Dysfunctional Neurotransmitter Systems in Fibromyalgia, Their Role in Central Stress Circuitry and Pharmacological Actions on These Systems

Fibromyalgia is considered a stress-related disorder, and hypo- as well as hyperactive stress systems (sympathetic nervous system and hypothalamic-pituitary-adrenal axis) have been found. Some observations raise doubts on the view that alterations in these stress systems are solely responsible for fibromyalgia symptoms. Cumulative evidence points at dysfunctional transmitter systems that may underlie the major symptoms of the condition. In addition, all transmitter systems found to be altered in fibromyalgia influence the body's stress systems. Since both transmitter and stress systems change during chronic stress, it is conceivable that both systems change in parallel, interact, and contribute to the phenotype of fibromyalgia. As we outline in this paper, subgroups of patients might exhibit varying degrees and types of transmitter dysfunction, explaining differences in symptomatoloy and contributing to the heterogeneity of fibromyalgia. The finding that not all fibromyalgia patients respond to the same medications, targeting dysfunctional transmitter systems, further supports this hypothesis

Doubling your payoff: winning pain relief engages endogenous pain inhibition

When in pain, pain relief is much sought after, particularly for individuals with chronic pain. In analogy to augmentation of the hedonic experience (“liking”) of a reward by the motivation to obtain a reward (“wanting”), the seeking of pain relief in a motivated state might increase the experience of pain relief when obtained. We tested this hypothesis in a psychophysical experiment in healthy human subjects, by assessing potential pain-inhibitory effects of pain relief “won” in a wheel of fortune game compared with pain relief without winning, exploiting the fact that the mere chance of winning induces a motivated state. The results show pain-inhibitory effects of pain relief obtained by winning in behaviorally assessed pain perception and ratings of pain intensity. Further, the higher participants scored on the personality trait novelty seeking, the more pain inhibition was induced. These results provide evidence that pain relief, when obtained in a motivated state, engages endogenous pain-inhibitory systems beyond the pain reduction that underlies the relief in the first place. Consequently, such pain relief might be used to improve behavioral pain therapy, inducing a positive, perhaps self-amplifying feedback loop of reduced pain and improved functionality

The influence of social signals on the self-experience of pain: A neuroimaging review

Researchers in cognitive neuroscience have investigated extensively how psychological factors shape the processing and perception of pain using behavioral, physiological, and neuroimaging methods. However, social influences of pain, an essential part of biopsychosocial pain models, have received relatively little attention. This is particularly true for the neurobiological mechanisms underlying social modulations on pain. Therefore, this review discusses the findings of recent neuroimaging studies measuring the effects of social manipulations on pain perception (e.g., verbal and non-verbal social signals, social interaction style, conformity, social support, and sociocultural mediators). Finally, a schematic summary of the different social modulatory themes is presented

Improving magnetic resonance spectroscopy in the brainstem periaqueductal gray using spectral registration

Purpose: Functional understanding of the periaqueductal gray (PAG), a clinically relevant brainstem region, can be advanced using ¹H‐MRS. However, the PAG's small size and high levels of physiological noise are methodologically challenging. This study aimed to (1) improve ¹H‐MRS quality in the PAG using spectral registration for frequency and phase error correction; (2) investigate whether spectral registration is particularly useful in cases of greater head motion; and (3) examine metabolite quantification using literature‐based or individual‐based water relaxation times. Methods: Spectra were acquired in 33 healthy volunteers (50.1 years, SD = 17.19, 18 females) on a 3 T Philipps MR system using a point‐resolved spectroscopy (PRESS) sequence optimized with very selective saturation pulses (OVERPRESS) and voxel‐based flip angle calibration (effective volume of interest size: 8.8 × 10.2 × 12.2 mm³). Spectra were fitted using LCModel and SNR, NAA peak linewidths and Cramér‐Rao lower bounds (CRLBs) were measured after spectral registration and after minimal frequency alignment. Results: Spectral registration improved SNR by 5% (p = 0.026, median value post‐correction: 18.0) and spectral linewidth by 23% (p < 0.001, 4.3 Hz), and reduced the metabolites' CRLBs by 1% to 15% (p < 0.026). Correlational analyses revealed smaller SNR improvements with greater head motion (p = 0.010) recorded using a markerless motion tracking system. Higher metabolite concentrations were detected using individual‐based compared to literature‐based water relaxation times (p < 0.001). Conclusion: This study demonstrates high‐quality ¹H‐MRS acquisition in the PAG using spectral registration. This shows promise for future ¹H‐MRS studies in the PAG and possibly other clinically relevant brain regions with similar methodological challenges

Self-reported attitudes, skills and use of evidence-based practice among Swiss chiropractors: a national survey

STUDY OBJECTIVES The high burden of disease associated with musculoskeletal disorders severely impacts patients' well-being. As primary care providers, Swiss chiropractors ought to contribute towards identifying and using effective treatment strategies. An established approach is the full integration of evidence-based practice (EBP). This study aimed to investigate the attitudes, skills and use of EBP among Swiss chiropractors, as well as investigating potential facilitators and barriers for its adoption. METHODS AND MATERIAL All 329 members of the Swiss Association of Chiropractic (ChiroSuisse) were invited in March 2021 to participate in this cross-sectional survey. Data were acquired anonymously online, using the Evidence-Based practice Attitude and utilization SurvEy (EBASE). The survey encompassed 55 questions measuring attitudes (n = 8, response range 1-5; total score range of 8-40), skills (n = 13, response range 1-5; total score range of range of 13-65) and use of EBP (n = 6, response range 0-4; total score range of 0-24). RESULTS 228 (69.3%) chiropractors returned complete EBASE questionnaires. This sample was representative of all ChiroSuisse members with respect to gender, age groups and proportion of chiropractic residents. Respondents generally held positive attitudes towards EBP, as indicated by the high mean (31.2) and median (31) attitude sub-score (range 11-40). Self-reported skills had a mean sub-score of 40.2 and median of 40 (range 13-65). Knowledge about EBP-based clinical practice had been primarily obtained in chiropractic under- or postgraduate education (33.8% and 26.3%, respectively). Use of EBP achieved a lower sub-score, with mean and median values of 7.4 and 6, respectively (range 0-24). The most commonly identified barriers preventing EBP uptake were lack of time (67.9%) and lack of clinical evidence in chiropractic/manual therapy-related health fields (45.1%). CONCLUSION Swiss chiropractors held favourable attitudes and reported moderate to moderate-high skill levels in EBP. Nevertheless, similar to chiropractors in other countries, the self-reported use of EBP was relatively low, with lack of time and lack of clinical evidence being the most named barriers

Healthy women show more experimentally induced central sensitization compared with men

Women more often experience chronic pain conditions than men. Central sensitization (CS) is one key mechanism in chronic pain that can differ between the sexes. It is unknown whether CS processes are already more pronounced in healthy women than in men. In 66 subjects (33 women), a thermal CS induction protocol was applied to the dorsum of one foot and a sham protocol to the other. Spatial extent [cm$^{2}$] of secondary mechanical hyperalgesia (SMH) and dynamic mechanical allodynia were assessed as subjective CS proxy measures, relying on verbal feedback. Changes in nociceptive withdrawal reflex magnitude (NWR-M) and response rate (NWR-RR) recorded through surface electromyography at the biceps and rectus femoris muscles were used as objective CS proxies. The effect of the CS induction protocol on SMH was higher in women than in men (effect size 2.11 vs 1.68). Nociceptive withdrawal reflex magnitude results were statistically meaningful for women (effect size 0.31-0.36) but not for men (effect size 0.12-0.29). Differences between men and women were not meaningful. Nociceptive withdrawal reflex response rate at the rectus femoris increased in women after CS induction and was statistically different from NWR-RR in men (median differences of 13.7 and 8.4% for 120 and 140% reflex threshold current). The objective CS proxy differences indicate that dorsal horn CS processes are more pronounced in healthy women. The even larger sex differences in subjective CS proxies potentially reflect greater supraspinal influence in women. This study shows that sex differences are present in experimentally induced CS in healthy subjects, which might contribute to women's vulnerability for chronic pain

Role of brain imaging in disorders of brain-gut interaction: a Rome Working Team Report.

Imaging of the living human brain is a powerful tool to probe the interactions between brain, gut and microbiome in health and in disorders of brain-gut interactions, in particular IBS. While altered signals from the viscera contribute to clinical symptoms, the brain integrates these interoceptive signals with emotional, cognitive and memory related inputs in a non-linear fashion to produce symptoms. Tremendous progress has occurred in the development of new imaging techniques that look at structural, functional and metabolic properties of brain regions and networks. Standardisation in image acquisition and advances in computational approaches has made it possible to study large data sets of imaging studies, identify network properties and integrate them with non-imaging data. These approaches are beginning to generate brain signatures in IBS that share some features with those obtained in other often overlapping chronic pain disorders such as urological pelvic pain syndromes and vulvodynia, suggesting shared mechanisms. Despite this progress, the identification of preclinical vulnerability factors and outcome predictors has been slow. To overcome current obstacles, the creation of consortia and the generation of standardised multisite repositories for brain imaging and metadata from multisite studies are required

Evidence for dopaminergic involvement in endogenous modulation of pain relief

Relief of ongoing pain is a potent motivator of behavior, directing actions to escape from or reduce potentially harmful stimuli. Whereas endogenous modulation of pain events is well characterized, relatively little is known about the modulation of pain relief and its corresponding neurochemical basis. Here, we studied pain modulation during a probabilistic relief-seeking task (a ‘wheel of fortune’ gambling task), in which people actively or passively received reduction of a tonic thermal pain stimulus. We found that relief perception was enhanced by active decisions and unpredictability, and greater in high novelty-seeking trait individuals, consistent with a model in which relief is tuned by its informational content. We then probed the roles of dopaminergic and opioidergic signaling, both of which are implicated in relief processing, by embedding the task in a double-blinded cross-over design with administration of the dopamine precursor levodopa and the opioid receptor antagonist naltrexone. We found that levodopa enhanced each of these information-specific aspects of relief modulation but no significant effects of the opioidergic manipulation. These results show that dopaminergic signaling has a key role in modulating the perception of pain relief to optimize motivation and behavior