Jürgen Lorenz

Activation of the opioidergic descending pain control system underlies placebo analgesia.

Placebo analgesia involves the endogenous opioid system, as administration of the opioid antagonist naloxone decreases placebo analgesia. To investigate the opioidergic mechanisms that underlie placebo analgesia, we combined naloxone administration with functional magnetic resonance imaging. Naloxone reduced both behavioral and neural placebo effects as well as placebo-induced responses in pain-modulatory cortical structures, such as the rostral anterior cingulate cortex (rACC). In a brainstem-specific analysis, we observed a similar naloxone modulation of placebo-induced responses in key structures of the descending pain control system, including the hypothalamus, the periaqueductal gray (PAG), and the rostral ventromedial medulla (RVM). Most importantly, naloxone abolished placebo-induced coupling between rACC and PAG, which predicted both neural and behavioral placebo effects as well as activation of the RVM. These findings show that opioidergic signaling in pain-modulating areas and the projections to downstream effectors of the descending pain control system are crucially important for placebo analgesia.

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.

A Unique Representation of Heat Allodynia in the Human Brain

Skin inflammation causes innocuous heat to become painful. This condition, called heat allodynia, is a common feature of pathological pain states. Here, we show that heat allodynia is functionally and neuroanatomically distinct from normal heat pain. We subtracted positron emission tomography scans obtained during painful heating of normal skin from scans during equally intense but normally innocuous heating of capsaicin-treated skin. This comparison reveals the specific activation of a medial thalamic pathway to the frontal lobe during heat allodynia. The results suggest that different central pathways mediate the intensity and certain qualitative aspects of pain. In making this differentiation, the brain recognizes unique physiological features of different painful conditions, thus permitting adaptive responses to different pain states.

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.

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.

Differentiation of conversive sensory loss and malingering by P300 in a modified oddball task

WE applied the methodology of evoked potentials (EP) to reveal the functional level of abnormality in a patient with circumscribed complete anaesthesia due to conversion disorder. EP components related to sensory and perceptual processing of both innocuous electrical and noxious laser stimuli were normal. However, a P300 component indicating cognitive processing failed to appear when using a modified oddball task with rare stimuli applied to the anaesthetic right hand. P300 was present with this paradigm stimulating the healthy left hand, as well as in a ‘malingerer’ – a healthy subject who was instructed to feign the same deficit. These results suggest cognitive deficits underlying sensory loss as conversion symptom which can be differentiated from malingering by use of P300.

Habituation to pain: further support for a central component.

&NA; Habituation to repetitive painful stimulation may represent an important protection mechanism against the development of chronic pain states. However, the exact neurobiological mechanisms of this phenomenon remain unclear. In this study we (i) explore the somatotopic specificity of pain attenuation over time and (ii) investigate the role of the endogenous opioid system in its development. We investigated 24 healthy volunteers with a paradigm of daily painful stimulation of the left volar forearm for 1 week. Habituation was assessed by comparing pain‐related responses (ratings and thresholds) between days 1 and 8. To test whether a repetition‐dependent attenuation of pain is restricted to the site of stimulus application or induces additional systemic effects indicative of a central mechanism, we also measured pain‐related responses at the contralateral arm and the left leg. To assess the role of the endogenous opioid system in this mechanism, we used the opioid‐receptor antagonist naloxone in a double‐blind design. Repetitive painful stimulation over several days resulted in a significant habituation to pain at the site of daily stimulation. In addition, we also observed significant pain attenuation at the non‐stimulated limbs. This effect was less pronounced at the untreated arm compared to the treated arm and even weaker in the leg, displaying a significant Stimulation‐Site × Time interaction. The development of pain habituation was unaffected by the opioid antagonist naloxone. Taken together, these results strongly support the role of central components in the mechanism of pain habituation that do not directly involve the endogenous opioid system.

Fear-conditioned cues of impending pain facilitate attentional engagement.

AIMS OF STUDY Selective attention to signals of impending pain allows the avoidance of bodily harm. In order to identify the attentional components involved in the selection of pain signals over competing demands, we used an emotional modification of an exogenous cueing task. METHODS Fifty-two pain-free volunteers detected visual targets of which the location was correctly or incorrectly predicted by a spatial cue. Cues were emotionally modulated using differential classical conditioning. The conditioned cue (CS+) was sometimes followed by an electrocutaneous stimulus (UCS), thus becoming a pain signal, whereas the UCS never followed the other cue (CS-), referred to as safety signal. RESULTS Analyses of response times showed that pain signals facilitated the directing of attention to their location in comparison to safety signals. In contrast, pain signals did not impair disengagement of attention from their location in comparison to safety signals. CONCLUSION It is concluded that attention is more strongly engaged to a signal of impending pain compared with a cue signalling its absence. We explore why disengagement from the pain signal is not impaired compared to the safety signal. The findings are discussed in terms of the defensive importance of pain anticipation.

Insights into the pathophysiology of neuropathic pain through functional brain imaging

We present here an example case of neuropathic pain with heat allodynia as a major symptom to illustrate how the functional imaging of pain may provide new insights into the pathophysiology of painful sensory disorders. Tissue injury of almost any kind, but especially peripheral or central neural tissue injury, can lead to long-lasting spinal and supraspinal re-organization that includes the forebrain. These forebrain changes may be adaptive and facilitate functional recovery, or they may be maladaptive, preventing or prolonging the painful condition, and interfering with treatment. In an experimental model of heat allodynia, we used functional brain imaging to show that: (1) the forebrain activity during heat allodynia is different from that during normal heat pain, and (2) during heat allodynia, specific cortical areas, specifically the dorsolateral prefrontal cortex, can attenuate specific components of the pain experience, such as affect, by reducing the functional connectivity of subcortical pathways. The forebrain of patients with chronic neuropathic pain may undergo pathologically induced changes that can impair the clinical response to all forms of treatment. Functional imaging, including PET, fMRI, and neurophysiological techniques, should help identify brain mechanisms that are critical targets for more effective and more specific treatments for chronic, neuropathic pain.

Cognitive and weight-related correlates of flexible and rigid restrained eating behaviour.

OBJECTIVES Examine the association between components of restrained eating, cognitive performance and weight loss maintenance. METHODS 106 women, all members of a commercial slimming organisation for at least 6 months (mean±SD: 15.7±12.4 months), were studied who, having lost 10.1±9.7 kg of their initial weight, were hoping to sustain their weight loss during the 6 month study. Dietary restraint subcomponents flexible and rigid restraint, as well as preoccupying cognitions with food, body-shape and diet were assessed using questionnaires. Attentional bias to food and shape-related stimuli was measured using a modified Stroop test. Working memory performance was assessed using the N-back test. These factors, and participant weight, were measured twice at 6 month intervals. RESULTS Rigid restraint was associated with attentional bias to food and shape-related stimuli (r=0.43, p<0.001 resp. r=0.49, p<0.001) whereas flexible restraint correlated with impaired working memory (r=-0.25, p<0.05). In a multiple regression analyses, flexible restraint was associated with more weight lost and better weight loss maintenance, while rigid restraint was associated with less weight loss. CONCLUSIONS Rigid restraint correlates with a range of preoccupying cognitions and attentional bias to food and shape-related stimuli. Flexible restraint, despite the impaired working memory performance, predicts better long-term weight loss. Explicitly encouraging flexible restraint may be important in preventing and treating obesity.