Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Modulatory Network

Central sensitization is a driving mechanism in many chronic pain patients, and manifests as hyperalgesia and allodynia beyond any apparent injury. Recent studies have demonstrated analgesic effects of motor cortex (M1) stimulation in several chronic pain disorders, yet its neural mechanisms remain uncertain. We evaluated whether anodal M1 transcranial direct current stimulation (tDCS) would mitigate central sensitization as measured by indices of secondary hyperalgesia. We used a capsaicin-heat pain model to elicit secondary mechanical hyperalgesia in 27 healthy subjects. In an assessor and subject-blind randomized, sham-controlled, crossover trial, anodal M1 tDCS decreased the intensity of pinprick hyperalgesia more than cathodal or sham tDCS. To elucidate the mechanism driving analgesia, subjects underwent fMRI of painful mechanical stimuli prior to and following induction of the pain model, after receiving M1 tDCS. We hypothesized that anodal M1 tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical stimuli. Anodal tDCS normalized the effects of central sensitization on neurophysiological responses to mechanical pain in the medial prefrontal cortex, pregenual anterior cingulate cortex, and periaqueductal gray, important regions in the DPM network. Taken together, these results provide support for the hypothesis that anodal M1-tDCS reduces central sensitization-induced hyperalgesia through the DPM network in humans

Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex

Introduction: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). Methods: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN. Results: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free\u3epain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection\u27s FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction Conclusion: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions

Biological sex influences psychological aspects of the biopsychosocial model related to chronic pain intensity and interference among South Korean patients with chronic secondary musculoskeletal pain in rheumatic diseases

IntroductionPain is a prominent contributor to negative personal and social outcomes, including increased disability and mortality, in many rheumatic diseases. In the Biopsychosocial model of chronic pain, psychological and social factors share roles with the biology of the injury in determining each patient’s pain and suffering. The current study explored factors associated with clinical pain intensity and interference among patients with chronic secondary musculoskeletal pain in rheumatic diseases.MethodsIn total, 220 patients experiencing chronic secondary musculoskeletal pain participated. Biological factors (age, biological sex, pain condition, pain duration, pain sensitivity, and comorbidity), socio-economic factors, psychological factors (pain catastrophizing and depressive symptoms), and pain intensity and interference were measured. Descriptive, multivariable linear regression and partial correlation analyses were conducted. Subgroup analysis by sex was conducted to examine differences in how different factors affect the pain experience.ResultsThe mean age of the participants was 52.3 years (SD = 12.07) and ranged from 22 to 78. Average pain intensity was 3.01 (0–10 scale) and average total pain interference score was 21.07 (0–70 scale). Partial correlation found positive correlations between pain intensity and interference with depression (intensity: R = 0.224; p = 0.0011; interference: R = 0.351; p < 0.001) and pain catastrophizing (intensity: R = 0.520; p < 0.001; interference: R = 0.464; p < 0.001). In males, pain condition (β = −0.249, p = 0.032) and pain catastrophizing (R = 0.480, p < 0.001) were associated with pain intensity. In males, the simple correlation between pain intensity and depression (R = 0.519; p < 0.001) was driven by pain catastrophizing. In females, pain catastrophizing (R = 0.536, p < 0.001) and depressive symptoms (R = 0.228, p = 0.0077) were independently associated with pain intensity. Age (β = −0.251, p = 0.042) and pain catastrophizing (R = 0.609, p < 0.001) were associated with pain interference in males, while depressive symptoms (R = 0.439, p < 0.001) and pain catastrophizing (R = 0.403, p < 0.001) were associated with pain interference in females. Again, in males, the simple correlation between pain interference and depression (R = 0.455; p < 0.001) was driven by pain catastrophizing.DiscussionIn this study, females were more directly affected by depressive symptoms than males, regarding pain intensity and interference. Pain catastrophizing was a significant factor influencing chronic pain for both males and females. Based on these findings, a sex-specific approach to the Biopsychosocial model should be considered in understanding and managing pain among Asians with chronic secondary musculoskeletal pain

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement

Background: Low intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation (tACS or tDCS), applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional magnetic resonance imaging (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. Objective: To develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency, and reproducibility (ContES Checklist). Methods: A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists (EP) through the International Network of the tES-fMRI (INTF) Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC based on a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed using the checklist. Results: Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (1) technological factors, (2) safety and noise tests, and (3) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. Conclusions: Use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies, and increase methodological transparency and reproducibility

Table_1_Biological sex influences psychological aspects of the biopsychosocial model related to chronic pain intensity and interference among South Korean patients with chronic secondary musculoskeletal pain in rheumatic diseases.xlsx

IntroductionPain is a prominent contributor to negative personal and social outcomes, including increased disability and mortality, in many rheumatic diseases. In the Biopsychosocial model of chronic pain, psychological and social factors share roles with the biology of the injury in determining each patient’s pain and suffering. The current study explored factors associated with clinical pain intensity and interference among patients with chronic secondary musculoskeletal pain in rheumatic diseases.MethodsIn total, 220 patients experiencing chronic secondary musculoskeletal pain participated. Biological factors (age, biological sex, pain condition, pain duration, pain sensitivity, and comorbidity), socio-economic factors, psychological factors (pain catastrophizing and depressive symptoms), and pain intensity and interference were measured. Descriptive, multivariable linear regression and partial correlation analyses were conducted. Subgroup analysis by sex was conducted to examine differences in how different factors affect the pain experience.ResultsThe mean age of the participants was 52.3 years (SD = 12.07) and ranged from 22 to 78. Average pain intensity was 3.01 (0–10 scale) and average total pain interference score was 21.07 (0–70 scale). Partial correlation found positive correlations between pain intensity and interference with depression (intensity: R = 0.224; p = 0.0011; interference: R = 0.351; p DiscussionIn this study, females were more directly affected by depressive symptoms than males, regarding pain intensity and interference. Pain catastrophizing was a significant factor influencing chronic pain for both males and females. Based on these findings, a sex-specific approach to the Biopsychosocial model should be considered in understanding and managing pain among Asians with chronic secondary musculoskeletal pain.</p

A Cross-Sectional Time Course of COVID-19 Related Worry, Perceived Stress, and General Anxiety in the Context of Post-Traumatic Stress Disorder-like Symptomatology

The COVID-19 pandemic within the United States of America resulted in over 800,000 deaths as of February 2022 and has been addressed by social distancing or stay-at-home measures. Collective prolonged multimodal trauma on this scale is likely to elicit symptomatology in the general population consistent with post-traumatic stress disorder (PTSD), somatization, anxiety, and stress. The psychological component of this response contributes substantially to the burden of this disease worldwide. This cross-sectional study examines the relationship between COVID-19-related concern, anxiety, and perceived stress on PTSD-like symptomatology over the course of the COVID-19 pandemic. Participants were recruited via social media within the United States of America between 8th May 2020 and 11th August 2021 to complete an internet questionnaire including mood, personality, and COVID-19-specific scales. General anxiety and PTSD-like symptomatology were above the screening cutoffs for most respondents. These measures increased in severity over the pandemic, with the change point of our Concern scale preceding that of the other significant measures. Measures of COVID-19-related concern, generalized anxiety, and PTSD-like symptomatology were strongly correlated with each other. Anxiety, perceived stress, and PTSD-like symptomatology are strongly interrelated, increase with pandemic length, and are linked to reported levels of concern over COVID-19. These observations may aid future research and policy as the pandemic continues