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Background and Purpose: Somatoform pain disorder is characterized by chronic pain and various psychological symptoms including increased attention to mental and physical processes. Given that the medial prefrontal cortex (mPFC) of the default mode network (DMN) and the anterior insula of the salience network are critically involved in intrinsic and attentional processes, we investigated the involvement of these networks during the distraction from physical pain in somatoform pain patients., Methods: During painful and nonpainful heat stimulation, attentional distraction from physical processes was modulated with a Stroop task. Thirteen patients were investigated with functional magnetic resonance imaging (fMRI) and compared to 13 controls. Main outcomes were spatial maps of coherent fMRI activity based on independent component analysis and functional connectivity (FC) resulting from psychophysiological interaction analysis., Results: Behavioral pain intensity ratings were reduced during the distraction task in both groups. At brain level, we found deviant network activities in the DMN (particularly in the mPFC) and in the salience network (bilaterally in the anterior insula) in patients. During pain stimulation, Stroop-induced distraction decreased the FC between the mPFC and anterior insula in controls but not in patients., Conclusions: Modulating the FC between the mPFC and the insula may be highly relevant for shifting the attention away from external stimuli, including nociceptive input. The observed alterations in somatoform pain patients may foster new strategies in cognitive behavioral training tools for these patients., (© 2018 by the American Society of Neuroimaging.)

Previous research in health and disease has shown that exposure to pain changes the density of cortical grey matter (GM). Such structural changes of the brain might, however, depend crucially on how this pain experience is evaluated and processed in the brain. In the present study we aimed to detect pain-rating patterns and underlying GM changes after the application of repetitive painful stimulation using voxel-based morphometry (VBM). Healthy volunteers were investigated (n=27), receiving 8 noxious and 8 innocuous thermal stimuli on the right forearm for 11 consecutive working days. Data were compared with a control group without any intervention (n=18). Behavioural data demonstrated that a subgroup of volunteers (n=14) sensitised, whereas the others (n=13) habituated over the stimulation days. The VBM analysis revealed no increase but a significant reduction of GM density, eg, in the anterior cingulate cortex, the insular cortex and the frontal cortex, exclusively in the group of sensitisers. By contrast, pain habituaters did not show any density changes in the GM. Depending on the individual perception of pain during the time course of stimulation, the repetitive application of painful stimuli changed the GM density in pain-processing brain regions exclusively in those subjects who were characterised by the lack of habituation. Because VBM studies investigating patients experiencing chronic pain observed similar decreases in GM density and increasing pain ratings over time, the sensitisers in our study may have a higher vulnerability to developing chronic pain syndromes in later life., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Central post-stroke pain of thalamic origin is an extremely distressing and often refractory disorder. There are no well-established predictors for pain development after thalamic stroke, and the role of different thalamic nuclei is unclear. Here, we used structural magnetic resonance imaging to identify the thalamic nuclei, specifically implicated in the generation of central post-stroke pain of thalamic origin. Lesions of 10 patients with central post-stroke pain of thalamic origin and 10 control patients with thalamic strokes without pain were identified as volumes of interest on magnetic resonance imaging data. Non-linear deformations were estimated to match each image with a high-resolution template and were applied to each volume of interest. By using a digital atlas of the thalamus, we elucidated the involvement of different nuclei with respect to each lesion. Patient and control volumes of interest were summed separately to identify unique areas of involvement. Voxelwise odds ratio maps were calculated to localize the anatomical site where lesions put patients at risk of developing central post-stroke pain of thalamic origin. In the patients with pain, mainly lateral and posterior thalamic nuclei were affected, whereas a more anterior-medial lesion pattern was evident in the controls. The lesions of 9 of 10 pain patients overlapped at the border of the ventral posterior nucleus and the pulvinar, coinciding with the ventrocaudalis portae nucleus. The lesions of this area showed an odds ratio of 81 in favour of developing thalamic pain. The high odds ratio at the ventral posterior nucleus-pulvinar border zone indicates that this area is crucial in the pathogenesis of thalamic pain and demonstrates the feasibility of identifying patients at risk of developing central post-stroke pain of thalamic origin early after thalamic insults. This provides a basis for pre-emptive treatment studies.

Recent neuroimaging studies have revealed a persistent architecture of intrinsic connectivity networks (ICNs) in the signal of functional magnetic resonance imaging (fMRI) of humans and other species. ICNs are characterized by coherent ongoing activity between distributed brain regions during rest, in the absence of externally oriented behavior. While these networks strongly reflect anatomical connections, the relevance of ICN activity for human behavior remains unclear. Here, we investigated whether intrinsic brain activity adapts to repeated pain and encodes an individual's experience. Healthy subjects received a short episode of heat pain on 11 consecutive days. Across this period, subjects either habituated or sensitized to the painful stimulation. This adaptation was reflected in plasticity of a sensorimotor ICN (SMN) comprising pain related brain regions: coherent intrinsic activity of the somatosensory cortex retrospectively mirrored pain perception; on day 11, intrinsic activity of the prefrontal cortex was additionally synchronized with the SMN and predicted whether an individual would experience more or less pain during upcoming stimulation. Other ICNs of the intrinsic architecture remained unchanged. Due to the ubiquitous occurrence of ICNs in several species, we suggest intrinsic brain activity as an integrative mechanism reflecting accumulated experiences., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Functional neuroimaging methods such as positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) provide fascinating insights into the cerebral processing of pain. Neuroimaging studies have shown that no clearly defined "pain centre" exists. Rather, an entire network of brain regions is involved in the processing of nociceptive information, which leads to the subjective impression of "pain". Sophisticated study designs nowadays permit the characterisation of different components of pain processing. In this review, we summarise neuroimaging studies, which contributed to the characterisation of these different aspects of cerebral pain processing, such as somatosensory (discrimination of different stimulus modalities, noxious vs non-noxious, summation), emotional, cognitive (attention, anticipation, distraction), vegetative (homeostasis) and motor aspects.

Mu-opioidergic agonists are believed to induce euphoria, whereas kappa-agonists are thought to lead to dysphoria. Our study investigated mood effects of remifentanil, a mu-receptor opioid agonist, in healthy male volunteers. Moreover, we examined interactions between mood and pain. Three conditions were investigated in 21 volunteers: saline, 0.05 and 0.15 microg kg(-1) min(- 1) remifentanil. Each condition was investigated during non-painful heat and during painful heat stimulation. Mood was measured with the von Zerssen's mood scale (Bf-S score) and pain intensity using a Visual Analogue Scale (VAS). High Bf-S scores are reflecting discontent and dysphoria. Changes were tested for significance using a linear mixed model approach. Remifentanil significantly increased Bf-S scores during painful heat (+91.4%), indicating a negative mood effect, although it reduced VAS scores of painful heat intensity (-49.0%). The type of sensory stimulation (non-painful versus painful) had no effect on mood. There was no interaction between remifentanil dose and type of stimulation. Our results provide evidence for negative mood effects of remifentanil. These effects occur with and without pain. Taken into account that remifentanil reduces pain, one could have expected analgesia-related amelioration of mood instead. In clinical practice, these remifentanil effects should be considered and a comedication might be advisable.

Objective: To investigate whether the functional changes in pain disorder might be reflected by structural brain changes. Pain disorder assessed with the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria is characterized by persistent and distressing chronic pain at one or more body sites which cannot be fully explained by a physiological process or somatic disorder. Psychological factors are thought to play a major role. Recent neuroimaging studies evidenced altered pain processing in patients suffering from this disorder., Methods: Fourteen right-handed women fulfilling the DSM-IV criteria for pain disorder and 25 healthy age-matched women were investigated with magnetic resonance imaging. In the voxel-based morphometry analysis, we compared both groups for changes of gray-matter density. We included age and Beck Depression Inventory scores as nuisance variables to minimize possible confounding effects of age or depressive comorbidity., Results: In the patient group, we found significant gray-matter decreases in the prefrontal, cingulate, and insular cortex. These regions are known to be critically involved in the modulation of subjective pain experiences., Conclusions: In the context of similar results in patients with other functional pain syndromes, such as fibromyalgia and chronic back pain, we suggest that structural changes in fronto-limbic brain circuits represent not only an objective marker of these pain syndromes but also constitute a critical pathophysiological element. These findings represent a further proof of the important role of central changes in pain disorder.

Pain evoked potentials offer a possibility for the evaluation of nociceptive pathways. Contact heat evoked potentials (CHEPS) represent a novel technique allowing to investigate peripheral pain pathways represented by small-diameter nerve fibers (A-delta and C fibers) and to study the spinothalamic tract. In contrast to more time-consuming methods such as quantitative sensory testing, CHEPS enables an objective investigation of pain pathways. This article reviews and discusses the technique, possible indications, and pitfalls in the context of clinical cases.

Idiopathic chronic pain conditions with a mismatch between anatomical abnormalities and symptoms can be categorized as somatoform pain disorder according to the DSM-IV criteria. A dysfunction of pain processing circuits has been suggested as one underlying pathophysiological factor. There is accumulating evidence for a crucial role of affect regulating brain structures such as the medial frontal cortex in this context. We investigated the cerebral processing of noxious heat stimuli as objective marker for pain sensation in 12 right handed women with somatoform pain disorder fulfilling DSM-IV criteria and 13 age-matched healthy volunteers using functional MRI. The average ratings for experimentally induced pain were not significantly different between controls and patients concerning pain intensity and pain unpleasantness. Comparing patients with controls a pain related hypoactive state of the ventromedial prefrontal/orbitofrontal cortex (BA 10/11) and a hyperactive state of the parahippocampal gyrus, amygdala and anterior insula were found in the patient group. Our findings of an altered cerebral processing of experimentally induced pain in patients with somatoform pain disorder support the hypothesis of dysfunctional pain processing, especially in affect regulating regions.

Over the last decades, functional imaging studies have fostered our knowledge of cerebral pain processing in humans. A lively interest has been focussing on possible opioidergic mechanisms of pain transmission and modulation. Today, reliable knowledge of the in vivo distribution of opioid receptors in healthy human subjects is available from positron emission tomography (PET) studies of opioidergic neurotransmission. Gender dependent differences in receptor distribution and ligand metabolism have been demonstrated. Moreover, an increasing number of studies are reporting alterations in receptor distribution patterns in states involving painful diseases. Various acute painful challenges have also been shown to induce measurable changes in receptor availability in multiple brain areas. The perigenual anterior cingulate cortex (ACC) has been identified as one brain region with a major impact on opioidergic pain modulation. Thereby, the ACC apparently executes cortical top-down control on brainstem structures in (exogenous) pharmacological opioid analgesia. In addition, accumulating evidence suggests that non-pharmacological treatment approaches also utilize similar endogenous opioid dependent pathways to exert pain modulation. This article summarizes our current knowledge of PET studies of the opioidergic system and outlines future perspectives.

Six articles are presented which illustrate the activities at the summer workshop "Pain and awareness" held 27-28 May 2005 in Marienfeld by the German Interdisciplinary Collaboration for Pain Therapy (DIVS). One article on pain constructs in the mind explains the advantages of functional imaging methods: these enable characterization of partial aspects of pain processing in the brain and the mechanisms that lead to chronic states of pain syndromes. A further overview explains the influence of different drugs on pain perception and various conscious states. How back pain patients experience their illness was analyzed in a study using an explanatory model interview: somatic aspects were dominant, but in three-fourths of the patients psychological illness attributions also played a role. A summary from the perspective of religious history and theology explores how pain is interpreted and accepted in various religious communities. Another article addresses hypnosis as a complementary technique to anesthesia procedures in surgical medicine, for treating chronic pain and experimental acute pain. The last contribution deals with how people in different cultures experience pain: ethnocentric bias can lead to difficulties in communication and misjudgments when treating foreign-born patients. All in all the workshop highlighted important formative factors in pain processing in a condensed form and offered stimulating perspectives for this area of pain research and future treatment options.

Background: Previous imaging studies have demonstrated a number of cortical and subcortical brain structures to be activated during noxious stimulation and infusion of narcotic analgesics. This study used O-water and positron emission tomography to investigate dose-dependent effects of the short-acting mu-selective opioid agonist remifentanil on regional cerebral blood flow during experimentally induced painful heat stimulation in healthy male volunteers., Methods: Positron emission tomography measurements were performed with injection of 7 mCi O-water during nonpainful heat and painful heat stimulation of the volar forearm. Three experimental conditions were used during both sensory stimuli: saline, 0.05 microg x kg x min remifentanil, and 0.15 microg x kg x min remifentanil. Cardiovascular and respiratory parameters were monitored noninvasively. Across the three conditions, dose-dependent effects of remifentanil on regional cerebral blood flow were analyzed on a pixel-wise basis using a statistical parametric mapping approach., Results: During saline infusion, regional cerebral blood flow increased in response to noxious thermal stimulation in a number of brain regions as previously reported. There was a reduction in pain-related activations with increasing doses of remifentanil in the thalamus, insula, and anterior and posterior cingulate cortex. Increasing activation occurred in the cingulofrontal cortex (including the perigenual anterior cingulate cortex) and the periaqueductal gray., Conclusions: Remifentanil induced regional cerebral blood flow increases in the cingulofrontal cortex and periaqueductal gray during pain stimulation, indicating that mu-opioidergic activation modulates activity in pain inhibitory circuitries. This provides direct evidence that opioidergic analgesia is mediated by activation of established descending antinociceptive pathways.

Little is known about the effects of low-dose S-(+)-ketamine on the cerebral processing of pain. We investigated the effects of subanesthetic IV S-(+)-ketamine doses on the perception of experimental painful heat stimuli. Healthy volunteers were evaluated with functional magnetic resonance imaging (fMRI) while receiving the painful stimuli in conjunction with placebo and increasing doses (0.05, 0.1, 0.15 mg x kg(-1) x h(-1)) of ketamine infusion. Vital variables were monitored and all subjects rated pain intensity and unpleasantness on a numerical rating scale. Alterations in consciousness were measured using a psycho-behavioral questionnaire. Pain unpleasantness declined as ketamine dosage was increased (55.1% decrease, placebo versus 0.15 mg x kg(-1) x h(-1) ketamine). Pain intensity ratings also decreased with increasing ketamine dosage but to a lesser extent (23.1% decrease). During placebo administration, a typical pain activation network (thalamus, insula, cingulate, and prefrontal cortex) was found, whereas decreased pain perception with ketamine was associated with a dose-dependent reduction of pain-induced cerebral activations. Analysis of the dose-dependent ketamine effects on pain processing showed a decreasing activation of the secondary somatosensory cortex (S2), insula and anterior cingulate cortex. This part of the anterior cingulate cortex (midcingulate cortex) has been linked with the affective pain component that underlines the potency of ketamine in modulating affective pain processing.

Neuroimaging studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have delineated a human pain network in vivo. Despite the recognition of cerebral structures engaged in pain transmission, the cerebral mechanisms involved in pain modulation are still not well understood. Here, we investigated healthy volunteers using fMRI during experimental heat pain and distraction induced by a visual incongruent color-word Stroop task. A factorial design permitted categorical and covariation analysis of four conditions, namely innocuous and noxious heat; with and without distraction. Pain without distraction evoked an activation pattern similar to that observed in previous neuroimaging pain studies. Distraction was associated with a significant reduction of the visual analogue scale (VAS) ratings for pain intensity and unpleasantness and a reduction of pain-related activation in multiple brain areas, particularly in the so-called 'medial pain system'. Distraction significantly increased the activation of the cingulo-frontal cortex including the orbitofrontal and perigenual anterior cingulate cortex (ACC), as well as the periaquaeductal gray (PAG) and the posterior thalamus. Covariation analysis revealed functional interaction between these structures during pain stimulation and distraction, but not during pain stimulation per se. According to our results, the cingulo-frontal cortex may exert top-down influences on the PAG and posterior thalamus to gate pain modulation during distraction.

μ-opioidergic agonists are believed to induce euphoria, whereas κ-agonists are thought to lead to dysphoria. Our study investigated mood effects of remifentanil, a μ-receptor opioid agonist, in healthy male volunteers. Moreover, we examined interactions between mood and pain. Three conditions were investigated in 21 volunteers: saline, 0.05 and 0.15 μg kg-1 min-1 remifentanil. Each condition was investigated during non-painful heat and during painful heat stimulation. Mood was measured with the von Zerssen's mood scale (Bf-S score) and pain intensity using a Visual Analogue Scale (VAS). High Bf-S scores are reflecting discontent and dysphoria. Changes were tested for significance using a linear mixed model approach. Remifentanil significantly increased Bf-S scores during painful heat (+91.4%), indicating a negative mood effect, although it reduced VAS scores of painful heat intensity (-49.0%). The type of sensory stimulation (non-painful versus painful) had no effect on mood. There was no interaction between remifentanil dose and type of stimulation. Our results provide evidence for negative mood effects of remifentanil. These effects occur with and without pain. Taken into account that remifentanil reduces pain, one could have expected analgesia-related amelioration of mood instead. In clinical practice, these remifentanil effects should be considered and a comedication might be advisable. [ABSTRACT FROM AUTHOR]

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Neuroimaging studies have explored cerebral activation patterns in patients with cluster headache (CH) during attacks and have revealed activation of multiple brain areas known to belong to the general pain-processing network. However, it is still unclear which changes in brain metabolism are inherent to the shift from the 'in bout' to the 'out of bout' period. We measured cerebral glucose metabolism in 11 episodic CH patients during the cluster and again during the remission period with (18)F-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) and compared these data with 11 healthy controls. 'In bout' compared with 'out of bout' scans were associated with increases of metabolism in the perigenual anterior cingulate cortex (ACC), posterior cingulate cortex, prefrontal cortex, insula, thalamus and temporal cortex. Decreases in metabolism were observed in the cerebellopontine area. Compared with healthy volunteers, hypometabolism in the patient group ('in bout' and 'out of bout') was found in the perigenual ACC, prefrontal and orbitofrontal cortex. Thus, FDG-PET in CH patients revealed 'in bout' activation of brain structures which are involved in descending pain control. Compared with controls, the regional brain metabolism was constitutively decreased in most of these structures, irrespective of the bout. This finding indicates a deficient top-down modulation of antinociceptive circuits in CH patients. We suggest that trigger mechanisms of CH are insufficiently controlled and thus promote the initiation of the bout period and acute attack. [ABSTRACT FROM AUTHOR]