Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex.

INTRODUCTION: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). METHODS: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN. RESULTS: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

During vigilance to painful stimuli: slower response rate is related to high trait anxiety, whereas faster response rate is related to high state anxiety.

A pathological increase in vigilance, or hypervigilance, may be related to pain intensity in some clinical pain syndromes and may result from attention bias to salient stimuli mediated by anxiety. During a continuous performance task where subjects discriminated painful target stimuli from painful nontargets, we measured detected targets (hits), nondetected targets (misses), nondetected nontargets (correct rejections), and detected nontargets (false alarms). Using signal detection theory, we calculated response bias, the tendency to endorse a stimulus as a target, and discriminability, the ability to discriminate a target from nontarget. Owing to the relatively slow rate of stimulus presentation, our primary hypothesis was that sustained performance would result in a more conservative response bias reflecting a lower response rate over time on task. We found a more conservative response bias with time on task and no change in discriminability. We predicted that greater state and trait anxiety would lead to a more liberal response bias. A multivariable model provided partial support for our prediction; high trait anxiety related to a more conservative response bias (lower response rate), whereas high state anxiety related to a more liberal bias. This inverse relationship of state and trait anxiety is consistent with reports of effects of state and trait anxiety on reaction times to threatening stimuli. In sum, we report that sustained attention to painful stimuli was associated with a decrease in the tendency of the subject to respond to any stimulus over time on task, whereas the ability to discriminate target from nontarget remains unchanged.NEW & NOTEWORTHY During a series of painful stimuli requiring subjects to respond to targets, we separated response willingness from ability to discriminate targets from nontargets. Response willingness declined during the task, with no change in subjects' ability to discriminate, consistent with previous vigilance studies. High trait anxious subjects were less willing to respond and showed slower reaction times to hits than low anxious subjects. This study reveals an important role of trait anxiety in pain vigilance.

Missed targets, reaction times, and arousal are related to trait anxiety and attention to pain during an experimental vigilance task with a painful target.

Although hypervigilance may play a role in some clinical pain syndromes, experimental vigilance toward painful stimuli has been studied infrequently. We evaluated vigilance toward pain by using a continuous performance task (CPT), in which subjects responded to moderately intense painful target stimuli, occurring in a train of mildly painful nontargets. We assessed nondetected targets (misses), reaction times (RTs), and psychological activation (tense arousal). During time on task in CPTs of other sensory modalities, there is an increase in misses and RTs (vigilance decrement). We hypothesized that our CPT would influence vigilance performance related to pain, anxiety, and limitation of attentional resources. The results showed a decrement in vigilance over time as misses increased, although RTs were unchanged. While mind-wandering did not influence vigilance performance, intrinsic attention to pain drove both hit RTs and number of misses. This resulted in pain-focused subjects performing worse on the CPT pain task with slower RTs and more misses per block. During the CPT, the change in stimulus salience was related to the change in pain intensity, while pain unpleasantness correlated with tense arousal. CPT performance during experimental vigilance to pain and psychological activation were related to trait anxiety, as measured by the Spielberger State-Trait Anxiety Inventory and neuroticism, as measured by the NEO five factor inventory. Trait anxiety and neuroticism may play important roles in an individual's predisposition to dwell on pain and interpret pain as threatening.NEW & NOTEWORTHY Subjects detected moderately painful target stimuli in a train of mildly painful nontarget stimuli, which resulted in vigilance performance metrics including missed targets, reaction times, and psychological activation. These performance metrics were related to intrinsic attention to pain and trait anxiety. Subjects with high trait anxiety and neuroticism scores, with a predisposition to attend to pain, had greater tense arousal and poorer vigilance performance, which may be important psychological aspects of vigilance to pain.

A functional substitution in the L-aromatic amino acid decarboxylase enzyme worsens somatic symptoms via a serotonergic pathway.

OBJECTIVE: Heightened somatic symptoms are reported by a wide range of patients with chronic pain and have been associated with emotional distress and physical dysfunction. Despite their clinical significance, molecular mechanisms leading to their manifestation are not understood. METHODS: We used an association study design based on a curated list of 3,295 single nucleotide polymorphisms mapped to 358 genes to test somatic symptoms reporting using the Pennebaker Inventory of Limbic Languidness questionnaire from a case-control cohort of orofacial pain (n = 1,607). A replication meta-analysis of 3 independent cohorts (n = 3,189) was followed by functional validation, including in silico molecular dynamics, in vitro enzyme assays, and measures of serotonin (5-HT) plasma concentration. RESULTS: An association with the T allele of rs11575542 coding for an arginine to glutamine substitution in the L-aromatic amino acid decarboxylase (AADC) enzyme was replicated in a meta-analysis of 3 independent cohorts. In a combined meta-analysis of all cohorts, this association reached p = 6.43 × 10-8 . In silico studies demonstrated that this substitution dramatically reduces the conformational dynamics of AADC, potentially lowering its binding capacity to a cofactor. in vitro enzymatic assays showed that this substitution reduces the maximum kinetic velocity of AADC, hence lowering 5-HT levels. Finally, plasma samples from 90 subjects showed correlation between low 5-HT levels and heightened somatic symptoms. INTERPRETATION: Using functional genomics approaches, we identified a polymorphism in the AADC enzyme that contributes to somatic symptoms through reduced levels of 5-HT. Our findings suggest a molecular mechanism underlying the pathophysiology of somatic symptoms and opens up new treatment options targeting the serotonergic system. ANN NEUROL 2019;86:168-180.

Acute Pain Characteristics in Patients with and without Chronic Pain following Lower Extremity Injury.

Many patients with injuries to lower extremities report chronic pain. High pain intensity at time of admission for injury is a risk factor for chronic pain, but it is not clear whether specific acute pain patterns following injury influence the development of chronic pain. To examine the relationship between the pain trajectory, the mean pain score, and the frequency of pain documentation during the immediate hospitalization following injury, with the report of chronic pain. This was a descriptive, retrospective cohort study of adults admitted with lower extremity fractures to an academic urban trauma center. Participants, 6-45 months postinjury, rated their current pain, worst pain, and average pain over the last 3 months. Pain scores from hospitalization associated with the injury were obtained through a retrospective chart review. The pain trajectory, mean pain score, and frequency of pain documentation was compared between patients with and without chronic pain. A total of 129 patients were enrolled in this study and 78% reported chronic pain at the site of injury. The mean pain score (5.1 vs. 4.2) and first pain score (5.6 vs. 3.4) were higher for patients with chronic pain compared to patients with no chronic pain. Consistent with other studies, high pain intensity at time of injury was associated with chronic pain. The findings contribute valuable information about acute pain characteristics associated with chronic pain and provide insight into the importance of early and adequate acute pain treatment.

Neuronal responses to tactile stimuli and tactile sensations evoked by microstimulation in the human thalamic principal somatic sensory nucleus (ventral caudal).

The normal organization and plasticity of the cutaneous core of the thalamic principal somatosensory nucleus (ventral caudal, Vc) have been studied by single-neuron recordings and microstimulation in patients undergoing awake stereotactic operations for essential tremor (ET) without apparent somatic sensory abnormality and in patients with dystonia or chronic pain secondary to major nervous system injury. In patients with ET, most Vc neurons responded to one of the four stimuli, each of which optimally activates one mechanoreceptor type. Sensations evoked by microstimulation were similar to those evoked by the optimal stimulus only among rapidly adapting neurons. In patients with ET, Vc was highly segmented somatotopically, and vibration, movement, pressure, and sharp sensations were usually evoked by microstimulation at separate sites in Vc. In patients with conditions including spinal cord transection, amputation, or dystonia, RFs were mismatched with projected fields more commonly than in patients with ET. The representation of the border of the anesthetic area (e.g., stump) or of the dystonic limb was much larger than that of the same part of the body in patients with ET. This review describes the organization and reorganization of human Vc neuronal activity in nervous system injury and dystonia and then proposes basic mechanisms.

Characteristics of Patients with Lower Extremity Trauma with Improved and Not Improved Pain During Hospitalization: A Pilot Study.

Up to 62% of patients report chronic pain at the injury site 6-12 months after blunt trauma, with pain from lower extremity fractures exceeding that from other sites. High pain intensity at time of injury is a risk factor for chronic pain, but it is not clear what patient characteristics influence the pain intensity level during the immediate hospitalization following injury. The purpose of this pilot study was to determine the feasibility of collecting pain scores from medical records to calculate pain trajectories and to determine whether it is possible to examine patient characteristics by classifying them into those whose pain improved and those whose pain did not improve. This descriptive study retrospectively reviewed medical records of 18 randomly chosen patients admitted to an academic trauma center. Patient characteristics and pain scores were collected form electronic and handwritten medical records. The pain trajectories calculated from routinely collected pain scores during the inpatient stay showed that for 44% of patients the pain improved during the hospitalization, for 39% the pain remained the same, and for 17% the pain worsened. The variables age, smoking, weight, abbreviated injury scores, length of hospital stay, mean pain score, and opioid equianalgesic dose differed based on pain trajectory. While patient characteristics differed based on pain trajectory, any significant effects seen from individual tests should be considered tentative, given the number of analyses conducted on this data set. However, feasibility and significance of conducting a larger study has been established.

Focused Ultrasound Central Lateral Thalamotomy for the Treatment of Refractory Neuropathic Pain: Phase I Trial.

BACKGROUND AND OBJECTIVES: Magnetic resonance-guided focused ultrasound (MRgFUS) central lateral thalamotomy (CLT) has not yet been validated for treating refractory neuropathic pain (NP). Our aim was to assess the safety and potential efficacy of MRgFUS CLT for refractory NP. METHODS: In this prospective, nonrandomized, single-arm, investigator-initiated phase I trial, patients with NP for more than 6 months related to phantom limb pain, spinal cord injury, or radiculopathy/radicular injury and who had undergone at least one previous failed intervention were eligible. The main outcomes were safety profile and pain as assessed using the brief pain inventory, the pain disability index, and the numeric rating scale. Medication use and the functional connectivity of the default mode network (DMN) were also assessed. RESULTS: Ten patients were enrolled, with nine achieving successful ablation. There were no serious adverse events and 12 mild/moderate severity events. The mean age was 50.9 years (SD: 12.7), and the mean symptom duration was 12.3 years (SD: 9.7). Among eight patients with a 1-year follow-up, the brief pain inventory decreased from 7.6 (SD: 1.1) to 3.8 (SD: 2.8), with a mean percent decrease of 46.3 (SD: 40.6) (paired t -test, P = .017). The mean pain disability index decreased from 43.0 (SD: 7.5) to 25.8 (SD: 16.8), with a mean percent decrease of 39.3 (SD: 41.6) ( P = .034). Numeric rating scale scores decreased from a mean of 7.2 (SD: 1.8) to 4.0 (SD: 2.8), with a mean percent decrease of 42.8 (SD: 37.8) ( P = .024). Patients with predominantly intermittent pain or with allodynia responded better than patients with continuous pain or without allodynia, respectively. Some patients decreased medication use. Resting-state functional connectivity changes were noted, from disruption of the DMN at baseline to reactivation of connectivity between DMN nodes at 3 months. CONCLUSION: MRgFUS CLT is feasible and safe for refractory NP and has potential utility in reducing symptoms as measured by validated pain scales.

Chronic temporomandibular disorders are not necessarily associated with a compromised endogenous analgesic system.

AIMS: To test whether temporomandibular disorders (TMD) case-control differences in conditioned pain modulation (CPM) exist, using a mechanically evoked temporal summation (TS) model. METHODS: A series of 10 repetitive, mildly noxious, mechanical stimuli were applied to the fingers of 30 women with TMD, who had a primary diagnosis of masticatory myofascial pain, and 30 age-matched healthy women. The subjects rated the pain intensity caused by the 1st, 5th, and 10th stimuli in the series. To evaluate CPM, the same series of mechanical stimulations were applied with concomitant exposure of the other hand to a painfully cold water bath. Statistical inferences were based on t tests, chi-square tests, or analysis of variance (ANOVA), as appropriate. RESULTS: Pain ratings increased significantly with stimulus repetition (P < .01) and CPM significantly reduced TS of pain (P < .01). Of particular note, both groups showed very similar degrees of CPM, with no significant group difference. CONCLUSION: Painful TMD is not necessarily associated with a compromised ability to engage the endogenous analgesic system in an experimental setting.

Brain responses to painful electrical stimuli and cognitive tasks interact in the precuneus, posterior cingulate cortex, and inferior parietal cortex and do not vary across the menstrual cycle.

INTRODUCTION: Bidirectional effects between cognition and pain have been extensively reported. Although brain regions involved in cognitive and pain processing seem to partly overlap, it is unknown what specific brain regions are involved in the interaction between pain and cognition. Furthermore, the role of gonadal hormones on these interacting effects has not been examined. This study investigated brain activation patterns of the interaction between pain and cognition over different phases of the naturally occurring menstrual cycle. METHODS: Fifteen healthy normally cycling females were examined over the course of 4 different cycle phases. Sensory stimulation was applied using electrical pulses and cognitive performance was assessed using the Multi-Source Interference Task. Brain imaging consisted of functional magnetic resonance imaging using a repeated measures ANOVA group analysis approach. RESULTS: Sensory stimulation was found to interact with task performance in the left precuneus, left posterior cingulate cortex and right inferior parietal lobule. No effects of cycle phase were observed to interact with main effects of stimulation, task or interaction effects between task performance and sensory stimulation. CONCLUSION: Potential neural correlates of shared resources between pain and cognition were demonstrated providing further insights into the potential mechanisms behind cognitive performance difficulties in pain patients and opening avenues for new treatment options including targeting specific cognitive factors in pain treatment such as cognitive interference.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility.

Association of Hormonal Contraceptive Use with Headache and Temporomandibular Pain: The OPPERA Study.

AIMS: To determine the relationship between hormonal contraceptive (HC) use and painful symptoms, particularly those associated with headache and painful temporomandibular disorders (TMD). METHODS: Data from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study were used. During the 2.5-year median follow-up period, quarterly health update (QHU) questionnaires were completed by 1,475 women aged 18 to 44 years who did not have TMD, menopause, hysterectomy, or hormone replacement therapy use at baseline. QHU questionnaires evaluated HC use, symptoms of headache and TMD, and pain of ≥ 1 day duration in 12 body regions. Participants who developed TMD symptoms were examined to classify clinical TMD. Headache symptoms were classified based on the International Classification of Headache Disorders 3 (ICHD-3). Associations between HC use and pain symptoms were analyzed using generalized estimating equations and Cox models. RESULTS: HC use, endorsed in 33.7% of QHU questionnaires, was significantly associated with concurrent symptoms of TMD (odds ratio [OR]: 1.20, 95% CI: 1.06 to 1.35) and headache (OR: 1.26, 95% CI: 1.11 to 1.43). HC use was also significantly associated with concurrent pain of ≥ 1 day duration in the head (OR: 1.38, 95% CI: 1.16 to 1.63), face (OR: 1.44, 95% CI: 1.13 to 1.83), and legs (OR: 1.22, 95% CI: 1.01 to 1.47), but not elsewhere. Initiation of HC use was associated with increased odds of subsequent TMD symptoms (OR: 1.37, 95% CI: 1.13 to 1.66) and pain of ≥ 1 day in the head (OR: 1.37, 95% CI: 1.01 to 1.85). Discontinuing HC use was associated with lower odds of subsequent headache (OR: 0.82, 95% CI: 0.67 to 0.99). HC use was not significantly associated with subsequent onset of examiner-classified TMD. CONCLUSION: These findings imply that HC influences craniofacial pain, and that this pain diminishes after cessation of HC use.

During capsaicin-induced central sensitization, brush allodynia is associated with baseline warmth sensitivity, whereas mechanical hyperalgesia is associated with painful mechanical sensibility, anxiety and somatization.

BACKGROUND: Mechanical hyperalgesia and allodynia incidence varies considerably amongst neuropathic pain patients. This study explored whether sensory or psychological factors associate with mechanical hyperalgesia and brush allodynia in a human experimental model. METHODS: Sixty-six healthy volunteers (29 male) completed psychological questionnaires and participated in two quantitative sensory testing (QST) sessions. Warmth detection threshold (WDT), heat pain threshold (HPT) and suprathreshold mechanical pain (STMP) ratings were measured before exposure to a capsaicin-heat pain model (C-HP). After C-HP exposure, brush allodynia and STMP were measured in one session, whilst mechanical hyperalgesia was measured in another session. RESULTS: WDT and HPT measured in sessions separated by 1 month demonstrated significant but moderate levels of reliability (WDT: ICC = 0.5, 95%CI [0.28, 0.77]; HPT: ICC = 0.62, 95%CI [0.40, 0.77]). Brush allodynia associated with lower WDT (z = -3.06, p = 0.002; ϕ = 0.27). Those with allodynia showed greater hyperalgesia intensity (F = 7.044, p = 0.010, ηp 2  = 0.107) and area (F = 9.319, p = 0.004, ηp 2  = 0.163) than those without allodynia. No psychological self-report measures were significantly different between allodynic and nonallodynic groups. Intensity of hyperalgesia in response to lighter mechanical stimuli was associated with lower HPT, higher STMP ratings and higher Pain Sensitivity Questionnaire scores at baseline. Hyperalgesia to heavier probe stimuli associated with state anxiety and to a lesser extent somatic awareness. Hyperalgesic area associated with lower baseline HPT and higher STMP ratings. Hyperalgesic area was not correlated with allodynic area across individuals. CONCLUSIONS: These findings support research in neuropathic pain patients and human experimental models that peripheral sensory input and individual sensibility are related to development of mechanical allodynia and hyperalgesia during central sensitization, whilst psychological factors play a lesser role. SIGNIFICANCE: We evaluated differential relationships of psychological and perceptual sensitivity to the development of capsaicin-induced mechanical allodynia and hyperalgesia. Fifty percent of healthy volunteers failed to develop mechanical allodynia. Baseline pain sensitivity was greater in those developing allodynia and was related to the magnitude and area of hyperalgesia. State psychological factors, whilst unrelated to allodynia, were related to mechanical hyperalgesia. This supports that the intensity of peripheral sensory input and individual sensibility are related to development of mechanical allodynia and hyperalgesia during central sensitization, whilst psychological factors play a lesser role.

Effects of sex on placebo effects in chronic pain participants: a cross-sectional study.

ABSTRACT: Sex-related differences can influence outcomes of randomized clinical trials and may jeopardize the effectiveness of pain management and other therapeutics. Thus, it is essential to understand the mechanistic and translational aspects of sex differences in placebo outcomes. Recently, studies in healthy participants have shed light on how sex-related placebo effects might influence outcomes, yet no research has been conducted in a patient population. Herein, we used a tripartite approach to evaluate the interaction of prior therapeutic experience (eg, conditioning), expectations, and placebo effects in 280 chronic (orofacial) pain patients (215 women). In this cross-sectional study, we assessed sex differences in placebo effects, conditioning as a proxy of prior therapeutic effects, and expectations evaluated before and after the exposure to positive outcomes, taking into account participant-experimenter sex concordance and hormonal levels (estradiol and progesterone assessed in premenopausal women). We used mediation analysis to determine how conditioning strength and expectations impacted sex differences in placebo outcomes. Independent of gonadal hormone levels, women showed stronger placebo effects than men. We also found significant statistical sex differences in the conditioning strength and reinforced expectations whereby reinforced expectations mediated the sex-related placebo effects. In addition, the participant-experimenter sex concordance influenced conditioning strength, reinforced expectations, and placebo effects in women but not in men. Our findings suggest that women experience larger conditioning effects, expectations, and placebo effects emphasizing the need to consider sex as a biological variable when placebo components of any outcomes are part of drug development trials and in pain management.

Phenotypic profile clustering pragmatically identifies diagnostically and mechanistically informative subgroups of chronic pain patients.

ABSTRACT: Traditional classification and prognostic approaches for chronic pain conditions focus primarily on anatomically based clinical characteristics not based on underlying biopsychosocial factors contributing to perception of clinical pain and future pain trajectories. Using a supervised clustering approach in a cohort of temporomandibular disorder cases and controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment study, we recently developed and validated a rapid algorithm (ROPA) to pragmatically classify chronic pain patients into 3 groups that differed in clinical pain report, biopsychosocial profiles, functional limitations, and comorbid conditions. The present aim was to examine the generalizability of this clustering procedure in 2 additional cohorts: a cohort of patients with chronic overlapping pain conditions (Complex Persistent Pain Conditions study) and a real-world clinical population of patients seeking treatment at duke innovative pain therapies. In each cohort, we applied a ROPA for cluster prediction, which requires only 4 input variables: pressure pain threshold and anxiety, depression, and somatization scales. In both complex persistent pain condition and duke innovative pain therapies, we distinguished 3 clusters, including one with more severe clinical characteristics and psychological distress. We observed strong concordance with observed cluster solutions, indicating the ROPA method allows for reliable subtyping of clinical populations with minimal patient burden. The ROPA clustering algorithm represents a rapid and valid stratification tool independent of anatomic diagnosis. ROPA holds promise in classifying patients based on pathophysiological mechanisms rather than structural or anatomical diagnoses. As such, this method of classifying patients will facilitate personalized pain medicine for patients with chronic pain.

Multi-ethnic GWAS and meta-analysis of sleep quality identify MPP6 as a novel gene that functions in sleep center neurons.

Poor sleep quality can have harmful health consequences. Although many aspects of sleep are heritable, the understandings of genetic factors involved in its physiology remain limited. Here, we performed a genome-wide association study (GWAS) using the Pittsburgh Sleep Quality Index (PSQI) in a multi-ethnic discovery cohort (n = 2868) and found two novel genome-wide loci on chromosomes 2 and 7 associated with global sleep quality. A meta-analysis in 12 independent cohorts (100 000 individuals) replicated the association on chromosome 7 between NPY and MPP6. While NPY is an important sleep gene, we tested for an independent functional role of MPP6. Expression data showed an association of this locus with both NPY and MPP6 mRNA levels in brain tissues. Moreover, knockdown of an orthologue of MPP6 in Drosophila melanogaster sleep center neurons resulted in decreased sleep duration. With convergent evidence, we describe a new locus impacting human variability in sleep quality through known NPY and novel MPP6 sleep genes.

New Developments in Non-invasive Brain Stimulation in Chronic Pain.

PURPOSE OF REVIEW: The goal of this review is to present a summary of the recent literature of a non-invasive brain stimulation (NIBS) to alleviate pain in people with chronic pain syndromes. This article reviews the current evidence for the use of transcranial direct current (tDCS) and repetitive transcranial magnetic stimulation (rTMS) to improve outcomes in chronic pain. Finally, we introduce the reader to novel stimulation methods that may improve therapeutic outcomes in chronic pain. RECENT FINDINGS: While tDCS is approved for treatment of fibromyalgia in Canada and the European Union, no NIBS method is currently approved for chronic pain in the United States. Increasing sample sizes in randomized clinical trials (RCTs) seems the most efficient way to increase confidence in initial promising results. Trends at funding agencies reveal increased interest and support for NIBS such as recent Requests for Application from the National Institutes of Health. NIBS in conjunction with cognitive behavioral therapy and physical therapy may enhance outcomes in chronic pain. Novel stimulation methods, such as transcranial ultrasound stimulation, await rigorous study in chronic pain.

Premorbid and concurrent predictors of TMD onset and persistence.

BACKGROUND: Multiple risk factors predict temporomandibular disorders (TMD) onset, but temporal changes in risk factors and their contribution to risk of TMD have not been evaluated. The study aims were to (a) describe changes occurring in premorbid TMD risk factors when re-measured at TMD onset and 6 months later, and (b) determine if measures of change improve accuracy in predicting TMD incidence compared to premorbid measures alone. METHODS: In this observational prospective cohort study at four university research clinics, 3,258 community-based, 18- to 44-year-olds without TMD were enrolled. During the 3-year median follow-up, 260 incident cases of first-onset TMD were identified, and 196 TMD-free subjects were selected as matched controls. Six-months later, 147 of 260 incident cases (56.6%) were re-examined revealing 72 (49%) with 'persistent TMD' and 75 (51%) whose condition had resolved ('transient TMD'). Virtually all (126) of the 127 re-examined controls remained without TMD. Questionnaires and clinical measurements evaluated risk factors from clinical, health, psychological and behavioural and neurosensory domains. RESULTS: Most risk factors across all four domains increased with TMD onset, remained elevated in the persistent group and declined in the transient group (i.e., significant ANOVA interactions, p < .05). Accuracy in predicting first-onset TMD, quantified as area under the receiver operating characteristic curve was 0.71 (95% CL 0.68, 0.73) using only premorbid measures of risk factors, which increased to 0.91 (95% CL 0.89, 0.94) after addition of change measures. CONCLUSIONS: TMD pain onset and persistence appear to be determined by enduring characteristics of the person as well as mutually interactive with temporally evolving variables. SIGNIFICANCE: TMD is known to be a complex disorder, in which onset and persistence are associated with disease-related variables in multiple domains, including environmental exposure, clinical, psychological, health status, and pain processing variables. Using a more dynamic approach in order to capture change across time, many aspects of those domains were found to worsen prior to the reporting of pain, with bidirectional influences between domains and pain emergence likely. TMD onset appears to represent the cumulative effect of multiple system dysregulation.

Decreased grey matter volume in mTBI patients with post-traumatic headache compared to headache-free mTBI patients and healthy controls: a longitudinal MRI study.

Traumatic brain injury (TBI) occurs in 1.7 million people annually and many patients go on to develop persistent disorders including post-traumatic headache (PTH). PTH is considered chronic if it continues past 3 months. In this study we aimed to identify changes in cerebral grey matter volume (GMV) associated with PTH in mild TBI patients. 50 mTBI patients (31 Non-PTH; 19 PTH) underwent MRI scans: within 10 days post-injury, 1 month, 6 months and 18 months. PTH was assessed at visit 4 by a post-TBI headache questionnaire. Healthy controls (n = 21) were scanned twice 6 months apart. Compared to non-PTH, PTH patients had decreased GMV across two large clusters described as the right anterior-parietal (p = 0.012) and left temporal-opercular (p = 0.027). Compared to healthy controls non-PTH patients had decreased GMV in the left thalamus (p = 0.047); PTH patients had decreased GMV in several extensive clusters: left temporal-opercular (p = 0.003), temporal-parietal (p = 0.041), superior frontal gyrus (p = 0.008) and right middle frontal/superior frontal gyrus (0.004) and anterior-parietal (p = 0.003). Differences between PTH and non-PTH patients were most striking at early time points. These early changes may be associated with an increased risk of PTH. Patients with these changes should be monitored for chronic PTH.

Menstrual Cycle Variations in Gray Matter Volume, White Matter Volume and Functional Connectivity: Critical Impact on Parietal Lobe.

The role of gonadal hormones in neural plasticity remains unclear. This study aimed to examine the effects of naturally fluctuating hormone levels over the menstrual cycle in healthy females. Gray matter, functional connectivity (FC) and white matter changes over the cycle were assessed by using functional magnetic resonance imaging (fMRI), resting state fMRI, and structural MRIs, respectively, and associated with serum gonadal hormone levels. Moreover, electrocutaneous sensitivity was evaluated in 14 women in four phases of their menstrual cycle (menstrual, follicular, ovulatory, and luteal). Electrocutaneous sensitivity was greater during follicular compared to menstrual phase. Additionally, pain unpleasantness was lower in follicular phase than other phases while pain intensity ratings did not change over the cycle. Significant variations in cycle phase effects on gray matter volume were found in the left inferior parietal lobule (IPL) using voxel-based morphometry. Subsequent Freesurfer analysis revealed greater thickness of left IPL during the menstrual phase when compared to other phases. Also, white matter volume fluctuated across phases in left IPL. Blood estradiol was positively correlated with white matter volume both in left parietal cortex and whole cortex. Seed-driven FC between left IPL and right secondary visual cortex was enhanced during ovulatory phase. A seed placed in right IPL revealed enhanced FC between left and right IPL during the ovulatory phase. Additionally, we found that somatosensory cortical gray matter was thinner during follicular compared to menstrual phase. We discuss these results in the context of likely evolutionary pressures selecting for enhanced perceptual sensitivity across modalities specifically during ovulation.