Identification of traits and functional connectivity-based neurotraits of chronic pain.

Psychological and personality factors, socioeconomic status, and brain properties all contribute to chronic pain but have essentially been studied independently. Here, we administered a broad battery of questionnaires to patients with chronic back pain (CBP) and collected repeated sessions of resting-state functional magnetic resonance imaging (fMRI) brain scans. Clustering and network analyses applied on the questionnaire data revealed four orthogonal dimensions accounting for 56% of the variance and defining chronic pain traits. Two of these traits-Pain-trait and Emote-trait-were associated with back pain characteristics and could be related to distinct distributed functional networks in a cross-validation procedure, identifying neurotraits. These neurotraits showed good reliability across four fMRI sessions acquired over five weeks. Further, traits and neurotraits all related to the income, emphasizing the importance of socioeconomic status within the personality space of chronic pain. Our approach is a first step in providing metrics aimed at unifying the psychology and the neurophysiology of chronic pain applicable across diverse clinical conditions.

Hippocampal morphology mediates biased memories of chronic pain.

Experiences and memories are often mismatched. While multiple studies have investigated psychological underpinnings of recall error with respect to emotional events, the neurobiological mechanisms underlying the divergence between experiences and memories remain relatively unexplored in the domain of chronic pain. Here we examined the discrepancy between experienced chronic low back pain (CBP) intensity (twice daily ratings) and remembered pain intensity (n = 48 subjects) relative to psychometric properties, hippocampus morphology, memory capabilities, and personality traits related to reward. 77% of CBP patients exaggerated remembered pain, which depended on their strongest experienced pain and their most recent mood rating. This bias persisted over nearly 1 year and was related to reward memory bias and loss aversion. Shape displacement of a specific region in the left posterior hippocampus mediated personality effects on pain memory bias, predicted pain memory bias in a validation CBP group (n = 21), and accounted for 55% of the variance of pain memory bias. In two independent groups (n = 20/group), morphology of this region was stable over time and unperturbed by the development of chronic pain. These results imply that a localized hippocampal circuit, and personality traits associated with reward processing, largely determine exaggeration of daily pain experiences in chronic pain patients.

Corticolimbic anatomical characteristics predetermine risk for chronic pain.

SEE TRACEY DOI101093/BRAIN/AWW147 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Mechanisms of chronic pain remain poorly understood. We tracked brain properties in subacute back pain patients longitudinally for 3 years as they either recovered from or transitioned to chronic pain. Whole-brain comparisons indicated corticolimbic, but not pain-related circuitry, white matter connections predisposed patients to chronic pain. Intra-corticolimbic white matter connectivity analysis identified three segregated communities: dorsal medial prefrontal cortex-amygdala-accumbens, ventral medial prefrontal cortex-amygdala, and orbitofrontal cortex-amygdala-hippocampus. Higher incidence of white matter and functional connections within the dorsal medial prefrontal cortex-amygdala-accumbens circuit, as well as smaller amygdala volume, represented independent risk factors, together accounting for 60% of the variance for pain persistence. Opioid gene polymorphisms and negative mood contributed indirectly through corticolimbic anatomical factors, to risk for chronic pain. Our results imply that persistence of chronic pain is predetermined by corticolimbic neuroanatomical factors.

Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain.

In addition to their well-established role in signaling rewarding outcomes and reward-predictive cues and in mediating positive reinforcement, there is growing evidence that nucleus accumbens (NAc) neurons also signal aversive events and cues that predict them. Here we use diffusion tractography to subdivide the right NAc into lateral-rostral (putative core, pcore) and medial-caudal (putative shell, pshell) subdivisions in humans. The two subregions exhibited differential structural connectivity, based on probabilistic tractography, to prefrontal cortical and subcortical limbic regions. We also demonstrate unique roles for each of the two subdivisions for monetary reward and thermal pain perception tasks: pshell signaling impending pain and value predictions for monetary gambles and pcore activating with anticipation of cessation of thermal pain (signaling reward value of analgesia). We examined functional connectivity for resting state, monetary reward, and thermal pain tasks, and for all three conditions observed that pcore and pshell of right NAc exhibit distinct patterns of synchrony (functional connectivity) to prefrontal cortical and subcortical limbic targets within the right hemisphere. To validate the NAc segregation, we mirrored the coordinates of right NAc pcore and pshell onto the left hemisphere and examined structural and resting state connectivity in the left hemisphere. This latter analysis closely replicated target-specific connections we obtained for the right hemisphere. Overall, we demonstrate that the human NAc can be parceled based on structural and functional connectivity, and that activity in these subdivisions differentially encodes values for expected pain relief and for expected monetary reward.

Addressing neuroethics issues in practice: Lessons learnt by tech companies in AI ethics.

Neurotechnologies raise ethical concerns overlapping with those of other technologies, like artificial intelligence (AI). We discuss how to leverage the experience and lessons learnt by tech companies addressing AI ethics issues to accelerate going from neuroethics principles to scaled neuroethical industry practice.

Assessing Pain Research: A Narrative Review of Emerging Pain Methods, Their Technosocial Implications, and Opportunities for Multidisciplinary Approaches.

Pain research traverses many disciplines and methodologies. Yet, despite our understanding and field-wide acceptance of the multifactorial essence of pain as a sensory perception, emotional experience, and biopsychosocial condition, pain scientists and practitioners often remain siloed within their domain expertise and associated techniques. The context in which the field finds itself today-with increasing reliance on digital technologies, an on-going pandemic, and continued disparities in pain care-requires new collaborations and different approaches to measuring pain. Here, we review the state-of-the-art in human pain research, summarizing emerging practices and cutting-edge techniques across multiple methods and technologies. For each, we outline foreseeable technosocial considerations, reflecting on implications for standards of care, pain management, research, and societal impact. Through overviewing alternative data sources and varied ways of measuring pain and by reflecting on the concerns, limitations, and challenges facing the field, we hope to create critical dialogues, inspire more collaborations, and foster new ideas for future pain research methods.

Validating a biosignature-predicting placebo pill response in chronic pain in the settings of a randomized controlled trial.

ABSTRACT: The objective of this study is to validate a placebo pill response predictive model-a biosignature-that classifies chronic pain patients into placebo responders (predicted-PTxResp) and nonresponders (predicted-PTxNonR) and test whether it can dissociate placebo and active treatment responses. The model, based on psychological and brain functional connectivity, was derived in our previous study and blindly applied to current trial participants. Ninety-four chronic low back pain (CLBP) patients were classified into predicted-PTxResp or predicted-PTxNonR and randomized into no treatment, placebo treatment, or naproxen treatment. To monitor analgesia, back pain intensity was collected twice a day: 3 weeks baseline, 6 weeks of treatment, and 3 weeks of washout. Eighty-nine CLBP patients were included in the intent-to-treat analyses and 77 CLBP patients in the per-protocol analyses. Both analyses showed similar results. At the group level, the predictive model performed remarkably well, dissociating the separate effect sizes of pure placebo response and pure active treatment response and demonstrating that these effects interacted additively. Pain relief was about 15% stronger in the predicted-PTxResp compared with the predicted-PTxNonR receiving either placebo or naproxen, and the predicted-PTxNonR successfully isolated the active drug effect. At a single subject level, the biosignature better predicted placebo nonresponders, with poor accuracy. One component of the biosignature (dorsolateral prefrontal cortex-precentral gyrus functional connectivity) could be generalized across 3 placebo studies and in 2 different cohorts-CLBP and osteoarthritis pain patients. This study shows that a biosignature can predict placebo response at a group level in the setting of a randomized controlled trial.

Quantitative language features identify placebo responders in chronic back pain.

ABSTRACT: Although placebo effect sizes in clinical trials of chronic pain treatments have been increasing, it remains unknown if characteristics of individuals' thoughts or previous experiences can reliably infer placebo pill responses. Research using language to investigate emotional and cognitive processes has recently gained momentum. Here, we quantified placebo responses in chronic back pain using more than 300 semantic and psycholinguistic features derived from patients' language. This speech content was collected in an exit interview as part of a clinical trial investigating placebo analgesia (62 patients, 42 treated; 20 not treated). Using a nested leave-one-out cross-validated approach, we distinguished placebo responders from nonresponders with 79% accuracy using language features alone; a subset of these features-semantic distances to identity and stigma and the number of achievement-related words-also explained 46% of the variance in placebo analgesia. Importantly, these language features were not due to generic treatment effects and were associated with patients' specific baseline psychological traits previously shown to be predictive of placebo including awareness and personality characteristics, explaining an additional 31% of the variance in placebo analgesia beyond that of personality. Initial interpretation of the features suggests that placebo responders differed in how they talked about negative emotions and the extent that they expressed awareness to various aspects of their experiences; differences were also seen in time spent talking about leisure activities. These results indicate that patients' language is sufficient to identify a placebo response and implie that specific speech features may be predictive of responders' previous treatment.

Brain and psychological determinants of placebo pill response in chronic pain patients.

The placebo response is universally observed in clinical trials of pain treatments, yet the individual characteristics rendering a patient a 'placebo responder' remain unclear. Here, in chronic back pain patients, we demonstrate using MRI and fMRI that the response to placebo 'analgesic' pills depends on brain structure and function. Subcortical limbic volume asymmetry, sensorimotor cortical thickness, and functional coupling of prefrontal regions, anterior cingulate, and periaqueductal gray were predictive of response. These neural traits were present before exposure to the pill and most remained stable across treatment and washout periods. Further, psychological traits, including interoceptive awareness and openness, were also predictive of the magnitude of response. These results shed light on psychological, neuroanatomical, and neurophysiological principles determining placebo response in RCTs in chronic pain patients, and they suggest that the long-term beneficial effects of placebo, as observed in clinical settings, are partially predictable.

Risky monetary behavior in chronic back pain is associated with altered modular connectivity of the nucleus accumbens.

BACKGROUND: The nucleus accumbens (NAc) has a well established role in reward processing. Yet, there is growing evidence showing that NAc function, and its connections to other parts of the brain, is also critically involved in the emergence of chronic back pain (CBP). Pain patients are known to perform abnormally in reward-related tasks, which suggests an intriguing link between pain, NAc connectivity, and reward behavior. In the present study, we compared performance on a gambling task (indicating willingness to risk losing money) between healthy pain-free controls (CON) and individuals with CBP. We then measured modular connectivity of each participants' NAc with resting state functional MRI to investigate how connectivity accounts for reward behavior in the presence and absence of pain. RESULTS: We found gain sensitivity was significantly higher in CBP patients. These scores were significantly correlated to connectivity within the NAc module defined by CON subjects ( which had strong connections to the frontal cortex), but not within that defined by CBP patients ( which was more strongly connected to subcortical areas). An important part of our study was based on the precedence that a range of behaviors, from simple to complex, can be predicted from brain activity during rest. Thus, to corroborate our results we compared them closely to an independent study correlating the same connectivity metric to impulsive behaviors in healthy participants. We found that our CBP patients were highly similarin connectivity to this study's highly-impulsive healthy subjects, strengthening the notion that there is an important link between the brain systems that support chronic pain and reward processing. CONCLUSIONS: Our results support previous findings that chronic back pain is accompanied by altered connectivity of the NAc. This lends itself to riskier behavior in these patients, a finding which establishes a potential cognitive consequence or co-morbidity of long-term pain and provides a behavioral link to growing research showing that chronic pain is related to abnormal changes in the dopaminergic system.