Endogenous opioid system dysfunction potentially contributes to chronic pain in fibromyalgia (FM), but it is unknown if this dysfunction is related to established neurobiological markers of ...hyperalgesia. We previously reported that µ-opioid receptor (MOR) availability was reduced in patients with FM as compared with healthy controls in several pain-processing brain regions. In the present study, we compared pain-evoked functional magnetic resonance imaging with endogenous MOR binding and clinical pain ratings in female opioid-naive patients with FM (n = 18) using whole-brain analyses and regions of interest from our previous research. Within antinociceptive brain regions, including the dorsolateral prefrontal cortex (r = 0.81, P < 0.001) and multiple regions of the anterior cingulate cortex (all r > 0.67; all P < 0.02), reduced MOR availability was associated with decreased pain-evoked neural activity. Additionally, reduced MOR availability was associated with lower brain activation in the nucleus accumbens (r = 0.47, P = 0.050). In many of these regions, pain-evoked activity and MOR binding potential were also associated with lower clinical affective pain ratings. These findings are the first to link endogenous opioid system tone to regional pain-evoked brain activity in a clinical pain population. Our data suggest that dysregulation of the endogenous opioid system in FM could lead to less excitation in antinociceptive brain regions by incoming noxious stimulation, resulting in the hyperalgesia and allodynia commonly observed in this population. We propose a conceptual model of affective pain dysregulation in FM.
Objective
There is increasing demand for prediction of chronic pain treatment outcomes using machine‐learning models, in order to improve suboptimal pain management. In this exploratory study, we ...used baseline brain functional connectivity patterns from chronic pain patients with fibromyalgia (FM) to predict whether a patient would respond differentially to either milnacipran or pregabalin, 2 drugs approved by the US Food and Drug Administration for the treatment of FM.
Methods
FM patients participated in 2 separate double‐blind, placebo‐controlled crossover studies, one evaluating milnacipran (n = 15) and one evaluating pregabalin (n = 13). Functional magnetic resonance imaging during rest was performed before treatment to measure intrinsic functional brain connectivity in several brain regions involved in pain processing. A support vector machine algorithm was used to classify FM patients as responders, defined as those with a ≥20% improvement in clinical pain, to either milnacipran or pregabalin.
Results
Connectivity patterns involving the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) individually classified pregabalin responders versus milnacipran responders with 77% accuracy. Performance of this classification improved when both PCC and DLPFC connectivity patterns were combined, resulting in a 92% classification accuracy. These results were not related to confounding factors, including head motion, scanner sequence, or hardware status. Connectivity patterns failed to differentiate drug nonresponders across the 2 studies.
Conclusion
Our findings indicate that brain functional connectivity patterns used in a machine‐learning framework differentially predict clinical response to pregabalin and milnacipran in patients with chronic pain. These findings highlight the promise of machine learning in pain prognosis and treatment prediction.
Abstract
Background
Mounting evidence suggests that central nervous system amplification, similar to that seen in fibromyalgia (FM), contributes to the pain experience in a subset of patients with ...temporomandibular disorders (TMD).
Methods
In this prospective observational study, patients with TMD completed the 2011 FM survey questionnaire, a surrogate measure of “centralized” pain. The influence of centralized pain on TMD pain, dysfunction, and disability was assessed dichotomously by determining the incidence of FM-positive cases in the sample and by using FM survey scores as a continuous measure of “fibromyalgia-ness” (“FM-ness”).
Results
The patients meeting criteria for FM diagnosis (17 of 89) had significantly more disease burden on numerous measures. FM-ness was positively associated with pain at rest, negative mood, tenderness to palpation, perceived jaw functional limitation, and pain-related disability, and it was negatively associated with comfortable pain-free jaw opening. The impact of FM-ness on perceived jaw functional limitation and disability was mediated by levels of spontaneous, ongoing pain in the orofacial region. Importantly, this pattern of findings was still present even in those not meeting the criteria for FM diagnosis.
Conclusion
Together, these results imply that higher FM-ness increases TMD patient burden by amplifying spontaneous pain and further hampering painless jaw function, even in patients who do not meet criteria for FM diagnosis. These results are highly relevant for the clinical management of TMD, as they imply that targeting the central nervous system in the treatment of patients with TMD with evidence of pain centralization may help ameliorate both pain and jaw dysfunction.
Chronic overlapping pain conditions (COPCs) are characterized by aberrant central nervous system processing of pain. This "centralized pain" phenotype has been described using a large and diverse set ...of symptom domains, including the spatial distribution of pain, pain intensity, fatigue, mood imbalances, cognitive dysfunction, altered somatic sensations, and hypersensitivity to external stimuli. Here, we used 3 cohorts, including patients with urologic chronic pelvic pain syndrome, a mixed pain cohort with other COPCs, and healthy individuals (total n = 1039) from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network to explore the factor structure of symptoms of centralized pain. Using exploratory and confirmatory factor analysis, we identified 2 general factors in all 3 cohorts, one characterized by a broad increased sensitivity to internal somatic sensations,environmental stimuli, and diffuse pain, termed Generalized Sensory Sensitivity, and one characterized by constitutional symptoms-Sleep, Pain, Affect, Cognition, Energy (SPACE). Longitudinal analyses in the urologic chronic pelvic pain syndrome cohort found the same 2-factor structure at month 6 and 1 year, suggesting that the 2-factor structure is reproducible over time. In secondary analyses, we found that Generalized Sensory Sensitivity particularly is associated with the presence of comorbid COPCs, whereas SPACE shows modest associations with measures of disability and urinary symptoms. These factors may represent an important and distinct continuum of symptoms that are indicative of the centralized pain phenotype at high levels. Future research of COPCs should accommodate the measurement of each factor.
Until recently, the predominant pathology of chronic pelvic pain conditions was thought to reside in the peripheral tissues. However, mounting evidence from neuroimaging studies suggests an important ...role of the central nervous system in the pathogenesis of these conditions. In the present cross-sectional study, proton magnetic resonance spectroscopy (1H-MRS) of the brain was conducted in female patients with urologic chronic pelvic pain syndrome (UCPPS) to determine if they exhibit abnormal concentrations of brain metabolites (e.g. those indicative of heightened excitatory tone) in regions involved in the processing and modulation of pain, including the anterior cingulate cortex (ACC) and the anterior and posterior insular cortices. Compared to a group of age-matched healthy subjects, there were significantly higher levels of choline (p=0.006, uncorrected) in the ACC of UCPPS patients. ACC choline levels were therefore compared with the region's resting functional connectivity to the rest of the brain. Higher choline was associated with greater ACC-to-limbic system connectivity in UCPPS patients, contrasted with lower connectivity in controls (i.e. an interaction). In patients, ACC choline levels were also positively correlated with negative mood. ACC γ-aminobutyric acid (GABA) levels were lower in UCPPS patients compared with controls (p=0.02, uncorrected), but this did not meet statistical correction for the 4 separate regional comparisons of metabolites. These results are the first to uncover abnormal GABA and choline levels in the brain of UCPPS patients compared to controls. Low GABA levels have been identified in other pain syndromes and might contribute to CNS hyper-excitability in these conditions. The relationships between increased ACC choline levels, ACC-to-limbic connectivity, and negative mood in UCPPS patients suggest that this metabolite could be related to the affective symptomatology of this syndrome.
•Chronic pelvic pain patients (UCPPS;n=18) and healthy controls (HC;n=20) participated•Anterior cingulate cortex (ACC) choline (Cho) levels significantly ↑ in UCPPS vs. HC.•ACC γ-aminobutyric acid (GABA) levels marginally ↓ in UCPPS vs. HC.•↑ ACC Cho related to ↑ negative mood and ↑ limbic system connectivity in UCPPS•ACC metabolic activity and functional connectivity may contribute to UCPPS pathology.
Mule deer (Odocoileus hemionus) are important economically, culturally, and recreationally to the Pueblo of Santa Ana in central New Mexico, USA. Studies of habitat selection improve our ...understanding of mule deer ecology in central New Mexico and provide the Tribe with valuable information for management of mule deer. We used global positioning system telemetry‐collar data collected on mule deer around the Pueblo of Santa Ana to create resource selection functions from proximity‐based habitat predictors using a generalized linear mixed model. We created separate resource selection functions for females and males during summer and winter at different times of the day. Season generally had a greater effect on mule deer habitat use than the time of day. Female and male mule deer selected for similar habitats but were sexually segregated in their summer distributions. These findings are consistent with results from other locations where mule deer partitioned habitat similarly between seasons and sexes. Supported models reaffirm accepted patterns of habitat selection for mule deer to the Pueblo of Santa Ana where local results were lacking. Our results can help managers identify locations in and around the Pueblo of Santa Ana where future development such as highway expansion are likely to conflict with mule deer activity and locations where habitat enhancement projects such as adding water sources can have the greatest effect for the deer population.
Mule deer are important economically, culturally, and recreationally to the Pueblo of Santa Ana in central New Mexico, USA. We used geospatial positioning system telemetry‐collar data collected on female and male mule deer around the Pueblo of Santa Ana to create resource selection functions from proximity‐based habitat predictors using a generalized linear mixed model. Season generally had a greater effect on mule deer habitat use than the time of day.
Stimulation of zona incerta in rodent models has been shown to modulate behavioral reactions to noxious stimuli. Sensory changes observed in Parkinsonian patients with subthalamic deep brain ...stimulation suggest that this effect is translatable to humans. Here, we utilized the serendipitous placement of subthalamic deep brain stimulation leads in 6 + 5 Parkinsonian patients to directly investigate the effects of zona incerta stimulation on human pain perception. We found that stimulation at 20 Hz, the physiological firing frequency of zona incerta, reduces experimental heat pain by a modest but significant amount, achieving a 30% reduction in one fifth of implants. Stimulation at higher frequencies did not modulate heat pain. Modulation was selective for heat pain and was not observed for warmth perception or pressure pain. These findings provide a mechanistic explanation of sensory changes seen in subthalamic deep brain stimulation patients and identify zona incerta as a potential target for neuromodulation of pain.
A proportion of subjects with internal derangements of the temporomandibular joint (TMJ) may have a central sensitization disorder that may affect pain perception after surgery. This study aims to ...estimate the association between fibromyalgianess (FMness) score, a summed score of the Widespread Pain Index (WPI) and Symptom Severity Sore (SSS), and outcomes following TMJ arthroscopy.
A retrospective cohort study including individuals who received arthroscopy for TMJ internal derangement at Michigan Medicine between 2011 and 2020 was performed. A predictor variable, FMness score, was assigned via the sum of WPI and SSS. Univariate and bivariate analyses were performed. Linear-mixed effects models were used to analyze 6 different outcomes, each in their own model: pain, jaw functional limitation scale (JFLS), JFLS-mobility domain, pain-related disability, comfortable maximum interincisal opening, and active maximum interincisal opening. Covariance structure was selected based on null model fit separately for each outcome.
Thirty-one subjects were included in the study sample. Twenty-eight subjects were female. Average age was 45.9 years. Bivariate analysis demonstrated that subject's FMness score was not correlated with pain (b = 0.03 −0.10, 0.17 P = .59) or JFLS score (b = 1.00 −.80, 2.81 P = .27). However, subject's FMness score was significant for predicting JFLS-mobility domain score (b = .61, 0.05, 1.18 P = .04).
A greater extent of central sensitization was associated with lower comfortable mouth opening after surgery, greater limitations in opening wide enough to eat various foods (higher JFLS-mobility scores), and higher pain-related disability. Future studies with larger sample sizes and reconstructive TMJ operations such as total TMJ arthroplasty may help clarify the impact of SSS and WPI scores on outcomes of TMJ surgery.
The thermal grill illusion is affected by warm and cool preadaptation in ways that shed light on its mechanism.
We investigated the contributions of warm and cool signals in generating the thermal ...grill illusion (TGI), a phenomenon in which interlaced warm and cool bars generate an experience of burning, and under some conditions painful, heat. Each subject underwent 3 runs, 2 of which tested the effects of preadapting subjects to the grill’s warm or cool bars (while the interlaced bars were thermally neutral) on the subsequent intensity of the illusion. In a control run, all bars were neutral during the adaptation phase. Thermal visual analogue scale ratings during the warm and cool adaptation periods revealed significant and equivalent adaptation to the 2 temperatures. Adaptation to the grill’s cool bars significantly reduced pain and perceived thermal intensity of the TGI, compared to the control condition, while adaptation to the grill’s warm bars had little effect. These results suggest that the cool stimulus triggers the pain signals that produce the illusion. The inability of warm adaptation to attenuate the TGI is at odds with theories suggesting that the illusion depends upon a simple addition of warm and cool signals. While the grill’s cool bars are necessary for the TGI’s painfulness, we also observed that the more often a participant reported feeling coolness or coldness, the less pain he or she experienced from the TGI. These results are consistent with research showing that cool temperatures generate activity in both thermoreceptive-specific, pain-inhibitory neurons and nociceptive dorsal horn neurons.
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