Influence Pain Processing Research Articles

Non-Invasive Brain Stimulation Beyond the Motor Cortex: A Systematic Review and Meta-Analysis Exploring Effects on Quantitative Sensory Testing in Clinical Pain.

Non-invasive brain stimulation (NIBS) has been investigated increasingly as a means of treating pain. The effectiveness of NIBS in the treatment of pain has traditionally focused upon protocols targeting the primary motor cortex (M1). However, over time, the effectiveness of M1 NIBS has been attributed to effects on interconnected cortical and subcortical sites rather than M1 itself. While previous reviews have demonstrated the effectiveness of non-M1 NIBS in improving subjective reports of pain intensity, the neurophysiological mechanisms underlying these effects remain incompletely understood. As chronic pain is associated with pain hypersensitivity and impaired endogenous descending pain modulation, it is plausible that non-M1 NIBS promotes analgesic effects by influencing these processes. The aim of this systematic review and meta-analysis was therefore to evaluate the effect of NIBS over non-M1 sites on quantitative sensory testing measures in clinical pain populations. A systematic search of electronic databases was conducted from inception to January 2024. Included articles (13trials, n = 565 participants) were appraised using PEDro and GRADE and a random effects model was used to meta-analyse outcomes where possible. A small number of studies found that NIBS applied to DLPFC may improve pain modulation in patients with fibromyalgia, and that stimulation of the posterior superior insula and prefrontal cortex could improve pain sensitivity in chronic neuropathic and osteoarthritic pain, respectively. However, findings varied between studies and there remains a paucity of primary research. This review indicates that current literature does not provide clear evidence that NIBS over non-M1 sites influences pain processing.

Effects of virtual reality on psychophysical measures of pain: superiority to imagination and nonimmersive conditions.

Virtual reality (VR) has been shown to be effective in pain management. However, to date, little is known about the mechanisms by which immersive experiences influence pain processing. The aim of this study was to investigate the direct effects of an immersive VR environment on the perception of experimental pain in individuals with chronic pain and pain-free controls. The immersion in a VR landscape was compared with mental imagery and a nonimmersive control condition. Using a randomized within-crossover design, pressure pain detection and tolerance thresholds, spatial and temporal summation (SSP, TSP), and conditioned pain modulation (CPM) were measured in 28 individuals with chronic pain and 31 pain-free controls using phasic cuff pressure on the legs. Direct comparison between the groups showed that although individuals with pain had significantly lower pain thresholds, reduced CPM effects, and increased TSP, the VR condition had the same pain-inhibitory effect on pain thresholds as in pain-free controls. Conditioned pain modulation effects were reduced by all conditions compared with baseline. There were no significant differences between conditions and baseline for TSP and SSP. Overall, pain modulatory effects were largest for VR and smallest for imagery. These results demonstrate that immersion in a VR environment has an increasing effect on pain thresholds, reduces pain inhibition in a CPM paradigm, and has no effects on TSP. This applies for participants with chronic pain and pain-free controls. These VR effects exceeded the effects of mental imagery on the nonimmersive control condition. This indicates that VR effectively modulates pain perception in both patients and controls irrespective of differences in pain perception.

Exploring the Tryptophan Metabolic Pathways in Migraine-Related Mechanisms

Migraine is a complex neurovascular disorder, which causes intense socioeconomic problems worldwide. The pathophysiology of disease is enigmatic; accordingly, therapy is not sufficient. In recent years, migraine research focused on tryptophan, which is metabolized via two main pathways, the serotonin and kynurenine pathways, both of which produce neuroactive molecules that influence pain processing and stress response by disturbing neural and brain hypersensitivity and by interacting with molecules that control vascular and inflammatory actions. Serotonin has a role in trigeminal pain processing, and melatonin, which is another product of this pathway, also has a role in these processes. One of the end products of the kynurenine pathway is kynurenic acid (KYNA), which can decrease the overexpression of migraine-related neuropeptides in experimental conditions. However, the ability of KYNA to cross the blood-brain barrier is minimal, necessitating the development of synthetic analogs with potentially better pharmacokinetic properties to exploit its therapeutic potential. This review summarizes the main translational and clinical findings on tryptophan metabolism and certain neuropeptides, as well as therapeutic options that may be useful in the prevention and treatment of migraine.

Interoception visualization relieves acute pain

Interoception is the sensation of the physiological state inside one’s body. Growing evidence suggests that visual feedback of interoception improves body self-consciousness (BSC) and reduces pain perception among patients with chronic pain. However, whether the integration of exteroception and interoception influences pain processing in healthy individuals remains largely unknown. To examine this question, we combined the rubber hand illusion (RHI) paradigm with visualized interoception –flashing of an LED light on the rubber hand synchronously or asynchronously with participants’ real-time heartbeats. Under these conditions, we tested pain thresholds and corresponding event-related potentials. The interoceptive visual feedback inhibited the P2 component of pain, and the RHI inhibited pre-stimulus alpha-band brain activity. BSC had no significant effect on the processing of pain. These findings demonstrate that interoceptive signals with visual feedback inhibit pain processing, and that this psychophysiological process is largely independent of reported self-consciousness, in healthy individuals.

Investigations of the functional role of connexin36 in sensory and sympathetic systems in adult mice

Electrical synapses formed by gap junctions composed of connexin36 (Cx36) occur between neurons in widespread areas of the mammalian central nervous system and enable neuron-to-neuron electrical coupling. We previously reported that dorsal root ganglia (DRG) sensory neurons containing transient receptor potential (TRP) channels, including TRPV1 and TRPM8, and those containing substance P in nociceptive DRG neurons express high levels of Cx36. It has also been reported that Cx36 is expressed in sympathetic preganglionic neurons (SPNs). Here we examined the functional roles of electrical synapses in primary afferent and SPN neural networks by using mice with global knockout (ko) of the Cx36 gene (Cx36 ko mice) and their wildtype (Wt) counterparts. Based on previous evidence showing that spinal neurons in Cx36 ko mice have attenuated responses to nociceptive stimulation when examined ex vivo; our hypothesis was that responses to nociceptive stimulation would be attenuated in vivo in intact Cx36 ko mice compared to Wt. To examine the role of coupling between DRG neurons, in vivo imaging was used to measure the fluorescence signal of Evans blue dye extravasation in skin of live animals after nociceptor activation. The extravasation levels relative to baseline fluorescence were 61.7±4% in Wt mice and 33.2±7% Cx36 ko mice (n=5 matched pairs, all males) after hind paw pinprick. Xylene applied topically on one of the ears induced more extravasation in the wt (255.4 ±3%) than in the Cx36 ko mice (204.6 ±1%). Using a fibre optic blood pressure monitoring system, we found that topical xylene application under isoflurane anesthesia changes the blood pressure, the heart rate, and the respiratory rate additionally to evoking the plasma extravasation. The attenuated extravasation response in the Cx36 ko mice suggests that electrical synapses known to occur between peripheral unmyelinated sensory fibers impact signal transmission from peripheral nerve endings and release other mediators that cause this response. To examine functional roles of coupling between SPNs, we compared physiological responses to colorectal distension (CRD) in Wt and Cx36 ko) mice in mice under isoflurane anesthesia. Mean arterial blood pressure during CRD increased to 108 ± 8% of baseline in Wt mice (n = 7), while this parameter did not change significantly in Cx36 ko mice (n = 12), but did show a tendency to decrease (to 97 ± 2%). Heart rate did not show significant changes, but we found that respiratory rate changes also occurred as part of the systemic response to CRD in both lines of mice. These data show differential regulation of sympathetic activity associated with electrical coupling between SPNs in Wt vs. Cx36 ko mice. In Wt mice with mid-thoracic complete spinal transection (n = 2), CRD also increased blood pressure when tested at 6-8 days after injury. The results taken together, point to the possibility that Cx36 in DRG and SPNs of adult mice has a significant functional role and warrant further research to understand how the presence of Cx36 in DRG and SPNs influences pain processing and associated autonomic responses.

The Effects of Brief Social Exclusion on Pain Perception and Pain Memory in Adolescents

PurposePeer relationship problems are associated with pain complaints; however, experimental data linking the two are lacking. The purpose of this study was to determine whether brief social exclusion influences pain processing in healthy adolescents. MethodsA total of 40 adolescents were randomly assigned to a social exclusion or social inclusion/control condition; they then completed a cold pressor task and provided pain ratings. Two weeks later, participants provided ratings for their memory for pain during the cold pressor (nanalyzed = 33). ResultsSocial exclusion had no immediate effect on pain ratings; however, adolescents assigned to the exclusion condition recalled the pain as being less intense compared with adolescents in the inclusion/control condition. ConclusionsIn healthy adolescents, brief social exclusion may represent an emotionally salient event that inhibits subsequent rumination or focus on physical pain. Findings should be replicated, and future studies should include youth with chronic pain and/or personal histories of peer victimization.

Neuronal aromatase expression in pain processing regions of the medullary and spinal cord dorsal horn.

In both acute and chronic pain conditions, women tend to be more sensitive than men. This sex difference may be regulated by estrogens, such as estradiol, that are synthesized in the spinal cord and brainstem and act locally to influence pain processing. To identify a potential cellular source of local estrogen, here we examined the expression of aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol. Our studies focused on primary afferent neurons and on their central targets in the spinal cord and medulla as well as in the nucleus of the solitary tract, the target of nodose ganglion-derived visceral afferents. Immunohistochemical staining in an aromatase reporter mouse revealed that many neurons in laminae I and V of the spinal cord dorsal horn and caudal spinal trigeminal nucleus and in the nucleus of the solitary tract express aromatase. The great majority of these cells also express inhibitory interneuron markers. We did not find sex differences in aromatase expression and neither the pattern nor the number of neurons changed in a sciatic nerve transection model of neuropathic pain or in the Complete Freund's adjuvant model of inflammatory pain. A few aromatase neurons express Fos after cheek injection of capsaicin, formalin, or chloroquine. In total, given their location, these aromatase neurons are poised to engage nociceptive circuits, whether it is through local estrogen synthesis or inhibitory neurotransmitter release.

Effects of a Pain Catastrophizing Induction on Sensory Testing in Women with Chronic Low Back Pain: A Pilot Study.

Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic low back pain were assigned in blocks to an experimental condition, either a psychologist-led 10-minute pain catastrophizing induction or a control (10-minute rest period). All participants underwent a baseline round of several quantitative sensory testing (QST) tasks, followed by the pain catastrophizing induction or the rest period, and then a second round of the same QST tasks. The catastrophizing induction appeared to increase state pain catastrophizing levels. Changes in QST pain were detected for two of the QST tasks administered, weighted pin pain and mechanical allodynia. Although there is a need to replicate our preliminary results with a larger sample, study findings suggest a potential relationship between induced pain catastrophizing and central sensitization of pain. Clarification of the mechanisms through which catastrophizing affects pain modulatory systems may yield useful clinical insights into the treatment of chronic pain.

Fibromyalgia syndrome: novel therapeutic targets.

Fibromyalgia syndrome (FMS) is a chronic disorder characterized by widespread pain and tenderness, accompanied by disturbed sleep, chronic fatigue and multiple additional functional symptoms. FMS continues to pose an unmet need regarding pharmacological treatment and many patients fail to achieve sufficient relief from existing treatments. As FMS is considered to be a condition in which pain amplification occurs within the CNS, therapeutic interventions, both pharmacological and otherwise, have revolved around attempts to influence pain processing in the CNS. In the current review, we present an update on novel targets in the search for effective treatment of FMS.

The respiratory cycle modulates brain potentials, sympathetic activity, and subjective pain sensation induced by noxious stimulation

To test the hypothesis that a respiratory cycle influences pain processing, we conducted an experimental pain study in 10 healthy volunteers. Intraepidermal electrical stimulation (IES) with a concentric bipolar needle electrode was applied to the hand dorsum at pain perceptual threshold or four times the perceptual threshold to produce first pain during expiration or inspiration either of which was determined by the abrupt change in an exhaled CO2 level. IES-evoked potentials (IESEPs), sympathetic skin response (SSR), digital plethysmogram (DPG), and subjective pain intensity rating scale were simultaneously recorded. With either stimulus intensity, IES during expiration produced weaker pain feeling compared to IES during inspiration. The mean amplitude of N200/P400 in IESEPs and that of SSR were smaller when IES was applied during expiration. The magnitude of DPG wave gradually decreased after IES, but a decrease in the magnitude of DPG wave was less evident when IES was delivered during expiration. Regardless of stimulus timing or stimulus intensity, pain perception was always concomitant with appearance of IESEPs and SSR, and changes in DPG. Our findings suggest that pain processing fluctuates during normal breathing and that pain is gated within the central nervous system during expiration.

The implementation of the Neuroid in the Gate Control System leads to new ideas about pain processing

INTRODUCTION: Several theories have been proposed to elucidate the mechanisms related with pain perception, among which, the Gate Control Theory (GCT) provides one of the most explicit explanations. This theory, as elegantly conceived, is unable to explain how the Frequency-Intensity (F-I) curves exhibited by Aβ- and C-fibres influence pain processing. In this paper, a novel neuron-model known as the Neuroid, which emphasizes the functional rather the physiological character of nerve cells, was used as the main building block to replicate the Gate Control System (GCS). METHODS: Two Aβ-fibre models were built: one model that preserved the paradoxical relation between the activation threshold and the F-I curve slope, and one model based on the hypothetical average response across the receptive field. RESULTS: The results suggest that the average response of the Aβ-fibres does not increase monotonically but reaches a plateau for high intensity stimuli. In addition, it was seen that activation of C-fibres does not necessarily imply the activation of projection neurons and, therefore, the onset of pain sensation. Also, we observed that the activation of Aβ-fibres may both, decrease and increase the activity of the projections neurons, an aspect which has not been directly described in previous works. CONCLUSION: Hypothetical implications arise as a consequence of the implementation of the Neuroid, specifically, about the correlation between the intensity of stimulation and the physiological pain threshold.

Pain processing in multisensory environments

Abstract “Don’t look and it won’t hurt” is common ad­vice heard before receiving an injection, but is there any truth in this statement? Pain pro­cessing can be separated into two major components: a sensory-discriminative com­ponent, which reflects the location and inten­sity of a painful event, and an affective-mo­tivational component that reflects the un­pleasantness of pain. The differentiation be­tween these components and the effects of additional sensory inputs on them becomes apparent if you watch a needle penetrating your skin: On the one hand, it may be some­what reassuring to know precisely when and where to expect the pinprick, on the other hand, you eye-witness damage inflicted on your body, which can increase personal dis­tress. Here we review recent studies, which demonstrate that a host of variables such as onset timing, spatial alignment, semantic meaning, and attention differentially affect how visual inputs influence pain processing. These studies also indicate that there is some truth in the opening statement.

Zentrale Schmerzverarbeitung bei funktionellen somatischen Syndromen

Functional pain syndromes usually are characterized by a local or generalized increase in pain sensitivity, spontaneous ongoing pain, and a variety of other common symptoms. Classification or definition of a syndrome is usually somewhat arbitrarily based on the predominantly affected body region or a main symptom, resulting in significant overlap between conditions. Support for the involvement of the central nervous system (CNS) comes from the frequent comorbidity of affective disorders and symptomatology, disturbances in cognitive function, changes in neuroendocrine function, and dysregulation of the autonomic nervous system, although only subgroups of patients are affected. Findings of neuroimaging studies in functional pain syndromes typically reveal plausible correlates for the patients' subjective complaints and indicate a central augmentation in pain processing but also in other sensory systems including a postulated interoceptive system. The pathophysiology of this augmentation is not clear, and the importance of peripheral input remains unresolved, as well as the contribution of spinal and supraspinal mechanisms. Affective and cognitive factors clearly influence pain processing in these syndromes, but do not fully explain the observed augmentation. For FMS, chronic low back pain, and irritable bowel syndrome a dysfunction of the descending inhibitory systems is supported by these findings. However, longitudinal studies are needed to confirm the causality of the reported associations and to establish a primary role of the CNS in these syndromes. Current techniques like VBM and H-MRS have revealed potential yet highly variable structural abnormalities of the CNS in several of the syndromes, but clinical relevance and conclusions from these studies remain far from clear. New theoretical concepts should drive prospective and interdisciplinary research based on well-defined hypotheses to use the full potential of the current neuroimaging techniques.

Endogenous N-Acetylaspartylglutamate (NAAG) Inhibits Synaptic Plasticity/Transmission in the Amygdala in a Mouse Inflammatory Pain Model

BackgroundThe peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is widely expressed throughout the vertebrate nervous system, including the pain processing neuraxis. Inhibitors of NAAG peptidases are analgesic in animal models of pain. However, the brain regions involved in NAAG's analgesic action have not been rigorously defined. Group II metabotropic glutamate receptors (mGluR2/3) play a role in pain processing in the laterocapsular part of the central nucleus of the amygdala (CeLC). Given the high concentration of NAAG in the amygdala and its activation of group II mGluRs (mGluR3 > mGluR2), this study was undertaken using the mouse formalin model of inflammatory pain to test the hypothesis that NAAG influences pain processing in the amygdala. Evoked excitatory postsynaptic currents (eEPSCs) were studied in neurons in the CeLC of mouse brain slices following stimulation of the spinoparabrachial amygdaloid afferents.ResultsApplication of a NAAG peptidase inhibitor, ZJ43, dose dependently inhibited the amplitude of the eEPSCs by up to 50% in control CeLC demonstrating the role of NAAG in regulation of excitatory transmission at this synapse. A group II mGluR agonist (SLx-3095-1) similarly inhibited eEPSC amplitude by about 30%. Both effects were blocked by the group II mGluR antagonist LY341495. ZJ43 was much less effective than SLx in reducing eEPSCs 24 hours post inflammation suggesting an inflammation induced reduction in NAAG release or an increase in the ratio of mGluR2 to mGluR3 expression. Systemic injection of ZJ43 proximal to the time of inflammation blocked peripheral inflammation-induced increases in synaptic transmission of this pathway 24 hrs later and blocked the induction of mechanical allodynia that developed by this time point.ConclusionsThe main finding of this study is that NAAG and NAAG peptidase inhibition reduce excitatory neurotransmission and inflammation-induced plasticity at the spinoparabrachial synapse within the pain processing pathway of the central amygdaloid nucleus.

Human evidence of a supra‐spinal modulating role of dopamine on pain perception

Over the last decades, remarkable progresses have been accomplished regarding the understanding of the neurophysiologic and neuropharmacological bases of pain. A growing preclinical literature supports a role for substance P, endogenous opioids, glutamate, serotonin, and norepinephrine in pain perception. Recently, a series of studies explored the function of dopamine in pain perception, which we review here, while focusing on human studies. The literature was screened using electronic databases. We found evidence from genetics, brain imaging, neuropsychiatry, and pharmacology of an involvement of dopamine in pain processing. Using positron emission tomography and molecular genetics, studies have been performed in healthy volunteers and patients suffering from chronic pain conditions, showing a key role of dopamine in pain perception. Moreover, abnormal pain perception has been documented in neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, where dopamine has a pathophysiological role. Lastly, pharmacological studies have shown that dopaminergic drugs (antipsychotics, antiparkinsonian drugs, atypical antidepressants, psychostimulants) modify pain perception. Although there is growing evidence supporting a role of dopamine in pain perception, the mechanisms by which dopamine influences pain processing remains to be determined. On the basis of preliminary findings, we put forth the hypothesis that dopamine is involved in endogenous pain modulation systems, and further discuss the implications of this hypothesis for the understanding of the physiopathology of chronic pain disorders associated with dysfunctional endogenous pain modulation systems.

Reduced heat pain thresholds after sad-mood induction are associated with changes in thalamic activity

Negative affective states influence pain processing in healthy subjects in terms of augmented pain experience. Furthermore, our previous studies revealed that patients with major depressive disorder showed increased heat pain thresholds on the skin. Potential neurofunctional correlates of this finding were located within the fronto-thalamic network. The aim of the present study was to investigate the neurofunctional underpinnings of the influence of sad mood upon heat pain processing in healthy subjects. For this purpose, we used a combination of the Velten Mood Induction procedure and a piece of music to induce sad affect.Initially we assessed heat pain threshold after successful induction of sad mood outside the MR scanner in Experiment 1. We found a highly significant reduction in heat pain threshold on the left hand and a trend for the right. In Experiment 2, we applied thermal pain stimuli on the left hand (37, 42, and 45°C) in an MRI scanner. Subjects were scanned twice, one group before and after sad-mood induction and another group before and after neutral-mood induction, respectively. Our main finding was a significant group×mood-induction interaction bilaterally in the ventrolateral nucleus of the thalamus indicating a BOLD signal increase after sad-mood induction and a BOLD signal decrease in the control group. We present evidence that induced sad affect leads to reduced heat pain thresholds in healthy subjects. This is probably due to altered lateral thalamic activity, which is potentially associated with changed attentional processes.

Gender differences in brain activity evoked by muscle and cutaneous pain: A retrospective study of single-trial fMRI data

Gender greatly influences pain processing. Not only do females display greater pain sensitivity, many chronic pain conditions affect females more than males. Although gender-based differences in pain sensitivity may be related to cultural and social factors, animal studies also reveal gender differences in pain sensitivity, suggesting that physiological factors may contribute to differences in the processing of pain in males and females. It has been recently reported that noxious cutaneous heat stimuli evoke gender-based differences in activity in some brain regions. Given that most chronic pain conditions, including those with gender bias are of “deep” origin (e.g. arising in muscle, joints or viscera), we investigated whether gender differences also exist in the central processing of muscle pain. In 24 healthy adults we used functional magnetic resonance imaging (fMRI) to measure signal intensity changes during muscle and cutaneous pain induced by intramuscular and subcutaneous injections of hypertonic saline, respectively. In addition to activating the “pain neuromatrix”, i.e. cingulate, insular, somatosensory and cerebellar cortices, both muscle pain and cutaneous pain evoked gender-based differences in the mid-cingulate cortex, dorsolateral prefrontal cortex, hippocampus and cerebellar cortex. These differences may reflect differences in emotional processing of noxious information in men and women and may underlie the gender bias that exists in many chronic pain conditions.

Galaninergic mechanisms at the spinal level: Focus on histochemical phenotyping

The 29/30 amino acid neuropeptide galanin is present in a small population of DRG neurons under normal condition but is strongly upregulated after nerve injury. There is evidence that this upregulated galanin has trophic actions, for example promoting neurite outgrowth as well as influencing pain processing. In fact, both pro- and antinociceptive effects have been reported, probably relating to activation of different receptors. It has been proposed that presynaptic GalR2 receptors are pro-nociceptive by enhancing release of excitatory transmitters in the dorsal horn, and anti-nociceptive via an action on GalR1-positive interneurons. These neurons have recently been shown to be glutamatergic. Several other peptides and molecules are also regulated by nerve injury. Here we focus on neuropeptide tyrosine (NPY), which is upregulated in parallel with galanin. We review data reporting on coexistence between galanin and NPY and between these two peptides and the two NPY receptors Y1 and Y2. The data show considerable overlap, and it will be an important task to analyse how cross-talk between these neuropeptides can influence pain processing. It is proposed that such cross-talk can occur by release of peptides from DRGs neuron somata within dorsal root ganglia. To what extent these mechanisms shown to exist in rodents also occur in human is important, if one wants to discuss novel strategies for pain treatment on the basis of these findings. So far information is limited, but it has been demonstrated that galanin is expressed in DRGs and possibly also regulated.

Influence of social support and emotional context on pain processing and magnetic brain responses in fibromyalgia

To examine the effects of social support provided by the presence of patient's significant other on pain ratings, pain thresholds, and brain activity associated with tactile stimulation in 18 fibromyalgia (FM) patients and 18 migraine patients (controls), and to assess the influence of emotional context on thermal pain perception and processing of non-pain-related information. Thermal pain thresholds and somatosensory brain magnetic responses elicited by tactile stimulation at the elbow (a painful tender point in the FM group) and at the finger (nonpainful site) were evaluated under 2 experimental conditions of social support: patient alone and patient's significant other present. Brain activity was recorded using a 151-channel whole-head magnetoencephalography system. Additionally, the emotional context during presentation of tactile stimuli was manipulated by presenting aversive, pain-related pictures and neutral pictures and asking the patients to imagine that they were experiencing the situations depicted. Thermal pain thresholds indicated greater sensitivity in FM patients than in migraine patients, as well as enhanced sensitivity at the elbow than at the fingers. Specifically, in FM patients, there were significant reductions in pain sensitivity and subjective pain ratings when patients were stimulated at the painful tender point in the presence of their significant others as compared with the ratings when the patients were alone. Brain activity elicited by elbow stimulation was also significantly reduced in FM patients when a significant other was present as compared with the activity when the patient was alone. These effects were not observed in the migraine patients. When the significant other was present, FM patients reported less pain and thermal pain sensitivity and showed diminished brain activity elicited upon tactile stimulation of a tender point compared with these levels when the patients were alone. These findings are consistent with the hypothesis that social support through the presence of a significant other can influence pain processing at the subjective-behavioral level as well as the central nervous system level.

The impact of HIV infection on primary headache. Unexpected findings from retrospective, cross-sectional, and prospective analyses

Headache is one of the most important factors influencing the quality of life in patients infected with the human immunodeficiency virus type 1 (HIV). However, only symptomatic headache but not changes or primary headache types during HIV infection have been studied to date. Therefore, we aimed to determine the impact of an HIV infection on frequency and semiology of different primary headache types. Patients with confirmed HIV type 1 infection underwent a neurological examination, neuroimaging or EEG, and a standardized interview. Time pattern and symptoms of headaches (cross-sectional analysis), changes of headaches preexisting to their infection (longitudinal retrospective analysis), and changes of primary headaches during a 2-year follow-up (longitudinal prospective analysis) were evaluated as were the correlations between these headache patterns and different markers of HIV infection. One hundred thirty-one consecutive HIV-infected patients without evidence of a cerebral manifestation except mild encephalopathy were enrolled. The point prevalence of migraine was 16.0% (confidence interval (CI) 10.1–25.4%), of headache with a semiology of tension-type headache 45.8% (CI 33.7–62.2%), and of other headache types 6.1% (CI 3.0–12.5%). During the natural course of infection, the migraine frequency significantly decreased in the retrospective and in the prospective analyses, whereas the frequency of the headache with a semiology of tension-type headache significantly increased in all three analyses. In 20% of all patients, the tension-type headache could be considered as symptomatic due to the infection but not due to focal or general cerebral lesions. Changes of primary headache were significantly associated with different stages of the infection and with the presence of mild encephalopathy but not with antiretroviral treatment or CD4 cell count. HIV infection seems to be associated with a progressive decrease in migraine frequency and intensity which probably is related to the immunological state of the patients. Tension-type headache becomes more frequent during HIV infection. However, this can in part be related to secondary headache caused by the HIV in less than 50% of patients with tension-type headache. The progressing immunological deficiency of HIV-infected patients seems to influence pain processing of primary headache types in different ways.