Despite functional connectivity network dysfunction among individuals with headaches, no studies have examined functional connectivity neural correlates and anatomical differences in coping with headaches.

This study investigated inter-individual variability in whole-brain functional connectivity and anatomical differences among 37 individuals with primary headaches and 24 age- and gender-matched controls, and neural correlates of psychological flexibility (PF) that was previously found to contribute to headache adjustment. Participants (84% women; M headache severity = 4/10; M age = 43 years) underwent functional magnetic resonance imaging scans and completed questionnaires to examine global and subnetwork brain areas, and their relations with PF components, controlling for age, gender, education, and head-motion.

Seed and voxel-based contrast analyses between groups showed atypical functional connectivity of regions involved in pain matrix and core resting-state networks. Pain acceptance was the sole PF component that correlated with the cerebellum (x, y, z: 28, -72, -34, p-false discovery rate <0.001), where individuals with headaches showed higher grey matter density compared to controls.

The cerebellum, recently implicated in modulating emotional and cognitive processes, was indicated to process information resembling what individuals do when practicing pain acceptance. Our findings establish for the first time this connection of the cerebellum and its role in pain acceptance. We propose that pain acceptance might be a behavioural biomarker target that could modulate problematic headache perceptions and brain networks abnormalities.

This study highlights the potential use of emerging behavioural biomarkers in headache management, such as pain acceptance, and their role in modifying the headache experience. Notably, grey matter reorganization in the cerebellum and other known brain pain networks, could indicate brain networks that can be modified from targeted behavioural interventions to help decode the nociplastic mechanisms that predominates in headaches.

Investigating how the interaction between the orbitofrontal cortex (OFC) and various brain regions/functional networks in major depressive disorder (MDD) patients with a history of suicide attempt (SA) holds importance for understanding the neurobiology of this population.

We employed resting-state functional magnetic resonance imaging (rs-fMRI) to analyze the OFC's functional segregation in 586 healthy individuals. A network analysis framework was then applied to rs-fMRI data from 86 MDD-SA patients and 85 MDD-Control patients, utilizing seed mappings of OFC subregions and a multi-connectivity-indicator strategy involving cross-correlation, total interdependencies, Granger causality, and machine learning.

Four functional subregions of left and right OFC, were designated as seed regions of interest. Relative to the MDD-Control group, the MDD-SA group exhibited enhanced functional connectivity (FC) and attenuated interaction between the OFC and the sensorimotor network, imbalanced communication between the OFC and the default mode network, enhanced FC and interaction between the OFC and the ventral attention network, enhanced interaction between the OFC and the salience network, and attenuated FC between the OFC and the frontoparietal network.

The medication and treatment condition of patients with MDD was not controlled, so the medication effect on the alteration model cannot be affirmed.

The findings suggest an imbalanced interaction pattern between the OFC subregions and a set of cognition- and emotion-related functional networks/regions in the MDD-SA group.

Diabetic distal symmetric polyneuropathy, affecting up to 50% of adults with diabetes, often leads to painful symptoms; yet current treatments are largely ineffective with standard therapies providing limited relief. The aim of this systematic review is to address the knowledge gap in understanding the neural networks associated with painful diabetic polyneuropathy (P-DPN). By synthesizing evidence from neuroimaging studies, it seeks to identify potential targets for neuromodulation-based treatments, ultimately guiding clinicians and researchers in developing novel, more effective therapeutic interventions for P-DPN.

A comprehensive search following the preferred reporting items for systematic reviews and meta-analysis was conducted across Embase, PsycINFO, and MEDLINE databases to identify relevant neuroimaging studies from 2010 to May 2024. The search focused on studies involving P-DPN and excluded animal research. After the removal of duplicates and irrelevant studies, 18 studies were included and critically appraised for their contributions to understanding the neural correlates of P-DPN.

The review highlights that P-DPN is associated with alterations in brain networks involved in pain perception, particularly in the primary somatosensory cortex highlighting its role in sensory and pain perception. Regions such as the anterior cingulate cortex and thalamus exhibit altered functional connectivity, with the former showing responses to pain treatment. The review also identified increased connectivity between the cingulate cortex, medial prefrontal cortex, medial temporal region, and insula in individuals with P-DPN, pointing to the involvement of these regions in the emotional and cognitive aspects of pain processing.

This review provides a foundational understanding of the neural networks involved in P-DPN, offering potential targets for future neuromodulation therapies. Further research is required to deepen the understanding of these brain alterations and to explore how they can be leveraged for more effective P-DPN treatments.

This study investigates the differences in brain functional activity and connectivity patterns between Cancer Pain (CP) patients and Healthy Controls (HCs) using resting-state functional magnetic resonance imaging (rs-fMRI) to identify potential neuroimaging biomarkers.

This study collected rs-fMRI data from 25 CP patients and 25 hCs, processed the functional MRI images, and calculated metrics such as amplitude of low-frequency fluctuation (ALFF), Regional Homogeneity (ReHo), and FC. Through statistical analysis, differences in brain functional activity and connectivity between the cancer pain group and the healthy control group were investigated, followed by machine learning classification.

The results showed that compared to the normal group, reductions in the ALFF were primarily observed in the bilateral inferior temporal gyrus; ReHo increased in the right middle temporal gyrus and decreased in the left cerebellum Crus2. Using the statistically different brain areas as seed points to construct FC networks and performing statistical analysis, it was found that the regions with decreased FC connection strength between the cancer pain group and the normal group were mainly in the prefrontal cortex (PFC), the postcentral gyrus of the parietal lobe, and the cerebellum. Statistical results indicated that there was no significant correlation between pain scores (Numeric Rating Scale, NRS) and neuroimaging metrics. According to the machine learning classification, the FC features of the right precentral gyrus achieved higher diagnostic efficacy (AUC = 0.804) compared to ALFF and ReHo in distinguishing between CP patients and HCs.

Brain activity and FC in CP patients show abnormalities in regions such as the inferior temporal gyrus, middle temporal gyrus, prefrontal cortex, parietal lobe, and cerebellum. These areas may be interconnected through neural networks and jointly participate in functions related to pain perception, emotion regulation, cognitive processing, and motor control. However, the precise connections and mechanisms of action require further research.

This study aimed to elucidate the mechanisms of chiropractic care using resting electroencephalography (EEG), somatosensory evoked potentials (SEPs), clinical health assessments (Fitbit), and Patient-reported Outcomes Measurement Information System (PROMIS-29).

Seventy-six people with chronic low back pain (mean age ± SD: 45 ± 11 years, 33 female) were randomised into control (n = 38) and chiropractic (n = 38) groups. EEG and SEPs were collected pre and post the first intervention and post 4 weeks of intervention. PROMIS-29 was measured pre and post 4 weeks. Fitbit data were recorded continuously.

Spectral analysis of resting EEG showed a significant increase in Theta, Alpha and Beta, and a significant decrease in Delta power in the chiropractic group post intervention. Source localisation revealed a significant increase in Alpha activity within the Default Mode Network (DMN) post intervention and post 4 weeks. A significant decrease in N30 SEP peak amplitude post intervention and post 4 weeks was found in the chiropractic group. Source localisation demonstrated significant changes in Alpha and Beta power within the DMN post-intervention and post 4 weeks. Significant improvements in light sleep stage were observed in the chiropractic group along with enhanced overall quality of life post 4 weeks, including significant reductions in anxiety, depression, fatigue, and pain.

These findings indicate that many health benefits of chiropractic care are due to altered brain activity.

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.

Pain catastrophizing is a prominent psychological factor that is strongly correlated with pain. Although the complex properties of pain catastrophizing vary across different pain phases, the contribution of chronic pain to its progression from a general trait to a higher state remains unclear. This study aimed to examine the neural mechanisms and degree to which pain catastrophizing is reinforced in the context of primary dysmenorrhea (PDM), one of the most prevalent gynaecological complaints experienced by women of reproductive age. Altogether, 29 women with moderate-to-severe PDM were included in this study. Arterial spin labelling was used to quantify the cerebral blood flow (CBF) in each participant in both the pain-free and painful phases. The pain catastrophizing scale (PCS) was completed in two phases, and the Short-Form McGill Pain Questionnaire was completed in the painful phase. Compared with pain catastrophizing in the pain-free phase (PCSpf), pain catastrophizing in the painful phase (PCSp) is higher and positively correlated with the composite factor of menstrual pain. CBF analysis indicated that the PCSp is positively associated with CBF in the frontal cortex, hippocampus and amygdala. The reinforcement of pain catastrophizing correlates with CBF in the prefrontal cortex. Specifically, the medial prefrontal cortex, which correlates with pain state, plays a crucial role in mediating the reinforcing effect of pain in the PCSp. These results promote the mechanical comprehension of pain catastrophizing management in individuals with chronic pain.

Despite major advancements in our understanding of its fundamental causes, pain-both acute and chronic-remains a serious health concern. Various preclinical investigations utilizing diverse animal, cellular, and alternative models are required and frequently demanded by regulatory approval bodies to bridge the gap between the lab and the clinic. Investigating naturally occurring painful disorders can speed up medication development at the preclinical and clinical levels by illuminating molecular pathways. A wide range of animal models related to pain have been developed to elucidate pathophysiological mechanisms and aid in identifying novel targets for treatment. Pain sometimes drugs fail clinically, causing high translational costs due to poor selection and the use of preclinical tools and reporting. To improve the study of pain in a clinical context, researchers have been creating innovative models over the past few decades that better represent pathological pain conditions. In this paper, we provide a summary of traditional animal models, including rodents, cellular models, human volunteers, and alternative models, as well as the specific characteristics of pain diseases they model. However, a more rigorous approach to preclinical research and cutting-edge analgesic technologies may be necessary to successfully create novel analgesics. The research highlights from this review emphasize new opportunities to develop research that includes animals and non-animals using proven methods pertinent to comprehending and treating human suffering. This review highlights the value of using a variety of modern pain models in animals before human trials. These models can help us understand the different mechanisms behind various pain types. This will ultimately lead to the development of more effective pain medications.

It is estimated that approximately a third of patients undergoing certain surgeries may report some degree of persistent pain postoperatively. Chronic postsurgical pain (CPSP) reduces quality of life, is challenging to treat, and has significant socio-economic impact.

From an epidemiological perspective, factors that predispose patients to the development of CPSP may be considered in relation to the patient, the procedure or, the care environment. Prevention or management of transition from acute to chronic pain often need a multidisciplinary approach beginning early in the preoperative period and continuing beyond surgical admission. The current concepts regarding the role of central and peripheral nervous systems in chronification of pain may provide targets for future therapies but, the current evidence seems to suggest that a multimodal analgesic approach of preventive analgesia along with a continued follow-up and treatment after hospital discharge may hold the key to identify and manage the transitioning of acute to chronic pain.

A comprehensive multidisciplinary approach with prior identification of risk factors, minimizing the surgical insult and a culture of utilizing multimodal analgesia and continued surveillance beyond the period of hospitalization is an important step towards reducing the development of chronic pain. A transitional pain service model may accomplish many of these goals.

Zoster-associated pain (ZAP) is frequently concomitant with psychiatric comorbidities. However, the underlying neuropathological mechanisms of ZAP with psychiatric comorbidities remain poorly understood.

Rest-stating functional MRI (rs-fMRI) data from 41 ZAP patients without anxiety or depression (noA/D-ZAP), 11 ZAP patients with anxiety or depression (A/D-ZAP) and 29 healthy controls (HCs) were acquired. Degree centrality (DC) based on rs-fMRI was used to explore the node changes in the brain functional network in these subjects. Moreover, correlations and receiver operating characteristic curve analysis were performed.

One-way analysis of variance revealed abnormal DC values in the right middle frontal gyrus (MFG) and bilateral precuneus among the three groups. Compared with HCs, A/D-ZAP showed increased DC values in the bilateral pons, while noA/D-ZAP showed increased DC values in the right pons, left brainstem and rectal gyrus and decreased DC values in the right cingulate gyrus and bilateral precuneus. A/D-ZAP showed increased DC values in the left MFG and precentral gyrus (PG) compared with noA/D-ZAP. The DC value of the left pons in A/D-ZAP was positively correlated with the self-rating anxiety scale score. Areas under the curve of DC values in the left PG and MFG for distinguishing A/D-ZAP from the noA/D-ZAP group were 0.907 and 1.000, respectively.

This study revealed the node differences in the brain functional network of ZAP patients with or without psychiatric comorbidities. In particular, abnormal DC values of the left MFG and PG may play an important role in the neuropathologic mechanism of the disease.

Functional magnetic resonance imaging, in conjunction with models of peripheral and/or central sensitization, has been used to assess analgesic efficacy in healthy humans. This review aims to summarize the use of these techniques to characterize brain mechanisms of hyperalgesia/allodynia and to evaluate the efficacy of analgesics.

Searches were performed (PubMed-Medline, Cochrane, Web of Science and Clinicaltrials.gov) to identify and review studies. A co-ordinate based meta-analysis (CBMA) was conducted to quantify neural activity that was reported across multiple independent studies in the hyperalgesic condition compared to control, using GingerALE software.

Of 217 publications, 30 studies met the inclusion criteria. They studied nine different models of hyperalgesia/allodynia assessed in the primary (14) or secondary hyperalgesia zone (16). Twenty-three studies focused on neural correlates of hyperalgesic conditions and showed consistent changes in the somatosensory cortex, prefrontal cortices, insular cortex, anterior cingulate cortex, thalamus and brainstem. The CBMA on 12 studies that reported activation coordinates for a contrast comparing the hyperalgesic state to control produced six activation clusters (significant at false discovery rate of 0.05) with more peaks for secondary (17.7) than primary zones (7.3). Seven studies showed modulation of brain activity by analgesics in five of the clusters but also in four additional regions.

This meta-analysis revealed substantial but incomplete overlap between brain areas related to neural mechanisms of hyperalgesia and those reflecting the efficacy of analgesic drugs. Studies testing in the secondary zone were more sensitive to evaluate analgesic efficacy on central sensitization at brainstem or thalamocortical levels.

Experimental pain models that provide a surrogate for features of pathological pain conditions in healthy humans and functional imaging techniques are both highly valuable research tools. This review shows that when used together, they provide a wealth of information about brain activity during pain states and analgesia. These tools are promising candidates to help bridge the gap between animal and human studies, to improve translatability and provide opportunities for identification of new targets for back-translation to animal studies.

Chronic pain is a pathological state defined as daily pain sensation over three consecutive months. It affects up to 30% of the general population. Although significant research efforts have been made in the past 30 years, only a few and relatively low effective molecules have emerged to treat chronic pain, with a considerable translational failure rate. Most preclinical models have focused on sensory neurotransmission, with particular emphasis on the dorsal horn of the spinal cord as the first relay of nociceptive information. Beyond impaired nociceptive transmission, chronic pain is also accompanied by numerous comorbidities, such as anxiety-depressive disorders, anhedonia and motor and cognitive deficits gathered under the term "pain matrix". The emergence of cutting-edge techniques assessing specific neuronal circuits allow in-depth studies of the connections between "pain matrix" circuits and behavioural outputs. Pain behaviours are assessed not only by reflex-induced responses but also by various or more complex behaviours in order to obtain the most complete picture of an animal's pain state. This review summarises the latest findings on pain modulation by brain component of the pain matrix and proposes new opportunities to unravel the mechanisms of chronic pain.

Positron emission tomography (PET) is a noninvasive molecular imaging technique that utilizes biologically active radiolabeled compounds to image biochemical processes. As such, PET can provide important pathophysiological information associated with pain of different etiologies. As such, the information obtained using PET often combined with MRI or CT can provide useful information for diagnosing and monitoring changes associated with pain. This review covers the most important PET tracers that have been used to image pain including tracers for fundamental biological processes such as glucose metabolism and cerebral blood flow to receptor-specific tracers such as ion channels and neurotransmitters. For tracer type, we describe the structure and radiochemical synthesis of the tracer followed by a brief summary of the available preclinical and clinical studies. By providing a summary of the PET tracers that have been employed for PET imaging of pain, this review aims to serve as a reference for preclinical, translational and clinical investigators interested in molecular imaging of pain. Finally, the review ends with an outlook of the needs and opportunities in this area.

Autonomic nervous system dysfunction has been reported to be associated with impaired activities of daily living (ADL) among patients with chronic pain, but the association has not been fully addressed in general populations. This study cross-sectionally investigated the association between autonomic nervous system function and the presence of subjective symptoms affecting ADL in community-dwelling residents with chronic pain.

A total of 888 residents with chronic pain, aged 40-79 years, who underwent a health examination in 2017-2018 were included. Based on heart rate variability measured by fingertip pulse wave, the standard deviation of normal-to-normal intervals (SDNN), root mean square of successive RR interval differences (RMSSD), low frequency (LF) power, and high frequency (HF) power were calculated. Symptoms affecting ADL were defined as those scoring ≥1 on the modified Rankin Scale. Odds ratios (ORs) and their 95% confidence intervals (CIs) for symptoms affecting ADL were estimated using a logistic regression analysis.

The overall prevalence of symptoms affecting ADL was 39.4%. The ORs for symptoms affecting ADL increased significantly per 1-standard-deviation decrement in log-transformed SDNN (OR 1.23 [95% CI 1.06-1.44]), RMSSD (1.25 [1.08-1.45]), LF power (1.29 [1.11-1.52]), and HF power (1.29 [1.11-1.51]) after adjusting for age, sex, education, hypertension, diabetes, serum total cholesterol level, body mass index, past medical history, current smoking, current drinking, exercise, depressive symptoms, and pain intensity.

Decreased heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community.

Decrease in heart rate variability was associated with the presence of symptoms affecting ADL among individuals with chronic pain in a Japanese community. This article could help scientists understand the significance of autonomic nervous system dysfunction in the pathology of chronic pain. Approaches that target autonomic nervous system dysfunction may be an option to relieve or prevent symptoms affecting ADL for chronic pain sufferers.

Chronic musculoskeletal pain is associated with decreased parasympathetic and increased sympathetic activity in the autonomic nervous system. The objective of this study was to determine the associations between objective measures of heart rate variability (a measure of autonomic nervous system function), actigraphy (a measure of activity and sleep quality), respiration rates, and subjective patient-reported outcome measures (PROMs) of central sensitization, kinesiophobia, disability, the effect of pain on sleep, and life quality.

Thirty-eight study subjects were divided into two subgroups, including low symptoms of central sensitization (n = 18) and high symptoms of central sensitization (n = 20), based on patient-reported scores on the Central Sensitization Inventory (CSI). Heart rate variability (HRV) and actigraphy measurements were carried out simultaneously in 24 h measurement during wakefulness and sleep.

A decrease in HRV during the first 2 h of sleep was stronger in the low CSI subgroup compared to the high CSI subgroup. Otherwise, all other HRV and actigraphy parameters and subjective measures of central sensitization, disability, kinesiophobia, the effect of pain on sleep, and quality of life showed only little associations.

The high CSI subgroup reported significantly more severe symptoms of disability, kinesiophobia, sleep, and quality of life compared to the low CSI subgroup. However, there were only small and nonsignificant trend in increased sympathetic nervous system activity and poorer sleep quality on the high central sensitization subgroup. Moreover, very little differences in respiratory rates were found between the groups.

This study aims to investigate the effectiveness of cupping therapy on low back pain (LBP).

Medline, Embase, Scopus and WANFANG databases were searched for relevant cupping RCTs on low back pain articles up to 2023. A complementary search was manually made on 27 September for update screening. Full-text English and Chinese articles on all ethnic adults with LBP of cupping management were included in this study. Studies looking at acute low back pain only were excluded. Two independent reviewers screened and extracted data, with any disagreement resolved through consensus by a third reviewer. The methodological quality of the included studies was evaluated independently by two reviewers using an adapted tool. Change-from-baseline outcomes were treated as continuous variables and calculated according to the Cochrane Handbook. Data were extracted and pooled into the meta-analysis by Review Manager software (version 5.4, Nordic Cochrane Centre).

Eleven trials involving 921 participants were included. Five studies were assessed as being at low risk of bias, and six studies were of acceptable quality. High-quality evidence demonstrated cupping significantly improves pain at 2-8 weeks endpoint intervention (d=1.09, 95% CI: [0.35-1.83], p = 0.004). There was no continuous pain improvement observed at one month (d=0.11, 95% CI: [-1.02-1.23], p = 0.85) and 3-6 months (d=0.39, 95% CI: [-0.09-0.87], p = 0.11). Dry cupping did not improve pain (d=1.06, 95% CI: [-0.34, 2.45], p = 0.14) compared with wet cupping (d=1.5, 95% CI: [0.39-2.6], p = 0.008) at the endpoint intervention. There was no evidence indicating the association between pain reduction and different types of cupping (p = 0.2). Moderate- to low-quality evidence showed that cupping did not reduce chronic low back pain (d=0.74, 95% CI: [-0.67-2.15], p = 0.30) and non-specific chronic low back pain (d=0.27, 95% CI: [-1.69-2.24], p = 0.78) at the endpoint intervention. Cupping on acupoints showed a significant improvement in pain (d=1.29, 95% CI: [0.63-1.94], p < 0.01) compared with the lower back area (d=0.35, 95% CI: [-0.29-0.99], p = 0.29). A potential association between pain reduction and different cupping locations (p = 0.05) was found. Meta-analysis showed a significant effect on pain improvement compared to medication therapy (n = 8; d=1.8 [95% CI: 1.22 - 2.39], p < 0.001) and usual care (n = 5; d=1.07 [95% CI: 0.21- 1.93], p = 0.01). Two studies demonstrated that cupping significantly mediated sensory and emotional pain immediately, after 24 h, and 2 weeks post-intervention (d= 5.49, 95% CI [4.13-6.84], p < 0.001). Moderate evidence suggested that cupping improved disability at the 1-6 months follow-up (d=0.67, 95% CI: [0.06-1.28], p = 0.03). There was no immediate effect observed at the 2-8 weeks endpoint (d=0.40, 95% CI: [-0.51-1.30], p = 0.39). A high degree of heterogeneity was noted in the subgroup analysis (I2 >50%).

High- to moderate-quality evidence indicates that cupping significantly improves pain and disability. The effectiveness of cupping for LBP varies based on treatment durations, cupping types, treatment locations, and LBP classifications. Cupping demonstrated a superior and sustained effect on pain reduction compared with medication and usual care. The notable heterogeneity among studies raises concerns about the certainty of these findings. Further research should be designed with a standardized cupping manipulation that specifies treatment sessions, frequency, cupping types, and treatment locations. The actual therapeutic effects of cupping could be confirmed by using objective pain assessments. Studies with at least six- to twelve-month follow-ups are needed to investigate the long-term efficacy of cupping in managing LBP.

This systematic review was initially registered on PROSPERO with registration code: CRD42021271245 on 08 September 2021.

Although the pediatric perioperative pain management has been improved in recent years, the valid and reliable pain assessment tool in perioperative period of children remains a challenging task. Pediatric perioperative pain management is intractable not only because children cannot express their emotions accurately and objectively due to their inability to describe physiological characteristics of feeling which are different from those of adults, but also because there is a lack of effective and specific assessment tool for children. In addition, exposure to repeated painful stimuli early in life is known to have short and long-term adverse sequelae. The short-term sequelae can induce a series of neurological, endocrine, cardiovascular system stress related to psychological trauma, while long-term sequelae may alter brain maturation process, which can lead to impair neurodevelopmental, behavioral, and cognitive function. Children's facial expressions largely reflect the degree of pain, which has led to the developing of a number of pain scoring tools that will help improve the quality of pain management in children if they are continually studied in depth. The artificial intelligence (AI) technology represented by machine learning has reached an unprecedented level in image processing of deep facial models through deep convolutional neural networks, which can effectively identify and systematically analyze various subtle features of children's facial expressions. Based on the construction of a large database of images of facial expressions in children with perioperative pain, this study proposes to develop and apply automatic facial pain expression recognition software using AI technology. The study aims to improve the postoperative pain management for pediatric population and the short-term and long-term quality of life for pediatric patients after operational event.

Chronic Painful Temporomandibular Disorders (TMD) are challenging to diagnose and manage due to their complexity and lack of understanding of brain mechanism. In the past few decades' neural mechanisms of pain regulation and perception have been clarified by neuroimaging research. Advances in the neuroimaging have bridged the gap between brain activity and the subjective experience of pain. Neuroimaging has also made strides toward separating the neural mechanisms underlying the chronic painful TMD. Recently, Artificial Intelligence (AI) is transforming various sectors by automating tasks that previously required humans' intelligence to complete. AI has started to contribute to the recognition, assessment, and understanding of painful TMD. The application of AI and neuroimaging in understanding the pathophysiology and diagnosis of chronic painful TMD are still in its early stages. The objective of the present review is to identify the contemporary neuroimaging approaches such as structural, functional, and molecular techniques that have been used to investigate the brain of chronic painful TMD individuals. Furthermore, this review guides practitioners on relevant aspects of AI and how AI and neuroimaging methods can revolutionize our understanding on the mechanisms of painful TMD and aid in both diagnosis and management to enhance patient outcomes.

Pain is a multifaceted process that encompasses unpleasant sensory and emotional experiences. The essence of the pain process is aversion, or perceived negative emotion. Central sensitization plays a significant role in initiating and perpetuating of chronic pain. Melzack proposed the concept of the "pain matrix", in which brain regions associated with pain form an interconnected network, rather than being controlled by a singular brain region. This review aims to investigate distinct brain regions involved in pain and their interconnections. In addition, it also sheds light on the reciprocal connectivity between the ascending and descending pathways that participate in pain modulation. We review the involvement of various brain areas during pain and focus on understanding the connections among them, which can contribute to a better understanding of pain mechanisms and provide opportunities for further research on therapies for improved pain management.

The human body has the ability to influence its sensation of pain by modifying the transfer of nociceptive information at the spinal level. This modulation, known as descending pain inhibition, is known to originate supraspinally and can be activated by a variety of ways including positive mental imagery. However, its exact mechanisms remain unknown. We investigated, using a longitudinal fMRI design, the brain activity leading up and in response to painful electrical stimulation when applying positive mental imagery before and after undergoing a previously established RIII-feedback paradigm. Time course analysis of the time preceding painful stimulation shows increased haemodynamic activity during the application of the strategy in the PFC, ACC, insula, thalamus, and hypothalamus. Time course analysis of the reaction to painful stimulation shows decreased reaction post-training in brainstem and thalamus, as well as the insula and dorsolateral PFC. Our work suggests that feedback training increases activity in areas involved in pain inhibition, while simultaneously decreasing the reaction to painful stimuli in brain areas related to pain processing, which points to an activation of decreased spinal nociception. We further suggest that the insula and the thalamus may play a more important role in pain modulation than previously assumed.

We previously found Spanish-English bilingual adults reported higher pain intensity when exposed to painful heat in the language of their stronger cultural orientation. Here, we elucidate brain systems involved in language-driven alterations in pain responses. During separate English- and Spanish-speaking fMRI scanning runs, 39 (21 female) bilingual adults rated painful heat intermixed between culturally evocative images and completed sentence reading tasks. Surveys of cultural identity and language use measured relative preference for US-American vs Hispanic culture (cultural orientation). Participants produced higher intensity ratings in Spanish compared to English. Group-level whole-brain differences in pain-evoked activity between languages emerged in somatosensory, cingulate, precuneus and cerebellar cortex. Regions of interest associated with semantic, attention and somatosensory processing showed higher average pain-evoked responses in participants' culturally preferred language, as did expression of a multivariate pain-predictive pattern. Follow-up moderated mediation analyses showed somatosensory activity mediated language effects on pain intensity, particularly for Hispanic oriented participants. These findings relate to distinct ('meddler', 'spotlight' and 'inducer') hypotheses about the nature of language effects on perception and cognition. Knowledge of language influences on pain could improve efficacy of culturally sensitive treatment approaches across the diversity of Hispanic adults to mitigate documented health disparities in this population.

Millions of people survive injuries to the central or peripheral nervous system for which neurorehabilitation is required. In addition to the physical and cognitive impairments, many neurorehabilitation patients experience pain, often not widely recognised and inadequately treated. This is particularly true for multiple sclerosis (MS) patients, for whom pain is one of the most common symptoms. In clinical practice, pain assessment is usually conducted based on a subjective estimate. This approach can lead to inaccurate evaluations due to the influence of numerous factors, including emotional or cognitive aspects. To date, no objective and simple to use clinical methods allow objective quantification of pain and the diagnostic differentiation between the two main types of pain (nociceptive vs neuropathic). Wearable technologies and artificial intelligence (AI) have the potential to bridge this gap by continuously monitoring patients' health parameters and extracting meaningful information from them. Therefore, we propose to develop a new automatic AI-powered tool to assess pain and its characteristics during neurorehabilitation treatments using physiological signals collected by wearable sensors.

We aim to recruit 15 participants suffering from MS undergoing physiotherapy treatment. During the study, participants will wear a wristband for three consecutive days and be monitored before and after their physiotherapy sessions. Measurement of traditionally used pain assessment questionnaires and scales (ie, painDETECT, Doleur Neuropathique 4 Questions, EuroQoL-5-dimension-3-level) and physiological signals (photoplethysmography, electrodermal activity, skin temperature, accelerometer data) will be collected. Relevant parameters from physiological signals will be identified, and AI algorithms will be used to develop automatic classification methods.

The study has been approved by the local Ethical Committee (285-2022-SPER-AUSLBO). Participants are required to provide written informed consent. The results will be disseminated through contributions to international conferences and scientific journals, and they will also be included in a doctoral dissertation.

NCT05747040.

Low back pain (LBP) disproportionately affects older black adults, often leading to inadequate treatment due to clinician biases. Objective pain measures are imperative, and Functional Near-Infrared Spectroscopy (fNIRS) shows promise for pain detection.

To determine the impact of listening to home-based preferred web app-based music on underlying pain processing mechanisms at the central nervous level in older black adults aged ≥65 with LBP.

Twenty older black adults with LBP listened to preferred music twice daily for four days using the MUSIC CARE® app. Neuroimaging data were collected using fNIRS. Data were transformed to changes in oxy-hemoglobin and deoxy-hemoglobin concentrations and analyzed.

Significant cortical activation pattern differences were observed between pre-and post-intervention scans, particularly in somatosensory regions. Post-intervention scans showed significantly reduced hemodynamic activities.

Preferred music listening has the potential to alleviate pain, and fNIRS emerges as a promising tool for exploring cortical-level pain-related neural circuits.

To explore the central processing mechanism of pain perception in chronic low back pain (cLBP) using multi-voxel pattern analysis (MVPA) based on the static and dynamic fractional amplitude of low-frequency fluctuations (fALFF) analysis, and spectral dynamic causal modeling (spDCM). Thirty-two patients with cLBP and 29 matched healthy controls (HCs) for the first cohort and 24 patients with cLBP and 22 HCs for the validation cohort underwent resting-state fMRI scan. The alterations in static and dynamic fALFF were as classification features to distinguish patients with cLBP from HCs. The brain regions gotten from the MVPA results were used for further spDCM analysis. We found that the most discriminative brain regions that contributed to the classification were the right supplementary motor area (SMA.R), left paracentral lobule (PCL.L), and bilateral cerebellar Crus II. The spDCM results displayed decreased excitatory influence from the bilateral cerebellar Crus II to PCL.L in patients with cLBP compared with HCs. Moreover, the conversion of effective connectivity from the bilateral cerebellar Crus II to SMA.R from excitatory influence to inhibitive influence, and the effective connectivity strength exhibited partially mediated effects on Chinese Short Form Oswestry Disability Index Questionnaire (C-SFODI) scores. Our findings suggest that the cerebellum and its weakened or inhibited connections to the motor cortex may be one of the underlying feedback pathways for pain perception in cLBP, and partially mediate the degree of dysfunction.

[Formula: see text] Advances in neuroimaging, combined with developments in artificial intelligence software, have allowed researchers to noninvasively decode the brain and 'read the mind'.

To unravel the complexity of the neuropathic pain experience, researchers have tried to identify reliable pain signatures (biomarkers) using electroencephalography (EEG) and skin conductance (SC). Nevertheless, their use as a clinical aid to design personalized therapies remains scarce and patients are prescribed with common and inefficient painkillers. To address this need, novel non-pharmacological interventions, such as transcutaneous electrical nerve stimulation (TENS) to activate peripheral pain relief via neuromodulation and virtual reality (VR) to modulate patients' attention, have emerged. However, all present treatments suffer from the inherent bias of the patient's self-reported pain intensity, depending on their predisposition and tolerance, together with unspecific, pre-defined scheduling of sessions which does not consider the timing of pain episodes onset. Here, we show a Brain-Computer Interface (BCI) detecting in real-time neurophysiological signatures of neuropathic pain from EEG combined with SC and accordingly triggering a multisensory intervention combining TENS and VR. After validating that the multisensory intervention effectively decreased experimentally induced pain, the BCI was tested with thirteen healthy subjects by electrically inducing pain and showed 82% recall in decoding pain in real time. Such constructed BCI was then validated with eight neuropathic patients reaching 75% online pain precision, and consequently releasing the intervention inducing a significant decrease (50% NPSI score) in neuropathic patients' pain perception. Our results demonstrate the feasibility of real-time pain detection from objective neurophysiological signals, and the effectiveness of a triggered combination of VR and TENS to decrease neuropathic pain. This paves the way towards personalized, data-driven pain therapies using fully portable technologies.

This randomized, controlled, single-blinded trial assessed the effect of magnesium (Mg)-Teadiola (Mg, vitamins B6, B9, B12, Rhodiola, and green tea/L-theanine) versus placebo on the brain response to stressful thermal stimulus in chronically stressed, but otherwise healthy subjects. Impacts on stress-related quality-of-life parameters (depression, anxiety, sleep, and perception of pain) were also explored.

The study recruited a total of 40 adults (20 per group), suffering from stress for more than 1 month and scaling ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire at the time of inclusion. Individuals received oral Mg-Teadiola or placebo for 28 days (D). fMRI analysis was used to visualize the interplay between stress and pain cerebral matrices, using thermal stress model, at baseline (D0) and after D28.

Based on blood-oxygen-level-dependent (BOLD) signal variations during the stress stimulation (before pain perception), a significantly increased activation between D0 and D28 was observed for left and right frontal area (p = 0.001 and p = 0.002, respectively), left and right anterior cingulate cortex (ACC) (p = 0.035 and p = 0.04, respectively), and left and right insula (p = 0.034 and p = 0.0402, respectively) in Mg-Teadiola versus placebo group. During thermal pain stimulation, a significantly diminished activation of the pain matrix was observed between D0 and D28, for left and right prefrontal area (both p = 0.001), left and right insula (p = 0.008 and p = 0.019, respectively), and left and right ventral striatum (both p = 0.001) was observed in Mg-Teadiola versus placebo group. These results reinforce the clinical observations, showing a perceived benefit of Mg-Teadiola on several parameters. After 1 month of treatment, DASS-42 stress score significantly decreased in Mg-Teadiola group [effect size (ES) -0.46 (-0.91; -0.01), p = 0.048]. Similar reductions were observed on D14 (p = 0.011) and D56 (p = 0.008). Sensitivity to cold also improved from D0 to D28 for Mg-Teadiola versus placebo [ES 0.47 (0.02; 0.92) p = 0.042].

Supplementation with Mg-Teadiola reduced stress on D28 in chronically stressed but otherwise healthy individuals and modulated the stress and pain cerebral matrices during stressful thermal stimulus.

Bone cancer pain is a complex condition characterized by persistent, sudden, spontaneous pain accompanied by hyperalgesia that typically arises from bone metastases or primary bone tumors, causing severe discomfort and significantly diminishing cancer patients' quality of life and confidence in their ability to overcome the disease. It is widely known that peripheral nerves are responsible for detecting harmful stimuli, which are then transmitted to the brain via the spinal cord, resulting in the perception of pain. In the case of bone cancer, tumors and stromal cells within the bone marrow release various chemical signals, including inflammatory factors, colony-stimulating factors, chemokines, and hydrogen ions. Consequently, the nociceptors located at the nerve endings within the bone marrow sense these chemical signals, generating electrical signals that are then transmitted to the brain through the spinal cord. Subsequently, the brain processes these electrical signals in a complex manner to create the sensation of bone cancer pain. Numerous studies have investigated the transmission of bone cancer pain from the periphery to the spinal cord. However, the processing of pain information induced by bone cancer within the brain remains unclear. With the continuous advancements in brain science and technology, the brain mechanism of bone cancer pain would become more clearly understood. Herein, we focus on summarizing the peripheral nerve perception of the spinal cord transmission of bone cancer pain and provide a brief overview of the ongoing research regarding the brain mechanisms involved in bone cancer pain.

Machine learning is becoming an increasingly common component of routine data analyses in clinical research. The past decade in pain research has witnessed great advances in human neuroimaging and machine learning. With each finding, the pain research community takes one step closer to uncovering fundamental mechanisms underlying chronic pain and at the same time proposing neurophysiological biomarkers. However, it remains challenging to fully understand chronic pain due to its multidimensional representations within the brain. By utilizing cost-effective and non-invasive imaging techniques such as electroencephalography (EEG) and analyzing the resulting data with advanced analytic methods, we have the opportunity to better understand and identify specific neural mechanisms associated with the processing and perception of chronic pain. This narrative literature review summarizes studies from the last decade describing the utility of EEG as a potential biomarker for chronic pain by synergizing clinical and computational perspectives.

Chronic low back pain (CLBP) is a leading cause of disability globally. Exercise therapies are one of the commonly prescribed treatment options for CLBP. The specific exercise therapies for CLBP most commonly target movement dysfunction, but seldom brain-based pain modulation. Exercise therapies with specific breathing techniques (SBTs) have been shown to influence and enhance brain-based structural and functional pain modulation.

To assess the feasibility of the SBTs protocol, eligibility criteria, randomization, and dropout rates. To quantify the changes in patient outcome measures and choose the most relevant measure for larger-scale study. To quantify self-adherence levels to home exercise and monitor and record possible pain medication and other treatment modality usage, and adverse events during exercise.

A parallel randomised analyst-blinded feasibility trial with two-month follow-up.

Feasibility related to aims and objectives. Multiple pain- and health-related patient-reported outcome measures of pain intensity, disability, central sensitization, anxiety, kinesiophobia, catastrophising, self-efficacy, sleep quality, quality of life, and health and well-being status. Exercise adherence, pain medication and other treatment modality usage, and possible adverse events related to exercises will be monitored and recorded.

Thirty participants will be randomized to movement control exercise with SBTs (15 subjects in experimental group) or movement control exercise without SBTs (15 subjects in control group) in private chiropractic practice setting with two-month follow-up. Trial registration number; NCT05268822.

The clinical difference in effectiveness between practically identical exercise programs in uniform study settings with or without SBTs has not been studied before. This study aims to inform feasibility and help determine whether progression to a full-scale trial is worthwhile.

We aimed to evaluate the efficacy of electroacupuncture in relieving acute pain after total knee arthroplasty (TKA) and related mechanism.

In this randomized, single-blind, and sham-acupuncture controlled study. Forty patients with postoperative acute pain were recruited and randomly divided electroacupuncture group (n = 20) and sham-acupuncture group (n = 20) from November 2020 to October 2021. All patients received electroacupuncture or sham-acupuncture for 5 days after TKA. Their brain regions were scanned with resting-state functional magnetic resonance imaging before and after intervention. Pain was scaled. Another 40 matched healthy controls underwent scanning once. The amplitude of low-frequency fluctuation (ALFF) values was compared. Pearson's correlation analysis was utilized to explore the correlation of ALFF with clinical variables in patients after intervention.

Compared with the HCs, patients with acute pain following TKA had significantly decreased ALFF value in right middle frontal gyrus, right supplementary motor area, bilateral precuneus, right calcarine fissure and surrounding cortex, and left triangular part of inferior frontal gyrus (false discovery rate corrected p < .05). Patients had higher ALFF value in bilateral precuneus, right cuneus, right angular gyrus, bilateral middle occipital gyrus, and left middle temporal gyrus after electroacupuncture (AlphaSim corrected p < .01). Correlation analysis revealed that the change (postoperative day 7 to postoperative day 3) of ALFF in bilateral precuneus were negatively correlated with the change of NRS scores (r = -0.706; p = .002; 95% CI = -0.890 to -0.323) in EA group.

The functional activities of related brain regions decreased in patients with acute pain after TKA. The enhancement of the functional activity of precuneus may be the neurobiological mechanism of electroacupuncture in treating pain following TKA.

Studies of consciousness are hindered by the complexity of the brain, but it is possible to study the consciousness of a sensation, namely pain. Three systems are necessary to experience pain: the somatosensory system conveys information about an injury to the thalamus where an awareness of the injury but not the painfulness emerges. The thalamus distributes the information to the affective system, which modulates the intensity of the pain, and to the cognitive system that imparts attention to the pain. Imaging of patients in pain and those experiencing placebo and hypnosis-induced analgesia shows that two essential cortical circuits for pain and attention are located within the anterior cingulate cortex. The circuits are activated when a high-frequency input results in the development of a long-term potentiation (LTP) at synapses on the apical dendrites of pyramidal neurons. The LTP acts via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors, and an anterior cingulate cortex-specific type-1 adenylate cyclase is necessary for both the LTP and the pain. The apical dendrites form an extensive network such that the input from serious injuries results in the emergence of a local field potential. Using mouse models, I propose experiments designed to test the hypothesis that the local field potential is necessary and sufficient for the consciousness of pain.

In a healthy state, pain plays an important role in natural biofeedback loops and helps to detect and prevent potentially harmful stimuli and situations. However, pain can become chronic and as such a pathological condition, losing its informative and adaptive function. Efficient pain treatment remains a largely unmet clinical need. One promising route to improve the characterization of pain, and with that the potential for more effective pain therapies, is the integration of different data modalities through cutting edge computational methods. Using these methods, multiscale, complex, and network models of pain signaling can be created and utilized for the benefit of patients. Such models require collaborative work of experts from different research domains such as medicine, biology, physiology, psychology as well as mathematics and data science. Efficient work of collaborative teams requires developing of a common language and common level of understanding as a prerequisite. One of ways to meet this need is to provide easy to comprehend overviews of certain topics within the pain research domain. Here, we propose such an overview on the topic of pain assessment in humans for computational researchers. Quantifications related to pain are necessary for building computational models. However, as defined by the International Association of the Study of Pain (IASP), pain is a sensory and emotional experience and thus, it cannot be measured and quantified objectively. This results in a need for clear distinctions between nociception, pain and correlates of pain. Therefore, here we review methods to assess pain as a percept and nociception as a biological basis for this percept in humans, with the goal of creating a roadmap of modelling options.

Chronic pain impacts one in five Americans and is difficult to manage, costing ~USD 600 billion annually. The subjective experience of pain is a complex processing of central nervous system input. Recent advances in magnetic resonance imaging revealed the prefrontal cortex as vital to the perception of pain and that changes in the cerebral hemodynamics can be used to detect painful sensations. Current pain monitoring is dependent on the subjective rating provided by patients and is limited to a single time point. We have developed a biomarker for the objective, real-time and continuous chronic pain assessment using proprietary algorithms termed ROPA and cerebral optical spectrometry. Using a forehead sensor, the cerebral optical spectrometry data were collected in two clinical sites from 41 patients (19 and 22, respectively, from sites 1 and 2), who elected to receive an epidural steroid injection for the treatment of chronic pain. Patients rated their pain on a numeric rating scale, ranging from 0-10, which were used to validate the ROPA objective pain scoring. Multiple time points, including pre- and post-procedure were recorded. The steroid injection was performed per standard medical practice. There was a significant correlation between the patient's reported numeric rating scale and ROPA, for both clinical sites (Overall ~0.81). Holding the subjective pain ratings on a numeric rating scale as ground truth, we determined that the area under the receiver operator curves for both sites revealed at least good (AUC: 64%) to excellent (AUC > 98%) distinctions between clinically meaningful pain severity differentiations (no/mild/moderate/severe). The objective measure of chronic pain (ROPA) determined using cerebral optical spectrometry significantly correlated with the subjective pain scores reported by the subjects. This technology may provide a useful method of detection for the objective and continuous monitoring and treatment of patients with chronic pain, particularly in clinical circumstances where direct assessment is not available, or to complement the patient-reported pain scores.

Patients with the genetic blistering skin condition epidermolysis bullosa (EB) report severe pain as a consequence of skin and mucous membrane lesions including blisters, wounds, and scars. Adequate symptom alleviation is not often achieved using conventional pharmacologic interventions. Finding novel approaches to pain care in EB is imperative to improve the quality of life of patients living with EB. There are several anecdotal reports on the use of cannabinoid-based medicines (CBMs) by EB patients to reduce the burden of symptoms. However, controlled clinical investigations assessing these reported effects are lacking. As the pain quality "unpleasantness" delineates EB pain, we hypothesize the modulation of affective pain processing in the brain by way of intervention with CBMs comprising the cannabinoids Δ-9-tetrahydrocannabinol and cannabidiol-objectified by functional magnetic resonance imaging (fMRI). The C4EB study is an investigator-initiated, single-centre, randomized, double-blind, placebo-controlled and crossover trial. Adult patients with the diagnosis epidermolysis bullosa, reporting chronic pain will be eligible to participate. Following baseline measurements, participants will be randomized to receive the sublingually administered interventions placebo and Transvamix® in forward or reversed orders, each for two weeks and separated by a washout. The primary outcome is the difference in numeric rating scale pain scores between grouped interventions, using affective descriptors within the Short-form McGill Pain Questionnaire-2. Secondary outcomes include pain self-efficacy, concomitant analgesic medication-use and adverse events. Additionally, fMRI will be employed to assess brain connectivity related to neuroanatomic pain circuits at baseline, placebo and Transvamix® interventions. The study was approved by the ethical committee at the University Medical Center of Groningen in the Netherlands. Results will be submitted for publication in a peer-reviewed journal. Trial registration number: Netherlands Trial Register: NL9347 (Acronym: C4EB).

Psychological pain is a robust predictor of suicide attempts in patients with major depressive disorder (MDD). However, whether suicide and psychological pain share a common neural basis remains unclear. Patients with MDD (n = 64) and healthy controls (HC) (n = 35) were recruited and patients were allocated to two groups: those with a history of suicide attempts (MDD-SA) (n = 25) and those without such a history (MDD-NSA) (n = 39). All participants completed the measurements and underwent functional magnetic resonance imaging to investigate the resting-state static and dynamic brain functional networks in default mode (DMN), central executive (CEN), salience (SN), and basal ganglia (BGN) networks. The MDD-SA group scored higher in pain avoidance than the MDD-NSA and HC groups. Functional connectivity within the dorsal DMN in the MDD-SA group was greater than that in the MDD-NSA and HC groups, and was significantly correlated with pain avoidance and suicide attempts. Dynamic functional connectivity analysis revealed that the proportion of State I in the fraction windows in the MDD-SA group was higher than those in the MDD-NSA and HC groups. Therefore, the increased functional connectivity within the dorsal DMN and segregation of networks may represent potential biological markers for suicide attempts related to psychological pain processing.

Music interventions have been proposed in recent years as a treatment for chronic pain. However, the mechanisms by which music relieves pain are unclear, and the effects of music intervention on physiological indicators in patients with chronic pain remain to be explored. This study aimed to explore whether a music intervention would have effects on subjective pain ratings, heart rate variability, and functional connectivity of the cerebral cortex in patients with chronic pain.

A randomized controlled study was conducted on 37 pain patients aged 18-65 years, with the control group receiving usual care, and the intervention group receiving music intervention (8-150 Hz, 50-70 dB) for 30 min before bedtime for 7 days on top of usual care. Pain visual analog scale and heart rate variability were used as subjective and objective physiological indices before and after the music intervention, respectively. Changes in oxyhemoglobin and deoxyhemoglobin concentrations in the cerebral cortex were measured by functional near-infrared spectroscopy, and whole-brain correlation analysis was used to quantify the connectivity of prefrontal brain regions associated with the pain response.

Results showed that patients with chronic pain in the intervention group had significantly lower visual assessment scale scores, as well as significantly lower overall voluntary mobility during pain episodes, resulting in relatively higher vagal innervation compared to the control group. In addition, connections between the bilateral dorsolateral prefrontal cortex (BA9, BA46) and frontal areas (BA10) were significantly higher in the intervention group.

This study demonstrates the effectiveness of the combined application of music interventions with usual care in reducing pain levels in patients with chronic pain and provides insight into the pathological mechanisms of music interventions for analgesia, providing direction for new baseline indicators for quantitative clinical assessment of pain. The study was registered in the Chinese Clinical Trial Registry (No. ChiCTR2100052993).

[https://www.chictr.org.cn/showproj.aspx?proj=136268], identifier [ChiCTR2100052993].

Neuropathic pain affects 7-10% of the adult population. Being able to accurately monitor biological changes underlying neuropathic pain will improve our understanding of neuropathic pain mechanisms and facilitate the development of novel therapeutics. Positron emission tomography (PET) is a noninvasive molecular imaging technique that can provide quantitative information of biochemical changes at the whole-body level by using radiolabeled ligands. One important biological change underlying the development of neuropathic pain is the overexpression of α2δ-1 subunit of voltage-dependent calcium channels (the target of gabapentin). Thus, we hypothesized that a radiolabeled form of gabapentin may allow imaging changes in α2δ-1 for monitoring the underlying pathophysiology of neuropathic pain. Here, we report the development of two 18F-labeled derivatives of gabapentin (trans-4-[18F]fluorogabapentin and cis-4-[18F]fluorogabapentin) and their evaluation in healthy rats and a rat model of neuropathic pain (spinal nerve ligation model). Both isomers were found to selectively bind to the α2δ-1 receptor with trans-4-[18F]fluorogabapentin having higher affinity. Both tracers displayed around 1.5- to 2-fold increased uptake in injured nerves over the contralateral uninjured nerves when measured by gamma counting ex vivo. Although the small size of the nerves and the signal from surrounding muscle prevented visualizing these changes using PET, this work demonstrates that fluorinated derivatives of gabapentin retain binding to α2δ-1 and that their radiolabeled forms can be used to detect pathological changes in vitro and ex vivo. Furthermore, this work confirms that α2δ-1 is a promising target for imaging specific features of neuropathic pain.

Chronic neuropathic pain (CNP) affects around 10% of the general population and has a significant social, emotional, and economic impact. Current diagnosis techniques rely mainly on patient-reported outcomes and symptoms, which leads to significant diagnostic heterogeneity and subsequent challenges in management and assessment of outcomes. As such, it is necessary to review the approach to a pathology that occurs so frequently, with such burdensome and complex implications. Recent research has shown that imaging methods can detect subtle neuroplastic changes in the central and peripheral nervous system, which can be correlated with neuropathic symptoms and may serve as potential markers. The aim of this paper is to review available imaging methods used for diagnosing and assessing therapeutic efficacy in CNP for both the preclinical and clinical setting. Of course, further research is required to standardize and improve detection accuracy, but available data indicate that imaging is a valuable tool that can impact the management of CNP.

Pain is an unpleasant sensory and emotional experience. Understanding the neural mechanisms of acute and chronic pain and the brain changes affecting pain factors is important for finding pain treatment methods. The emergence and progress of non-invasive neuroimaging technology can help us better understand pain at the neural level. Recent developments in identifying brain-based biomarkers of pain through advances in advanced imaging can provide some foundations for predicting and detecting pain. For example, a neurologic pain signature (involving brain regions that receive nociceptive afferents) and a stimulus intensity-independent pain signature (involving brain regions that do not show increased activity in proportion to noxious stimulus intensity) were developed based on multivariate modeling to identify processes related to the pain experience. However, an accurate and comprehensive review of common neuroimaging techniques for evaluating pain is lacking. This paper reviews the mechanism, clinical application, reliability, strengths, and limitations of common neuroimaging techniques for assessing pain to promote our further understanding of pain.