Burkhart Bromm

Neurophysiological evaluation of pain

Neurophysiological techniques for the evaluation of pain in humans have made important advances in the last decade. A number of features of neuroanatomy and physiology of nociception qualifies pain as a multidimensional phenomenon which is rather unique among the sensory systems and which poses a number of technical and procedural requirements for its appropriate diagnostic assessment. Various stimulation techniques to induce defined pain in humans and used in combination with the methodology of evoked electrical brain potentials and magnetic fields are presented. Most recent knowledge gathered from scalp topography and dipole source analysis of pain-relevant evoked potentials and fields is discussed. Particular emphasis is put upon laser-evoked potentials and their application for diagnosis, pathophysiological description and monitoring of patients with neurological disorders and abnormal pain states. Future perspectives in this growing field of research are discussed briefly.

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

&NA; 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.

Subcortical structures involved in pain processing: evidence from single-trial fMRI

&NA; Pain is processed in multiple cortical and subcortical brain areas. Subcortical structures are substantially involved in different processes that are closely linked to pain processing, e.g. motor preparation, autonomic responses, affective components and learning. However, it is unclear to which extent nociceptive information is relayed to and processed in subcortical structures. We used single‐trial functional magnetic resonance imaging (fMRI) to identify subcortical regions displaying hemodynamic responses to painful stimulation. Thulium–YAG (yttrium–aluminum–granate) laser evoked pain stimuli, which have no concomitant tactile component, were applied to either hand of healthy volunteers in a randomized order. This procedure allowed identification of areas displaying differential fMRI responses to right‐ and left‐sided stimuli. Hippocampal complex, amygdala, red nucleus, brainstem and cerebellum were activated in response to painful stimuli. Structures related to the affective processing of pain showed bilateral activation, whereas structures involved in the generation of withdrawal behavior, namely red nucleus, putamen and cerebellum displayed differential (i.e. asymmetric) responses according to the side of stimulation. This suggests that spatial information about the nociceptive stimulus is made available in these structures for the guidance of defensive and withdrawal behavior.

Late somatosensory evoked cerebral potentials in response to cutaneous heat stimuli

Late components of cerebral potentials evoked by brief heat pulses applied to various skin sites were used to monitor the afferent pathways of pain and temperature sensitivity. Radiation at 10.6 micron wave length generated by a CO2 laser stimulator predominantly activates superficial cutaneous A delta and C nociceptors and elicits late and ultralate cerebral potentials. This paper deals with the investigation of the component structure and topography of the A delta fibre mediated late potentials, which were compared with the corresponding late potentials in response to standard electrical nerve stimuli. In the upper limb both stimulus types evoked a large positive potential (nerve: 260 msec, skin: 390 msec latency), preceded by a negativity (nerve: 140 msec, skin: 250 msec). Whereas these components were always maximal at the vertex, an earlier negativity appeared over the somatosensory projection area (nerve: 70 msec, skin: 170 msec). After stimulation of the lower limb all latencies were delayed by 20-30 msec. As a rule, the heat-evoked potentials appeared about 100 msec later than the corresponding potentials after electrical nerve stimulation. Similarities in interpeak latencies and scalp topography indicated similar cerebral processing.

Brain electrical source analysis of laser evoked potentials in response to painful trigeminal nerve stimulation.

Cerebral generators of long latency brain potentials in response to painful heat stimuli were identified from potential distributions in 31 EEG leads, using the brain electrical source analysis (BESA) programme in the multiple spatio-temporal dipole mode. Data were taken from a study with 10 young healthy male subjects who participated in 3 identical sessions, 1 week apart, with 4 blocks of 40 stimuli (randomized intensities above mean pain threshold). Brief infrared laser heat pulses were applied to the right temple; laser evoked brain potentials (LEPs) were averaged over 40 stimuli per block. BESA was applied to the grand mean maps averaged over the 10 subjects, 3 sessions and 4 stimulus blocks per session, as well as to the individual maps. In all cases 4 generators could consistently be identified by BESA, which were able to explain up to 98.8% of the total variance in scalp distributions at certain time intervals: dipole I with a maximum activity at 106.3 msec in the contralateral somatosensory trigeminal cortex, 19.0 mm beneath the surface; dipole II with a maximum activity at 112.1 msec at the corresponding ipsilateral area at a depth of 13.6 mm; dipole III with a maximum activity at 130.4 msec in the frontal cortex; dipole IV with 2 relative maximum activities at 150.6 and 220.5 msec, localized centrally under the vertex at a depth of 33.1 mm, which described both the late vertex negativity and the consecutive positivity. BESA applied to the individual LEP maps of each individual and session yielded again 4 major generators with sites, strengths and orientations comparable to those of the grand mean evaluations. The standard deviation (S.D.) of site coordinates within subjects was less than 3 mm for dipoles I, II and IV (5 mm for dipole III). The between-subject standard deviation was considerably larger (15 mm), which was attributed to individual differences in head geometry, size and anatomy. Dipoles I and II are assumed to be generators in secondary somatosensory areas of the trigeminal nerve system with bilateral representation, though significantly stronger in the contralateral site. Dipole III in the frontal cortex may be related to attention and arousal processes, as well as to motor cortical initiation for eye movements and muscle effects. The central dipole IV describing all late activity between 150 and 220 msec is probably a representative of perceptual activation and cognitive information processing; it was located in deep midline brain structure, e.g., the cingular gyrus.

Human cerebral potentials evoked by CO2 laser stimuli causing pain

SummaryBrief radiant heat pulses, generated by a CO2 laser, were used to activate slowly conducting afferents in the hairy skin in man. In order to isolate C-fibre responses a preferential A-fibre block was applied by pressure to the radial nerve at the wrist. Stimulus estimation and evoked cerebral potentials (EP), as well as reaction times, motor and sudomotor activity were recorded in response to each stimulus. With intact nerve, the single supra-threshold stimulus induced a double pain sensation: A first sharp and stinging component (mean reaction time 480 ms) was followed by a second burning component lasting for seconds (mean reaction time 1350 ms). Under A-fibre block only one sensation remained with characteristics and latencies of second pain. The heat pulse evoked potential consisted of a late vertex negativity at 240 ms (N240) followed by a prominent late positive peak at 370 ms (P370). Later activity was not reliably present. Under A-fibre block this late EP was replaced by an ultralate EP beyond 1000 ms, which in the conventional average looked like a slow halfwave of 800 ms duration. This potential was distinct from eye movements, skin potentials or muscle artefacts. With cross-correlation methods waveforms similar to the N240/P370 were detected in the latency range from 900 to 1500 ms during A-fibre block, indicating a much greater latency jitter of the ultralate EP. Latency corrected averaging with a modified Woody filter yielded a grand mean ultralate EP (N1050/P1250), the shape of which was surprisingly similar to the late EP (N240/P370). The similarity of these components indicates that both EPs may be secondary responses to afferent input into neural centers, onto which myelinated and unmyelinated fibres converge. Such convergence may also explain through the known mechanisms of short term habituation and selective attention, why ultralate EPs are not reliably present without peripheral nerve block.

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

&NA; 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 categorial 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.

Evoked cerebral potential correlates of C-fibre activity in man☆

CO2 laser emitted radiant heat pulses of 20 ms duration were used to activate predominantly slowly conducting nociceptive cutaneous afferents in man. Stimuli of two-fold individual pain threshold caused stinging and burning pain and elicited cerebral potentials with latencies consistent with A delta-fibre activity. After preferential block of the myelinated nerve fibres by pressure only the burning pain remained with significantly increased reaction time (about 1433 ms). The A delta-fibre-induced evoked potential components disappeared, and a marked ultralate positive component became visible with mean peak latency of 1260 ms, consistent with C-fibre activity.

Single trial fMRI reveals significant contralateral bias in responses to laser pain within thalamus and somatosensory cortices.

Pain is processed in multiple brain areas, indicating the complexity of pain perception. The ability to locate pain plays a pivotal role in immediate defense and withdrawal behavior. However, how the brain localizes nociceptive information without additional information from somatotopically organized mechano-receptive pathways is not well understood. We used single-trial functional magnetic resonance imaging (fMRI) to assess hemodynamic responses to right and left painful stimulation. Thulium-YAG-(yttrium-aluminium-granate)-laser-evoked pain stimuli, without concomitant tactile component, were applied to either hand in a randomized order. A contralateral bias of the BOLD response was investigated to determine areas involved in the coding of the side of stimulation, which we observed in primary (SI) and secondary (SII) somatosensory cortex, insula, and the thalamus. This suggests that these structures provide spatial information of selective nociceptive stimuli. More importantly, this contralateral bias of activation allowed functionally segregated activations within the SII complex, the insula, and the thalamus. Only distinct subregions of the SII complex, the posterior insula and the lateral thalamus, but not the remaining SII complex, the anterior insula and the medial thalamus, showed a contralaterally biased representation of painful stimuli. This result supports the hypothesis that sensory-discriminative attributes of painful stimuli, such as those related to body side, are topospecifically represented within the forebrain projections of the nociceptive system and highlights the concept of functional segregation and specialization within these structures.

Pain related cerebral potentials: late and ultralate components.

Brief CO2 laser radiant heat pulses activate both A delta- and C-fibres. In the evoked potential (EP) late and ultralate components can be seen as correlates of first and second pain. Usually the ultralate EP appears to be suppressed. It could be uncovered by a preferential A-fibre block, and in two neurological patients with tabes dorsalis and with a polyneuropathy involving myelinated fibre loss. Due to a strong latency jittering the shape of the ultralate component is distorted in the conventional average. Latency corrected averaging, adaptive filters or parametric spectral estimators are needed to analyze these EP components. As a result the filtered ultralate waveforms look very similar to the late EP components. Clinical application of CO2 laser EPs promises to nonivasively assess A delta- and C-fibre function.