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We briefly review the evidence for distinct neuroanatomical substrates that underlie interoception in humans, and we explain how they substantialize feelings from the body (in the insular cortex) that are conjoined with homeostatic motivations that guide adaptive behaviours (in the cingulate cortex). This hierarchical sensorimotor architecture coincides with the limbic cortical architecture that underlies emotions, and thus we regard interoceptive feelings and their conjoint motivations as homeostatic emotions. We describe how bivalent feelings, emotions and sympathovagal balance can be organized and regulated efficiently in the bicameral forebrain as asymmetric positive/negative, approach/avoidance and parasympathetic/sympathetic components. We provide original evidence supporting this organization from studies of cardiorespiratory vagal activity in monkeys and functional imaging studies in healthy humans showing activation modulated by paced breathing and passively viewed emotional images. The neuroanatomical architecture of interoception provides deep insight into the functional organization of all emotional feelings and behaviours in humans. This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’.

Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.

People commonly cope with chronic low back pain (cLBP) by ignoring and distraction. Can mindful interoceptive exposure to the pain sensation itself and its phenomenological components be an alternative approach? Single-arm feasibility study in patients with cLBP using a 2-minute attention exercise guided by a smartphone app several times per day over 8 weeks. We assessed feasibility, pre/post pain, function, and psychological parameters using mixed methods: standard questionnaires, ecological momentary assessment, and exit interviews that included micro-phenomenology technique and subsequent reflexive thematic qualitative analysis. We enrolled 31 participants, mostly female, mean age 48, the majority had pain for >5 years; 29 completed. Mean pain intensity [0-10] improved from 4.8 ±1.7 to 3.1 ±1.9 (p < .0001); mean PEG scores (intensity and interference with daily life; range 0-30) improved from 13.7 ±6.2 to 8.4 ±6.6 (p < .0001); pain impact (9 items incl physical function) 22.3 ±8.7 to 19.7 ±8.1 (p = .0010). Twenty-one of 29 improved PEG score ≥30%. There were significant improvements in PCS Rumination and MAIA Not-Worrying. Participants became aware of their usual habit of avoidance and the challenge of and resistance to focusing on pain. They were surprised how pain sensations varied over time, and that pain intensity and the threat value of pain could diminish by focusing on it. They described a variety of 3D pain shapes (e.g., football, pool ball, rod, nail, brick, stars) with a range of colors, transparency, temperature, and density that for some changed with mindful attention. Most struggled to find appropriate words for sensory awareness and attention regulation and found that the threat value of their pain diminished. Mindful interoceptive exposure to the sensations of their cLBP using a 2-minute attention exercise with a phone app-rather than ignoring and distracting from it-may be a beneficial intervention for cLBP. ClinicalTrials.gov #NCT06186193.

Chronic pain is not a singular disorder and presents in various forms and phenotypes. Here we show data from a cohort of patients seeking treatment in a transdisciplinary pain clinic. Patients completed a multidimensional patient-reported battery as part of routine initial evaluation at baseline and at each of the four subsequent visits over 1-year follow-up (0, 1, 3, 6, 12 months). The goal of this work was to use unsupervised modeling approach to identify whether patients with chronic pain undergoing transdisciplinary intensive rehabilitation treatment: (1) can be derived based upon self-reported outcome measures at baseline (or before treatment initiation), (2) are clinically validated based on their clinical diagnosis and medication use, and (3) differ in treatment trajectories over 1 year of transdisciplinary treatment. We applied unsupervised clustering on baseline outcomes using nine patient-reported symptoms and examined treatment trajectories. The three-cluster solution was internally validated. Psychiatric diagnosis, chronic back pain-related disability and symptoms severity determined cluster assignment and treatment prognosis. Conversely, clinical pain severity had lesser effect. Furthermore, clusters showed stability over time despite symptoms improvement. The accurate and meaningful subgrouping of the underlying chronic pain phenotypes would greatly enhance treatment and provide personalized and effective pain management.

Bud Craig, an outstanding neuroscientist, died on 15 July 2023 at age 71. Bud made unique contributions to the fields of pain and interoception, challenging major dogmas and offering powerful explanations for various phenomena including central pain and the subjective awareness of feelings, with great implications for our understanding of consciousness.

Abstract Objective Despite empirical support for interdisciplinary pain rehabilitation programs improving functioning and quality of life, access to this treatment approach has decreased dramatically over the last 20 years within the United States but has grown significantly in the Department of Veterans Affairs (VA). Between 2009 and 2019, VA pain rehabilitation programs accredited by the Commission on Accreditation of Rehabilitation Facilities increased 10-fold in the VA, expanding from two to 20. The aim of this collaborative observational evaluation was to examine patient outcomes across a subset of six programs at five sites. Methods Outcomes were assessed using agreed-upon measures of patient-reported pain intensity, pain interference across various domains, pain catastrophizing, and sleep. Results A total of 931 patients enrolled in the selected VA interdisciplinary pain programs, with 84.1% of participants completing the full course of treatment. Overall, all programs showed significant improvements from pretreatment to posttreatment in nearly all patient-reported outcomes. The effect sizes ranged from medium to large. Notably, the results demonstrate that positive outcomes were typical despite differences in structure and resources across programs. Conclusions The adverse impacts of opioid use have highlighted the importance of chronic pain treatment approaches that emphasize team-based care focused on functional improvements. This study represents the first and largest analysis of outcomes across chronic pain rehabilitation programs and demonstrates the need for increased access to similar comprehensive approaches to pain management across the health care system. Further, it suggests that a variety of structures may be effective, encouraging flexibility in adopting this interdisciplinary approach.

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n = 15 sham and n = 15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group × time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group × time × GSR analysis showed a significantly decreased response in the nVNS group (p < .0005) bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output.

Mindfulness-Based Stress Reduction (MBSR) has shown efficacy for alleviating chronic low back pain (cLBP) and is included in current treatment guidelines. However, benefits are moderate. We aimed to optimize MBSR for chronic pain by using recent research to develop Mindfulness-Based Pain Reduction (MBPR) and test it in patients with cLBP. Phase 1: We modified the MBSR curriculum with theory-driven components and convened focus groups with local and international mindfulness and clinical pain management experts to refine an 8-week MBPR program. Phase 2: We recruited participants with cLBP from Northern California using outreach in newsletters, social media, and other methods to test and iteratively modify the curriculum. MBPR was delivered in a group format by videoconference. The first three groups received MBPR; a fourth group was randomized to MBSR or MBPR to assess randomization feasibility. We assessed feasibility and acceptability by attendance, practice logs, and exit interviews. We assessed changes in patient-reported outcome measures for low back pain trials using a single arm (treatment group only) approach at 2 and 6 months with linear mixed models (primary: pain intensity and interference (PEG) scores). Phase 1: The MBPR curriculum included: 1) mindful interoceptive exposure to pain, 2) pain neuroscience education, and 3) yoga postures specifically for cLBP. Phase 2: we enrolled 58 patients in 4 cohorts; 49 completed post-intervention and 41 completed 6-month follow-up assessments; 29 of the 41 received MBPR. Participants attended a mean of 80% of sessions and 23 of 24 participants accepted randomization in the 4th cohort. Mean PEG scores improved for 20 of 29 MBPR participants in a clinically meaningful way (PEG scores >30%). MBPR was feasible and acceptable. Two-thirds of MBPR participants experienced clinically meaningful improvements in pain intensity and interference scores. MBPR warrants further investigation through a randomized, controlled trial.

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are highly comorbid conditions that often co-occur with chronic pain. We have shown that women with PTSD subsequent to intimate partner violence show attenuated brain response to repeated experimental pain that was related to symptoms of avoidance. The aim of this study was to extend our past findings to males with combat trauma and to examine brain response to experimental pain in men with and without PTSD who sustained mTBI during combat. Seventy male veterans performed an experimental pain paradigm during functional magnetic resonance imaging fMRI. Of the 70 total subjects, 46 self-reported a history of mTBI during combat (46 of 70). Of those with mTBI, 26 also met criteria for PTSD (26 of 46). As in our previous study, we examined change in brain activity to repeated heat pain with linear mixed-effects modeling for group by administration interaction effects. We observed a significant group by administration interaction to repeated heat pain within insular, frontal, and parietal cortices, such that the control group showed increased activation over time, whereas mTBI groups (mTBI-only, mTBI + PTSD) showed decreased activation within bilateral anterior insulas (AIs) between administrations. Importantly, change in the right AI response was inversely correlated with avoidance symptoms, but only in those with comorbid mTBI + PTSD. Further, in the comorbid group, greater AI attenuation was associated with decreased connectivity with anterior cingulate (ACC). The current study provides further evidence that repeated exposure to brief painful stimuli results in attenuation of insula activation over time in traumatized individuals. Further, in PTSD, AI shows greatest attenuation in those with the highest level of avoidance—a finding that was replicated across diverse samples. Thus, this mechanism may be a generalized mechanism of maladaptive response to experimental pain in those with significant trauma.