Sickle cell disease (SCD) is the most prevalent inherited haemoglobinopathy characterised by chronic pain with acute painful episodes due to vaso-occlusion. The effective management of pain by adults with SCD influences their health outcomes. Opioids remain essential for most pain syndromes, but non-pharmacological interventions are preferred for daily pain due to the risk of addiction. However, their effectiveness is variable. Understanding the underlying processes associated with pain is crucial for developing more effective non-pharmacological strategies. This study aimed to enhance comprehension of the pain mechanisms in SCD to identify potential areas of action for effective non-pharmacological interventions.

An evaluation was conducted on the severity and interference of pain, pain-related cognitions and emotions. We used network analysis to simultaneously examine the intricate relationships between these variables.

A pain intensity exceeding 4 at a steady state distinguishes a subgroup at elevated risk of negative pain-related emotions and cognitions. The network analysis revealed intricate interconnections, with three distinct subgroups of variables mimicking the Neuromatrix model (cognitive-evaluative, motivational-affective and sensory-discriminative subgroups). The derived directed acyclic graph suggests potential mechanisms between these three subgroups, with catastrophising having a pivotal role.

This study extends previous research by providing a comprehensive network analysis of pain-related variables in SCD, offering novel insights into the complex interplay between pain experience, cognitions and emotions. These findings have important clinical implications, as they suggest that targeting dysfunctional pain cognitions and/or negative emotions may be beneficial for improving pain management and quality of life in SCD.

This study was the first to use network analyses to understand simultaneously multiple relationships between variables referring to pain, and pain-related negative emotions and cognitions in adults with SCD. Findings, providing support to the Neuromatrix model, offer novel insight to better understand pain and the associated negative emotions and cognition in SCD. The derived directed acyclic graph explored potential underlying psychological processes associated with pain that could be specifically targeted by future effective psychological interventions.

Life satisfaction and physical pain are key aspects of human well-being. Yet, evidence on the direction of their association and potential explanatory factors is relatively scarce. We address these questions across two studies. In Study 1, we explore the cross-lagged association between life satisfaction and physical pain using 22 waves from Australian longitudinal data (Household, Income and Labour Dynamics of Australia; N = 233,854), individual fixed effects regressions, and Random Intercept Cross-Lagged Panel Models. We found a bidirectional relationship between life satisfaction and pain, which is virtually identical across both methods. In Study 2, we use data from the 1970 British Cohort Study (N = 4,002) and Ordinary Least Squares regressions with a wide set of covariates. We found that people who reported greater life satisfaction at age 26 (vs. lower) reported lower physical pain at age 46. We document factors that partially explain this link, including psychological distress and past unemployment.

Persistent musculoskeletal pain is associated with altered functional and effective connectivity (EC) between cortical regions involved in pain processing. Especially, disruptions in the infraslow fluctuation (ISF) frequency band can contribute to pain persistence. ISF electroencephalography-neurofeedback (EEG-NF) has emerged as a potential non-invasive neuromodulatory intervention targeting cortical brain regions to restore balance and modulate pain-related pathways. However, limited research explores its effect on EC, a measure of directional information flow critical to pain experience and modulation.

A secondary analysis was performed using data from a randomized, double-blind, sham-controlled feasibility clinical trial. Participants with chronic painful knee osteoarthritis (OA) were randomized to receive either ISF-NF or sham-NF. Nine neurofeedback sessions targeted the pregenual anterior cingulate cortex (pgACC), dorsal anterior cingulate cortex (dACC), and bilateral primary somatosensory cortex (SSC: S1Lt & S1Rt). EEG data was collected at baseline and post-intervention. Granger causality was used to measure EC changes, and between-group statistical analyses were conducted with adjustments for multiple comparisons.

Twenty-one participants (mean age: 61.7 ± 7.6 years; 62% female) completed the study. ISF-NF training significantly improved EC between pgACC and dACC, pgACC and SSC, and other targeted regions, while reducing EC from S1Rt to dACC. Changes were observed predominantly in the ISF frequency band, indicating enhanced cortical communication and modulation of pain pathways.

ISF-NF training enhanced EC in cortical regions implicated in pain processing, supporting its potential as a neuromodulatory intervention for chronic musculoskeletal pain. Further trials are needed to confirm clinical efficacy and optimize protocol designs.

Migraine is a heritable primary headache disorder which pathophysiology involves altered hypothalamic activity during migraine attacks. To explore the relationship between hypothalamic functional connectivity (HYPT FC) and genetic predisposition characterised by polygenic risk scores (PRS), in migraine, this research examines two types of PRS: one based on all migraine patients (PRSALL) regardless of their time of diagnosis and other disorders, and another on migraine-first patients (PRSFIRST), whose first diagnosed condition was migraine in their lifetime. In an independent sample of 35 migraine patients and 38 healthy controls, using resting-state functional magnetic resonance (rfMRI, 3T) brain imaging, the study reveals significant hypoconnectivity of hypothalamus with the two investigated PRS scores but with different brain areas. While weakened hypothalamic connections in relations with PRSALL highlight regions involved in pain modulation, correlation with PRSFIRST emphasizes decreased connections with sensory and integrative brain areas, suggesting a link between migraine-first genetic risk and cortical hyperexcitability. Our results demonstrate that the polygenic risk of different migraine subgroups may advance our insight into the specific genetic and neural underpinnings of migraine, advancing precision medicine approaches in this field.

According to a widely shared belief, an explanation of phenomenal experience in terms of neural mechanisms is impossible in principle. The reason for this "Explanatory Gap" is supposed to be a basic incompatibility between phenomenal and neuroscientific knowledge: while the latter is framed in terms of functional relationships, it is impossible to capture phenomenal experience in functional terms. Here, we will take three steps to avert this conclusion and show what an explanation of the qualitative character of phenomenal experience might look like. In Step I, we show that two pivotal assumptions underlying the "Explanatory Gap" argument are unfounded. This means that the problem of phenomenal experience can be solved with the familiar methods of hypothesis development and testing. In Step II, we hypothesize that paradigmatic sorts of phenomenal experience like affective pain can be captured in functional terms, provided the function is framed in cognitive rather than behavioral terms: feeling affective pain is feeling an urge to avoid. In Step III, we will present empirical evidence corroborating this claim. We will also indicate how this functional description can help to identify the neural mechanisms underlying affective pain experience. We take this as a proof of principle showing that the qualitative character of phenomenal experience can be explained in objective neuroscientific terms. We will conclude with some remarks on how our approach might contribute to future progress in our understanding of consciousness in general.

Understanding how threats drive fear memory formation is crucial to understanding how organisms adapt to environments and treat threat-related disorders such as PTSD. While traditional Pavlovian conditioning studies have provided valuable insights, the exclusive reliance on electric shock as a threat stimulus has limited our understanding of diverse threats. To address this, we developed a conditioning paradigm using a looming visual stimulus as an unconditioned stimulus (US) in mice and identified a distinct neural circuit for visual threat conditioning. Parabrachial CGRP neurons were necessary for both conditioning and memory retrieval. Upstream neurons in the posterior insular cortex (pIC) responded to looming stimuli, and their projections to the parabrachial nucleus (PBN) induced aversive states and drove conditioning. However, this pIC-to-PBN pathway was not required for foot-shock conditioning. These findings reveal how non-nociceptive visual stimuli can drive aversive states and fear memory formation, expanding our understanding of aversive US processing beyond traditional models.

Comorbid depression in chronic pain is a prevalent health problem, yet the underlying neural mechanisms remain largely unexplored. This study identified a dedicated neural circuit connecting the hind limb region of the primary somatosensory cortex (S1HL) to the basolateral amygdala (BLA) that mediated neuropathic pain-induced depression. We demonstrated that depressive-like behaviors in the chronic phase of a mouse neuropathic pain model were associated with heightened activity in the S1HL and BLA. Using viral tracing and RNAscope in situ hybridization, we characterized the circuit architecture of S1HL glutamatergic projections to BLA cholecystokinin (CCK) neurons (S1HLGlu → BLACCK). In vivo fiber photometry calcium imaging revealed that both the S1HL BLA-projecting afferents and the BLA S1HL-innervating neurons exhibited hyperactivity in neuropathic pain-induced depressive states. Chemogenetic inhibition of the S1HL → BLA circuit could block neuropathic pain-induced depressive-like behaviors. In addition, specific knockdown of CCK expression in BLA S1HL-innervating neurons alleviated these depressive-like behaviors. Our findings demonstrated that the cortical-amygdala circuit S1HLGlu → BLACCK drove the transition from chronic pain to depression, thus suggesting a potential neural circuit basis for treating chronic pain-related depressive disorders.

This study aims to psychometrically validate the Psychache Scale (PAS) and investigate its prognostic value in predicting postoperative outcomes.

This is a prospective single-center study. Adults undergoing lumbar or thoracolumbar surgery were recruited. Participants completed PAS preoperatively and patient-reported outcome measures evaluating mental health, pain, physical function, and disability preoperatively and at one and six months postoperatively. PAS internal consistency was evaluated by Cronbach's alpha coefficient, and factor structure was evaluated using confirmatory factor analysis. Construct validity was assessed by examining correlations between PAS and measures of mental and physical health. PAS prognostic utility was evaluated by assessing its association with short- and longer-term surgical outcomes.

We included 166 patients. Mean (SD) age was 59.7 (12) years, with 55% females. PAS reliability was high (Cronbach's alpha = 0.95), and factor analysis confirmed the hypothesized one-factor structure. PAS showed strong correlations with PHQ-9 (r = 0.64), PROMIS anxiety (r = 0.64), pain catastrophizing scale (PCS) (r = 0.7), and its helplessness (r = 0.72), magnification (r = 0.59), and rumination (r = 0.59) subscales. However, it shows weak to moderate correlations with non-mental health-related metrics (0.07 < r < 0.44). Preoperative PAS was moderately correlated with one-month pain interference, and six-month PHQ-9 and PROMIS anxiety scores. In predicting outcomes, the addition of PAS to models including baseline values improved the prediction of all outcomes except for PROMIS physical function.

Our study suggests PAS may be a valuable tool for assessing psychological distress in this patient population. Further research is needed to understand its relevance in spine surgery practice.

II.

Patients with depressive disorder with migraine (DDWM) are common, yet the neural mechanisms and brain function changes associated with this comorbidity remain partially understood. This study explores regional homogeneity (ReHo) abnormalities in resting-state functional magnetic resonance imaging (fMRI) and cognitive function in DDWM patients. We recruited 29 patients with DDWM, 34 patients with depressive disorder without migraine (DDWOM), and 43 matched healthy controls (HC). All participants underwent rs-fMRI scans, and imaging data were analyzed using ReHo. Cognitive function was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status. We also employed support vector machine (SVM) analysis to evaluate whether abnormal ReHo values could distinguish DDWM. he DDWM group exhibited significantly lower ReHo values in the left cuneus and left calcarine compared to the DDWOM group. ReHo values in these regions were negatively correlated with pain scores on the Visual Analogue Scale (r = - 0.3628, p = 0.0001; r = - 0.3142, p = 0.001) and positively correlated with the List_Recall score on RBANS (r = 0.260, p = 0.007). SVM analysis indicated that the left cuneus ReHo value could distinguish DDWM from DDWOM with 78.09% accuracy, 87.66% sensitivity, and 74.33% specificity. The left cuneus and left calcarine are potential biomarkers for migraine symptoms in DDWM, with the left cuneus affecting cognitive function related to memory.

To investigate the effects of targeting the PI3K-mTOR signaling pathway in the anterior cingulate cortex (ACC) on pain responses, locomotor activity, and emotional behavior in rats with bone cancer pain.

Bone cancer pain was induced by implanting Walker 256 cells into the rat. Pain responses were assessed using paw withdrawal threshold and latency measurements, while locomotor activity and negative mood were evaluated through open field and conditioned place aversion tests, respectively.

The results showed that the bone cancer pain model led to allodynia, hyperalgesia, decreased ambulation, and ACC microglial activation. Morphine treatment improved pain responses but did not affect locomotor activity or mTOR protein expression. In contrast, rapamycin treatment reduced pain, improved locomotor activity, and decreased negative mood. It also downregulated PI3K-mTOR protein expression. Furthermore, inhibiting the PI3K-mTOR pathway with a PI3K inhibitor or rapamycin not only improved pain responses and locomotor activity but also reduced depression and anxiety-like behaviors. These effects were accompanied by changes in paw withdrawal threshold, latency, static time, and PI3K-mTOR protein expression.

Targeting the PI3K-mTOR signaling pathway in the ACC effectively alleviates pain-related symptoms and emotional disturbances in rats with bone cancer pain. This approach holds promise for alleviating pain and allaying negative emotion after further study.

Pain is a common medical experience, and patient access to pain management could be improved with novel intervention formats. Emerging evidence indicates brief, asynchronous, single-session interventions delivered in the clinic waiting room can improve patient outcomes, but only a few treatment modalities have been investigated to date. Breathwork is a promising approach to managing acute clinical pain that could be delivered asynchronously in the clinic waiting room. However, the direct impact of a breathwork intervention (e.g., brief cyclic sighing) on patients' pain and psychological distress (e.g., anxiety and depression symptoms) while waiting in the clinic waiting room remains unexamined. This single-site, pilot, randomized controlled trial examined the impact of a 4-minute, asynchronous, cyclic sighing intervention on participants' acute clinical symptoms in the x-ray waiting room of a walk-in orthopedic clinic relative to a time- and attention-matched injury management control condition. Pain unpleasantness, pain intensity, anxiety symptoms, and depression symptoms were measured in the study. Participants receiving the cyclic sighing intervention reported significantly less pain unpleasantness and pain intensity while waiting for an x-ray relative to controls. Anxiety symptoms and depression symptoms were not found to differ by condition. Results from this RCT indicate a brief, asynchronous, cyclic sighing intervention may be capable of quickly decreasing pain in the waiting room. Continued investigation is now needed to determine if embedding brief, asynchronous, cyclic sighing interventions in clinic waiting rooms has the potential to help people experiencing acute pain feel better faster. CLINICAL TRIAL REGISTRATIONS: NCT06292793.

Pain catastrophizing is an amplified negative thought process that emerges during actual or perceived pain moments. There is limited information on the role of labour pain in the development of pain catastrophizing during the postpartum period. We sought to investigate whether labour pain, pain, and psychological vulnerabilities are associated with high pain catastrophizing (defined as a Pain Catastrophizing Scale [PCS] ≥ 25) at 6-10 weeks postpartum.

We conducted a secondary analysis of a randomized controlled trial that recruited pregnant individuals at term prior to labour and delivery. Participants filled in the predelivery questionnaires on labour pain, pain, and psychological vulnerabilities upon written consent. The recruited parturients also completed an online survey 6-10 weeks postpartum to determine the status of pain catastrophizing.

Among the 820 parturients who completed the postpartum online survey, 116 (14.4%) were high pain catastrophizing. Multivariate logistic regression analysis found that greater enormity of labour pain (adjusted odds ratio [aOR], 1.04; 95% confidence interval [CI], 1.02 to 1.06), choosing nonepidural over epidural analgesia (aOR, 1.84; 95% CI, 1.17 to 2.91), having a family history of other mental disorders (aOR, 31.3; 95% CI, 5.7 to 173.7), greater predelivery pain catastrophizing (aOR, 2.70; 95% CI, 1.68 to 4.36), greater predelivery activity avoidance (aOR, 1.06; 95% CI, 1.04 to 1.09), and greater predelivery state anxiety (aOR, 1.03; 95% CI, 1.01 to 1.05) were associated with postpartum pain catastrophizing at 6-10 weeks postpartum. Having greater infant weight was protective against the risk of postpartum pain catastrophizing (aOR, 0.43; 95% CI, 0.23 to 0.78). The area under the curve of the generated multivariable model was 0.82 (95% CI, 0.78 to 0.86).

Predelivery pain and psychological vulnerabilities were associated with postpartum pain catastrophizing among healthy parturients undergoing labour. Future prospective studies are needed to evaluate whether such risk factors can allow earlier intervention to reduce pain catastrophizing.

ClinicalTrials.gov ( NCT03167905 ); first submitted 30 May 2017.

Previous investigations on pain modulatory effects of the rubber hand illusion (RHI) yielded mixed results. However, these studies used separate stimuli to induce pain and the RHI. Using a visual-thermal stimulation approach, the illusion-inducing stimulus was simultaneously the pain stimulus which ensured that participants focused entirely on the illusion-inducing stimulus.

In this study, we investigated the time course of pain modulation induced by illusionary body ownership over artificial hands using the visual-thermal RHI and the influence of the stimulation intensity.

In a 2 × 4 within-subject design, participants received thermal stimulation on their hidden real left hand, while the rubber hand synchronously lit up red. Four stimulation intensities were used: moderate pain (+0°C), -0.75°C, +0.75°C, and +1.5°C. For control trials, the rubber hand was rotated by 180°. With the right hand, participants provided continuous pain ratings using a slide knob.

Embodiment ratings were higher in the RHI compared with the control condition. Continuous pain ratings were lower in the RHI condition for all temperature levels except for +0.75°C. Rubber hand illusion-induced pain reduction was observed throughout most of the stimulation interval, absent only at the very beginning and end.

These findings suggest that visual-thermal induction of the RHI is consistently associated with increased embodiment ratings, regardless of the temperature level presented. The illusion is further accompanied by reduced pain ratings throughout major parts of the stimulation interval. On the whole, these findings speak for the robustness of the effect and the practicality of our visual-thermal stimulation approach.

The astroglial glutamate transporter in the hippocampus and anterior cingulate cortex (ACC) is critically involved in chronic pain-induced cognitive and psychiatric abnormalities. We have previously reported that LDN-212320, a glutamate transporter-1 (GLT-1) activator, attenuates complete Freund's adjuvant (CFA)-induced acute and chronic nociceptive pain. However, the cellular and molecular mechanisms underlying GLT-1 modulation in the hippocampus and ACC during chronic pain-induced cognitive deficit-like and anxiety-like behaviors remain unknown. Here, we have investigated the effects of LDN-212320 on CFA-induced chronic pain associated with cognitive deficit-like and anxiety-like behaviors in mice. We have evaluated the effects of LDN-212320 on CFA-induced impaired spatial, working, and recognition memory using Y-maze and object-place recognition tests. In addition, we have determined the effects of LDN-21230 on chronic pain-induced anxiety-like behaviors using elevated plus maze and marble burying test. We have also examined the effects of LDN-212320 on cAMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BDNF), protein kinase A (PKA), and Ca2 +/calmodulin-dependent protein kinase II (CaMKII) expression in the hippocampus and ACC during CFA-induced cognitive deficit-like and anxiety-like behaviors using the Western blot analysis and immunofluorescence assay. Pretreatment with LDN-212320 (20 mg/kg) significantly attenuated CFA-induced impaired spatial, working, and recognition memory. Furthermore, LDN-212320 (20 mg/kg) significantly reduced CFA-induced anxiety-like behaviors. Additionally, LDN-212320 (20 mg/kg) significantly reversed CFA-induced decreased pCREB, BDNF, PKA and CaMKII expression in the hippocampus and ACC. Overall, these results suggest that the LDN-212320 prevents CFA-induced cognitive deficit-like and anxiety-like behaviors by activating CaMKII/CREB/BDNF signaling pathway in the hippocampus and ACC. Therefore, LDN-212320 could be a potential treatment for chronic pain associated with cognitive impairment and anxiety-like behaviors.

The experience of pain is a combined product of bottom-up and top-down influences mediated by attentional and emotional factors. Meditation states and traits are characterized by enhanced attention/emotion regulation and expanded self-awareness that can be expected to modify pain processing. The main objective of the present study was to explore the effects of long-term meditation on neural mechanisms of pain processing. EEG pain-related oscillations (PROs) were analysed in highly experienced practitioners and novices during a non-meditative resting state with respect to (a) local frequency-specific and temporal synchronizing characteristics to reflect mainly bottom-up mechanisms, (b) spatial synchronizing patterns to reflect the neural communication of noxious information, (c) pre-stimulus oscillations to reflect top-down mechanisms during pain expectancy, and (d) the P3b component of the pain-related potential to compare the emotional/cognitive reappraisal of pain events by expert and novice meditators. Main results demonstrated that in experienced (long-term) meditators as compared to non-experienced (short-term) meditators (1) the temporal and spatial synchronizations of multispectral (from theta-alpha to gamma) PROs were substantially suppressed at primary and secondary somatosensory regions contra-lateral to pain stimulation within 200 ms after noxious stimulus; (2) pre-stimulus alpha activity was significantly increased at the same regions, which predicted the suppressed synchronization of PROs in long-term meditators; (3) the decrease of the P3b component was non-significant. These novel observations provide evidence that even when subjected to pain outside of meditation, experienced meditators exhibit a pro-active top-down inhibition of somatosensory areas resulting in suppressed processing and communication of sensory information at early stages of painful input. The emotional/cognitive appraisal of pain is reduced but remains preserved revealing a capacity of experienced meditators to dissociate pro-active and reactive top-down processes during pain control.

Nature exposure has numerous health benefits and might reduce self-reported acute pain. Given the multi-faceted and subjective quality of pain and methodological limitations of prior research, it is unclear whether the evidence indicates genuine analgesic effects or results from domain-general effects and subjective reporting biases. This preregistered neuroimaging study investigates how nature modulates nociception-related and domain-general brain responses to acute pain. Healthy participants (N = 49) receiving electrical shocks report lower pain when exposed to virtual nature compared to matched urban or indoor control settings. Multi-voxel signatures of pain-related brain activation patterns demonstrate that this subjective analgesic effect is associated with reductions in nociception-related rather than domain-general cognitive-emotional neural pain processing. Preregistered region-of-interest analyses corroborate these results, highlighting reduced activation of areas connected to somatosensory aspects of pain processing (thalamus, secondary somatosensory cortex, and posterior insula). These findings demonstrate that virtual nature exposure enables genuine analgesic effects through changes in nociceptive and somatosensory processing, advancing our understanding of how nature may be used to complement non-pharmacological pain treatment. That this analgesic effect can be achieved with easy-to-administer virtual nature exposure has important practical implications and opens novel avenues for research on the precise mechanisms by which nature impacts our mind and brain.

Visual stimulation to the embodied virtual body could modulate human perception, however the associated neurophysiological mechanisms have not elucidated yet. The present study aimed to reveal the underlying neurophysiological mechanisms from a neurophysiological viewpoint. Fifteen healthy participants were subjected to three visual conditions (i.e., fire, water, and non-visual effect conditions) and psychological pain stimulation (thermal grill stimulation). Oscillatory neural activities during stimulation were measured with electroencephalogram. The association between accessory visual stimulation applied to the embodied virtual body, induced by virtual reality, and perception was examined through neuronal oscillatory analysis using electroencephalogram data. Regression analysis was performed to obtain data on brain regions contributing to sensory modulation with body illusion. The results of subjective measures under the fire and water conditions showed that thermal perception were modulated by a visual stimulus to the virtual hand. Furthermore, we found that the insula was commonly associated with thermal perception under the fire and water conditions. This result indicate that the insula may control sensory information as a gatekeeper as well as facilitate the access to human attention and cognition as a hub, suggesting the influence on perception and cognition.

Habituation to painful stimuli reflects an endogenous pain alleviation mechanism, and reduced pain habituation has been demonstrated in many chronic pain conditions. In ethology, animals exhibit reduced fear responses while habituating to repeated threatening stimuli. It remains unclear whether pain habituation in humans involves a fear reduction mechanism. In an fMRI experiment, we investigated pain-related brain responses before and after the development of habituation to pain induced by repetitive painful stimulation in healthy adults. In another behavioral experiment, we examined emotional responses in another group of healthy adults to assess pain habituation-related emotional changes. Pain habituation at the repetitively stimulated forearm site entailed reduced fear and engaged the neural system implicated in fear reduction, which included the amygdala, anterior cingulate, and ventromedial prefrontal cortex (vmPFC). Individual pain-related fear, assessed via a questionnaire, predicted neural activity within the periaqueductal gray (a pain-modulating center), which covaried with vmPFC responsivity. Moreover, pain habituation also occurred at nonstimulated sites, and its extent was predicted by habituation at the repetitively stimulated site. This phenomenon again involved the vmPFC, which has also been implicated in safety generalization under threat. These results suggest a role of fear reduction in pain habituation that is related to individual pain fearfulness. The reduced fear acquired at the repetitively stimulated site can be generalized to other body parts to cope with similar aversive situations. The identified link between fear and pain habituation helps explain why impaired fear reduction and reduced pain habituation coexist in chronic pain conditions.

Introduction. Chronic pain is a percept due to an imbalance in the activity between sensory-discriminative, motivational-affective, and descending pain-inhibitory brain regions. Evidence suggests that electroencephalography (EEG) infraslow fluctuation neurofeedback (ISF-NF) training can improve clinical outcomes. It is unknown whether such training can induce EEG activity and functional connectivity (FC) changes. A secondary data analysis of a feasibility clinical trial was conducted to determine whether EEG ISF-NF training can significantly alter EEG activity and FC between the targeted cortical regions in people with chronic painful knee osteoarthritis (OA). Methods. A parallel, two-arm, double-blind, randomized, sham-controlled clinical trial was conducted. People with chronic knee pain associated with OA were randomized to receive sham NF training or source-localized ratio ISF-NF training protocol to down-train ISF bands at the somatosensory (SSC), dorsal anterior cingulate (dACC), and uptrain pregenual anterior cingulate cortices (pgACC). Resting state EEG was recorded at baseline and immediate post-training. Results. The source localization mapping demonstrated a reduction (P = .04) in the ISF band activity at the left dorsolateral prefrontal cortex (LdlPFC) in the active NF group. Region of interest analysis yielded significant differences for ISF (P = .008), slow (P = .007), beta (P = .043), and gamma (P = .012) band activities at LdlPFC, dACC, and bilateral SSC. The FC between pgACC and left SSC in the delta band was negatively correlated with pain bothersomeness in the ISF-NF group. Conclusion. The EEG ISF-NF training can modulate EEG activity and connectivity in individuals with chronic painful knee osteoarthritis, and the observed EEG changes correlate with clinical pain measures.

Observational fear (OF) is the ability to vicariously experience and learn from another's fearful situation, enabling adaptive responses crucial for survival. It has been shown that the anterior cingulate cortex (ACC) and basolateral amygdala (BLA) are crucial for OF. A subset of neurons in the ACC is activated when observing aversive events in the demonstrator, which elicits OF. However, the neural circuit mechanisms underlying the expression of OF-related activity in the ACC remain unexplored. Previous studies have shown that the mediodorsal thalamus (MD) is crucial for OF, and MD neurons project to the ACC. Therefore, we hypothesize that the projection from MD to ACC may facilitate the OF-related activity in the ACC. By utilizing in vivo calcium imaging combined with the optogenetic terminal inhibition of MD-ACC pathway, we found that a subset of ACC neurons was activated when observing demonstrator's fearful situation in male mice. Furthermore, the optogenetic inhibition of the MD-ACC projection during the demonstrator's aversive moments significantly suppressed the OF-related activity in the ACC. Our data suggests that the MD-ACC projection plays a role in OF-related activity in ACC neurons.

Affect sharing, the ability to vicariously feel others' emotions, constitutes the primary component of empathy. However, the neural basis for encoding others' distress and representing shared affective experiences remains poorly understood. Here, using miniature endoscopic calcium imaging, we identify distinct and dynamic neural ensembles in the anterior cingulate cortex (ACC) that encode observational fear across both excitatory and inhibitory neurons in male mice. Notably, we discover that the population dynamics encoding vicarious freezing information are conserved in ACC pyramidal neurons and are specifically represented by affective, rather than sensory, responses to direct pain experience. Furthermore, using circuit-specific imaging and optogenetic manipulations, we demonstrate that distinct populations of ACC neurons projecting to the periaqueductal gray (PAG), but not to the basolateral amygdala (BLA), selectively convey affective pain information and regulate observational fear. Taken together, our findings highlight the critical role of ACC neural representations in shaping empathic freezing through the encoding of affective pain.

Readiness for discharge for a SCD vaso-occlusive crisis is dictated by factors far beyond pain control, including physical function/activity. We therefore designed and tested a functional status-based pain assessment questionnaire in SCD patients hospitalized with vaso-occlusive crises.

Sickle cell disease patients on a preselected nursing unit rated 10 draft Functional status-Based Pain Assessment items of activities of daily living on a five-point Likert scale (0-5) from "very easy" to "very difficult" daily on each day of their admission until discharge, at approximately the same time. Concurrently, they reported Numeric Rating Scale (0-10) pain intensity. For validation, we used exploratory factor analysis, confirmatory factor analysis, and item response theory analysis.

We analyzed 503 observations from 175 admissions of 88 patients. Half were female, the mean age was 32.1 ± 11.8 years, and the mean length of stay was 7.1 ± 6.9 days. The mean Numeric Rating Scale (6.8 ± 1.9) was inversely correlated with the mean Functional Status-based Pain Assessment (0-50) score (27 ± 8.0, r = -0.4342, P < .0001). Functional Status-based Pain Assessment item means ranged from 2.1 to 3.3. Cronbach's alpha was 0.91. Exploratory factor analysis showed that all Functional Status-based Pain Assessment items loaded on a single factor. Confirmatory factor analysis found adequate convergent and discriminant validity and showed strong fit of the model to the data. Item response theory analysis showed item discrimination ranging from 0.56 to 4.1, while difficulty ranged from -2.8 to 7.5.

The Functional Status-based Pain Assessment shows strong correlation with daily Numeric Rating Scale, is multidimensional, and demonstrates strong construct validity. It may improve assessment of SCD vaso-occlusive crisis pain and may enhance vaso-occlusive crisis discharge discussions.

Background/Objectives: Fake pain expressions are more intense, prolonged, and include non-pain-related actions compared to genuine ones. Despite these differences, individuals struggle to detect deception in direct tasks (i.e., when asked to detect liars). Regarding neural correlates, while pain observation has been extensively studied, little is known about the neural distinctions between processing genuine, fake, and suppressed pain facial expressions. This study seeks to address this gap using authentic pain stimuli and an implicit emotional processing task. Methods: Twenty-four healthy women underwent an fMRI study, during which they were instructed to complete an implicit gender discrimination task. Stimuli were video clips showing genuine, fake, suppressed pain, and neutral facial expressions. After the scanning session, participants reviewed the stimuli and rated them indirectly according to the intensity of the facial expression (IE) and the intensity of the pain (IP). Results: Mean scores of IE and IP were significantly different for each category. A greater BOLD response for the observation of genuine pain compared to fake pain was observed in the pregenual anterior cingulate cortex (pACC). A parametric analysis showed a correlation between brain activity in the mid-cingulate cortex (aMCC) and the IP ratings. Conclusions: Higher IP ratings for genuine pain expressions and higher IE ratings for fake ones suggest that participants were indirectly able to recognize authenticity in facial expressions. At the neural level, pACC and aMCC appear to be involved in unveiling the genuine vs. fake pain and in coding the intensity of the perceived pain, respectively.

In recent years, the impact of professional training on brain structure has sparked extensive research interest. Research into pilots as a high-demand, high-load, and high-cost occupation holds significant academic and economic value. The aim of this study is to investigate the effects of flight training on the brain structure and cognitive functions of flying cadets. The structural magnetic resonance imaging (sMRI) data from 39 flying cadets and 37 general college students underwent analysis using voxel-based morphometry (VBM) and surface-based morphometry (SBM) methods to quantitatively detect and compute multiple indicators, including gray matter volume (GMV), curvature, mean curvature of the white matter surface (MC-WMS), the percentage of surface white matter gray matter (WM-GM percentage), surface Jacobi (S-Jacobi), and Gaussian curvature of white matter surface (GC-WMS). At the voxel level, the GMV in the left temporal pole: middle temporal gyrus region of flying cadets significantly decreased (Gaussian random field, GRF, P < 0.05). At the surface level, there was a significant increase in curvature, MC-WMS, and S-Jacobi in the lateral occipital region of flight cadets (Monte Carlo block level correction, MCBLC, P<0.05), a significant increase in WM-GM percentage in the cuneus region of flight cadets (MCBLC, P<0.05), and a significant increase in GC-WMS in the middle temporal region of flight cadets (MCBLC, P<0.05). In addition, these changes were correlated with behavioral tests. Research suggested that flight training might induce changes in certain brain regions of flying cadets, enabling them to adapt to evolving training content and environments, thereby enhancing their problem-solving and flight abilities. By analyzing multiple indicators at the voxel and surface levels in an integrated manner, it advances our understanding of brain structure, function, and plasticity, while also facilitating a more profound exploration of the neural mechanisms within the pilot's brain.

Chronic pain is a public health problem that significantly reduces quality of life. Although the aetiology is often unknown, recent evidence suggests that susceptibility can be transmitted intergenerationally, from parent to child. Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder, often associated with chronic pain, that has high prevalence rates in military personnel and Veterans. Therefore, we aimed to characterise the epigenetic mechanisms by which paternal trauma, such as PTSD, is transmitted across generations to confer risk in the next generation, specifically focusing on Veterans where possible. Numerous overlapping neurological pathways are implicated in both PTSD and chronic pain; many of which are susceptible to epigenetic modification, such as DNA methylation, histone modifications, and RNA regulation. Hence, epigenetic changes related to pain perception, inflammation, and neurotransmission may influence an individual's predisposition to chronic pain conditions. We also examine the effects of PTSD on parenting behaviours and discuss how these variations could impact the development of chronic pain in children. We highlight the need for further research regarding the interactions between paternal trauma and epigenetic processes to ultimately generate effective prevention and therapeutic strategies for Veterans who have been affected by PTSD and chronic pain.

Depression and comorbid pain are frequently encountered clinically, and the comorbidity complicates the overall medical management. However, the mechanism whereby depression triggers development of pain needs to be further elucidated. Here, by using the chronic restraint stress (CRS) mouse model of depression and comorbid pain, we showed that CRS hyperactivated the glutamatergic neurons in the anterior cingulate cortex (ACC), as well as increasing the dendrite complexity and number. Chemogenetic activation of these neurons can induce depression and pain, while chemogenetic blockade can reverse such depression-induced pain. Moreover, we utilized translating ribosome affinity purification (TRAP) in combination with c-Fos-tTA strategy and pharmacological approaches and identified SIGMAR1 as a potential therapeutic molecular target. These results revealed a previously unknown neural mechanism for depression and pain comorbidity and provided new mechanistic insights into the antidepressive and analgesic effects of the disease.

Empathy for pain encompasses the processes of perceiving, understanding, and responding to the pain of others, playing a crucial role in social interaction and individual development. The increasing interest in this field has led to a surge in related publications; however, the overall quantity and quality of these works remain uncertain. To address this issue, we conducted a bibliometric analysis of research on empathy for pain. Our study meticulously examined 479 publications to provide a comprehensive analysis of bibliographic elements such as annual publication trends, authorship, country of origin, institutional affiliations, journals, and keywords. Our findings indicate that, although there has been a rise in research on empathy for pain in recent years, the volume remains insufficient and is predominantly concentrated in a few countries, authors, and institutions. Additionally, current research mainly focuses on four primary areas: perception, pain, empathy, and emotion. We assert that future research will likely explore the relationship between EEG measurements and empathy for pain to determine if such measurements can effectively quantify empathy, thereby enhancing clinical management. This article is part of the Special Issue on "Empathic Pain".

To assess the efficacy of horticultural therapy (HT) on anterior cingulate cortex (ACC) activity and the changes in rumination and catastrophizing scores in individuals with chronic low back pain (LBP). We conducted a randomized, controlled, cross-over, 3-week pilot study (ClinicalTrials.gov Identifier: NCT04656158). The departments of physical medicine and rehabilitation (hospital grounds and occupational therapy room) and imaging research were involved. The participants were adults with non-specific chronic LBP. All participants underwent two 90-min HT sessions and two 90-min handiwork sessions per week. The activity sequence order was randomized, and the activities were separated by a wash-out period of 1 week. Each participant underwent 3 brain MRIs: before, after the first, and after the second activity. The primary outcome was the change in ACC perfusion in ml/100g/min using arterial spin labeling MRI. The secondary outcomes were the changes in self-reported rumination and catastrophizing scores after each activity compared to baseline. Sixteen participants were included: 14 women (87.5%), LBP intensity (numeric rating scale) mean (SD) 45.1 (27.2)/100, specific activity limitation (Roland Morris disability questionnaire) 9.3 (4.1)/24. Change in ACC perfusion from baseline was -0.1 (10.7), 95% CI [-5.6, 5.8] ml (blood)/100g (tissue)/min after handiwork and -0.1 (8.7), [-4.7, 4.6] after HT and did not differ between the 2 activities (p = 0.91). Change in rumination [-0.5 (4.4) after handiwork and -0.3 (2.8) after HT] and catastrophizing scores [-2 (2.8) after handiwork and -1.4 (2.3) after HT] did not differ between activities (p = 0.99 and 0.22, respectively). Limited exposure to the interventions and the sample profile (moderate levels of pain) may explain our results. Our results highlight the need for future studies using the most appropriate outcomes to determine the exact effects of nature experiences in people with chronic musculoskeletal disease.

Cognitive impairment refers to abnormalities in learning, memory and cognitive judgment, mainly manifested as symptoms such as decreased memory, impaired orientation and reduced computational ability. As the fundamental unit of information processing in the brain, neural circuits have recently attracted great attention due to their functions in regulating pain, emotion and behavior. Furthermore, a growing number of studies have suggested that neural circuits play an important role in cognitive impairment. Neural circuits can affect perception, attention and decision-making, they can also regulate language skill, thinking and memory. Pathological conditions crucially affecting the integrity and preservation of neural circuits and their connectivity will heavily impact cognitive abilities. Nowadays, technological developments have led to many novel methods for studying neural circuits, such as brain imaging, optogenetic techniques, and chemical genetics approaches. Therefore, neural circuits show great promise as a potential target in mitigating cognitive impairment. In this review we discuss the pathogenesis of cognitive impairment and the regulation and detection of neural circuits, thus highlighting the role of neural circuits in cognitive impairment. Hence, therapeutic agents against cognitive impairment may be developed that target neural circuits important in cognition.

Patients with chronic migraine (CM) often exhibit structural and functional alterations in pain-matrix regions, but it remains unclear how preventive treatment affects these changes. Therefore, this study aimed to investigate the structural and functional changes in pain-matrix regions in CM patients after 6-month treatment. A total of 24 patients with CM and 15 healthy controls were recruited for this study. Patients were divided into responder group (N = 9) and non-responder group (N = 15). After completing the Migraine Disability Assessment (MIDAS) questionnaire, all patients underwent whole-brain high-resolution T1-weighted images, diffusion-weighted imaging, and resting-state functional magnetic resonance imaging at baseline and 6-month follow-up. Whole brain gray matter volume and white matter diffusion indices were analyzed using voxel-based analysis. Structural and functional connectivity analyses were performed to understand brain changes in patients after 6-month preventive treatment. The responder group exhibited significantly higher MIDAS scores than the non-responder group at baseline, but no significant difference between the two groups at follow-up. No significant interval change was noted in gray matter volume, white matter diffusion indices, and structural connectivity in CM patients after 6-month treatment. Nonetheless, the functional connectivity was significantly increased between occipital, temporal lobes and cerebellum, and was significantly decreased between parietal and temporal lobes after 6-month preventive treatment. We concluded that resting-state functional connectivity was suitable for investigating the preventive treatment effect on CM patients.

The rise of psychedelics in contemporary medicine has sparked interest in their potential therapeutic applications. While traditionally associated with countercultural movements and recreational use, recent research has shed light on the potential benefits of psychedelics in various mental health conditions. In this review, we explore the possible role of psychedelics in the management of chronic pain and opioid use disorder (OUD), 2 critical areas in need of innovative treatment options. Pain control remains a significant clinical challenge, particularly for individuals with OUD and those who receive long-term opioid therapy who develop marked tolerance to opioid-induced analgesia. Despite the magnitude of this problem, there is a scarcity of controlled studies investigating pain management alternatives for these populations. Drawing from preclinical and human evidence, we highlight the potential of psychedelics to act on shared neurobiological substrates of chronic pain and OUD, potentially reversing pain- and opioid-induced neuroadaptations, such as central sensitization. We elaborate on the multifaceted dimensions of the pain experience (sensory, affective and cognitive) and their intersections that overlap with opioid-related phenomena (opioid craving and withdrawal), hypothesizing how these processes can be modulated by psychedelics. After summarizing the available clinical research, we propose mechanistic insights and methodological considerations for the design of future translational studies and clinical trials, building on a shared clinical and neurobiological understanding of chronic pain and OUD. Our intention is to provide timely perspectives that accelerate the development and exploration of novel therapeutics for chronic pain and OUD amidst the escalating opioid crisis.

The experience of pain is complex, involving both sensory and affective components, yet the underlying neural mechanisms remain elusive. Here, we show that formalin-induced pain behaviors coincide with increased responses in glutamatergic neurons within the anterior paraventricular nucleus of the thalamus (PVA). Furthermore, we describe non-overlapping subpopulations of PVAVgluT2 neurons involved in sensory and affective pain processing, whose activity varies across different pain states. Activating PVA glutamatergic neurons is sufficient to induce mechanical hypersensitivity and aversion behaviors, whereas suppression ameliorates formalin-induced pain. Furthermore, we identify the segregation of PVAVgluT2 projections to the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAc), each influencing specific aspects of pain-like behavior. This finding provides an important insight into the mechanism of distinct components of pain, highlighting the pivotal role of PVA in mediating different aspects of pain-like behavior with distinct circuits.

The lack of clearly defined neuromodulation targets has contributed to the inconsistent results of real-time fMRI-based neurofeedback (rt-fMRI-NF) for the treatment of chronic pain. Functional neurosurgery (funcSurg) approaches have shown more consistent effects in reducing pain in patients with severe chronic pain.

This study aims to redefine rt-fMRI-NF targets for chronic pain management informed by funcSurg studies.

Based on independent systematic reviews, we identified the neuromodulation targets of the rt-fMRI-NF (in acute and chronic pain) and funcSurg (in chronic pain) studies. We then characterized the underlying functional networks using a subsample of the 7 T resting-state fMRI dataset from the Human Connectome Project. Principal component analyses (PCA) were used to identify dominant patterns (accounting for a cumulative explained variance >80%) within the obtained functional maps, and the overlap between these PCA maps and canonical intrinsic brain networks (default, salience, and sensorimotor) was calculated using a null map approach.

The anatomical targets used in rt-fMRI-NF and funcSurg approaches are largely distinct, with the middle cingulate cortex as a common target. Within the investigated canonical rs-fMRI networks, these approaches exhibit both divergent and overlapping functional connectivity patterns. Specifically, rt-fMRI-NF approaches primarily target the default mode network (P value range 0.001-0.002) and the salience network (P = 0.002), whereas funcSurg approaches predominantly target the salience network (P = 0.001) and the sensorimotor network (P value range 0.001-0.023).

Key hubs of the salience and sensorimotor networks may represent promising targets for the therapeutic application of rt-fMRI-NF in chronic pain.

Pain is a private experience observable through various verbal and non-verbal behavioural manifestations, each of which may relate to different pain-related functions. Despite the importance of understanding the cerebral mechanisms underlying those manifestations, there is currently limited knowledge of the neural correlates of the facial expression of pain. In this functional magnetic resonance imaging (fMRI) study, noxious heat stimulation was applied in healthy volunteers and we tested if previously published brain signatures of pain were sensitive to pain expression. We then applied a multivariate pattern analysis to the fMRI data to predict the facial expression of pain. Results revealed the inability of previously developed pain neurosignatures to predict the facial expression of pain. We thus propose a facial expression of pain signature (FEPS) conveying distinctive information about the brain response to nociceptive stimulations with minimal or no overlap with other pain-relevant brain signatures associated with nociception, pain ratings, thermal pain aversiveness, or pain valuation. The FEPS may provide a distinctive functional characterization of the distributed cerebral response to nociceptive pain associated with the socio-communicative role of non-verbal pain expression. This underscores the complexity of pain phenomenology by reinforcing the view that neurosignatures conceived as biomarkers must be interpreted in relation to the specific pain manifestation(s) predicted and their underlying function(s). Future studies should explore other pain-relevant manifestations and assess the specificity of the FEPS against simulated pain expressions and other types of aversive or emotional states.

Chronic nonspecific low back pain (cNLBP) accounts for approximately 90% of low back pain cases, affecting 65-80% of the population and significantly impacting life quality and productivity. This condition also leads to substantial financial burden. Although there have been advancements, a comprehensive understanding of the underlying etiology of cNLBP remains elusive, resulting in less than optimal treatment outcomes. This study aimed to examine the correlation between lipid variations and the development of cNLBP. The cohort consisted of 26 healthy volunteers (HV group) and 30 cNLBP patients, with an assessment of metabolites and lipid composition in both groups. Metabolomic results revealed significant alterations in lipid-associated metabolites between the HV and cNLBP groups. Subsequent lipid analysis revealed that monoacylglycerols (MAGs) increased approximately 1.2-fold (p = 0.016), diacylglycerols (DAGs) increased approximately 1.4-fold (p = 0.0003), and phosphatidylserine (PS) increased approximately 1.4-fold (p = 0.011). In contrast, triacylglycerol (TAG) decreased to about 0.7-fold (p = 0.035) in the cNLBP group compared to the HV group. The contrasting trends in MAG/DAG and TAG levels indicated that the imbalance between MAG/DAG and TAG may have an impact on the development of cNLBP. This study has provided new insights into the relationship between the progression of cNLBP and specific lipids, suggesting that these lipids could serve as therapeutic targets for cNLBP.

This chapter reviews the neuroanatomy of the nociceptive system and its functional organization. We describe three main compartments of the nervous system that underlie normal nociception and the resulting pain percept: Peripheral, Spinal Cord, and Brain. We focus on how ascending nociceptive processing streams traverse these anatomical compartments, culminating in the multidimensional experience of pain. We also describe neuropathic pain conditions, in which nociceptive processing is abnormal, not only because of the primary effects of a lesion or disease affecting peripheral nerves or the central nervous system (CNS), but also due to secondary effects on ascending pathways and brain networks. We discuss how the anatomical components (circuits/networks) reorganize under various etiologies of neuropathic pain and how these changes can give rise to pathological pain states.

Trigeminal neuralgia (TN) is characterized by recurrent episodes of transient severe pain in its distribution area, with abrupt onset and termination. With the progression of the disease, patients are prone to concurrent psychiatric disorders, such as anxiety and depression, which seriously affect patients' quality of life. Currently, anticonvulsant drugs are commonly used in clinical practice as the primary treatment, but long-term use of drugs is prone to drug resistance, limiting clinical application. Acupuncture and traditional Chinese medicine (TCM), as alternative and complementary therapies, can make up for the deficiencies in modern medicine and are accepted by patients with the advantages of safety and effectiveness. TCM therapy works by promoting the release of endogenous opioid peptides, adjusting the level of inflammatory factors, and improving negative emotions to exert analgesic effects. This paper discusses the clinical efficacy and safety of acupuncture combined with Chinese medicine in the treatment of TN from the perspective of modern medicine and provides a theoretical basis for seeking better therapeutic targets.

The neurotransmitter glycine is an agonist at the strychnine-sensitive glycine receptors. In addition, it has recently been discovered to act at two new receptors, the excitatory glycine receptor and metabotropic glycine receptor. Glycine's neurotransmitter roles have been most extensively investigated in the spinal cord, where it is known to play essential roles in pain, itch, and motor function. In contrast, less is known about supraspinal glycinergic functions, and their contributions to pain circuits are largely unrecognized. As glycinergic neurons are absent from cortical regions, a clearer understanding of how supraspinal glycine modulates pain could reveal new pharmacological targets. This review aims to synthesize the published research on glycine's role in the adult brain, highlighting regions where glycine signaling may modulate pain responses. This was achieved through a scoping review methodology identifying several key regions of supraspinal pain circuitry where glycine signaling is involved. Therefore, this review unveils critical research gaps for supraspinal glycine's potential roles in pain and pain-associated responses, encouraging researchers to consider glycinergic neurotransmission more widely when investigating neural mechanisms of pain.