Counting your chickens before they hatch: improvements in an untreated chronic pain population, beyond regression to the mean and the placebo effect.

Introduction: Isolating the effect of an intervention from the natural course and fluctuations of a condition is a challenge in any clinical trial, particularly in the field of pain. Regression to the mean (RTM) may explain some of these observed fluctuations. Objectives: In this paper, we describe and quantify the natural trajectory of questionnaire scores over time, based on initial scores. Methods: Twenty-seven untreated chronic low back pain patients and 25 healthy controls took part in this observational study, wherein they were asked to complete an array of questionnaires commonly used in pain studies during each of 3 visits (V1, V2, V3) at the 2-month interval. Scores at V1 were classified into 3 subgroups (extremely high, normal, and extremely low), based on z-scores. The average delta (∆ = V2 - V1) was calculated for each subgroup, for each questionnaire, to describe the evolution of scores over time based on initial scores. This analysis was repeated with the data for V2 and V3. Results: Our results show that high initial scores were widely followed by more average scores, while low initial scores tended to be followed by similar (low) scores. Conclusion: These trajectories cannot be attributable to RTM alone because of their asymmetry, nor to the placebo effect as they occurred in the absence of any intervention. However, they could be the result of an Effect of Care, wherein participants had meaningful improvements simply from taking part in a study. The improvement observed in patients with high initial scores should be carefully taken into account when interpreting results from clinical trials.

Paraspinal Muscle Changes in Individuals with and without Chronic Low Back Pain over a 4-Month Period: A Longitudinal MRI Study.

Background and Objectives: Previous research has shown associations between atrophy and fatty infiltration of the lumbar paraspinal musculature and low back pain (LBP). However, few studies have examined longitudinal changes in healthy controls and individuals with LBP without intervention. We aimed to investigate the natural variations in lumbar paraspinal musculature morphology and composition in this population over a 4-month period. Materials and Methods: Healthy controls and individuals with LBP were age- and sex-matched and completed several self-administered questionnaires. MRIs of L1-L5 were taken at baseline, 2 months, and 4 months to investigate cross-sectional area (CSA), along with DIXON fat and water images. A total of 29 participants had clear images for at least one level for all three time points. Means and standard deviations were calculated for the participant demographics. A two-way repeated measures ANOVA was performed to investigate CSA, fat signal fraction, and CSA asymmetry. Results: A total of 27 images at L3/L4, 28 images at L4/L5, and 15 images at L5/S1 were included in the final analysis. There were significant main effects of group for psoas CSA at the L3/L4 level (p = 0.02) and erector spinae (ES) CSA % asymmetry at the L3/L4 level (p < 0.001). There was a significant main effect of time for lumbar multifidus (LM) CSA % asymmetry at L4/L5 level (p = 0.03). Conclusions: This study provides insights into LM, ES, and psoas morphology in both healthy controls and affected individuals over a 4-month period without any intervention. Our findings suggest that psoas CSA at higher lumbar levels and CSA % asymmetry in general may be a better indicator of pathology and the development of pathology over time. Evaluating natural variations in paraspinal musculature over longer time frames may provide information on subtle changes in healthy controls and affected individuals and their potential role in chronic LBP.

Personalizing rehabilitation for individuals with musculoskeletal impairments: Feasibility of implementation of the Measures Associated to Prognostic (MAPS) tool.

INTRODUCTION: The Measures Associated to PrognoStic (MAPS) tool is a standardized questionnaire that integrates validated prognostic tools to detect the presence of biopsychosocial prognostic factors in patients consulting for musculoskeletal disorders. PURPOSE: The objectives were to assess the: 1) feasibility of implementation of the MAPS tool, 2) clinicians' acceptability of the dashboard, and 3) patients' acceptability of the MAPS tool. METHODS: Twenty physiotherapists and two occupational therapists from seven outpatient musculoskeletal clinics were recruited to implement the MAPS tool during a 3-month timeframe, where new patients completed the questionnaire upon initial assessment. The results were presented to the clinicians via a dashboard. Surveys and semi-structured interviews were conducted to measure feasibility and acceptability. RESULTS: Six out of 11 feasibility criteria (55%) and 21 out of 24 acceptability criteria (88%) reached the a priori threshold for success. The interviews allowed us to identify three main themes to facilitate implementation: 1) limiting the burden, 2) ensuring patients' understanding of the tool's purpose, and 3) integrating the dashboard as a clinical information tool. CONCLUSION: Our quantitative and qualitative results support the feasibility of implementation and acceptability of the MAPS tool pending minor adjustments. Depicting the patients' prognostic profile has the potential to help clinicians optimize their interventions for patients presenting with musculoskeletal disorders.

The assessment of paraspinal muscle epimuscular fat in participants with and without low back pain: A case-control study.

It remains unclear whether paraspinal muscle fatty infiltration in low back pain (LBP) is i) solely intramuscular, ii) is lying outside the epimysium between the muscle and fascial plane (epimuscular) or iii) or combination of both, as imaging studies often use different segmentation protocols that are not thoroughly described. Epimuscular fat possibly disturbs force generation of paraspinal muscles, but is seldomly explored. This project aimed to 1) compare epimuscular fat in participants with and without chronic LBP, and 2) determine whether epimuscular fat is different across lumbar spinal levels and associated with BMI, age, sex and LBP status, duration or intensity. Fat and water lumbosacral MRIs of 50 chronic LBP participants and 41 healthy controls were used. The presence and extent of epimuscular fat for the paraspinal muscle group (erector spinae and multifidus) was assessed using a qualitative score (0-5 scale; 0 = no epimuscular fat and 5 = epimuscular fat present along the entire muscle) and quantitative manual segmentation method. Chi-squared tests evaluated associations between qualitative epimuscular fat ratings and LBP status at each lumbar level. Bivariate and partial spearman's rho correlation assessed relationships between quantitative and qualitative epimuscular fat with participants' characteristics. Epimuscular fat was more frequent at the L4-L5 (X2 = 13.781, p = 0.017) and L5-S1 level (X2 = 27.825, p < 0.001) in participants with LBP compared to controls, which was not found for the higher lumbar levels. The total qualitative score (combined from all levels) showed a significant positive correlation with BMI, age, sex (female) and LBP status (r = 0.23-0.55; p < 0.05). Similarly, the total area of epimuscular fat (quantitative measure) was significantly correlated with BMI, age and LBP status (r = 0.26-0.57; p < 0.05). No correlations were found between epimuscular fat and LBP duration or intensity. Paraspinal muscle epimuscular fat is more common in chronic LBP patients. The functional implications of epimuscular fat should be further explored.

Establishing the prognostic profile of patients with work-related musculoskeletal disorders: Development and acceptability of the MAPS questionnaire.

PURPOSE: Work-related musculoskeletal disorders (WRMD) are the most common causes of disability worldwide and are associated with significant use of healthcare. One way to optimize the clinical outcomes of injured workers receiving rehabilitation is to identify and address individual prognostic factors (PF), which can facilitate the personalization of the treatment plan. As there is no pragmatic and systematic method to collect prognostic-related data, the purpose of the study was to develop and assess the acceptability of a set of questionnaires to establish the "prognostic profile" of workers with WRMD. METHODS: We utilized a multistep process to inform the acceptability of the Measures Associated to PrognoStic (MAPS) questionnaire. During STEP-1, a preliminary version of the was developed through a literature search followed by an expert consensus including a patient-advisor. During STEP-2, future users (rehabilitation professionals, healthcare administrators and compensation officers) were consulted through an online survey and were asked to rate the relevance of each content item; items that obtained ≥80% of "totally agree" answers were included. They were also asked to prioritize PF according to their usefulness for clinical decision-making, as well as perceived efficacy to enhance the treatment plan. RESULTS: The questionnaire was developed with three categories: the outcome predicted, the unique PF, and prognostic tools. Personal PF (i.e.: coping strategies, fear-avoidance beliefs), pain related PF (i.e.: pain intensity/severity, duration of pain), and work-related PF (i.e.: work physical demands, work accommodations) were identified to be totally relevant and included in the questionnaire. 84% of the respondents agreed that their patients could complete the MAPS questionnaire in their clinical setting, while 75% totally agreed that the questionnaire is useful to personalize rehabilitation interventions. CONCLUSION: The MAPS questionnaire was deemed acceptable to establish the "prognostic profile" of injured workers and help the clinicians in the treatment decision-making process.

Prognostic factors specific to work-related musculoskeletal disorders: An overview of recent systematic reviews.

PURPOSE: Work-related injuries affect a considerable number of people each year and represent a significant burden for society. To reduce this burden, optimizing rehabilitation care by integrating prognostic factors (PF) into the clinical decision-making process is a promising way to improve clinical outcomes. The aim of this study was to identify PF specific to work-related musculoskeletal disorders. METHODS: We performed an overview of systematic reviews reporting on PF that had the following outcomes of interest: Return to work, pain, disability, functional status, or poor outcomes. Each extracted PF was categorized according to its level of evidence (grade A or B) and whether it was modifiable or not. The risk of bias of each study was assessed with the ROBIS tool. RESULTS: We retrieved 757 citations from 3 databases. After removing 307 duplicates, 450 records were screened, and 20 studies were retained. We extracted a total of 20 PF with a Grade A recommendation, where 7 were deemed modifiable, 11 non-modifiable and 2 were index test. For example, return to work expectations, previous sick leave, delay in referral and pain intensity were found to be predictors of return-to-work outcomes. We also identified 17 PF with a Grade B recommendation, where 11 were deemed modifiable. For example, poor general health, negative recovery expectations, coping and fear-avoidance beliefs, pain severity, and particularly physical work were found to predict return to work outcomes. CONCLUSION: We found numerous modifiable PFs that can help clinicians personalize their treatment plan beyond diagnostic-related information for work-related musculoskeletal disorders.

The Canadian version of the National Institutes of Health minimum dataset for chronic low back pain research: reference values from the Quebec Low Back Pain Study.

ABSTRACT: The National Institutes of Health (NIH) minimum dataset for chronic low back pain (CLBP) was developed in response to the challenge of standardizing measurements across studies. Although reference values are critical in research on CLBP to identify individuals and communities at risk of poor outcomes such as disability, no reference values have been published for the Quebec (Canada) context. This study was aimed to (1) provide reference values for the Canadian version of the NIH minimum dataset among individuals with CLBP in Quebec, both overall and stratified by gender, age, and pain impact stratification (PIS) subgroups, and (2) assess the internal consistency of the minimum data set domains (pain interference, physical function, emotional distress or depression, sleep disturbance, and PIS score). We included 2847 individuals living with CLBP who completed the baseline web survey of the Quebec Low Back Pain Study (age: 44.0 ± 11.2 years, 48.1% women) and were recruited through social media and healthcare settings. The mean score was 6.1 ± 1.8 for pain intensity. Pain interference, physical function, emotional distress or depression, sleep disturbance, and PIS scores were 12.9 ± 4.1, 14.4 ± 3.9, 9.8 ± 4.4, 13.0 ± 3.6, and 26.4 ± 6.6, respectively. Emotional distress or depression showed floor effects. Good-to-excellent internal consistency was found overall and by language, gender, and age subgroups for all domains (alpha: 0.81-0.93) and poor-to-excellent internal consistency for PIS subgroups (alpha: 0.59-0.91). This study presents reference values and recommendations for using the Canadian version of the NIH minimum dataset for CLBP that can be useful for researchers and clinicians.

Low back pain definitions: effect on patient inclusion and clinical profiles.

Introduction: Numerous definitions of acute low back pain (aLBP) exist. The use of different definitions results in variability in reported prevalence or incidence, conflicting data regarding factors associated with the transition to chronic LBP (cLBP), and hampers comparability among studies. Objective: Here, we compare the impact of 3 aLBP definitions on the number of aLBP cases and participants' characteristics and explore the distribution of participants across definitions. Methods: A sample of 1264 participants from the Quebec Low Back Pain Study was included. Three definitions of aLBP were used: (1) not meeting the National Institutes of Health (NIH) cLBP definition ("nonchronic"), (2) pain beginning <3 months ago ("acute"), and (3) pain beginning <3 months with a preceding LBP-free period ("new episode"). Results: There were 847, 842, and 489 aLBP cases meeting the criteria for the 3 definitions, respectively. Participants included in the "nonchronic" had lower pain interference, greater physical function scores, and fewer participants reporting >5 years of pain than in the other definitions. Half the participants meeting the "acute" definition and one-third of participants meeting the "new episode" definition were also classified as cLBP based on the NIH definition. Conclusions: Our results highlight the importance of the definition used for aLBP. Different definitions influence the sample size and clinical profiles (group's characteristics). We recommended that cohort studies examining the transition from aLBP to cLBP ensure that the definitions selected are mutually exclusive (ie, participants included [aLBP] differ from the expected outcome [cLBP]).

Sex-Specific Pharmacotherapy for Back Pain: A Proof-of-Concept Randomized Trial.

BACKGROUND: Preventing transition to chronic back pain (CBP) is a long-sought strategy that could rescue patients from prolonged suffering. Recent rodent and human brain imaging studies suggest involvement of sexually dimorphic, dopaminergic-motivational, mesolimbic circuits in the transition to chronic pain (tCBP), and hint that the combination of carbidopa/levodopa and naproxen (LDP + NPX) may block tCBP. Here we evaluated, in people with recent-onset back pain, whether a 3-month treatment with LDP + NPX is safe, blocks tCBP, and whether its efficacy is sex-dependent. METHODS: A total of 72 participants were enrolled and stratified by risk for tCBP using brain-imaging biomarkers. Low-risk participants entered a no-treatment arm. Others were randomized to placebo + naproxen or LDP + NPX for 3 months. RESULTS: Both treatments resulted in more than 50% pain relief for approximately 75% of participants. A strong sex by treatment interaction was observed for daily pain intensity (phone NRS, P = 0.007), replicated on 4-week average pain (Pain/4w, P = 0.00001), and in intent-to-treat analysis (Pain/4w, P = 0.000004). Nucleus accumbens functional connectivity with medial prefrontal cortex, a predefined objective biomarker, showed sex dependence at baseline (P = 0.03) and sex-by-treatment interaction effect 3 months after treatment cessation (P = 0.031). Treatment modified the psychological profile of participants, and disrupted brain modeling-based predicted back pain intensity trajectories. Forty participants were queried 3.3 years from trial start; back pain ratings were similar between end of treatment and at 3.3 years (P = 0.62), indicating persistence of relief for this duration. CONCLUSIONS: These results provide the first evidence for preventing transition to chronic back pain using sex-specific pharmacotherapy. These provocative observations require confirmation in a larger study. ClinicalTrials.gov identifier: NCT01951105.

Diffusion properties of the fornix assessed by deterministic tractography shows age, sex, volume, cognitive, hemispheric, and twin relationships in young adults from the Human Connectome Project.

The fornix is the primary efferent pathway of the hippocampus and plays a central role in memory circuitry. Diffusion tensor imaging has shown changes in the fornix with typical development and aging. Here, the fornix was investigated in 903 healthy young adult participants aged 22-36 years old from the high-spatial resolution 1.25 mm isotropic Human Connectome Project (HCP) diffusion dataset. Manual deterministic tractography was used to assess relationships between fornix diffusion parameters and age, sex, laterality, hippocampus volume, memory scores, and genetic effects in a subgroup of mono- and dizygotic twins. Fornix diffusion metrics were weakly correlated with age over the given age span. While significant hemispheric and sex differences were observed (greater fractional anisotropy (FA) and volume in the right hemisphere; greater FA and volume in females), there was great overlap between the groups. Hippocampus volume measurements showed greater volume in the right hemisphere, were found to be larger in males, and were weakly correlated with fornix FA and volume. Interestingly, all fornix diffusion measurements correlated strongly with fornix volume, suggesting the presence of partial volume effects despite the high-spatial resolution of the data. Both fornix diffusion parameters and hippocampal volumes were able to explain some variance (0.6-5.5%) in the memory tests evaluated. The fornix diffusion parameters were influenced by both genetic and shared environmental factors, displaying greater variability in dizygotic than in monozygotic twins. These findings provide a comprehensive depiction of the fornix in healthy, young individuals, upon which future typical development/aging and pathological studies could anchor.

Data set describing the in vitro biological activity of JMV2009, a novel silylated neurotensin(8-13) analog.

Neurotensin (NT) is a tridecapeptide displaying interesting antinociceptive properties through its action on its receptors, NTS1 and NTS2. Neurotensin-like compounds have been shown to exert better antinociceptive properties than morphine at equimolar doses. In this article, we characterized the molecular effects of a novel neurotensin (8-13) (NT(8-13)) analog containing an unnatural amino acid. This compound, named JMV2009, displays a Silaproline in position 10 in replacement of a proline in the native NT(8-13). We first examined the binding affinities of this novel NT(8-13) derivative at both NTS1 and NTS2 receptor sites by performing competitive displacement of iodinated NT on purified cell membranes. Then, we evaluated the ability of JMV2009 to activate NTS1-related G proteins as well as to promote the recruitment of ß-arrestins 1 and 2 by using BRET-based cellular assays in live cells. We next assessed its ability to induce p42/p44 MAPK phosphorylation and NT receptors internalization using western blot and cell-surface ELISA, respectively. Finally, we determined the in vitro plasma stability of this NT derivative. This article is associated with the original article "Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog" published in European Journal of Pharmacology[1]. The reader is directed to the associated article for results interpretation, comments, and discussion.

Pain relief devoid of opioid side effects following central action of a silylated neurotensin analog.

Neurotensin (NT) exerts naloxone-insensitive antinociceptive action through its binding to both NTS1 and NTS2 receptors and NT analogs provide stronger pain relief than morphine on a molecular basis. Here, we examined the analgesic/adverse effect profile of a new NT(8-13) derivative denoted JMV2009, in which the Pro10 residue was substituted by a silicon-containing unnatural amino acid silaproline. We first report the synthesis and in vitro characterization (receptor-binding affinity, functional activity and stability) of JMV2009. We next examined its analgesic activity in a battery of acute, tonic and chronic pain models. We finally evaluated its ability to induce adverse effects associated with chronic opioid use, such as constipation and analgesic tolerance or related to NTS1 activation, like hypothermia. In in vitro assays, JMV2009 exhibited high binding affinity for both NTS1 and NTS2, improved proteolytic resistance as well as agonistic activities similar to NT, inducing sustained activation of p42/p44 MAPK and receptor internalization. Intrathecal injection of JMV2009 produced dose-dependent antinociceptive responses in the tail-flick test and almost completely abolished the nociceptive-related behaviors induced by chemical somatic and visceral noxious stimuli. Likewise, increasing doses of JMV2009 significantly reduced tactile allodynia and weight bearing deficits in nerve-injured rats. Importantly, repeated agonist treatment did not result in the development of analgesic tolerance. Furthermore, JMV2009 did not cause constipation and was ineffective in inducing hypothermia. These findings suggest that NT drugs can act as an effective opioid-free medication for the management of pain or can serve as adjuvant analgesics to reduce the opioid adverse effects.

Diffusion time dependency along the human corpus callosum and exploration of age and sex differences as assessed by oscillating gradient spin-echo diffusion tensor imaging.

Conventional diffusion imaging uses pulsed gradient spin echo (PGSE) waveforms with diffusion times of tens of milliseconds (ms) to infer differences of white matter microstructure. The combined use of these long diffusion times with short diffusion times (<10 â€‹ms) enabled by oscillating gradient spin echo (OGSE) waveforms can enable more sensitivity to changes of restrictive boundaries on the scale of white matter microstructure (e.g. membranes reflecting the axon diameters). Here, PGSE and OGSE images were acquired at 4.7 â€‹T from 20 healthy volunteers aged 20-73 years (10 males). Mean, radial, and axial diffusivity, as well as fractional anisotropy were calculated in the genu, body and splenium of the corpus callosum (CC). Monte Carlo simulations were also conducted to examine the relationship of intra- and extra-axonal radial diffusivity with diffusion time over a range of axon diameters and distributions. The results showed elevated diffusivities with OGSE relative to PGSE in the genu and splenium (but not the body) in both males and females, but the OGSE-PGSE difference was greater in the genu for males. Females showed positive correlations of OGSE-PGSE diffusivity difference with age across the CC, whereas there were no such age correlations in males. Simulations of radial diffusion demonstrated that for axon sizes in human brain both OGSE and PGSE diffusivities were dominated by extra-axonal water, but the OGSE-PGSE difference nonetheless increased with area-weighted outer-axon diameter. Therefore, the lack of OGSE-PGSE difference in the body is not entirely consistent with literature that suggests it is composed predominantly of axons with large diameter. The greater OGSE-PGSE difference in the genu of males could reflect larger axon diameters than females. The OGSE-PGSE difference correlation with age in females could reflect loss of smaller axons at older ages. The use of OGSE with short diffusion times to sample the microstructural scale of restriction implies regional differences of axon diameters along the corpus callosum with preliminary results suggesting a dependence on age and sex.

Structural and functional multi-platform MRI series of a single human volunteer over more than fifteen years.

We present MRI data from a single human volunteer consisting in over 599 multi-contrast MR images (T1-weighted, T2-weighted, proton density, fluid-attenuated inversion recovery, T2* gradient-echo, diffusion, susceptibility-weighted, arterial-spin labelled, and resting state BOLD functional connectivity imaging) acquired in over 73 sessions on 36 different scanners (13 models, three manufacturers) over the course of 15+ years (cf. Data records). Data included planned data collection acquired within the Consortium pour l'identification précoce de la maladie Alzheimer - Québec (CIMA-Q) and Canadian Consortium on Neurodegeneration in Aging (CCNA) studies, as well as opportunistic data collection from various protocols. These multiple within- and between-centre scans over a substantial time course of a single, cognitively healthy volunteer can be useful to answer a number of methodological questions of interest to the community.

Retroclavicular vs Infraclavicular block for brachial plexus anesthesia: a multi-centric randomized trial.

BACKGROUND: The coracoid approach is a simple method to perform ultrasound-guided brachial plexus regional anesthesia (RA) but its simplicity is counterbalanced by a difficult needle visualization. We hypothesized that the retroclavicular (RCB) approach is not longer to perform when compared to the coracoid (ICB) approach, and improves needle visualization. METHODS: This randomized, controlled, non-inferiority trial conducted in two hospitals, included patients undergoing distal upper limb surgery. Patients were randomly assigned to a brachial plexus block (ICB or RCB). The primary outcome was performance time (sum of visualization and needling time), and was analyzed with a non-inferiority test of averages. Depth of sensory and motor blockade, surgical success, total anesthesia time, needle visualization, number of needle passes and complications were also evaluated. Subgroup analysis restricted to patients with higher body mass index was completed. RESULTS: We included 109 patients between September 2016 and May 2017. Mean RCB performance time was 4.8 ± 2.0 min while ICB was 5.2 ± 2.3 min (p = 0.06) with a 95% CI reaching up to 5.8% longer. RCB conferred an ultrasound-needle angle closer to 0° and significantly improved needle visibility after the clavicle was cleared and before local anesthetic administration. No differences were found in the secondary outcomes. Similar results were found in the subgroup analysis. CONCLUSION: RCB approach for brachial plexus anesthesia was similar to ICB approach in terms of time performance. Needle visibility, which represent an important clinical variable, was superior and angle between needle and ultrasound probe was close to 0° in the RCB group. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT02913625), registered 26 September 2016.

Inferring distinct mechanisms in the absence of subjective differences: Placebo and centrally acting analgesic underlie unique brain adaptations.

Development and maintenance of chronic pain is associated with structural and functional brain reorganization. However, few studies have explored the impact of drug treatments on such changes. The extent to which long-term analgesia is related to brain adaptations and its effects on the reversibility of brain reorganization remain unclear. In a randomized placebo-controlled clinical trial, we contrasted pain relief (3-month treatment period), and anatomical (gray matter density [GMD], assessed by voxel-based morphometry) and functional connectivity (resting state fMRI nodal degree count [DC]) adaptations, in 39 knee osteoarthritis (OA) patients (22 females), randomized to duloxetine (DLX, 60 mg once daily) or placebo. Pain relief was equivalent between treatment types. However, distinct circuitry (GMD and DC) could explain pain relief in each group: up to 85% of variance for placebo analgesia and 49% of variance for DLX analgesia. No behavioral measures (collected at entry into the study) could independently explain observed analgesia. Identified circuitry were outside of nociceptive circuitry and minimally overlapped with OA-abnormal or placebo response predictive brain regions. Mediation analysis revealed that changes in GMD and DC can influence each other across remote brain regions to explain observed analgesia. Therefore, we can conclude that distinct brain mechanisms underlie DLX and placebo analgesia in OA. The results demonstrate that even in the absence of differences in subjective pain relief, pharmacological treatments can be differentiated from placebo based on objective brain biomarkers. This is a crucial step to untangling mechanisms and advancing personalized therapy approaches for chronic pain.

Brain Connectivity Predicts Placebo Response across Chronic Pain Clinical Trials.

Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo's effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia. Trial Registration ClinicalTrials.gov NCT02903238 ClinicalTrials.gov NCT01558700.

Global disruption of degree rank order: a hallmark of chronic pain.

Chronic pain remains poorly understood; yet it is associated with the reorganization of the nervous system. Here, we demonstrate that a unitary global measure of functional connectivity, defined as the extent of degree rank order disruption, kD, identifies the chronic pain state. In contrast, local degree disruption differentiates between chronic pain conditions. We used resting-state functional MRI data to analyze the brain connectome at varying scales and densities. In three chronic pain conditions, we observe disrupted kD, in proportion to individuals' pain intensity, and associated with community membership disruption. Additionally, we observe regional degree changes, some of which were unique to each type of chronic pain. Subjects with recent onset of back pain exhibited emergence of kD only when the pain became chronic. Similarly, in neuropathic rats kD emerged weeks after injury, in proportion to pain-like behavior. Thus, we found comprehensive cross-species evidence for chronic pain being a state of global randomization of functional connectivity.