be enhanced by a previous rTMS with an analgesic effect as low as 10% suggests that a 30% pain decrease threshold in therapeutic trials may be too severe because smaller analgesic effects may have a clinical significance too. Sham rTMS induces significant analgesia only when preceded by a successful active stimulation. Such a placebo modulation is probably related to an unconscious conditioned learning.

Afferent and efferent connections of the parabigeminal nucleus in cat revealed by retrograde axonal transport of horseradish peroxidase.

Afferent and efferent connections of the parabigeminal nucleus (PBG) of the cat have been demonstrated by means of horseradish peroxidase (HRP) tracing technique. Following HRP injection in the PBG, labelled cells were observed mainly in the deep layers of the ipsilateral superior colliculus (SC). The other labelled structures were the prepositus hypoglossi complex (PH), the ventral nucleus of the lateral geniculate body (LGV), the locus coeruleus, the cuneiform nucleus, the periaqueductal gray and the dorsomedial hypothalamic area. Efferent projections of the PBG were investigated by HRP injection in SC, LGV, PH, hypothalamus and in some acoustic relays, i.e. medial geniculate body and inferior colliculus. Only the PBG-SC projection appeared to be well systematized. The positive labelling of the PBG following injection of LGV and hypothalamus is discussed in terms of the specificity of the injection. The absence of afferent and efferent connections of the PGB with any acoustic relay tends to exclude this nucleus from the auditory system in contrast to previous suggestions. On the basis of the close reciprocal PBG-SC connections a possible role of the PBG within visuomotor tectal function is proposed.

Involvement of Medial Pulvinar Thalamic Nucleus in Human Temporal Lobe Seizures

Summary:  Purpose: Several animal studies suggest that the thalamus might be involved in the maintenance and propagation of epileptic seizures. However, electrophysiologic evidence for this implication in human partial epileptic seizures is still lacking. Considering the rich and reciprocal connectivity of the medial pulvinar (PuM) with the temporal lobe, we evaluated a potential participation of this thalamic nucleus in temporal lobe epilepsy (TLE).