Is There an Association Between Lateralization of Chronic Pain in the Body and Depression?

Depression commonly co-occurs with chronic pain and can worsen pain outcomes. Recent theoretical work has hypothesized that pain localized to the left hemibody is a risk factor for worse depression due to overlap in underlying neural substrates. This hypothesis has not been tested a priori. Using a large sample of treatment-seeking adults with mixed-etiology chronic pain (N = 1,185), our cross-sectional study tested whether patients with left-sided pain endorse worse depressive symptoms. We also examined differences in other pain-related functioning measures. We tested 4 comparisons based on painful body areas using the CHOIR body map: 1) only left-sided (OL) versus any right-sided pain; 2) only right-sided (OR) versus any left-sided pain; 3) OL versus OR versus bilateral pain; and 4) more left-sided versus more right-sided versus equal-sided pain. Analysis of variance models showed OL pain was not associated with worse depression (F = 5.50, P = .019). Any left-sided pain was associated with worse depression, though the effect was small (F = 8.58, P = .003, Cohens d = .29). Bilateral pain was associated with worse depression (F = 8.05, P < .001, Cohens d = .24-.33). Regardless of pain location, more body areas endorsed was associated with greater depression. Although a more rigorous assessment of pain laterality is needed, our findings do not support the hypothesis that left-lateralized pain is associated with worse depression. PERSPECTIVE: Pain lateralized to the left side of the body has been hypothesized as a risk factor for worse depression in chronic pain, despite never being tested in a large, real-world sample of patients with chronic pain. Findings showed that more widespread pain, not pain laterality, was associated with worse depression.

Perceived Injustice and Anger in Fibromyalgia With and Without Comorbid Mental Health Conditions: A Hebrew Validation of the Injustice Experience Questionnaire.

OBJECTIVES: Perceived injustice (PI), assessed by the Injustice Experience Questionnaire (IEQ), is an important trigger of anger. Both PI and anger are associated with adverse chronic pain outcomes, and with comorbid mental health severity. We aimed examined the roles of PI and anger in mediating pain across Fibromyalgia patients, with and without comorbid anxiety/depression (FM+A/D, FM-A/D, respectively), as well as rheumatoid arthritis (RA), and pain-free controls (PFC). We hypothesized the highest levels of PI, anger, and pain in FM+A/D patients, followed by FM-A/D, RA, and PFC, thus also validating a Hebrew version of the IEQ. METHODS: We translated the IEQ using the forward-backward method and collected data online. Based on self-reported anxiety/depression, the sample comprised 66 FM+A/D patients, 64 FM-A/D, 34 RA, and 32 PFCs. Assessments included the IEQ, state and trait anger, pain intensity, anxiety, depression, and pain catastrophizing. The structure and reliability of the Hebrew IEQ were examined using factor analysis and Cronbach alpha. Bootstrapped-based modeling was used to test the roles of state and trait anger in mediating and moderating the relationship between PI and pain intensity. RESULTS: We confirmed a one-factor structure of the IEQ, with excellent reliability. FM+A/D patients demonstrated the highest scores in all measures. Within this group, trait anger moderated the mediating effect of state anger in the relationship between PI and pain intensity. DISCUSSION: Our findings validate a Hebrew IEQ and highlight the importance of PI and state and trait anger in the differential manifestation of mental health comorbidity in FM.

Patient Responses to the Term Pain Catastrophizing: Thematic Analysis of Cross-sectional International Data.

Pain catastrophizing is understood as a negative cognitive and emotional response to pain. Researchers, advocates and patients have reported stigmatizing effects of the term in clinical settings and the media. We conducted an international study to investigate patient perspectives on the term pain catastrophizing. Open-ended electronic patient and caregiver proxy surveys were promoted internationally by collaborator stakeholders and through social media. 3,521 surveys were received from 47 countries (77.3% from the U.S.). The sample was mainly female (82.1%), with a mean age of 41.62 (SD 12.03) years; 95% reported ongoing pain and pain duration > 10 years (68.4%). Forty-five percent (n = 1,295) had heard of the term pain catastrophizing; 12% (n = 349) reported being described as a 'pain catastrophizer' by a clinician with associated high levels of feeling blamed, judged, and dismissed. We present qualitative thematic data analytics for responses to open-ended questions, with 32% of responses highlighting the problematic nature of the term. We present the patients' perspective on the term pain catastrophizing, its material effect on clinical experiences, and associations with negative gender stereotypes. Use of patient-centered terminology may be important for favorably shaping the social context of patients' experience of pain and pain care. PERSPECTIVE: Our international patient survey found that 45% had heard of the term pain catastrophizing, about one-third spontaneously rated the term as problematic, and 12% reported the term was applied to them with most stating this was a negative experience. Clinician education on patient-centered terminology may improve care and reduce stigma.

Self-evaluation of social-rank in socially anxious individuals associates with enhanced striatal reward function.

BACKGROUND: Negative self-views, especially in the domain of power (i.e. social-rank), characterize social anxiety (SA). Neuroimaging studies on self-evaluations in SA have mainly focused on subcortical threat processing systems. Yet, self-evaluation may concurrently invoke diverse affective processing, as motivational systems related to desired self-views may also be activated. To investigate the conflictual nature that may accompany self-evaluation of certain social domains in SA, we examined brain activity related to both threat and reward processing. METHODS: Participants (N = 74) differing in self-reported SA-severity underwent fMRI while completing a self-evaluation task, wherein they judged the self-descriptiveness of high- v. low-intensity traits in the domains of power and affiliation (i.e. social connectedness). Participants also completed two auxiliary fMRI tasks designated to evoke reward- and threat-related activations in the ventral striatum (VS) and amygdala, respectively. We hypothesized that self-evaluations in SA, particularly in the domain of power, involve aberrant brain activity related to both threat and reward processing. RESULTS: SA-severity was more negatively associated with power than with affiliation self-evaluations. During self-evaluative judgment of high-power (e.g. dominant), SA-severity associated with increased activity in the VS and ventromedial prefrontal cortex. Moreover, SA-severity correlated with higher similarity between brain activity patterns activated by high-power traits and patterns activated by incentive salience (i.e. reward anticipation) in the VS during the reward task. CONCLUSIONS: Our findings indicate that self-evaluation of high-power in SA involves excessive striatal reward-related activation, and pinpoint the downregulation of VS-VMPFC activity within such self-evaluative context as a potential neural outcome for therapeutic interventions.

Mindfulness-Based Stress Reduction, Cognitive Behavioral Therapy, and Acupuncture in Chronic Low Back Pain: Protocol for Two Linked Randomized Controlled Trials.

BACKGROUND: Nonpharmacologic mind-body therapies have demonstrated efficacy in low back pain. However, the mechanisms underlying these therapies remain to be fully elucidated. OBJECTIVE: In response to these knowledge gaps, the Stanford Center for Low Back Pain-a collaborative, National Institutes of Health P01-funded, multidisciplinary research center-was established to investigate the common and distinct biobehavioral mechanisms of three mind-body therapies for chronic low back pain: cognitive behavioral therapy (CBT) that is used to treat pain, mindfulness-based stress reduction (MBSR), and electroacupuncture. Here, we describe the design and implementation of the center structure and the associated randomized controlled trials for characterizing the mechanisms of chronic low back pain treatments. METHODS: The multidisciplinary center is running two randomized controlled trials that share common resources for recruitment, enrollment, study execution, and data acquisition. We expect to recruit over 300 chronic low back pain participants across two projects and across different treatment arms within each project. The first project will examine pain-CBT compared with MBSR and a wait-list control group. The second project will examine real versus sham electroacupuncture. We will use behavioral, psychophysical, physical measure, and neuroimaging techniques to characterize the central pain modulatory and emotion regulatory systems in chronic low back pain at baseline and longitudinally. We will characterize how these interventions impact these systems, characterize the longitudinal treatment effects, and identify predictors of treatment efficacy. RESULTS: Participant recruitment began on March 17, 2015, and will end in March 2023. Recruitment was halted in March 2020 due to COVID-19 and resumed in December 2021. CONCLUSIONS: This center uses a comprehensive approach to study chronic low back pain. Findings are expected to significantly advance our understanding in (1) the baseline and longitudinal mechanisms of chronic low back pain, (2) the common and distinctive mechanisms of three mind-body therapies, and (3) predictors of treatment response, thereby informing future delivery of nonpharmacologic chronic low back pain treatments. TRIAL REGISTRATION: ClinicalTrials.gov NCT02503475; https://clinicaltrials.gov/ct2/show/NCT02503475. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/37823.

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.

Confounds in neuroimaging: A clear case of sex as a confound in brain-based prediction.

Muscle weakness is common in many neurological, neuromuscular, and musculoskeletal conditions. Muscle size only partially explains muscle strength as adaptions within the nervous system also contribute to strength. Brain-based biomarkers of neuromuscular function could provide diagnostic, prognostic, and predictive value in treating these disorders. Therefore, we sought to characterize and quantify the brain's contribution to strength by developing multimodal MRI pipelines to predict grip strength. However, the prediction of strength was not straightforward, and we present a case of sex being a clear confound in brain decoding analyses. While each MRI modality-structural MRI (i.e., gray matter morphometry), diffusion MRI (i.e., white matter fractional anisotropy), resting state functional MRI (i.e., functional connectivity), and task-evoked functional MRI (i.e., left or right hand motor task activation)-and a multimodal prediction pipeline demonstrated significant predictive power for strength (R 2 = 0.108-0.536, p ≤ 0.001), after correcting for sex, the predictive power was substantially reduced (R 2 = -0.038-0.075). Next, we flipped the analysis and demonstrated that each MRI modality and a multimodal prediction pipeline could significantly predict sex (accuracy = 68.0%-93.3%, AUC = 0.780-0.982, p < 0.001). However, correcting the brain features for strength reduced the accuracy for predicting sex (accuracy = 57.3%-69.3%, AUC = 0.615-0.780). Here we demonstrate the effects of sex-correlated confounds in brain-based predictive models across multiple brain MRI modalities for both regression and classification models. We discuss implications of confounds in predictive modeling and the development of brain-based MRI biomarkers, as well as possible strategies to overcome these barriers.

A corticostriatal pathway mediating self-efficacy enhancement.

Forming positive beliefs about one's ability to perform challenging tasks, often termed self-efficacy, is fundamental to motivation and emotional well-being. Self-efficacy crucially depends on positive social feedback, yet people differ in the degree to which they integrate such feedback into self-beliefs (i.e., positive bias). While diminished positive bias of this sort is linked to mood and anxiety, the neural processes by which positive feedback on public performance enhances self-efficacy remain unclear. To address this, we conducted a behavioral and fMRI study wherein participants delivered a public speech and received fictitious positive and neutral feedback on their performance in the MRI scanner. Before and after receiving feedback, participants evaluated their actual and expected performance. We found that reduced positive bias in updating self-efficacy based on positive social feedback associated with a psychopathological dimension reflecting symptoms of anxiety, depression, and low self-esteem. Analysis of brain encoding of social feedback showed that a positive self-efficacy update bias associated with a stronger reward-related response in the ventral striatum (VS) and stronger coupling of the VS with a temporoparietal region involved in self-processing. Together, our findings demarcate a corticostriatal circuit that promotes positive bias in self-efficacy updating based on social feedback, and highlight the centrality of such bias to emotional well-being.

Brain circuits for pain and its treatment.

Pain is a multidimensional experience with sensory-discriminative, affective-motivational, and cognitive-evaluative components. Pain aversiveness is one principal cause of suffering for patients with chronic pain, motivating research and drug development efforts to investigate and modulate neural activity in the brain's circuits encoding pain unpleasantness. Here, we review progress in understanding the organization of emotion, motivation, cognition, and descending modulation circuits for pain perception. We describe the molecularly defined neuron types that collectively shape pain multidimensionality and its aversive quality. We also review how pharmacological, stimulation, neurofeedback, surgical, and cognitive-behavioral interventions alter activity in these circuits to relieve chronic pain.

Somatic engagement alters subsequent neurobehavioral correlates of affective mentalizing.

Socio-emotional encounters involve a resonance of others' affective states, known as affect sharing (AS); and attribution of mental states to others, known as theory-of-mind (ToM). Empathy necessitates the integration of both processes, yet their interaction during emotional episodes and subsequent generation of inferences on others' affective states has rarely been tested. To address this, we developed a novel experimental design, wherein we manipulated AS by presenting nonverbal emotionally negative movies twice-each time accompanied by one of two soundtracks that accentuated either somatic cues or externally generated sounds. Movies were followed by questions addressing affective-ToM (emotional inferences), cognitive-ToM (inferences on beliefs and knowledge), and non-ToM aspects. Results revealed a neural differentiation between AS, affective-ToM, and cognitive-ToM. AS movies activated regions that have been implicated in emotional (e.g., amygdala) and somatosensory processing, and synchronized brain activity between participants in the latter. Affective-ToM activated the middle insula, limbic regions, and both ventral and dorsal portions of the medial prefrontal cortex (ventral medial prefrontal cortex [VMPFC] and dorsal medial prefrontal cortex [DMPFC], respectively), whereas cognitive-ToM activated posteromedial and lateral-prefrontal and temporal cortices. Critically, AS movies specifically altered neural activation in AS and ToM-related regions during subsequent affective-ToM inferences, most notably in the DMPFC. Moreover, DMPFC-VMPFC connectivity correlated with affective-ToM accuracy, when such questions followed AS movies. Our results associate empathic processes with designated neural activations and shed light on how neuro-behavioral indices of affective ToM are shaped by preceding somatic engagement.

Classifying chronic pain using multidimensional pain-agnostic symptom assessments and clustering analysis.

Chronic pain conditions present in various forms, yet all feature symptomatic impairments in physical, mental, and social domains. Rather than assessing symptoms as manifestations of illness, we used them to develop a chronic pain classification system. A cohort of real-world treatment-seeking patients completed a multidimensional patient-reported registry as part of a routine initial evaluation in a multidisciplinary academic pain clinic. We applied hierarchical clustering on a training subset of 11,448 patients using nine pain-agnostic symptoms. We then validated a three-cluster solution reflecting a graded scale of severity across all symptoms and eight independent pain-specific measures in additional subsets of 3817 and 1273 patients. Negative affect­related factors were key determinants of cluster assignment. The smallest subset included follow-up assessments that were predicted by baseline cluster assignment. Findings provide a cost-effective classification system that promises to improve clinical care and alleviate suffering by providing putative markers for personalized diagnosis and prognosis.

Individual differences in perceived sleep quality do not predict negative affect reactivity or regulation.

Do people who have low-quality sleep tend to have more negative affect? This question is of great public interest, and many would assume the answer is "yes." However, previous findings have been mixed, possibly due to differing measures of sleep and affect, or to a failure to separately examine negative affect reactivity and regulation. Across two studies, we assessed adults' perceived sleep quality for at least two weeks and tested their negative affect reactivity and regulation in response to unpleasant pictures (Study 1) or painful thermal stimulation (Study 2) using both self-report and physiological measures. The relationships between perceived sleep quality, on the one hand, and negative affect reactivity and regulation, on the other, were non-significant. Furthermore, a Bayesian approach unanimously favored the null hypothesis. These results suggest that individual differences in perceived sleep quality may not predict negative affect reactivity or regulation across adult individuals.

The Decline in Task Performance After Witnessing Rudeness Is Moderated by Emotional Empathy-A Pilot Study.

Rude behaviors engulf societies across the world on a daily basis. Witnessing rudeness toward others increases negative affect and decreases performance in various tasks requiring behavioral and cognitive efforts, such as solving word puzzles or creative and flexible thinking. In this pilot study, we examined whether different levels of emotional empathy that may influence susceptibility to others' distress, moderated the declined performance in several such tasks. The study was conducted online as a naturalistic setting for witnessing movie-clips portraying rudeness. We hypothesized that all participants will demonstrate decreased task performance following a rude compared to a neutral condition, but more so for those higher on emotional empathy. Results confirmed each of these hypotheses in one of two different cognitive tasks. Findings suggest that after witnessing rudeness, those higher on emotional empathy perform worse in cognitive tasks. While requiring replication in a larger sample size, empathic processing seems to be a potential moderator of the effect of rudeness on task performance.

The impact of self-control training on neural responses following anger provocation.

Self-control training (SCT) is one way to enhance self-controlled behavior. We conducted a novel and exploratory functional magnetic resonance imaging experiment to examine how SCT affects neural responses in a situation that elicits a self-control response: anger provocation. Forty-five healthy young men and women completed two-weeks of SCT or a behavioral monitoring task and were then insulted during scanning. We found significant changes in functional activation and connectivity using a lenient error threshold, which were not observed using a stricter threshold. Activation in the posterior insula was greater for the control compared to the SCT group at post-provocation, trait aggression correlated with neural responses to SCT, and SCT was associated with specific amygdala-cortical connections. Neural changes occurred even though SCT did not affect participants' performance on an inhibition task, reports of trying to control their anger, or their experience of anger. This dissociation prevented clear interpretation about whether the neural changes were indicative of specific anger or anger control processes. Although replication with high-powered studies is needed, we provide evidence that SCT affects neural responses in the context of anger provocation.

What Is the Relationship between Pain and Emotion? Bridging Constructs and Communities.

Although pain is defined as a sensory and emotional experience, it is traditionally researched and clinically treated separately from emotion. Conceptual and mechanistic relationships between these constructs highlight the need for better understanding of their bi-directional influences and the value of bridging the pain and emotion research and clinical communities.

The feeling of anger: From brain networks to linguistic expressions.

This review of the neuroscience of anger is part of The Human Affectome Project, where we attempt to map anger and its components (i.e., physiological, cognitive, experiential) to the neuroscience literature (i.e., genetic markers, functional imaging of human brain networks) and to linguistic expressions used to describe anger feelings. Given the ubiquity of anger in both its normative and chronic states, specific language is used in humans to express states of anger. Following a review of the neuroscience literature, we explore the language that is used to convey angry feelings, as well as metaphors reflecting inner states of anger experience. We then discuss whether these linguistic expressions can be mapped on to the neural circuits during anger experience and to distinct components of anger. We also identify relationships between anger components, brain networks, and other affective research relevant to motivational states of dominance and basic needs for safety.

Evaluation of Candidate Items for Severe PTSD Screening for Patients With Chronic Pain: Pilot Data Analysis With the IRT Approach.

OBJECTIVES: Post-traumatic stress disorder (PTSD) commonly co-occurs with chronic pain. Although PTSD symptoms are associated with negative health outcomes in patients with chronic pain, PTSD is typically under-detected and under-treated in outpatient pain settings. There is a need for rapid, brief screening tools to identify those at greatest risk for severe PTSD symptoms. To achieve that goal, our aim was to use item response theory (IRT) to identify the most informative PTSD symptoms characterizing severe PTSD in patients with chronic pain. METHODS: Fifty-six patients (71% female, 61% White) with mixed etiology chronic pain completed the PTSD Checklist-Civilian Version (PCL-C) as part of their appointment with a pain psychologist at a tertiary outpatient pain clinic. We used an IRT approach to evaluate each item's discriminant (a) and severity (b) parameters. RESULTS: Findings revealed that "feeling upset at reminders" (a = 3.67, b = 2.44) and "avoid thinking or talking about it" (a = 3.61, b = 2.17) as being highly discriminant for severe PTSD. CONCLUSIONS: We identified 2 candidate items for a brief PTSD screener as they were associated with severe PTSD symptoms. These 2 items may provide clinical utility in outpatient pain treatment settings to identify those suffering from severe PTSD, enabling physicians to refer them to trauma-specific evaluation or therapy. Future research is needed to further validate and confirm these candidate PTSD items in a larger clinic sample. LAY SUMMARY: The current study used the IRT approach to identify candidate items for a brief screener for severe PTSD. We examined 17 items of the PCL-C, and identified 2 items that were highly discriminant for severe PTSD. The 2 items were "feeling upset at reminders" and "avoid thinking or talking about it." These 2 items may provide clinical utility, since they may enable physicians to screen and make a referral for further assessment or treatment for PTSD.

Negative Affect-Related Factors Have the Strongest Association with Prescription Opioid Misuse in a Cross-Sectional Cohort of Patients with Chronic Pain.

OBJECTIVE: Increased opioid prescription to relieve pain among patients with chronic pain is associated with increased risk for misuse, potentially leading to substance use disorders and overdose death. We aimed to characterize the relative importance and identify the most significant of several potential risk factors for the severity of self-reported prescribed opioid misuse behaviors. METHODS: A sample of 1,193 patients (mean age ± SD = 50.72 ± 14.97 years, 64.04% female) with various chronic pain conditions completed a multidimensional registry assessing four pain severity measures and 14 physical, mental, and social health status factors using the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS). A validated PROMIS measure of medication misuse was completed by 692 patients who endorsed currently taking opioid medication. Patients taking opioid medications were compared across all measures with those who do not take opioid medications. Subsequently, a data-driven regression analysis was used to determine which measures best explained variability in severity of misuse. We hypothesized that negative affect-related factors, namely anxiety, anger, and/or depression, would be key predictors of misuse severity due to their crucial role in chronic pain and substance use disorders. RESULTS: Patients taking opioid medications had significantly greater impairment across most measures. Above and beyond demographic variables, the only and most significant predictors of prescribed opioid misuse severity were as follows: anxiety (ß = 0.15, P = 0.01), anger (ß = 0.13, P = 0.02), Pain Intensity-worst (ß = 0.09, P = 0.02), and depression (ß = 0.13, P = 0.04). CONCLUSIONS: Findings suggest that anxiety, anger, and depression are key factors associated with prescribed opioid misuse tendencies in patients with chronic pain and that they are potential targets for therapeutic intervention.