Clonidine effects on pain evoked SII activity in humans.

We investigated pain evoked activity in the human secondary sensory cortex (SII) following clonidine administration in six healthy volunteers using multi-channel magnetoencephalography (MEG). Pain was elicited by electrical shocks applied intracutaneously to the fingertip. Subjects rated pain intensity and perceptions of tiredness and passiveness by numerical ranking scales. Each subject underwent two investigations, one week apart from each other, with clonidine doses of 1.5 or 3.0microg/kg, administered intravenously in a random order and double-blinded. We applied a total number of seven blocks, each consisting of 60 painful stimuli, with one adaptation block, one pre-medication block, four post-medication blocks and one recovery block at the end of the session. MEG data were analysed by dipole reconstruction using CURRY(R) (Neuroscan, Hamburg) software package. Cortical activity in the contralateral SII cortex appeared with peak latencies of 118.5+/-10ms. This activity was significantly reduced by clonidine, in parallel with a reduction of pain intensity and enhancement of subjective tiredness and passiveness. There was, however, no significant correlation between MEG and subjective effects. Although both clonidine doses had similar effects, the higher dose induced longer changes. Results indicate that intravenous clonidine is able to relieve pain, but the exact mechanism of clonidine at the level of the SII cortex remains unclear. It is possible that clonidine interacts with the brainstem ascending system regulating vigilance and arousal which would explain the observed decrement of pain induced activity in SII. An additional more specific analgesic action at spinal level cannot be excluded.

Cortical correlates of false expectations during pain intensity judgments--a possible manifestation of placebo/nocebo cognitions.

We investigated the effects of expectation on intensity ratings and somatosensory evoked magnetic fields and electrical potentials following painful infrared laser stimuli in six healthy subjects. The stimulus series contained trials preceded by different auditory cues which either contained valid, invalid or no information about the upcoming laser intensity. High and low intensities occurred equally probable across cue types. High intensity stimuli induced greater pain than low intensity across all cue types. Furthermore, laser intensity significantly interacted with cue validity: high intensity stimuli were perceived less painful and low intensity stimuli more painful following invalid compared to valid cues. The amplitude of the evoked magnetic field localized within the contralateral secondary somatosensory cortex (SII) at about 165 ms after laser stimuli varied also both with stimulus intensity and cue validity. The evoked electric potential peaked at about 300 ms after laser stimuli and yielded a single dipole source within a region encompassing the caudal anterior cingulate cortex and posterior cingulate cortex. Its amplitude also varied with stimulus intensity, but failed to show any cue validity effects. This result suggests a priming of early cortical nociceptive sensitivity by cues signaling pain severity. A possible contribution of the SII cortex to the manifestation of nocebo/placebo cognitions is discussed.

The involvement of the posterior cingulate gyrus in phasic pain processing of humans.

Cingulate cortex (CC) processing of phasic pain starts in caudal parts. This is evidenced by electrical brain source analysis (BESA(R)) and current reconstruction imaging (CURRY(R)) which identify the activated neuronal assemblies in the individual brain morphology, including the boundary element method for volume current calculation. Data were obtained from 30 subjects who experienced, in repeated sessions, infrared laser stimuli applied on temple, hand, and foot, or electrical shocks applied intracutaneously on finger tip. CC activity started around 230 ms (+/-20 ms; inter-subject SD.) and was localized in mid or posterior CC, in general in Brodmann's area 23 (intra-subject SD <5 mm; inter-subject SD <15 mm), independent of the kind and body site of noxious stimulation.

Sensory reinnervation of myocutaneous flaps revealed by infrared laser evoked sensations and brain potentials.

The aim of this study was to examine the recovery of sensory function in myocutaneous flaps comparing 2 test methods. Eight flaps in 7 patients were examined by using clinical neurological test procedures (CNT) in comparison with psychophysics and evoked brain potentials (LEP) following infrared laser stimuli. The authors found that only 3 out of 8 flaps in 7 patients exhibited signs of reinnervation when tested with CNT. Three grades of reinnervation appeared in 7 flaps when tested with the laser. Grade 1 indicated the recovery of unmyelinated C-fiber function in 7 flaps accounting for the ability to discriminate laser intensities by different degrees of warmth. Grade 2 appeared in 3 of these flaps and was characterized by the additional ability to sense pinprick pain and the elicitation of late components of LEP mediated by thinly myelinated A delta-nociceptors. Grade 3 involved the additional sensibility for superficial touch indicating the recovery of thickly myelinated A beta-fibers noted in 2 of these flaps. The authors conclude that the LEP method is more sensitive than standard neurological test procedures to objectively document early signs of reinnervation after reconstructive flap surgery. This result is promising to investigate greater patient populations comparing different surgical techniques in future studies.

Attentional modulation of human pain processing in the secondary somatosensory cortex: a magnetoencephalographic study.

The influence of attention on the processing of pain in the secondary somatosensory cortex (SII) was analyzed using magnetoencephalography in response to painful infra-red heat stimuli applied to the left hand in six male healthy subjects, aged 22-28 years. Three experimental paradigms were chosen to deliver attention dependent results under comparable levels of vigilance. Single moving dipole sources for the pain-evoked responses were calculated in the individual cortex anatomy determined by magnetic resonance imaging. Though pain stimuli followed the same intensity pattern in all paradigms, evoked SII activity increased markedly from the low attention task to the mid-level attention task (P < 0.001). In contrast, further increase of attention from mid-level to high was not accompanied by an additional enhancement of SII activity. It therefore is concluded that activation patterns of SII follow a saturation function which cannot be enlarged by maximizing the relevance of the painful stimuli.

Increased responsiveness of cortical neurons in contrast to thalamic neurons during isoflurane-induced EEG bursts in rats.

The neuronal mechanisms underlying the electroencephalographic (EEG) burst-suppression pattern are not yet understood, however, they are generally attributed to interactions within thalamocortical networks. In contrast, we report that the sensory cortex and the thalamus are disconnected, with thalamic sensory processing being unaffected by cortical EEG bursts. We studied the activity of single neurons of the somatosensory thalamocortical system in rats during burst-suppression EEG induced by the volatile anesthetic, isoflurane. In neurons of the thalamic ventrobasal complex, the discharge rate in response to tactile stimulation of their receptive fields did not differ significantly during EEG bursts and isoelectric periods. In contrast, in neurons of the primary somatosensory cortex, the response magnitude was significantly greater during EEG bursts as compared with isoelectric periods (mean increase to 293%). The results suggest that the profound suppression of cortical sensory information processing by isoflurane is suspended during EEG burst-induced elevated cortical excitation.

Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus.

Many lines of evidence implicate the somatosensory areas near the lateral sulcus (Sylvian fissure) in the cortical representation of pain. Anatomical tracing studies in the monkey show nociceptive projection pathways to the vicinity of the secondary somatosensory cortex in the parietal operculum, and to anterior parts of insular cortex deep inside the Sylvian fissure. Clinical observations demonstrate alterations in pain sensation following lesions in these two areas in human parasylvian cortex. Imaging studies in humans reveal increased blood flow in parasylvian cortex, both contralaterally and ipsilaterally, in response to painful stimuli. Painful stimuli (such as laser radiant heat) evoke potentials with a scalp maximum at anterior temporal positions (T3 and T4). Several dipole source analyses as well as subdural recordings have confirmed that the earliest evoked potential following painful laser stimulation of the skin derives from sources in the parietal operculum. Thus, imaging and electrophysiological studies in humans suggest that parasylvian cortex is activated by painful stimuli, and is one of the first cortical relay stations in the central processing of these stimuli. There is mounting evidence for closely located but separate representations of pain (deep parietal operculum and anterior insula) and touch (secondary somatosensory cortex and posterior insula) in parasylvian cortex. This anatomical separation may be one of the reasons why single unit recordings of nociceptive neurons are scarce within regions comprising low-threshold mechanoreceptive neurons. The functional significance (sensory-discriminative, affective-motivational, cognitive-evaluative) of the closely spaced parasylvian cortical areas in acute and chronic pain is only poorly understood. It is likely that some of these areas are involved in sensory-limbic projection pathways that may subserve the recognition of potentially tissue damaging stimuli as well as pain memory.

Cognitive performance, mood and experimental pain before and during morphine-induced analgesia in patients with chronic non-malignant pain.

This paper investigates subjective, behavioral and neurophysiological changes due to treatment with oral sustained-release morphine in six patients with severe non-malignant pain. Patients rated their mood and clinical pain on visual analog scales (VAS). Experimental pain reactions were quantified by ratings on categorical scales and evoked cerebral potentials (LEP) in response to standardized laser stimuli. A standard auditory oddball task provided reaction time (RT), errors, N1 and P2 of late auditory evoked potentials (AEP), and a P300 component. It was used to measure vigilance and cognitive performance. In parallel with clinical pain reduction, laser pain ratings and LEP amplitudes were significantly reduced. In contrast, auditory P2 and P300 amplitude were found to be even enlarged under morphine. RT and mood also failed to indicate any sedation. It is concluded that LEP indicated the analgesic morphine effects whereas late potentials and P300 from auditory stimuli reflected the perceptual-cognitive status which, instead of being deteriorated by morphine-induced sedation, improved probably due to the removal of pain as a mental stressor.