Pain Processing Areas Research Articles

Bout-associated intrinsic functional network changes in cluster headache: A longitudinal resting-state functional MRI study.

Background Previous imaging studies on the pathogenesis of cluster headache (CH) have implicated the hypothalamus and multiple brain networks. However, very little is known regarding dynamic bout-associated, large-scale resting state functional network changes related to CH. Methods Resting-state functional magnetic resonance imaging data were obtained from CH patients and matched controls. Data were analyzed using independent component analysis for exploratory assessment of the changes in intrinsic brain networks and their relationship between in-bout and out-of-bout periods, as well as correlations with clinical observations. Results Compared to healthy controls, CH patients had functional connectivity (FC) changes in the temporal, frontal, salience, default mode, somatosensory, dorsal attention, and visual networks, independent of bout period. Compared to out-of-bout scans, in-bout scans showed altered FC in the frontal and dorsal attention networks. Lower frontal network FC correlated with longer duration of CH. Conclusions The present findings suggest that episodic CH with dynamic bout period shifts may involve bout-associated FC changes in multiple discrete cortical areas within networks outside traditional pain processing areas. Dynamic changes in FC in frontal and dorsal attention networks between bout periods could be important for understanding episodic CH pathophysiology.

FMRI evidence for a reduction in affective processing of thermal pain in responders of transcutaneous vagal nerve stimulation (TVNS)

Background Although the transcutaneous vagal nerve stimulation (TVNS) is increasingly used in treatment of chronic pain, the underlying mechanism is unclear. The goal of this study was to analyse the cerebral effects of TVNS under experimental pain in fMRI. Methods Twenty healthy volunteers took part in two separate fMRI sessions (3 Tesla) with experimental pain, which was applied to the right forearm with MEDOC Sensory Analyser. During TVNS session the electrical stimulation was applied bilaterally to auricular concha with rectangle impulses (8 Hz frequency; 200 μs wave length); the intensity was maximal but not painful. During placebo session the stimulation device was switched off. The order of the sessions was randomised. Individual sensory thresholds were registered before and after each fMRI session. fMRI data was afterwards processed with standard settings in SPM8 and differences in BOLD effects between verum and placebo session were calculated. We used region of interest (ROI) based analysis on ROIs, which were previously identified in association with thermal pain. Results Cerebral pain processing areas were activated bilaterally under thermal stimulation. The group analysis did not show the differences in sensory parameters but revealed stronger activation of right amygdala under TVNS. The group of responders (subjects with increased pain threshold after TVNS, n = 8), showed a reduction in BOLD signal in the right nucleus caudate, the middle frontal cortex and left hypothalamus under TVNS in comparison to placebo. Conclusion Thermal stimulation elicited bilateral fMRI activation in pain processing regions of the brain in healthy volunteers. Responders to TVNS showed decreased activation in cerebral areas associated with affective processing of pain.

Attention guiding and hypnosis for acute pain management without medication

Background Acute and chronic pain is a burden to patients. To keep the medication with analgesic drugs as low as possible, additional non-pharmacological interventions prove to be useful. In chronic pain, long term hypnotic therapy is indicated. The targeted distraction, which needs no special setting, is defined as putting a non-specific sense stimulus near or in deliberately chosen distance from the site of pain. It's more a kind of confusion away from The hypnotic trance, however, is led by the patient imagined focusing, escorted by a specialist. A scheduled therapy session is arranged with the patient, which takes place under special conditions. It includes an induction, by means of which the patient is placed in an altered state of consciousness. After further deepening the trance, the perception changes with help of suggestions. At best the patient is devoid of symptoms. In means of chronical pain the patient experiences for the first time that he is no longer helpless. Material and methods A literature search via Pubmed, Medline and Embase and data extraction was performed. It aims to identify possible mechanism how hypnosis reduces pain. Results Although the results of research are still contradictory, two assumptions seem to be established: Hilgard´s dissociation [5, 6] and the associated change in the Default Network (DMN) [1, 2, 3, 7, 8, 9]. Hilgard ER et al. have postulated the fact, that the forwarding of nocispecific information is inhibited via the thalamus. Because the somatosensory cortex and the authorities responsible for pain processing areas of the brain remain fully active, it can be assumed, that communication between these parts is dissociated during trance - means diminished responsiveness to pain stimuli and movement requests, and a belief that this pain is not important. The default network usually relates to the processing of I-related information. In precuneus, which is also responsible for introspective processes [1, 9], an increased activity occurs in trances with paralysis-suggestions. This is also the case with specific suggestions for pain relief. Interestingly, there is no reaction with passive empty trance. This is right in line with Hildegard's concept of dissociation. Also some changes in the anterior cingulate Cortex (ACC) and in the orbitofrontal cortex take place. In addition to these results from fMRT- and PECT-investigations also changes in the EEG during the trance are found. Unfortunately, the results do not always match, which can be explained by the great number of different settings. Conclusions It is scientifically demonstrated, that both the attention distraction as well as the hypnotic trance represent two effective mechanisms in pain management. Declarations Competing interests The authors declare that they have no competing interests. Language: en

Nocebo context modulates long-term habituation to heat pain and influences functional connectivity of the operculum.

In the past, nocebo manipulations have been found to modulate pain perception and influence long-term habituation to pain. Recently, neural correlates accompanying this finding have been identified: habituation over days is mirrored by decreased activity in pain-processing brain areas, whereas nocebo-specific modulation specifically involves the opercular cortex. Focusing on duration and central network characteristics of nocebo information in a longitudinal heat pain paradigm, we investigated 40 healthy participants over a period of 21 consecutive days, whereof sessions on days 1, 8, 14, and 21 were performed during functional magnetic resonance imaging scanning. Negative context information was given to half of the participants, inducing a nocebo manipulation through verbal suggestions. The analysis was focused on brain areas associated with habituation and nocebo effects and identified coupled brain regions using functional connectivity analysis. Decreased pain perception over days was reflected in reduced blood oxygenation level dependent signal in pain-processing areas, such as the insula and somatosensory cortices, whereas increased rostral anterior cingulate cortex activation reflected the central correlate for habituation over time. Habituation was significantly less pronounced in the nocebo group. Consistent with previous results, the nocebo manipulation not only modulated pain perception but also was accompanied by the activation of the operculum over an extended period of time. Importantly, the operculum exhibited changes in coupling during nociceptive input over time, as demonstrated by decreased connectivity with the basal ganglia and pinpoints differences, depending on whether a nocebo context was given. These data suggest that negative verbal suggestions prognosticating increasing pain may prevail by modulating basal ganglia-thalamocortical loops.

Facial motor-respiratory coordination in Qigong activates brain default-mode network regions

Purpose: Although sham acupuncture as well as real acupuncture are known to reduce low back pain (LBP), the brain correlates of placebo effect in acupuncture is not clearly understood. So we dissociated the brain correlates of somatosensory needling from needling credibility effect induced by a novel form of sham acupuncture “phantom acupuncture”. Methods: Forty three LBP patients were randomized into the real (REAL, n=23) and phantom (PHNT, n=20) groups. In acupuncture session, the REAL got real acupuncture at left ST36, left SP11 and bilateral SP13 points (five times stimulation per each point in a random order with inter-stimulus interval of 17.8±1.7 seconds) at around 2Hz for two seconds per stimulation, while the PHNT sawonly a videoclip (recorded needling manipulation in REAL session) to create needling credibility. LBP intensity (VAS) was measured before and after acupuncture session. Results: PHNT experienced needling credibility with visual stimulation while REAL experienced both needling credibility and somatosensory stimulation. In PHNT we found activation in somatosensory processing areas including SI, SII and anteri or cingulate cortex but not in posterior insula and thalamus where activated in REAL. In unpaired t-test, REAL shows greater activation in sensory motor areas. Also activation in rewarding and pain processing areas (periaqueductal gray, nucleus accumbens and putamen) were observed in both REAL and PHNT. Activation in pain evaluation area (inferior frontal gyrus) is observed in PHNT while signal deactivation in cognitive processing area (dorsolateral prefrontal cortex) in REAL. Greater signal deactivation in default mode network (DMN) was observed in REAL. In difference map, differences in activation intensity in ACC, posterior insula were strongly observed. Conclusion: Somatosensory afference/needling induces greater deactivation in DMN area as well as sensory motor area, while needling credibility, a contributing factor for placebo effect, activated pain and rewarding processing areas and interestingly somatosensory areas which probably due to the visually induced sensory expectation. Contact: Meena M. Makary, mmakary@khu.ac.kr

Dissociation of somatosensory needling and needling credibility of the acupuncture effect on low back pain: fMRI study

Purpose: Although sham acupuncture as well as real acupuncture are known to reduce low back pain (LBP), the brain correlates of placebo effect in acupuncture is not clearly understood. So we dissociated the brain correlates of somatosensory needling from needling credibility effect induced by a novel form of sham acupuncture “phantom acupuncture”. Methods: Forty three LBP patients were randomized into the real (REAL, n=23) and phantom (PHNT, n=20) groups. In acupuncture session, the REAL got real acupuncture at left ST36, left SP11 and bilateral SP13 points (five times stimulation per each point in a random order with inter-stimulus interval of 17.8±1.7 seconds) at around 2Hz for two seconds per stimulation, while the PHNT sawonly a videoclip (recorded needling manipulation in REAL session) to create needling credibility. LBP intensity (VAS) was measured before and after acupuncture session. Results: PHNT experienced needling credibility with visual stimulation while REAL experienced both needling credibility and somatosensory stimulation. In PHNT we found activation in somatosensory processing areas including SI, SII and anteri or cingulate cortex but not in posterior insula and thalamus where activated in REAL. In unpaired t-test, REAL shows greater activation in sensory motor areas. Also activation in rewarding and pain processing areas (periaqueductal gray, nucleus accumbens and putamen) were observed in both REAL and PHNT. Activation in pain evaluation area (inferior frontal gyrus) is observed in PHNT while signal deactivation in cognitive processing area (dorsolateral prefrontal cortex) in REAL. Greater signal deactivation in default mode network (DMN) was observed in REAL. In difference map, differences in activation intensity in ACC, posterior insula were strongly observed. Conclusion: Somatosensory afference/needling induces greater deactivation in DMN area as well as sensory motor area, while needling credibility, a contributing factor for placebo effect, activated pain and rewarding processing areas and interestingly somatosensory areas which probably due to the visually induced sensory expectation. Contact: Meena M. Makary, mmakary@khu.ac.kr

Normal laser-evoked cortical responses in patients with chronic hemibody pain.

Patients with widespread unilateral chronic pain associated with recurrent herpes simplex virus (HSV) infections show functional and/or structural changes in the insula, anterior cingulate cortex, frontal and prefrontal cortices, as well as the thalamus, suggesting central dysfunction of the pain system in these patients. Central pain has been associated with attenuated laser-evoked cortical responses. We aimed to clarify whether the observed deficient activation of these areas to acute nociceptive stimuli is due to a lesion at a lower level of pain processing pathways. We explored the functional integrity of the ascending nociceptive pathways by recording the cortical-evoked responses to noxious laser stimulation using magnetoencephalography and electroencephalography in eight patients (age 41-51 years, mean 46) with recurrent HSV infections and a history of chronic, spontaneous, widespread unilateral pain, and in nine age-matched healthy control subjects. The cortical-evoked fields of the HSV patients originating from the secondary somatosensory and posterior parietal cortices, as well as the evoked potentials recorded from the midline, did not differ from those of the control subjects, indicating functionally intact ascending nociceptive pathways. The present results show that our patients with chronic hemibody pain do not show signs of spinothalamic tract lesion. This indicates normal processing of sensory aspects of painful stimuli, while higher pain processing areas show altered activation. We conclude that normal laser-evoked magnetic fields (LEF) or laser-evoked potentials (LEP) may not exclude central pain condition.

PO-0413 Trigeminal Odours Released By Healthcare Products Activate Olfactory And Pain Cortical Areas In Preterm And Full Term Newborns

Background/aim Hospitalised newborns are highly exposed to nosocomial odorous substances (OS) triggering possibly the intranasal trigeminal subsystem. Irritation of the nasal mucosa can induce pain and activations in pain processing areas in adults We aimed to evaluate cortical activation in trigeminal/olfactory and pain areas following OS exposure in newborns. Methods Forty-four newborns (17 full-terms, 12 preterms at term PMA and 15 preterms – water (control); – a hand rub (DES60 ® ) diluted to match the odour’s intensity released by hands; – an adhesive remover (Convacare ® ). We recorded bilaterally cortical activation in orbito-frontal gyri (OFG), prefrontal (PFC) and somatosensory (S1 and S2) cortices during 40s (10s-baseline, 10s-presentation, 20s-post-stimuli) by multichannel-NIRS. HbO2 changes were analysed from baseline (ANOVA) and by subgroups (Kruskall-Wallis). Results In the whole population, we observed: – no activations for water. – cortical activations (HbO 2 increase) for DES60 ® (p ® (p We noticed significant profiles of response for all infant’s subgroups, in at least one olfactory and one pain processing areas. The average magnitude of HbO 2 increase from baseline was higher in full-terms vs both subgroups of preterms: 8.5(2.8–12.6) µmol/l vs 5.9(2.6–10.4) and 5.7(1.8–9.2) µmol/l for DES60 ® (p Conclusion Full-term and preterm newborns can perceive OS at a cortical level. Exposure to OS can activate trigeminal/olfactory and pain processing areas and may induce discomfort/pain in newborns.

Altered hypothalamic functional connectivity in cluster headache: a longitudinal resting-state functional MRI study

BackgroundNeuroimaging studies implicate hypothalamic dysfunction in the pathogenesis of cluster headache (CH). Disruptions in non-traditional pain processing areas, including the cerebellum and visual cortex, have also been reported in CH....

Verum and sham acupuncture exert distinct cerebral activation in pain processing areas: a crossover fMRI investigation in healthy volunteers.

Although acupuncture is effective for treating pain, its site-specificity is questioned. The aim was to compare the cerebral responses of needling applied to an acupuncture point to the needling of a sham point, using functional magnetic resonance imaging (fMRI). Twenty-one healthy male volunteers were enrolled. Manual stimulation of the acupuncture (ST44) and sham points on the dorsum of the left foot was applied during fMRI in a crossover manner. fMRI data analysis was performed contrasting the ST44 and the sham conditions. Stimulation intensity, subjective discrimination of the needling site and the incidence of "Qi" sensation were additionally recorded. Stimulation of ST44 acupoint, in comparison to the sham procedure, was associated with an increased fMRI-activation in the primary somatosensory, the inferior parietal and the prefrontal cortex and the posterior insula. Sham needling was associated with increased activation in the anterior cingulate cortex and the anterior insula. Verum acupuncture increased the activity of discriminative somatosensory and cognitive pain processing areas of the brain, whereas sham needling activated the areas responsible for affective processing of pain. This may explain favorable effects of verum acupuncture in clinical studies about treatment of chronic pain patients.

Brain correlates of short‐term habituation to repetitive electrical noxious stimulation

Habituation to repetitive noxious stimuli is a well-known phenomenon. We investigated brain correlates of habituation to pain in a transdermal electrical pain model using functional magnetic resonance imaging (fMRI). Electrical painful stimulation with 1 Hz was applied to the volar forearm of 48 healthy subjects for 45 min. Before and after conditioning stimulation, psychophysical testing and fMRI were performed. During fMRI sessions, the subjects underwent blockwise painful electrical stimulation with a fixed percept-adapted current intensity. After fMRI 1 and fMRI 2 subjects rated the individual pain intensity of the electrical stimulus. Substantial habituation occurred during conditioning electrical stimulation. Accordingly, areas typically involved in pain processing showed decreased activity after conditioning stimulation. The blood oxygen level-dependent signal of the subgenual anterior cingulate gyrus, the superior parietal lobule and the supplemental motor area correlated positively with habituation. In contrast, activity in the periaqueductal grey, thalamus and insula correlated negatively. The results of the correlation analyses did not survive correction for multiple comparisons. With this study, we identified central components associated with habituation to repetitive painful stimuli. The results suggest that an increase in tonic inhibitory activity in cortical pain processing areas is a major mechanism contributing to habituation to phasic noxious stimuli. Moreover, areas involved in descending pain modulation were differentially modulated. This may hint at a simultaneous activation of facilitating and inhibiting nociceptive systems that are both altered in the transdermal electrical pain model.

Disentangling linear and nonlinear brain responses to evoked deep tissue pain

Pain stimuli evoke widespread responses in the brain. However, our understanding of the physiological significance underlying heterogeneous response within different pain-activated and -deactivated regions is still limited. Using functional magnetic resonance imaging, we evaluated brain responses to a wide range of stimulus intensity levels (1 innocuous, 7 painful) in order to estimate region-specific stimulus-response functions, which we hypothesized could illuminate that region’s functional relationship to pain. Linear and nonlinear brain responses to pain were estimated through independent Legendre polynomial transformations of pain ratings within a general linear model. This approach identified at least 5 different, regionally specific activity profiles in the brain. Linearly increasing (eg, primary somatosensory/motor cortex, insulae) and intensity-independent (eg, secondary somatosensory cortex) activation was noted in traditional pain-processing areas, potentially reflecting sensory encoding and all-or-none salience responses, respectively. Multiple activity profiles were seen in areas of the default mode network (DMN): intensity-independent deactivation (eg, posterior cingulate cortex), linearly decreasing (eg, contralateral inferior parietal lobule), and quadratic (U-shaped; eg, medial prefrontal cortex). The latter observation suggests that: (1) different DMN subregions exhibit functional heterogeneity and (2) some DMN subregions respond in a percept-related manner to pain, suggesting closer linkage between the DMN and pain processing than previously thought. Future studies should apply a similar approach using innocuous stimuli of multiple intensities to evaluate whether the response profiles reported here can also be generalized to nonpainful somatosensory processing.

Intranasal Application of Xenon Reduces Opioid Requirement and Postoperative Pain in Patients Undergoing Major Abdominal Surgery

Both central sensitization after peripheral tissue injury and the development of opioid tolerance involve activation of N-methyl-D-aspartate (NMDA) receptors. At subanesthetic doses the NMDA receptor antagonist xenon suppresses pain-evoked sensitization of pain-processing areas in the central nervous system. Although numerous studies describe the effect of NMDA receptor antagonists on postoperative pain, clinical studies elucidating their intraoperative analgesic potency when applied in a low dosage are still largely missing. To analyze the analgesic effect of low-dose xenon using new application methods, the authors tested nasally applied xenon as an add-on treatment for analgesia in 40 patients undergoing abdominal hysterectomy. Within a randomized double-blind placebo-controlled study design, intraoperative and postoperative requirement of opioids as well as postoperative subjective experiences of pain were measured as primary outcome variables. Intranasal application of xenon significantly reduced intraoperative opioid requirement (mean difference [MD] -2.0 μg/min; 95% CI [CI95]-0.53 to -3.51, Bonferroni correction adjusted P value [pcorr]= 0.028) without relevant side effects and significantly reduced postoperative pain (MD -1.34 points on an 11-point rating scale; CI95 -0.60 to -2.09, pcorr = 0.002). However, postoperative morphine consumption (MD -8.8 μg/min; CI95 1.2 to -18.8, pcorr = 0.24) was not significantly reduced in this study. Low-dose xenon significantly reduces intraoperative analgesic use and postoperative pain perception. Because NMDA receptor antagonists suppress central sensitization, prevent the development of opioid tolerance, and reduce postoperative pain, the intraoperative usage of NMDA receptor antagonists such as xenon is suggested to improve effectiveness of pain management within a concept of multimodal analgesia.

Pathophysiology of Chronic Migraine and Mode of Action of Preventive Medications

Evidence has accumulated in recent years indicating structural, physiologic, and biochemical alterations in the brain of patients with chronic migraine (CM). Altered pharmacologic responses to opioids and other analgesics have also been reported. Structural or morphologic changes include reduced cortical gray matter of the pain processing areas of the brain and iron accumulation in the periaqueductal gray matter (PAG), red nucleus, and basal ganglia structures. These changes correlate with the duration of migraine disorder and, therefore, are more marked in CM compared to episodic migraine (EM). A dysmodulation of trigeminovascular nociception resulting from changes in PAG may be an important factor in the pathophysiology of CM. Even though the pathophysiology and significance of subcortical white matter lesions and infarct like cerebellar lesions are not fully understood, their occurrence in patients with frequent migraine is further evidence of structural alterations in the brain in CM. Physiologic changes in CM are altered brain metabolism, excitability, and central sensitization of nociceptive pathways. CM is associated with alterations in the brain metabolism confirmed by positron emission tomography (PET) studies. Of special interest is the reversible hypometabolism in the insula, thalamus, anterior cingulate, and parietal lobe and sustained hypometabolism in the orbitofrontal cortex in medication overuse headache. Cortical excitability is increased in CM compared to EM, as confirmed by magnetic suppression of visual accuracy. Cutaneous allodynia, which is more often seen in CM, is a marker of central sensitization. Central sensitization generates free radicals that damage PAG. Cutaneous allodynia is correlated with frequency of migraine attacks and duration of migraine illness. Chronically sensitized central nociceptive neurons may account for CM and its resistance to treatment. Alterations in central glutamate neurotransmission have been reported in the anterior cingulate and insula using magnetic resonance spectroscopy. Medications affecting central glutamatergic neurotransmission may have a potential therapeutic role in CM. Frequent use of opioids and analgesics in EM leads to CM. Opioid-induced hyperalgesia, recognized in recent years, can lead to intractability of migraine. Better understanding of the pathophysiology of CM should lead to better ways to treat these patients. The various effective preventive agents used in migraine prophylaxis, such as topiramate, valproate, β-blockers, and tricyclic antidepressants, appear to have a common effect of suppressing cortical excitability (cortical spreading depression). Suppression of cortical spreading depression by these agents is correlated with the dosages and the duration of treatment. The beneficial effect of botulinum toxin in CM may be due to its antinociceptive effect. Changes in the glutamate and calcitonin gene-related peptide at the peripheral nerve endings reduce peripheral sensitization, which eventually leads to reduced central sensitization.

Halbseitenstörung nach Unfall

We present the case of a 48-year old man who, eight years after an industrial accident, presents with chronic right-sided nondermatomal pain and hypaesthesia to heat and touch. During symmetric peripheral touch functional magnetic resonance imaging revealed hypometabolism in the left thalamus, somatosensory cortex, and anterior cingulate cortex. Pain-associated nondermatomal somatosensory deficits (NDSDs) localizing to one side of the body are a frequent clinical entity, which are often triggered by an accident. The tendency of NDSDs to extend to adjunct ipsilateral body parts and to become chronic points to maladaptive adjustment of pain-processing areas in the central nervous system. Psychological stress prior to or around the triggering event seems an important risk factor for NDSDs.

Opioid-induced hyperalgesia: low-dose ketamine does work for some orthopaedic problems already

Editor—I read with interest the original article and accompanying editorial on opioid-induced hyperalgesia (OIH).1Minville V Fourcade O Girolami J-P Tack I Opiod-induced hyperalgesia in a mice model of orthopaedic pain: preventive effect of ketamine.Br J Anaesth. 2010; 104: 231-238doi:10.1093/bja/aep363Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar 2Colvin LA Fallon MT Opioid-induced hyperalgesia: a clinical challenge.Br J Anaesth. 2010; 104: 125-127doi:10.1093/bja/aep392Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar There are already clinical studies, which support some of the findings, although the type of pain may be slightly different. I have used low-dose ketamine, usually 0.15 mg kg−1, for the prevention of tourniquet-induced hypertension and pain3Segerdahl M Ekblom A Sollevi A The influence of adenosine, ketamine and morphine on experimentally induced ischemic pain in healthy volunteers.Anesth Analg. 1994; 79: 787-791doi:10.1213/00000539-199410000-00029Crossref PubMed Scopus (98) Google Scholar for a number of years. Low-dose ketamine is also successful at reducing morphine requirements after anterior cruciate reconstruction surgery.4Menigaux C Fletcher D Dupont X Guignard B Guirimand F Chauvin Ml The benefits of intraoperative small-dose ketamine on postoperative pain after anterior cruciate ligament repair.Anesth Analg. 2000; 90: 129-135doi:10.1097/00000539-200001000-00029Crossref PubMed Scopus (191) Google Scholar For orthopaedic lower limb arthroplasty surgery, I add ketamine 0.15 mg kg−1 to my analgesic mixture. I think that these clinical studies are good supporting evidence for the work done by Minville and colleagues.1Minville V Fourcade O Girolami J-P Tack I Opiod-induced hyperalgesia in a mice model of orthopaedic pain: preventive effect of ketamine.Br J Anaesth. 2010; 104: 231-238doi:10.1093/bja/aep363Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar I agree that more good-quality clinical studies are needed, and there is an urgent requirement for S-ketamine to be made available to anaesthetists in the UK. Editor—We thank Dr Griffiths for his interesting observations on the clinical use of ketamine. There is indeed an increasing number of clinical studies on the use of ketamine, with opioid-sparing effects in the postoperative period.5Berti M Baciarello M Troglio R Fanelli G Clinical uses of low-dose ketamine in patients undergoing surgery.Curr Drug Targets. 2009; 10: 707-715doi:10.2174/138945009788982496Crossref PubMed Scopus (33) Google Scholar A Cochrane review of perioperative ketamine deemed 37 randomized controlled trials, with a total of 2240 patients, to be of sufficient quality to include in their analysis—of these 27 trials found that subanaesthetic doses of ketamine were effective in pain control, reducing opioid requirements, and with minimal adverse effects.6Bell RF Dahl JB Moore RA Kalso E Perioperative ketamine for acute postoperative pain. 2006doi:10.1002/14651858.CD004603.pub2Crossref Google Scholar It seems clear from this that ketamine, or perhaps other N-methyl d-aspartate (NMDA) receptor antagonists, has a role in perioperative management. S-ketamine may have a better side-effect profile, or other agents, selective for different subtypes of the NMDA receptor, might have improved clinical utility. The specific role of ketamine in preventing OIH is also of interest: whether its site of action is in the spinal cord, where we know central sensitization involving the NMDA receptor occurs, or in higher centres does require further study. Clinical imaging studies have certainly demonstrated effects on pain processing areas in the brain, but the clinical significance of this is not yet understood.7Sprenger T Valet M Woltmann R et al.Imaging pain modulation by subanesthetic s-(+)-ketamine.Anesth Analg. 2006; 103: 729-737doi:10.1213/01.ane.0000231635.14872.40Crossref PubMed Scopus (57) Google Scholar 8Rogers R Wise RG Painter DJ Longe SE Tracey I An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging.Anesthesiology. 2004; 100: 292-301doi:10.1097/00000542-200402000-00018Crossref PubMed Scopus (102) Google Scholar By using a combination of approaches to the problem, with evidence from basic science studies, volunteer and clinical imaging studies, and good-quality clinical trials, it may be possible to develop clinical strategies to address OIH and minimize its impact on delivering effective analgesia in a variety of settings. None declared. L. A. Colvin* M. T. Fallon Edinburgh, UK E-mail: [email protected]

Aberrant temporal and spatial brain activity during rest in patients with chronic pain

In the absence of external stimuli, human hemodynamic brain activity displays slow intrinsic variations. To find out whether such fluctuations would be altered by persistent pain, we asked 10 patients with unrelenting chronic pain of different etiologies and 10 sex- and age-matched control subjects to rest with eyes open during 3-T functional MRI. Independent component analysis was used to identify functionally coupled brain networks. Time courses of an independent component comprising the insular cortices of both hemispheres showed stronger spectral power at 0.12 to 0.25 Hz in patients than in control subjects, with the largest difference at 0.16 Hz. A similar but weaker effect was seen in the anterior cingulate cortex, whereas activity of the precuneus and early visual cortex, used as a control site, did not differ between the groups. In the patient group, seed point-based correlation analysis revealed altered spatial connectivity between insulae and anterior cingulate cortex. The results imply both temporally and spatially aberrant activity of the affective pain-processing areas in patients suffering from chronic pain. The accentuated 0.12- to 0.25-Hz fluctuations in the patient group might be related to altered activity of the autonomic nervous system.

Role of Endocannabinoids in Neuron-Glial Crosstalk

Evidence shows bidirectional crosstalk between neurons and glia, suggesting that glia play an active role in synaptic plasticity leading to chronic pain. Importantly, gliosis has been implicated in the development and maintenance of hyperalgesia or allodynia following chronic inflammation or nerve injury. Anandamide (AEA) and 2- arachidonoylglycerol (2-AG), or the lipoamino acid N-arachydonoyldopamine (NADA), are fatty acid derivative neuro- transmitters, named endocannabinoids (eCBs). These perform several biological actions, via the activation of cannabinoid type 1 and 2 (CB1/CB2) receptors belonging to the G-protein-coupled receptor family. The eCBs are produced on de- mand by neurons or glial cells and it has been suggested that they might be involved in the crosstalk between astrocytes, microglia, oligodendrocytes and neurons. In chronic pain, the modified glial or neural activity also seems to be associated with changes in eCB levels in pain processing areas either in the spinal cord or the brain. The activation of the eCB sys- tem in microglia or astrocytes could be crucial in modulating axonal growth and synaptogenesis at the base of neural phe- notypic changes. Furthermore, changes in eCBs levels have been suggested to affect the destiny of cells: death or survival may depend on a specific pain condition. Thus, although eCBs are emerging as neurotransmitters responsible for the regu- lation of glia-neuron crosstalk in chronic pain, the precise mechanisms leading to eCB production, the origin and the time- course of eCB release, the eCB release switch from one cell type to the other and their movement or catabolism across the glial or neural cell membrane nevertheless still remain unknown. These issues together with alternative eCB targets will be addressed in the current review.

Brain perfusion in fibromyalgia patients and its differences between responders and poor responders to gabapentin

IntroductionThe aim of the present study was to determine the brain areas associated with fibromyalgia, and whether pretreatment regional cerebral blood flow (rCBF) can predict response to gabapentin treatment.MethodsA total of 29 women with fibromyalgia and 10 healthy women (without pain) matched for age were finally enrolled in the study. Technetium-99m ethyl cysteinate dimer single photon emission computed tomography (99mTc-ECD SPECT) was performed in the fibromyalgia patients and controls. A voxel-by-voxel group analysis was performed using Statistic Parametric Mapping 5 (SPM5). After treatment with gabapentin, 16 patients were considered 'responders', with decrease in pain of greater than 50% as evaluated by visual analogue scale (VAS). The remaining 13 patients were considered 'poor responders'.ResultsWe observed rCBF abnormalities, compared to control subjects, in fibromyalgia including hypoperfusion in the left culmen and hyperperfusion in the right precentral gyrus, right posterior cingulate, right superior occipital gyrus, right cuneus, left inferior parietal lobule, right middle temporal gyrus, left postcentral gyrus, and left superior parietal lobule. Compared to responders, poor responders exhibited hyperperfusion in the right middle temporal gyrus, left middle frontal gyrus, left superior frontal gyrus, right postcentral gyrus, right precuneus, right cingulate, left middle occipital gyrus, and left declive. The right middle temporal gyrus, left superior frontal gyrus, right precuneus, left middle occipital gyrus, and left declive exhibited high positive likelihood ratios.ConclusionsThe present study revealed brain regions with significant hyperperfusion associated with the default-mode network, in addition to abnormalities in the sensory dimension of pain processing and affective-attentional areas in fibromyalgia patients. Furthermore, hyperperfusion in these areas was strongly predictive of poor response to gabapentin.

Language and the pain experience

People in persistent pain have been reported to pay increased attention to specific words or descriptors of pain. The amount of attention paid to pain or cues for pain (such as pain descriptors), has been shown to be a major factor in the modulation of persistent pain. This relationship suggests the possibility that language may have a role both in understanding and managing the persistent pain experience. The aim of this paper is to describe current models of neuromatrices for pain and language, consider the role of attention in persistent pain states and highlight discrepancies, in previous studies based on the McGill Pain Questionnaire (MPQ), of the role of attention on pain descriptors. The existence of a pain neuromatrix originally proposed by Melzack (1990) has been supported by emerging technologies. Similar technologies have recently allowed identification of multiple areas of involvement for the processing of auditory input and the construction of language. As with the construction of pain, this neuromatrix for speech and language may intersect with neural systems for broader cognitive functions such as attention, memory and emotion. A systematic search was undertaken to identify experimental or review studies, which specifically investigated the role of attention on pain descriptors (as cues for pain) in persistent pain patients. A total of 99 articles were retrieved from six databases, with 66 articles meeting the inclusion criteria. After duplicated articles were eliminated, the remaining 41 articles were reviewed in order to support a link between persistent pain, pain descriptors and attention. This review revealed a diverse range of specific pain descriptors, the majority of which were derived from the MPQ. Increased attention to pain descriptors was consistently reported to be associated with emotional state as well as being a significant factor in maintaining persistent pain. However, attempts to investigate the attentional bias of specific pain descriptors highlighted discrepancies between the studies. As well as the diversity of pain descriptors used in studies, they were inconsistently categorized into domains of pain. A lack of consistent bias towards certain pain descriptors was observed, and may be explained simply by the fact that the words provided are not those which subjects themselves would use. These findings suggest that the multidimensional and individual nature of the persistent pain experience may not be adequately explained by pain questionnaires such as the MPQ. Personalized pain descriptors may communicate the pain experience more appropriately, but may also contribute to an increased sensitivity of cortical pain processing areas by capturing increased attention for that individual. The language used as part of communication between therapists and people with persistent pain may provide an, as yet, unexplored adjunct strategy in management.