Frontiers in Human Neuroscience

Part of the multifaceted pathophysiology of Complex Regional Pain syndrome (CRPS) has been ascribed to a lateralized maladaptive neuroplasticity in sensorimotor cortices, a finding that has been corroborated by behavioral studies indicating that CRPS patients indeed present difficulties in mentally representing their painful limb. Hand laterality judgment tasks (HLT) are widely used to measure such difficulties, with the laterality of hand stimuli corresponding to the affected hand judged more slowly than the one of hand stimuli corresponding to the unaffected hand. Importantly, the HLT is also regularly used in the rehabilitation of CRPS and other chronic pain disorders, with the aim to activate motor imagery and, consequently, restoring the cortical representation of the limb. The potential of these tasks to elicit motor imagery is thus critical to their use in therapy. Yet, the influence of the biomechanical constraints (BMC) on HLT reaction time, supposed to reflect the activation of motor imagery, is rarely verified. In the present study we investigated the influence of the BMC on the perception of hand postures and movements. The results of a first experiment, in which a HLT was used, showed that CRPS patients were significantly slower than controls in judging hand stimuli, whether or not the depicted hand corresponded to their affected hand, but that their performance did not differ from controls when they judged non-body stimuli. Results regarding reaction time patterns reflecting the BMC were inconclusive in CRPS and controls, questioning the validity of the task in activating motor imagery processes. In a second experiment we therefore directly investigated the influence of implicit knowledge of upper-limb BMC on perceptual judgments of hand movements with the apparent body movement perception task. Participants judge the perceived path of movement between two depicted hand positions, with only one of the two proposed paths that is biomechanically plausible. While the controls chose the biomechanically plausible path most of the time, CRPS patients did not, indicating that the perception and/or use of the BMC seems to be disturbed in CRPS. These findings show a non-lateralized body representation impairment in CRPS, which might be related to difficulties in using correct knowledge of the bodys biomechanics. Most importantly however, our results, in agreement with previous studies, indicate that it seems highly challenging to measure motor imagery and the indexes of BMC with the classical HLT task, which has important implications for the rehabilitation of chronic pain with these tasks.

Motor imagery is the ability to mentally simulate a motor task without actually performing it. Pain is an unpleasant sensory experience that involves different dimensions - sensory-discriminative, motivational-affective, and cognitive-evaluative - that are known to interfere with motor imagery. However, it remains unclear which specific pain dimension most significantly impairs motor imagery. This study aims to compare the effects of unpleasant auditory (primarily affective and cognitive) and thermal (primarily sensory) stimuli, which can be assimilated to pain, on discrete and continuous explicit motor imagery modalities. Eighteen healthy participants were exposed to unpleasant stimuli in addition to a control condition. Participants rated their motor imagery abilities after tasks involving rest, motor execution, and motor imagery in discrete and continuous wrist movement modalities. Results showed that during discrete motor imagery, only the aversive auditory stimulus significantly reduced motor imagery abilities, whereas thermal pain had no effect. In contrast, motor imagery abilities were preserved during the continuous modality. These findings suggest that explicit motor imagery may be more affected by the affective dimension of pain induced by aversive auditory stimuli. The preservation of motor imagery abilities in the continuous modality provides insight into the optimization of rehabilitation programs.

Embodied interoception refers to the perception of the bodys state and is a multidimensional cognitive process. It is proposed that the experience of pain also feeds interoceptive networks with information from the state of the body, and the subjective experience of pain would be influenced by an individuals trait embodied interoceptive profile. Here we developed and validated the Intero-10, a questionnaire designed to specifically evaluate embodied interoception based on trait interoceptive channels. Healthy adults (n=381) and people with neuropathic pain (n=86) were enrolled. The relationship between trait and state interoceptive responses was examined during experimentally evoked interoceptive psychophysics tasks, which were specific for each interoceptive channel. During these tests, embodied interoceptive state scores only correlated with trait ones for unpleasantness (P<0.05), but not for intensity rating, suggesting that the predicted negative valence of lived experience provided lower prediction errors than intensity estimations. The Intero-10 final version included embodied interoceptive perception intensity (heartbeat, heat, itching, dyspnea, sleep, muscle fatigue, and anguish) and unpleasantness (heartbeat, dyspnea, and nausea) categories. Intero-10 demonstrated adequate content validity, good internal consistency (Cronbachs alpha=0.81), good reliability (>0.75), and a single-factor structure. Patients with neuropathic pain filled in the Intero-10 alongside traditional pain, mood, sleep, and quality of life assessments. Embodied interoception scores correlated with mood, and quality of life, and partially mediated the correlation between pain interference and quality of life ({beta}=-0.0093). The specific assessment of embodied interoceptive channels may broaden our current assessment of people with chronic pain and of those at risk to develop it.

Fibromyalgia (FM) is a chronic condition marked by widespread pain, fatigue, sleep problems, cognitive decline, and other symptoms. Despite extensive research, the pathophysiology of FM remains poorly understood, complicating diagnosis and treatment, which often relies on self-report questionnaires. This study explored structural and functional brain changes in women with FM, identified potential biomarkers, and examined their relationship with FM severity. MRI data from 33 female FM patients and 33 matched healthy controls were utilized, focusing on T1-weighted MRI and resting-state fMRI scans. Functional connectivity (FC) analysis was performed using a machine learning framework to differentiate FM patients from healthy controls and predict FM symptom severity. No significant differences were found in brain structural features, such as gray matter volume, white matter volume, deformation-based morphometry, and cortical thickness. However, significant differences in FC were observed between FM patients and healthy controls, particularly in the default mode network (DMN), somatomotor network (SMN), visual network (VIS), and dorsal attention network (DAN). The FC metrics were significantly associated with FM severity. Our prediction model differentiated FM patients from healthy controls with an area under the curve of 0.65. FC measures accurately estimated FM symptom severities with a significant correlation (r = 0.45, p = 0.007). Functional connections in the DMN, VIS, and DAN were crucial in determining FM severity. These findings suggest that integrating brain FC measurements could serve as valuable biomarkers for early detection of FM and predicting FM symptom severity, improving diagnostic accuracy and facilitating the development of targeted therapeutic strategies.

Fibromyalgia is characterized by widespread musculoskeletal pain accompanied by sleep disturbances and cognitive dysfunction, among other symptoms. Patients frequently report difficulties with memory, but objective assessment of these impairments remains limited. This study aimed to evaluate working memory performance in fibromyalgia patients using two established paradigms: the change detection task, which primarily measures storage capacity, and the n-back task, which assesses both storage and manipulation of information. For the change detection task, the behavioral outcomes assessed were the hit rate, false alarm rate, capacity estimate and response times. The electrophysiological measure evaluated was the contralateral delayed activity. For the n-back, the behavioral outcomes were the same, except for the capacity estimate. Electrophysiologically, the P2 and P3 from the evoked potentials were the outcomes of the task. Behaviorally, results demonstrated that fibromyalgia patients exhibited lower memory capacity than controls (1.90 vs 2.64), in the change detection task, which involved differences in the hit rate and false alarm rate, whereas no behavioral differences were found for the n-back task. In contrast, no differences were found for any of the electrophysiological outcomes in any of the tasks. Taken together, we found evidence supporting a reduction in working memory capacity in fibromyalgia, although it is not reflected in electrophysiological measures.

Reward motivation is essential in shaping human behavior and cognition. Previous studies have shown altered reward motivation and reward brain circuitry in chronic pain conditions, including fibromyalgia. Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain, fatigue, cognitive problems, and mood-related symptoms. In this study, we analyzed brain reward networks in patients with fibromyalgia by using a data-driven approach with task-based fMRI data. fMRI data from 24 patients with fibromyalgia and 24 healthy controls were acquired while subjects performed a monetary incentive delay (MID) reward task. Functional networks were derived using independent component analysis (ICA) focused on the gain anticipation phase of the reward task. Functional activity in the motor, value-driven attention, and basal ganglia networks was evaluated during gain anticipation in both patient and healthy control groups. Compared to controls, the motor network was more engaged during gain anticipation in patients with fibromyalgia. Our findings suggest that reward motivation may lead to hyperactivity in the motor network, possibly related to altered motor processing, such as restricted movement or dysregulated motor planning in fibromyalgia. As an exploratory analysis, we compared levels of motor network engagement during early and late timepoints of the gain anticipation phase. Both groups showed greater motor network engagement during the late timepoint (i.e., closer to response), which reflected motor preparation prior to target response. Importantly, compared to controls and consistent with the initial findings described above, patients exhibited greater engagement of the motor network during both early and late timepoints. In summary, by using a novel data-driven ICA approach to analyze task-based fMRI data, we identified elevated motor network engagement during gain anticipation in fibromyalgia.

Early life adversity (ELA), indexed through Adverse Childhood Experiences (ACEs), is associated with long-term alterations in emotion regulation, stress responsivity, and social learning--factors that may shape learned pain modulation. Social observation in immersive virtual environments offers a powerful way to investigate these mechanisms. To examine whether ELA influences social observation-induced placebo analgesia and empathy responses in immersive and non-immersive contexts. Adults with self-reported low versus high ACE exposure completed an observational learning task in immersive virtual reality (VR) or a non-immersive format. Participants observed Human or Avatar demonstrators experiencing pain relief and then underwent self-pain testing. Measures included socially induced placebo analgesia and affective and cognitive components of state empathy. Individuals with high ACE exposure showed stronger social observation-induced placebo analgesia, particularly within immersive VR. High ACE participants exhibited reduced affective state empathy, while cognitive empathy remained comparable to the low ACE group. Elevated ELA is unexpectedly associated with enhanced responsiveness to socially learned placebo analgesia, especially in immersive VR settings. These findings highlight how early adversity may shape sensitivity to socially transmitted treatment cues, with implications for the design of VR-based therapeutic interventions.

The cognitive mechanisms linking chronic pain to motivational symptoms remain poorly understood. We demonstrate that individuals with chronic temporomandibular disorder (TMD), a common cause of chronic pain, exhibit a specific deficit in adaptive learning in uncertain environments, characterized by failure to reduce uncertainty over time and maintain efficient learning rates. Using a probabilistic reward task, we pioneered the application of a novel volatile Kalman filter to model behavior in 26 TMD participants and 39 matched controls, uniquely tracking trial-wise updates in uncertainty, volatility, and learning rate. Although surface-level performance did not differ across groups, model-based analysis revealed that those with TMD failed to reduce uncertainty and adapt their learning over time. TMD participants also reported significantly greater apathy, depression, and pain catastrophizing, as well as lower health-related quality of life. Mediation analysis confirmed that impaired uncertainty adaptation partially mediated the relationship specifically between TMD and apathy. These findings identify a computational signature of disrupted uncertainty adaptation in people with TMD and provide evidence for a mechanistic link between chronic pain and motivational dysfunction. This work lays a foundation for future studies examining how belief-updating deficits contribute to broader affective and cognitive symptoms in chronic pain.

Over 100 million Americans suffer from chronic pain (CP), which causes more disability than any other medical condition in the U.S. at a cost of $560-$635 billion per year (IOM, 2011). Opioid analgesics are frequently used to treat CP. However, long term use of opioids can cause brain changes such as opioid-induced hyperalgesia that, over time, increase pain sensation. Also, opioids fail to treat complex psychological factors that worsen pain-related disability, including beliefs about and emotional responses to pain. Cognitive behavioral therapy (CBT) can be efficacious for CP. However, CBT generally does not focus on important factors needed for long-term functional improvement, including attainment of personal goals and the psychological flexibility to choose responses to pain. Acceptance and Commitment Therapy (ACT) has been recognized as an effective, non-pharmacologic treatment for a variety of CP conditions. However, little is known about the neurologic mechanisms underlying ACT. We conducted an ACT intervention in women (n=9) with chronic musculoskeletal pain. Functional magnetic resonance imaging (fMRI) data were collected pre- and post-ACT, and changes in functional connectivity (FC) were measured using Network-Based Statistics (NBS). Behavioral outcomes were measured using validated assessments such as the Acceptance & Action Questionnaire (AAQ-II), the Chronic Pain Acceptance Questionnaire (CPAQ), the Center for Epidemiologic Studies Depression Scale (CES-D), and the NIH Toolbox Neuro-QoL (Quality of Life in Neurological Disorders) scales. Results suggest that, following the four-week ACT intervention, participants exhibited reductions in brain activation within and between key networks including self-reflection (default mode, DMN), emotion (salience, SN), and cognitive control (frontal parietal, FPN). These changes in connectivity strength were correlated with changes in behavioral outcomes including decreased depression and pain interference, and increased participation in social roles. This study is one of the first to demonstrate that improved function across the DMN, SN, and FPN may drive the positive outcomes associated with ACT. This study contributes to the emerging evidence supporting the use of neurophysiological indices to characterize treatment effects of alternative and complementary mind-body therapies. PerspectiveThis article identifies neural mechanisms that may mediate behavioral changes associated with Acceptance and Commitment Therapy (ACT) in persons with chronic musculoskeletal pain. This information could potentially help clinicians to determine which mind-body therapies may benefit specific patients as part of an integrative pain management approach.

Transcranial direct current stimulation (tDCS) might modulate neural activity and promote neural plasticity. This factorial randomized clinical trial compared a-tDCS on the left dorsolateral prefrontal cortex (l-DLPFC) or sham (s-tDCS), and a-tDCS or s-tDCS on the primary motor cortex (M1) in the connectivity analyses in eight regions of interest (ROIs) across eight resting-state electroencephalography (EEG) frequencies. We included 48 women with fibromyalgia, aged 30 to 65, randomly assigned to 2:1:2:1 to receive 20 sessions during 20 minutes of a-tDCS 2mA or s-tDCS at home, over l-DLPFC or M1, respectively. EEG recordings were obtained before and after treatment with eyes open (EO) and eyes closed (EC). In the EC condition, comparing pre to post-treatment, the a-tDCS on l-DLPFC decreased the lagged coherence connectivity in the delta frequency band between the right insula and left anterior cingulate cortex (ACC) (t=-3.542, p=.048). The l-DLPFC a-tDCS compared to s-tDCS decreased the lagged coherence connectivity in the delta frequency band between the right insula and left ACC (t=-4.000, p=.017). In the EO condition, the l-DLPFC a-tDCS compared to M1 s-tDCS increased the lagged coherence connectivity between the l-DLPFC and left ACC in the theta band (t=-4.059, p=.048). Regression analysis demonstrated that the a-tDCS effect on the l-DLPFC was positively correlated with sleep quality, while a-tDCS on l-DLPFC and M1 s-tDCS were positively correlated with pain catastrophizing. The application of a-tDCS over the l-DLPFC has modulated the connectivity between various brain regions involved in the affective-attentional aspects of pain, especially at lower EEG frequencies during the resting state. These findings suggest that the effects of a-tDCS on neural oscillations could serve as a neural marker associated with its impact on fibromyalgia symptoms.

BackgroundHigh-frequency (10 Hz) repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex (M1) is used to treat several neuropsychiatric disorders, but its main mechanism of action remains unclear. ObjectiveTo probe four cortical hubs used for rTMS (M1; dorsolateral-prefrontal cortex, DLPFC; anterior cingulate cortex, ACC; posterosuperior insula, PSI) with TMS coupled with high-density electroencephalography (TMS-EEG) and measure cortical excitability and oscillatory dynamics before and after active and sham rTMS to M1. MethodsBefore and immediately after active or sham M1-rTMS (15 min, 3,000 pulses at 10 Hz), single-pulse TMS evoked EEG were recorded at the four targets in 20 healthy individuals. Measures of cortical excitability and oscillatory dynamics were extracted at the main frequency bands ( [8-13 Hz], low-{beta} [14-24 Hz], high-{beta} [25-35 Hz]). ResultsComparing active and sham M1 rTMS, M1 TMS-EEG demonstrated an increase in high-{beta} synchronization in electrodes around M1 stimulation area and remotely in the contralateral hemisphere (p=0.026). The increase in high-{beta} synchronization (48-83 ms after TMS-EEG stimulation) was succeeded by an enhancement in low-{beta} power (86-144 ms after TMS-EEG stimulation) both locally and in the contralateral hemisphere (p=0.006). No significant differences were observed in TMS-EEG responses probing DLPFC, ACC, or PSI. ConclusionM1-rTMS engaged a sequence of enhanced phase synchronization, followed by an increase in power occurring within M1, that spread to remote areas and was measurable after the end of the stimulation session. These results are relevant to understanding the M1 neuroplastic effects of rTMS and associated changes in cortical activity dynamics.

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (Acute Pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (, {beta}1, and {beta}2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, Acute pain decreased -band oscillatory power locally and -band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all P<0.05). The remote (parietal-occipital) decrease in -band phase synchronization during Acute Pain correlated with the cold (P=0.001) and heat pain thresholds (P=0.023) and to local (M1) -band oscillatory power decrease (P=0.024). Over DLPFC, Acute Pain only decreased {beta}1-band power locally compared with non-noxious warm (P=0.015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of and {beta} band oscillations and may have relevance for pain therapies.

There is a long-held belief that physical activities such as lifting with a flexed spine is generally harmful for the back and can cause low back pain (LBP), potentially nurturing fear avoidance beliefs underlying pain-related fear. In chronic LBP patients, pain-related fear has been shown to be associated with reduced lumbar range of motion during lifting, indicating distinct and probably protective psychomotor responses to pain. However, despite short term beneficial effects for tissue health, recent evidence suggests that maintaining a protective trunk movement strategy may also pose a risk for (persistent) LBP due to possible pro-nociceptive consequences of altered spinal kinematics, reflected by increased loading on lumbar tissues and persistent muscle tension. Yet, it is unknown if similar psychomotor interactions already exist in pain-free individuals which would yield potential insights into how a person might react when they experience LBP. Therefore, the aim of this study is to test the impact of pain-related fear on spinal kinematics in a healthy cohort of pain-free adults without a history of chronic pain. The study subjects (N=57) filled out several pain-related fear questionnaires and were asked to perform a lifting task (5kg-box). High-resolution spinal kinematics were assessed using an optical motion capturing system. Time-sensitive analyses were performed based on statistical parametric mapping. The results demonstrated time-specific and negative relationships between self-report measures of pain-related fear and lumbar spine flexion angles during lifting, yielding important implications regarding unfavorable psychomotor interactions that might become relevant in a future LBP incident.

NFL players have a traumatic injury rate approaching 100%; chronic pain with decreased concentration occur commonly. This study examined the role of a novel focused muscle contraction therapy for the treatment of chronic pain and identified its impact on brain activity. Chronic pain was assessed by numerical score, neuropathic component, and impact on daily activities in 8 retired players. Brain activity was characterized by QEEG with low-resolution electromagnetic tomography analysis and functional measures of visual and auditory attention. Focused muscle contraction muscle therapy administered twice weekly for 6 months was tapered to twice monthly by 12 months. Brodmann Areas (BA) 4 and 9, known to associate with chronic pain, showed values outside the clinically normal range; mean pain duration was 16.5 {+/-} 12.9 years. At 6 months, 5/8 subjects reported pain scores of 0. High beta wave activity was seen in BA 19, 21, 29, 30, and 39, affecting auditory, visual, and body perceptions. Clinically relevant improvements were observed in auditory attention and visual stamina. Pain relief was sustained through 18 months of follow-up. Focused muscle contraction therapy appears to redirect brain activity to new areas of activity which are associated with long-lasting relief of chronic pain and its detriments. This study was registered with clinicaltrial.gov #NCT04822311.

IntroductionPost-traumatic headache (PTH) is a common consequence of mild traumatic brain injury (mTBI) that can severely impact an individuals quality of life and rehabilitation. However, the underlying neuropathogenesis mechanisms contributing to PTH are still poorly understood. This study utilized diffusion tensor imaging (DTI) to detect microstructural alterations in the brains of mTBI participants with or at risk of developing PTH. MethodThis study investigated associations between DTI metrics 1-month postinjury and pain sensitivity, as well as psychological assessments 6-months postinjury to identify differences between mTBI (n = 12) and healthy controls (HC; n = 10). MRI scans, including T1-weighted anatomical imaging and DTI were acquired at 1-month postinjury. Pain sensitivity assays included quantitative sensory testing and psychological assessment questionnaires at 1-month and 6-months postinjury. ResultsSignificant aberrations of mean axial diffusivity in the forceps major were observed in mTBI relative to HCs at 1-month postinjury (p =0.02). Within the mTBI group, DTI metrics at 1-month postinjury were significantly associated (ps < 0.05) with pain-related measures and psychological outcomes at 6-month postinjury in several white matter tracts (right sagittal stratum, left anterior thalamic radiation, left corticospinal tract, left insula, left superior longitudinal fasciculus). Notably, the associations between DTI metrics at 1-month postinjury and pain-related measures at 6-month postinjury showed significant group differences in the right sagittal stratum (ps < 0.01), white matter tract in left insula (p < 0.04), and left superior longitudinal fasciculus (ps < 0.05). ConclusionThis study suggests that "Post-Traumatic Stress Disorder for DSM-5" and "Center for Epidemiological Studies-Depression Scale" are the most sensitive psychological measures to early microstructural changes after mTBI, and that the DTI metrics are predictive of pain and psychological measures in mTBI. Together, these results suggest that white matter microstructure plays an important role in the PTH following mTBI.

Fluctuations of chronic pain levels are determined by a complex interplay of cognitive, emotional and perceptual variables. We introduce a pain tracking platform composed of wearable neurotechnology and a smartphone application to measure and predict chronic pain levels. Our method measures, dynamically, pain strength, phenomenal and neural time series collected with an online tool and low-density EEG. Here we used data from a single participant who performed an attention task at home for a period of 20 days to investigate the role of attention to different bodily systems in chronic pain. Our results show a relationship between emotions and pain strength while allocating attention to the heartbeat, the breathing, the affected or the unaffected limb. We found that pain was maximal when attending to the affected limb, and decreased when the participant focused on his breathing or his heartbeat. These results provide interesting insights regarding the role of attention to interoceptive signals in chronic pain. We found power changes in the delta, theta, alpha and beta (but not in the gamma) band between the four attention conditions. However, there was no reliable association of these changes to pain intensity ratings. Theta power was higher when attention was directed to the unaffected limb compared to the others. Further, the pain ratings, when attending to unaffected limb, were associated with alpha and theta power band changes. Overall, we demonstrate that our neurophysiology and experience tracking platform can capture how body attention allocation alters the dynamics of subjective measures and its neural correlates. This research approach is proof of concept for the development of personalized clinical assessment tools and a testbed for behavioural, subjective and biomarkers characterization.

Peripheral magnetic stimulation (PMS) is a noninvasive technique applicable to post-stroke rehabilitation, treatment of phantom limb pain (PLP) and generating neuroprosthetic sensations. Here we aimed to test whether PMS could be utilized to enable sensory feedback from hand prostheses and suppress PLP. Accordingly, we induced somatic sensations with PMS and conducted EEG measurements to assess sensory evoked potentials (SEPs) in 30 able-bodied participants (controls) and 11 individuals with transradial amputation. Single PMS pulses of varying amplitude were applied to the left arm locations overlying the median, radial, and ulnar nerves. Subjective accounts of sensations were collected using PerceptMapper, the University of Pittsburghs multitouch interface. After the best location for PMS was found, continuous stimulation (20 or 40 Hz, delivered in 5-min blocks with 5-7 min interblock intervals for patricipant breaks and EEG setup checks) was applied. The control participants reported experiencing sensations in their hands. The amputees felt sensations in their phantom hands. PMS evoked SEPs in both the controls and amputees. The analysis of intertrial coherence showed significant phase consistency of the stimulus-locked EEG responses across trials for the controls and amputees. The measurements of visual analogue scale (VAS) scale showed that PMS did not change PLP in 2 participants, increased it in 4, and decreased in 3. We propose that PMS could be used to assess the effects of peripheral nerve stimulation on somatic sensations, PLP and cortical activity prior to the surgical placement of electrode implants. Significance StatementPeople with amputation have two critical needs: (1) their prosthetic limbs being augmented with naturalistic somatic sensations, and (2) their PLP, which develops in the majority of cases, being suppressed. Electrical stimulation with peripheral nerve implants offers a solution for both needs, but invasiveness of this procedure poses a number of problems. Here we show that PMS offers a noninvasive tool for testing the effects of peripheral nerve stimulation before any invasive implants are placed. PMS causes somatic sensations, modulates PLP and evokes cortical responses evident in EEG recordings. These effects of PMS were documented in both healthy controls and amputees. The results suggest that PMS combined with EEG measurements could serve as tools for testing potential implantation sites.

Placebo analgesia in chronic pain is a widely studied clinical phenomenon, where expectations about the effectiveness of a treatment can result in substantial pain relief when using an inert treatment agent. While placebos offer an opportunity for non-pharmacological treatment in chronic pain, not everyone demonstrates an analgesic response. Prior research has identified biopsychosocial factors that determine the likelihood of an individual to respond to a placebo, yet generalizability and ecological validity in those studies have been limited due to the inability to account for dynamic personal and treatment effects--which are well-known to play a role. Here, we assessed the potential of using fine-tuned large language models (LLMs) to predict placebo responders in chronic low-back pain using contextual features extracted from patient interviews, as they speak about their lifestyle, pain, and treatment history. We re-analyzed data from two clinical trials where individuals performed open-ended interviews and used these to develop a predictive model of placebo response. Our findings demonstrate that semantic features extracted with LLMs accurately predicted placebo responders, achieving a classification accuracy of 74% in unseen data, and validating with 70% accuracy in an independent cohort. Further, LLMs eliminated the need for pre-selecting search terms or to use dictionary approaches, enabling a fully data-driven approach. This LLM method further provided interpretable insights into psychosocial factors underlying placebo responses, highlighting nuanced linguistic patterns linked to responder status, which tap into semantic dimensions such as "anxiety," "resignation," and "hope." These findings expand on prior research by integrating state-of-art NLP techniques to address limitations in interpretability and context sensitivity of standard methods like bag-of-words and dictionary-based approaches. This method highlights the role of language models to link language and psychological states, paving the way for a deeper yet quantitative exploration of biopsychosocial phenomena, and to understand how they relate to treatment outcomes, including placebo.

BackgroundChronic neuropathic pain is a complex experience, posing a major challenge in personalizing its treatment. Present treatments consist of non-specific, standardized drugs that are often addictive, leaving many patients non-respondent and with significant side effects. Designing individualized therapies requires targeting the multidimensionality of pain and developing objective endpoints to demonstrate their effectiveness. Currently, non-pharmacological alternatives are emerging, such as neurostimulation and Virtual Reality (VR), activating pain relief via peripheral neuromodulation and attention modulation. Similarly to drugs, many neurostimulation approaches are unspecific, targeting areas near the pain site and disregarding the neural pathway of pain. Above all, neurostimulation and VR are yet to be evaluated as a combined synergistic intervention, particularly in a randomized controlled trial (RCT). Methods and FindingsTo this aim, we developed a targeted neurostimulation congruent with immersive VR platform providing a multisensory pain intervention through the synergistic application of somatotopic electro-tactile and visual stimuli. The endpoints included measuring sensory, neurophysiological (EEG), and self-reported indicators of pain. We tested the efficacy of the multisensory intervention against the control consisting of VR-only intervention on four consecutive intervention days in an RCT (N=18 neuropathic patients). The multisensory intervention resulted in a clinically significant reduction of pain (>50%), lasting up to one-week follow-up. The provided analgesic effect was statistically stronger compared to the VR-only control across treatment days and at follow-up. The clinically relevant pain decrease was accompanied with objective improvements in tactile acuity, proprioceptive measures, and changes in EEG pain biomarkers for the multisensory intervention group only. ConclusionsThe developed multisensory treatment showed a clinically significant reductions in self-reported pain, supported by improvements in objective sensory and neurophysiological measures. These results represent a significant advancement in the treatment and assessment of pain, offering a non-invasive, accessible, and cost-effective solution for neuropathic pain, a major societal burden and one of the most prevalent neurological conditions worldwide. Clinical trial registrationThe trial was registered with ClinicalTrial.gov (NCT05483816).

BackgroundComplex Regional Pain Syndrome (CRPS) presents as chronic, continuous pain and sensory, autonomic, and motor abnormalities affecting one or more extremities. People with CRPS can also show changes in their perception of and attention to the affected body part and sensory information in the affected side of space. Prism Adaptation (PA) is a behavioural intervention targeted at reducing attention deficits in post-stroke hemispatial neglect. PA also appears to reduce pain and other CRPS symptoms; however, these therapeutic effects have been demonstrated only in small unblinded studies. This paper describes the protocol for an ongoing double-blind, randomized, sham-controlled clinical trial that will evaluate the efficacy of PA treatment for CRPS. The secondary aims of the study are to examine the relationships between neuropsychological changes (such as spatial attention, space and body representation, and motor spatial performance) and clinical manifestations of CRPS, as well as symptom improvement. MethodsForty-two participants with upper-limb CRPS type I will undergo two weeks of twice-daily PA treatment or sham treatment. The primary outcome measures are current pain intensity and CRPS severity score, measured immediately before and after the treatment period. Secondary outcome measures include the results of self-report questionnaires about pain, movement, symptoms interference, and body representation; clinical assessments of sensory, motor, and autonomic functions; and computer-based psychophysical tests of neuropsychological functions. Data are collected in four research visits: four weeks and one day before treatment, and one day and four weeks after the end of treatment. Additional follow-up through postal questionnaires is conducted three and six months post-treatment. DiscussionIt is hypothesised that participants undergoing PA treatment, compared to those receiving sham treatment, will show greater reduction in pain and CRPS severity score, and improvements on other clinical and neuropsychological measures. Also, more pronounced neuropsychological symptoms are predicted to correlate with more severe clinical CRPS symptoms. This study will provide the first randomized double-blind evaluation of the therapeutic effects of PA that could be implemented as a rehabilitation method for CRPS, and will contribute to the understanding of how neuropsychological changes in body representation and attention pertain to the manifestation and treatment of CRPS.