Ulf Baumgärtner

Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain.

&NA; Patients with sensory disturbances of painful and non‐painful character show distinct changes in touch and/or pain sensitivity. The patterns of sensory changes were compared to those of human surrogate models of neuropathic pain to assess the underlying mechanisms. We investigated 30 consecutive in‐patients with dysaesthesia of various origins (peripheral, spinal, and brainstem lesions) and 15 healthy subjects. Tactile thresholds were determined with calibrated von Frey hairs (1.1 mm ∅). Thresholds and stimulus–response functions for pricking pain were determined with a series of calibrated punctate mechanical stimulators (0.2 mm ∅). Allodynia was tested by light stroking with a brush, Q‐tip, and cotton wisp. Perceptual wind‐up was tested by trains of punctate stimuli at 0.2 or 1 Hz. Intradermal injection of capsaicin (n=7) and A‐fiber conduction blockade (n=8) served as human surrogate models for neurogenic hyperalgesia and partial nociceptive deafferentation, respectively. Patients without pain (18/30) showed a continuous distribution of threshold shifts in the dysaesthetic skin area with a low to moderate increase in pain threshold (by 1.52±0.45 log2 units). Patients with painful dysaesthesia presented as two separate groups (six patients each): one showing lowered pain thresholds (by −1.94±0.46 log2 units, hyperalgesia) and the other elevated pain thresholds (by 3.02±0.48 log2 units, hypoalgesia). The human surrogate model of neurogenic hyperalgesia revealed nearly identical leftward shifts in stimulus–response function for pricking pain as patients with spontaneous pain and hyperalgesia (by a factor of about 5 each). The sensory changes in the human surrogate model of deafferentation were similar to patients with hypoalgesia and spontaneous pain (rightward shift of the stimulus–response function with a decrease in slope). Perceptual wind‐up did not differ between symptomatic and control areas. There was no exclusive association of any parameter obtained by quantitative sensory testing with a particular disease (of either peripheral or central origin). Our findings suggest that neuropathic pain is based on two distinct mechanisms: (I) central sensitization (neurogenic hyperalgesia; in patients with minor sensory impairment) and (II) partial nociceptive deafferentation (painful hypoalgesia; in patients with major sensory deficit). This distinction as previously postulated for postherpetic neuralgia, is obviously valid also for other conditions. Our findings emphasize the significance of a mechanism‐based classification of neuropathic pain.

Peripheral and central components of habituation of heat pain perception and evoked potentials in humans

Abstract For the neurophysiological examination of nociceptive pathways, contact‐heat evoked potentials (contact‐heat EPs) are elicited by repetitive brief noxious heat stimuli. Suppression of heat responses in primary nociceptive neurons during repetitive stimulation has been shown in animal models in vivo and in vitro. We now investigated whether heat pain and contact‐heat EPs in humans display equivalent signs of habituation. Heat pain and EPs were elicited in 16 volunteers with a contact thermode (30 °C s−1). Heat pulses at three intensities (pain threshold, moderate noxious and maximum available) were applied to the right forearm either by moving the thermode after each pulse to variable locations or when fixed to one location (inter‐stimulus intervals 8–10 s). Contact‐heat EPs consisted of an early negativity in temporal leads (N1), followed by a biphasic response at the vertex (N2‐P2). Pain ratings and contact‐heat EPs (N1 and N2‐P2 components) displayed significant temperature dependence. N2‐P2 correlated positively with ratings. With stimulation at variable locations, both measures slowly decreased with time constants τ of 2 min (ratings) and 12 min (EPs). With stimulation at a fixed location, habituation was much faster for both, ratings (τ = 10 s) and EPs (τ = 33 s). As a consequence, both measures were significantly reduced (p < 0.005) leading to a rightward shift of the stimulus–response function by 5 °C. In conclusion, human heat pain perception and contact‐heat EPs display signs of rapid habituation when stimulation is restricted to a fixed location and thus, reflect fatigue of peripheral nociceptive neurons. Habituation within the central nervous system is slower and less pronounced.

Left-hemisphere dominance in early nociceptive processing in the human parasylvian cortex.

Pain perception comprises sensory and emotional dimensions. While the emotional experience is thought to be represented in the right hemisphere, we here report a left-hemisphere dominance for the early sensory component of pain perception using brain electrical source analysis of laser-evoked potentials. Ten right-handed subjects underwent several series of laser radiant heat stimuli to pairs of parallel lines on the dorsum of the left or right hand. Stimulus location and intensity were randomised independently. The sensory-discriminative aspects of pain were emphasised by asking the subjects to perform either a spatial or an intensity discrimination task and were contrasted with active distraction by mental arithmetics. Pain ratings obtained after each of the laser stimulus series revealed an analgesic effect of distraction (27%, P < 0.001). Four equivalent dipole sources were active in the latency range of 100-200 ms (bilateral operculoinsular cortex, midcingulate gyrus, postcentral gyrus). The sources in the operculoinsular cortex exhibited (a) the shortest peak latency (155 +/- 6 ms), (b) the most pronounced enhancement during spatial and intensity discrimination tasks compared to active distraction (43%, P < 0.001), and (c) a significantly stronger source activity in the left hemisphere independent of stimulation side (23%, P < 0.05). The distribution of these sources extended into the dorsal insula. The postcentral source had the longest peak latency (180 +/- 7 ms); its source strength was task-dependent (25%, P = 0.051) but exhibited no hemisphere dominance. The midcingulate source had an intermediate peak latency (169 +/- 7 ms). Its source strength was modulated by tasks, but this modulation was significant only in the latency range >200 ms (46%, P < 0.001). These findings suggest a dominant role of the left frontal operculum and adjacent dorsal insula in the early sensory-discriminative dimensions of pain processing. This region has been proposed to be the cortical projection target of nociceptive pathways from the spinal cord to the ventroposteroinferior and ventromedial (its posterior part: VMpo) thalamic nuclei.

Differential nociceptive deficits in patients with borderline personality disorder and self-injurious behavior: laser-evoked potentials, spatial discrimination of noxious stimuli, and pain ratings

&NA; Approximately 70–80% of women meeting criteria for borderline personality disorder (BPD) report attenuated pain perception or analgesia during non‐suicidal, intentional self‐mutilation. The aim of this study was to use laser‐evoked potentials (LEPs) and psychophysical methods to differentiate the factors that may underlie this analgesic state. Ten unmedicated female patients with BPD (according to DSM‐IV) and 14 healthy female control subjects were investigated using brief radiant heat pulses generated by a thulium laser and five‐channel LEP recording. Heat pulses were applied as part of a spatial discrimination task (two levels of difficulty) and during a mental arithmetic task. BPD patients had significantly higher heat pain thresholds (23%) and lower pain ratings (67%) than control subjects. Nevertheless, LEP amplitudes were either normal (N1, P2, P3) or moderately enhanced in BPD patients (N2). LEP latencies and task performance did not differ between patients and control subjects. The P3 amplitudes, the vertex potential (N2–P2), and the N1, which is generated near the secondary somatosensory cortex, were significantly reduced during distraction by mental arithmetic in both groups. In addition, P3 amplitudes reflected task difficulty. This study confirms previous findings of attenuated pain perception in BPD. Normal nociceptive discrimination task performance, normal LEPs, and normal P3 potentials indicate that this attenuation is neither related to a general impairment of the sensory‐discriminative component of pain, nor to hyperactive descending inhibition, nor to attention deficits. These findings suggest that hypoalgesia in BPD may primarily be due to altered intracortical processing similar to certain meditative states.

Multiple Somatotopic Representations of Heat and Mechanical Pain in the Operculo-Insular Cortex: A High-Resolution fMRI Study

Whereas studies of somatotopic representation of touch have been useful to distinguish multiple somatosensory areas within primary (SI) and secondary (SII) somatosensory cortex regions, no such analysis exists for the representation of pain across nociceptive modalities. Here we investigated somatotopy in the operculo-insular cortex with noxious heat and pinprick stimuli in 11 healthy subjects using high-resolution (2 × 2 × 4 mm) 3T functional magnetic resonance imaging (fMRI). Heat stimuli (delivered using a laser) and pinprick stimuli (delivered using a punctate probe) were directed to the dorsum of the right hand and foot in a balanced design. Locations of the peak fMRI responses were compared between stimulation sites (hand vs. foot) and modalities (heat vs. pinprick) within four bilateral regions of interest: anterior and posterior insula and frontal and parietal operculum. Importantly, all analyses were performed on individual, non-normalized fMRI images. For heat stimuli, we found hand-foot somatotopy in the contralateral anterior and posterior insula [hand, 9 ± 10 (SD) mm anterior to foot, P < 0.05] and in the contralateral parietal operculum (SII; hand, 7 ± 10 mm lateral to foot, P < 0.05). For pinprick stimuli, we also found somatotopy in the contralateral posterior insula (hand, 9 ± 10 mm anterior to foot, P < 0.05). Furthermore, the response to heat stimulation of the hand was 11 ± 12 mm anterior to the response to pinprick stimulation of the hand in the contralateral (left) anterior insula (P < 0.05). These results indicate the existence of multiple somatotopic representations for pain within the operculo-insular region in humans, possibly reflecting its importance as a sensory-integration site that directs emotional responses and behavior appropriately depending on the body site being injured.

Asymmetry in the human primary somatosensory cortex and handedness.

Brain asymmetry is a phenomenon well known for handedness and language specialization and has also been studied in motor cortex. Less is known about hemispheric asymmetries in the somatosensory cortex. In the present study, we systematically investigated the representation of somatosensory function analyzing early subcortical and cortical somatosensory-evoked potentials (SEP) after electrical stimulation of the right and left median nerve. In 16 subjects, we compared thresholds, the peripheral neurogram at Erb point, and, using MRI-based EEG source analysis, the P14 brainstem component as well as N20 and P22, the earliest cortical responses from the primary sensorimotor cortex. Handedness was documented using the Edinburgh Inventory and a dichotic listening test was performed as a measure for language dominance. Whereas thresholds, Erb potential, and P14 were symmetrical, amplitudes of the cortical N20 showed significant hemispheric asymmetry. In the left hemisphere, the N20 amplitude was higher, its generator was located further medial, and it had a stronger dipole moment. There was no difference in dipole orientation. As a possible morphological correlate, the size of the left postcentral gyrus exceeded that of the right. The cortical P22 component showed a lower amplitude and a trend toward weaker dipole strength in the left hemisphere. Across subjects, there were no significant correlations between laterality indices of N20, the size of the postcentral gyrus, handedness, or ear advantage. These data show that asymmetry of median nerve SEP occurs at the cortical level, only. However, both functional and morphological cortical asymmetry of somatosensory representation appears to vary independently of motor and language functions.

Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers

&NA; The experiment investigated the impact of sleep restriction on pain perception and related evoked potential correlates (laser‐evoked potentials, LEPs). Ten healthy subjects with good sleep quality were investigated in the morning twice, once after habitual sleep and once after partial sleep restriction. Additionally, we studied the impact of attentional focussing on pain and LEPs by directing attention to (intensity discrimination) or away from the stimulus (mental arithmetic). Laser stimuli directed to the hand dorsum were rated as 30% more painful after sleep restriction (49 ± 7 mm) than after a night of habitual sleep (38 ± 7 mm). A significant interaction between attentional focus and sleep condition suggested that attentional focusing was less distinctive under sleep restriction. Intensity discrimination was preserved. In contrast, the amplitude of the early parasylvian N1 of LEPs was significantly smaller after a night of partial sleep restriction (−36%, p < 0.05). Likewise, the amplitude of the vertex N2–P2 was significantly reduced (−34%, p < 0.01); also attentional modulation of the N2–P2 was reduced. Thus, objective (LEPs) and subjective (pain ratings) parameters of nociceptive processing were differentially modulated by partial sleep restriction. We propose, that sleep reduction leads to an impairment of activation in the ascending pathway (leading to reduced LEPs). In contradistinction, pain perception was boosted, which we attribute to lack of pain control distinct from classical descending inhibition, and thus not affecting the projection pathway. Sleep‐restricted subjects exhibit reduced attentional modulation of pain stimuli and may thus have difficulties to readily attend to or disengage from pain.

Laser guns and hot plates

Noxious heat stimuli are frequently used to study the nociceptive system, because they activate a nociceptivespecific transduction mechanism (Julius and Basbaum, 2001). Nociceptive nerve endings can be heated by either thermal conduction or thermal radiation. Both methods have their advantages and disadvantages. Conductive heating allows control over the temperature at the stimulator–tissue interface, but concomitant stimulation of low-threshold mechanoreceptors is a potentially confounding factor and uniform contact between the stimulator and the uneven surface of the skin depends critically on thermode pressure. Radiant heating avoids these problems, but variations in baseline temperature can lead to misinterpretations (Tjolsen et al., 1988). Cerebral potentials evoked by noxious heat stimuli allow to study human nociceptive brain processing with outstanding temporal resolution, and information from their source analysis is complementary to fMRI and PET results (Peyron et al., 2002). Although few early studies used thermodes, the breakthrough in this field came with the introduction of infrared laser stimulators (Bromm and Treede, 1984; Carmon et al., 1978), and laser-evoked potentials now have attained an important position in both basic and clinical research (Cruccu et al., 2004; Treede et al., 2003). In a previous issue of PAIN (volume 115, issue 3), Granovsky et al. (2005) report brain potentials evoked by a thermofoil thermode that allows much faster heating rates (nominally up to 70 8/s) than conventional Peltier thermodes. Similar rapid thermodes had been first developed in Aalborg (Chen et al., 2001). Granovsky and coworkers exploited the different threshold temperatures of C-fiber nociceptors (41 8C) and A-fiber nociceptors (46 8C) to study the difference in nociceptive innervation between hairy and glabrous skin. They report that late potentials consistent with A-fiber conduction velocities were evoked by 51 8 stimulation and ultralate potentials consistent with C-fiber conduction velocities were elicited by 41 8C stimulation in hairy skin. For glabrous skin, they found only ultralate

A cross-sectional investigation of discontinuation of self-injury and normalizing pain perception in patients with borderline personality disorder

Objective:  Several studies have shown reduced pain perception in patients with borderline personality disorder (BPD) and current self‐injurious behavior (SIB). The aim of the present study was to test whether pain perception in patients with current SIB is different from that of patients who had stopped SIB, and whether pain perception of the latter group differs from healthy controls (HC).

Mechanisms and predictors of chronic facial pain in lateral medullary infarction.

The purpose of this study was to identify clinical predictors and anatomical structures involved in patients with pain after dorsolateral medullary infarction. Eight out of 12 patients (67%) developed poststroke pain within 12 days to 24 months after infarction. The pain occurred in the ipsilateral face (6 patients) and/or the contralateral limbs and trunk (5 patients, 3 of whom also had facial pain). Ipsilateral facial pain was significantly correlated with lower medullary lesions, including those of the spinal trigeminal tract and/or nucleus, as documented by magnetic resonance imaging. The R2 blink reflex component was abnormal only in patients with facial pain. Likewise, pain and temperature sensation in the ipsilateral face was decreased in all patients with facial pain but not in patients without pain. Ipsilateral touch sensation in the face was also decreased in all patients with facial pain, but the lesions revealed on magnetic resonance imaging did not involve the principal sensory nucleus of the fifth cranial nerve, and the R1 blink reflex latencies were normal. Although facial pain was correlated with lesions of the spinal trigeminal tract and/or nucleus, none of the lesions involved the subnucleus caudalis, which contains most nociceptive neurons. These findings suggest that facial pain after medullary infarction is due to lesions of the lower spinal trigeminal tract (axons of primary afferent neurons), leading to deafferentation of spinal trigeminal nucleus neurons. Ann Neurol 2001;49:493–500