Endometriosis, psychiatric comorbidities and neuroimaging: Estimating the odds of an endometriosis brain.

Endometriosis is a chronic pain disorder that affects young women, impairing their physical, mental and social well-being. Apart from personal suffering, it imposes a significant economic burden on the healthcare system. We analyzed studies reporting comorbid mental disorders in endometriosis based on the ICD/DSM criteria, discussing them in the context of available neuroimaging studies. We postulate that at least one-third of endometriosis patients suffer from mental disorders (mostly depression or anxiety) and require psychiatric or psychotherapeutic support. According to three neuroimaging studies involving patients with endometriosis, brain regions related not only to pain processing but also to emotion, cognition, self-regulation and reward likely constitute the so-called "endometriosis brain". It is not clear, however, whether the neurobiological changes seen in these patients are caused by chronic pain, mental comorbidities or endometriosis itself. Given the paucity of high-quality data on mental comorbidities and neurobiological correlates in endometriosis, further research is needed.

Sonic Hedgehog Signaling Pathway: A Role in Pain Processing.

Pain, as one of the most prevalent clinical symptoms, is a complex physiological and psychological activity. Long-term severe pain can become unbearable to the body. However, existing treatments do not provide satisfactory results. Therefore, new mechanisms and therapeutic targets need to be urgently explored for pain management. The Sonic hedgehog (Shh) signaling pathway is crucial in embryonic development, cell differentiation and proliferation, and nervous system regulation. Here, we review the recent studies on the Shh signaling pathway and its action in multiple pain-related diseases. The Shh signaling pathway is dysregulated under various pain conditions, such as pancreatic cancer pain, bone cancer pain, chronic post-thoracotomy pain, pain caused by degenerative lumbar disc disease, and toothache. Further studies on the Shh signaling pathway may provide new therapeutic options for pain patients.

Identification of patients with chronic migraine by using sensory-evoked oscillations from the electroencephalogram classifier.

BACKGROUND: To examine whether the modulating evoked cortical oscillations could be brain signatures among patients with chronic migraine, we investigated cortical modulation using an electroencephalogram with machine learning techniques. METHODS: We directly record evoked electroencephalogram activity during nonpainful, painful, and repetitive painful electrical stimulation tasks. Cortical modulation for experimental pain and habituation processing was analyzed and used to differentiate patients with chronic migraine from healthy controls using a validated machine-learning model. RESULTS: This study included 80 participants: 40 healthy controls and 40 patients with chronic migraine. Evoked somatosensory oscillations were dominant in the alpha band. Longer latency (nonpainful and repetitive painful) and augmented power (nonpainful and repetitive painful) were present among patients with chronic migraine. However, for painful tasks, alpha increases were observed among healthy controls. The oscillatory activity ratios between repetitive painful and painful tasks represented the frequency modulation and power habituation among healthy controls, respectively, but not among patients with chronic migraine. The classification models with oscillatory features exhibited high performance in differentiating patients with chronic migraine from healthy controls. CONCLUSION: Altered oscillatory characteristics of sensory processing and cortical modulation reflected the neuropathology of patients with chronic migraine. These characteristics can be reliably used to identify patients with chronic migraine using a machine-learning approach.

Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice.

Although pain is a prevalent nonmotor symptom in Parkinson's disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD.

Synaptic Targets of Glycinergic Neurons in Laminae I-III of the Spinal Dorsal Horn.

A great deal of evidence supports the inevitable importance of spinal glycinergic inhibition in the development of chronic pain conditions. However, it remains unclear how glycinergic neurons contribute to the formation of spinal neural circuits underlying pain-related information processing. Thus, we intended to explore the synaptic targets of spinal glycinergic neurons in the pain processing region (laminae I-III) of the spinal dorsal horn by combining transgenic technology with immunocytochemistry and in situ hybridization accompanied by light and electron microscopy. First, our results suggest that, in addition to neurons in laminae I-III, glycinergic neurons with cell bodies in lamina IV may contribute substantially to spinal pain processing. On the one hand, we show that glycine transporter 2 immunostained glycinergic axon terminals target almost all types of excitatory and inhibitory interneurons identified by their neuronal markers in laminae I-III. Thus, glycinergic postsynaptic inhibition, including glycinergic inhibition of inhibitory interneurons, must be a common functional mechanism of spinal pain processing. On the other hand, our results demonstrate that glycine transporter 2 containing axon terminals target only specific subsets of axon terminals in laminae I-III, including nonpeptidergic nociceptive C fibers binding IB4 and nonnociceptive myelinated A fibers immunoreactive for type 1 vesicular glutamate transporter, indicating that glycinergic presynaptic inhibition may be important for targeting functionally specific subpopulations of primary afferent inputs.

Chronic cluster headache: A study of the telencephalic and cerebellar cortical thickness.

PURPOSE: Previous studies on brain morphological alterations in chronic cluster headache revealed inconsistent findings. METHOD: The present cross-sectional explorative study determined telencephalic and cerebellar cortex thickness alterations in a relatively wide sample of chronic cluster headache patients (n = 28) comparing them to matched healthy individuals. RESULTS: The combination of two highly robust state-of-the-art approaches for thickness estimation (Freesurfer, CERES), strengthened by functional characterization of the identified abnormal regions, revealed four main results: chronic cluster headache patients show 1) cortical thinning in the right middle cingulate cortex, left posterior insula, and anterior cerebellar lobe, regions involved in nociception's sensory and sensory-motor aspects and possibly in autonomic functions; 2) cortical thinning in the left anterior superior temporal sulcus and the left collateral/lingual sulcus, suggesting neuroplastic maladaptation in areas possibly involved in social cognition, which may promote psychiatric comorbidity; 3) abnormal functional connectivity among some of these identified telencephalic areas; 4) the identified telencephalic areas of cortical thinning present robust interaction, as indicated by the functional connectivity results, with the left posterior insula possibly playing a pivotal role. CONCLUSION: The reported results constitute a coherent and robust picture of the chronic cluster headache brain. Our study paves the way for hypothesis-driven studies that might impact our understanding of the pathophysiology of this condition.

Cortico-spinal imaging to study pain.

Functional magnetic resonance imaging of the brain has helped to reveal mechanisms of pain perception in health and disease. Recently, imaging approaches have been developed that allow recording neural activity simultaneously in the brain and in the spinal cord. These approaches offer the possibility to examine pain perception in the entire central pain system and in addition, to investigate cortico-spinal interactions during pain processing. Although cortico-spinal imaging is a promising technique, it bears challenges concerning data acquisition and data analysis strategies. In this review, we discuss studies that applied simultaneous imaging of the brain and spinal cord to explore central pain processing. Furthermore, we describe different MR-related acquisition techniques, summarize advantages and disadvantages of approaches that have been implemented so far and present software that has been specifically developed for the analysis of spinal fMRI data to address challenges of spinal data analysis.

Quantitative sensory testing in patients with the muscle pain subtype of temporomandibular disorder: a systemic review and meta-analysis.

OBJECTIVES: This meta-analysis aimed to evaluate quantitative sensory testing (QST) evidence for pain processing in patients with the muscle pain subtype of temporomandibular disorders (mTMD). MATERIALS AND METHODS: A comprehensive systematic electronic search strategy was performed in online literature databases. All full-text observational studies published up to July 2021 with the aim of investigating pain sensitization in humans with mTMD using QST measures were eligible for inclusion. Meta-analysis of QST data was performed using a random effects model, which included results comparing patients with mTMD to healthy controls, and standard mean difference (SMD) results were analyzed. RESULTS: Twelve studies with 732 participants (371 patients with mTMD and 361 healthy controls) were analyzed following screening and quality appraisal. Compared with healthy controls, patients with mTMD had significantly lower pressure pain threshold (SMD - 1.10, 95% confidence interval [CI] - 1.52 to - 0.68) with high heterogeneity (Tau2 = 0.61, I2 = 86%), and significantly lower mechanical pain threshold (SMD - 0.64, 95% CI - 0.95 to - 0.32) with no heterogeneity (Tau2 = 0.00, I2 = 0%). No difference was observed in the cold pain threshold (SMD 0.16, 95% CI - 0.13 to 0.45), heat pain threshold (SMD - 0.13, 95% CI - 0.40 to 0.15), and wind-up ratio (SMD 0.63, 95% CI - 0.11 to 1.38) between patients with mTMD and healthy controls. Other QST parameters were also discussed. CONCLUSIONS: The study results suggest that the pain processing of deep tissues is likely sensitized in mTMD and calls for more QST studies with standard procedures to reduce inter-study heterogeneity. CLINICAL RELEVANCE: The major findings of this meta-analysis support using PPT to examine the pain processing in patients with mTMD in clinical scenario.

Dorsal Root Ganglion Stimulation Normalizes Measures of Pain Processing in Patients with Chronic Low-Back Pain: A Prospective Pilot Study using Quantitative Sensory Testing.

BACKGROUND: Dorsal root ganglion stimulation (DRG-S) is used as a treatment for chronic low-back pain (CLBP), although its underlying mechanisms remain elusive. CLBP patients have been found to have reduced mechanoreceptive perception, reduced endogenous analgesia, as well as deep-tissue hyperalgesia when compared with healthy controls. Using quantitative sensory testing (QST), we studied if DRG-S in CLBP patients results in changes in pain processing. METHODS: Quantitative sensory testing was performed in patients before trial implantation of a DRG-S system for CLBP and just before the trial lead removal or at 1-month follow-up after the permanent implant. We determined the pressure pain threshold (PPT) and mechanical detection threshold (MDT) at the most painful lower-back location. PPT was also measured on the contralateral shoulder as a control. We obtained a measure of endogenous inhibitory pain modulation using conditioned pain modulation (CPM). RESULTS: We enrolled 11 patients (60 ± 16 years). Pain decreased from 8.5 ± 1.0 at baseline to 2.0 ± 1.5 on a 0-10 numerical rating scale with DRG-S (P < 0.01). From baseline to with DRG-S, PPT on the most painful location on the low back increased from 28.7 ± 13.6 to 43.4 ± 17.2 N/cm2 (P < 0.01). MDT on the same location decreased from 8.1 ± 10.4 to 3.4 ± 4.7 mN (P = 0.07). PPT on the control location and CPM did not change significantly. CONCLUSIONS: Our results suggest that DRG-S in CLBP patients reduces deep-tissue hyperalgesia in the low back, while improving mechanoreceptive perception. These changes in both neuropathic and nociceptive components of CLBP were accompanied by clinical improvements in pain and function.

Recovery of Impaired Endogenous Pain Modulation by Dopaminergic Medication in Parkinson's Disease.

BACKGROUND: Of patients with Parkinson's disease (PD), 30% to 85% report pain. However, mechanisms underlying this pain remain unclear. In line with known neuroanatomical impairments, we hypothesized that pain in PD is caused by alterations in emotional-motivational as opposed to sensory-discriminative pain processing and that dopamine recovers the capacity for endogenous emotional-motivational pain modulation in patients with PD. METHODS: A total of 20 patients with PD played a random reward paradigm with painful heat stimuli in addition to assessments of pain sensitivity once with and once without levodopa. RESULTS: Levodopa increased endogenous pain inhibition in terms of perceived pain intensity and un/pleasantness compared with a medication off state. Higher clinical pain was associated with higher increases in pain inhibition. Levodopa did not affect heat pain threshold, tolerance, or temporal summation. CONCLUSION: Patients with PD seem to be predominately impaired in emotional-motivational as opposed to sensory-discriminative pain processing. A differential understanding of pain in PD is urgently needed because effective treatment strategies are lacking. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

EphrinB2/ephB2-mediated myenteric synaptic plasticity: mechanisms underlying the persistent muscle hypercontractility and pain in postinfectious IBS.

Patients with irritable bowel syndrome (IBS) show pain hypersensitivity and smooth muscle hypercontractility in response to colorectal distension (CRD). Synaptic plasticity, a key process of memory formation, in the enteric nervous system may be a novel explanation. This study aimed to explore the regulatory role of ephrinB2/ephB2 in enteric synaptic plasticity and colonic hyperreactive motility in IBS. Postinfectious (PI)-IBS was induced by Trichinella spiralis infection in rats. Isometric contractions of colonic circular muscle strips, particularly neural-mediated contractions, were recorded ex vivo. Meanwhile, ephrinB2/ephB2-mediated enteric structural and functional synaptic plasticity were assessed in the colonic muscularis, indicating that ephrinB2 and ephB2 were located on enteric nerves and up-regulated in the colonic muscularis of PI-IBS rats. Colonic hypersensitivity to CRD and neural-mediated colonic hypercontractility were present in PI-IBS rats, which were correlated with increased levels of cellular homologous fos protein (c-fos) and activity-regulated cystoskeleton-associated protein (arc), the synaptic plasticity-related immediate early genes, and were ameliorated by ephB2Fc (an ephB2 receptor blocker) or MK801 (an NMDA receptor inhibitor) exposure. EphrinB2/ephB2 facilitated synaptic sprouting and NMDA receptor-mediated synaptic potentiation in the colonic muscularis of PI-IBS rats and in the longitudinal muscle-myenteric plexus cultures, involving the Erk-MAPK and PI3K-protein kinase B pathways. In conclusion, ephrinB2/ephB2 promoted the synaptic sprouting and potentiation of myenteric nerves involved in persistent muscle hypercontractility and pain in PI-IBS. Hence, ephrinB2/ephB2 may be an emerging target for the treatment of IBS.-Zhang, L., Wang, R., Bai, T., Xiang, X., Qian, W., Song, J., Hou, X. EphrinB2/ephB2-mediated myenteric synaptic plasticity: mechanisms underlying the persistent muscle hypercontractility and pain in postinfectious IBS.

Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis.

Increased colonic bile acid (BA) exposure, frequent in diarrhea-predominant irritable bowel syndrome (IBS-D), can affect gut function. Nerve growth factor (NGF) is implicated in the development of visceral hypersensitivity (VH). In this study, we tested the hypothesis that BAs cause VH via mucosal mast cell (MMC)-to-nociceptor signaling, which involves the farnesoid X receptor (FXR)/NGF/transient receptor potential vanilloid (TRPV)1 axis. BAs were intracolonically administered to rats for 15 d. Visceral sensitivity to colorectal distention and colonic NGF expression were examined. BAs caused VH, an effect that involved MMC-derived NGF and was accompanied by enhanced TRPV1 expression in the dorsal root ganglia. Anti-NGF treatment and TRPV1 antagonism inhibited BA-induced VH. BAs induced NGF mRNA and protein expression and release in cultured mast cells. Colonic supernatants from patients with IBS-D with elevated colonic BA content transcriptionally induced NGF expression. In FXR-/- mice, visceral sensitivity and colonic NGF expression were unaltered after BA treatment. Pharmacological antagonism and FXR silencing suppressed BA-induced NGF expression and release in mast cells. Mitogen-activated protein kinase kinase (MKK) 3/6/p38 MAPK/NF-κB signaling was mechanistically responsible for FXR-mediated NGF expression and secretion. The findings show an MMC-dependent and FXR-mediated pronociceptive effect of BAs and identify the BA/FXR/NGF/TRPV1 axis as a key player in MMC-to-neuron communication during pain processing in IBS.-Li, W.-T., Luo, Q.-Q., Wang, B., Chen, X., Yan, X.-J., Qiu, H.-Y., Chen, S.-L. Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis.

Cannabinoid Receptor Type 1 and Its Role as an Analgesic: An Opioid Alternative?

Understanding how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the increased financial burden to the medical care system. Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Modulation of the endocannabinoid system offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic). Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation. One major issue is the presence of psychotropic side effects associated with D9-tetrahydrocannabinol (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect prevents the appropriate degree of analgesia . Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells. The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release. This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R's role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception. We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoidmediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons. This work stands to reveal long-standing controversies in the cannabinoid analgesia area that have had an impact on failed clinical trials and implementation of therapeutics targeting this system.

Altered cerebral pain processing of noxious stimuli from inflamed joints in rheumatoid arthritis: An event-related fMRI study.

OBJECTIVE: To our knowledge, this is the first study assessing brain activation in response to painful stimulation over disease-relevant (finger joint) vs. neutral area (thumb nail) in patients suffering from rheumatoid arthritis (RA) compared to healthy controls (HC). METHOD: Thirty-one RA patients and 23 HC underwent functional magnetic resonance imaging (fMRI) while stimulated with subjectively calibrated painful pressures corresponding to a pain sensation of 50 mm on a 100 mm VAS scale (P50) at disease-affected finger joint and thumbnail (left hand), and corresponding sites in HC. RESULTS: Compared to controls, RA patients had significantly increased pain sensitivity (lower P50) at the inflamed joints but not at the thumbnail. RA patients exhibited significantly less activation in regions related to pain- and somatosensory processing (S1, M1, anterior insula, S2, SMG and MCC) during painful joint stimulation, compared to HC. No group difference in cerebral pain processing was found for the non-affected thumbnail. Within RA patients, significantly less brain activation was found in response to painful stimulation over disease-affected joint compared to non-affected thumbnail in bilateral S1, bilateral S2, and anterior insula. Further, RA patients exhibited a right-sided dlPFC deactivation, psycho-physiologically interacting (PPI) with the left dlPFC in response to painful stimulation at disease-affected joints. CONCLUSION: The results indicate normal pain sensitivity and cerebral pain processing in RA for non-affected sites, while the increased sensitivity at inflamed joints indicate peripheral/spinal sensitization. Brain imaging data suggest that disease-relevant pain processing in RA is marked by aberrations and a failed initiation of cortical top-down regulation.

Current understanding of thalamic structure and function in migraine.

OBJECTIVE: To review and discuss the literature on the role of thalamic structure and function in migraine. DISCUSSION: The thalamus holds an important position in our understanding of allodynia, central sensitization and photophobia in migraine. Structural and functional findings suggest abnormal functional connectivity between the thalamus and various cortical regions pointing towards an altered pain processing in migraine. Pharmacological nociceptive modulation suggests that the thalamus is a potential drug target. CONCLUSION: A critical role for the thalamus in migraine-related allodynia and photophobia is well established. Additionally, the thalamus is most likely involved in the dysfunctional pain modulation and processing in migraine, but further research is needed to clarify the exact clinical implications of these findings.

Ictal headache: Insights from two cases.

BACKGROUND: We report the first literature description of ictal epileptic headaches closely mimicking glossopharyngeal neuralgia and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. CASE 1: A 37-year-old man complained of short-lasting, electric-shock like headache, confined to the pharynx. During the episodes, he could not speak because he felt "words blocked at the throat". An EEG recorded epileptic discharges concomitant with headache; a brain MRI disclosed frontal polymicrogyria. CASE 2: A 66-year-old man complained of short-lasting, right periocular headache, associated with ipsilateral ptosis, conjunctival injection and lacrimation. Some episodes were followed by tonic contraction of the right facial and limb muscles; on one occasion, headache was followed by a generalized seizure. A brain MRI revealed hippocampal abnormalities. DISCUSSION: These cases highlight the complex relationship between headache and epilepsy, and suggest a possible contribution of cortical structures to the genesis of paroxysmal headaches such as glossopharyngeal neuralgia and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

[Influence of early childhood stress exposure and traumatic life events on pain perception]. / Einfluss frühkindlicher Stresserfahrungen und traumatisierender Lebensereignisse auf das Schmerzempfinden.

Adult pain perception is influenced substantially by interactions between mind, body, and social environment during early life. Early stress exposure and traumatic life events induce powerful psychophysical stress reactions that exert multiple neurofunctional processes. This has significant implications for pain perception and pain processing. As part of this review, the complex relationships between traumatic stress experiences and associated psychobiological mechanisms of chronic pain will be discussed. Based on selected studies, psychophysiological findings are presented and possible underlying mechanisms are discussed. The article concludes with a discussion of potential implications for treatment.

Structural Gray Matter Alterations in Chronic Migraine: Implications for a Progressive Disease?

OBJECTIVE: To identify possible gray matter alterations in patients with chronic migraine using voxel-based morphometry (VBM). BACKGROUND: VBM studies demonstrate structural alterations of gray matter (GM) in episodic migraine (EM) patients. Some of these alterations correlate with disease duration and headache frequency. We assessed GM alterations in chronic migraine (CM) and EM to evaluate the concept of migraine as a progressive disorder of the brain. METHODS: Individually age and sex-matched subjects with CM or EM (both without aura) and healthy controls (n = 21 per group) underwent magnetic resonance imaging-based VBM. RESULTS: We found an increase of GM volume (GMV) in amygdala and putamen, in CM compared to controls. GMV of EM compared to controls did not differ statistically significantly. Headache frequency in all migraineurs (EM and CM) correlated positively with GMV in putamen, frontal and temporal gyrus and negatively in left cuneus. CONCLUSION: CM is associated with structural changes in brain regions involved in pain processing but also in affective and cognitive aspects of pain. Some GM alterations are correlated with headache frequency assessed in EM and CM. The findings support the assumption that chronic pain alters brain plasticity. GMV increase may reflect a remodeling of the central nervous system due to repetitive headache attacks leading to chronic sensitization and a continuous ictal-like state of the brain in chronic migraineurs.

Assessing pain in patients with chronic disorders of consciousness: Are we heading in the right direction?

The deterioration of sensory-motor integration within the pain matrix in patients with chronic Disorders of Consciousness (DoC) is one of the principal mechanisms responsible for non-conscious pain perception. The present study aimed to assess whether the variability in the inter-peak interval (IPI) between the N2 and P2 components of laser evoked potentials (LEP) could represent an objective marker of the behavioral responsiveness to nociceptive stimulation, as measured by the Nociception Coma Scale-Revised (NCS-R), and regardless of the sensory part of pain processing. We found that only IPI variability showed a significant correlation with NCS-R score, independently of the stimulation intensity (that influences the sensory part of pain processing). It was thus concluded that IPI variability might represent an objective measure of pain processing, which may help clinicians in the development of effective pain management strategies.

Central Pain Processing in Patients with Shoulder Pain: A Review of the Literature.

BACKGROUND: Shoulder pain is a common health problem in which changes in shoulder structure cannot always explain the patient's perceived pain. Central sensitization (CS) might play a role in a subgroup of these patients. METHODS: The literature was systematically reviewed to address the role of CS in patients with shoulder pain. Electronic databases PubMed and Web of Knowledge were searched for relevant studies. RESULTS: Eighteen full-text articles were included, methodological quality was scored, and information was extracted. Studies were clustered on those studying patients with musculoskeletal (MSK) shoulder pain and those studying patients with hemiplegic shoulder pain (HSP). In particular, quantitative sensory testing revealed hyperalgesia for pressure pain in the MSK group, whereas these results were inconsistent in patients with HSP. Conditioned pain modulation was reduced in patients with MSK shoulder pain, but functioned normally in the HSP group. CONCLUSION: This review has shown that great progress has been made toward a better understanding of neurophysiologic pain mechanisms in patients with shoulder pain. The presence of generalized mechanical hyperalgesia, allodynia, and impaired conditioned pain modulation in patients with MSK shoulder pain indicates the involvement of the central nervous system. Widespread somatosensory abnormalities observed in patients with HSP could suggest a central origin for their shoulder pain and predispose patients with HSP to develop CS, although results are inconsistent. Additional research is required adopting different assessment methods (especially dynamic methods) to establish the role of CS in patients with shoulder pain.