Oral Delta-9-Tetrahydrocannabinol (THC) Increases Parasympathetic Activity and Supraspinal Conditioned Pain Modulation in Chronic Neuropathic Pain Male Patients: A Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Disordered autonomic nervous system regulation and supraspinal pain inhibition have been repeatedly described in chronic pain. We aimed to explore the effects of δ-9-tetrahydrocannabinol (THC), an emerging treatment option, on autonomic nervous system and central pain modulation measures in patients with chronic pain. METHODS: Twelve male patients with chronic radicular neuropathic pain participated in a randomized, double-blind, crossover, placebo-controlled, single-administration trial. Low/high frequency (LF/HF) heart rate variability (HRV) ratio and conditioned pain modulation (CPM) response were measured and resting-state functional magnetic resonance imaging (MRI) was performed at baseline and after sublingual administration of either 0.2 mg/kg oral THC or placebo. RESULTS: THC significantly reduced the LF/HF ratio compared with placebo (interaction effect F(1,11) = 20.5; p < 0.005) and significantly improved CPM responses (interaction effect F(1,9) = 5.2; p = 0.048). The THC-induced reduction in LF/HF ratio correlated with increased functional connectivity between the rostral ventrolateral medulla and the dorsolateral prefrontal cortex [T(10) = 6.4, cluster p-FDR < 0.005]. CONCLUSIONS: THC shifts the autonomic balance towards increased parasympathetic tone and improves inhibitory pain mechanisms in chronic pain. The increase in vagal tone correlates with connectivity changes in higher-order regulatory brain regions, suggesting THC exerts top-down effects. These changes may reflect a normalizing effect of THC on multiple domains of supraspinal pain dysregulation. CLINICAL TRIAL REGISTRY NUMBER: NCT02560545.

How Sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel Review.

Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal.

The brainstem's red nucleus was evolutionarily upgraded to support goal-directed action.

The red nucleus is a large brainstem structure that coordinates limb movement for locomotion in quadrupedal animals (Basile et al., 2021). The humans red nucleus has a different pattern of anatomical connectivity compared to quadrupeds, suggesting a unique purpose (Hatschek, 1907). Previously the function of the human red nucleus remained unclear at least partly due to methodological limitations with brainstem functional neuroimaging (Sclocco et al., 2018). Here, we used our most advanced resting-state functional connectivity (RSFC) based precision functional mapping (PFM) in highly sampled individuals (n = 5) and large group-averaged datasets (combined N ~ 45,000), to precisely examine red nucleus functional connectivity. Notably, red nucleus functional connectivity to motor-effector networks (somatomotor hand, foot, and mouth) was minimal. Instead, red nucleus functional connectivity along the central sulcus was specific to regions of the recently discovered somato-cognitive action network (SCAN; (Gordon et al., 2023)). Outside of primary motor cortex, red nucleus connectivity was strongest to the cingulo-opercular (CON) and salience networks, involved in action/cognitive control (Dosenbach et al., 2007; Newbold et al., 2021) and reward/motivated behavior (Seeley, 2019), respectively. Functional connectivity to these two networks was organized into discrete dorsal-medial and ventral-lateral zones. Red nucleus functional connectivity to the thalamus recapitulated known structural connectivity of the dento-rubral thalamic tract (DRTT) and could prove clinically useful in functionally targeting the ventral intermediate (VIM) nucleus. In total, our results indicate that far from being a 'motor' structure, the red nucleus is better understood as a brainstem nucleus for implementing goal-directed behavior, integrating behavioral valence and action plans.

A developmental framework for understanding the influence of sex and gender on health: Pediatric pain as an exemplar.

Sex differences are a robust finding in many areas of adult health, including cardiovascular disease, psychiatric disorders, and chronic pain. However, many sex differences are not consistently observed until after the onset of puberty. This has led to the hypothesis that hormones are primary contributors to sex differences in health outcomes, largely ignoring the relative contributions of early developmental influences, emerging psychosocial factors, gender, and the interaction between these variables. In this paper, we argue that a comprehensive understanding of sex and gender contributions to health outcomes should start as early as conception and take an iterative biopsychosocial-developmental perspective that considers intersecting social positions. We present a conceptual framework, informed by a review of the literature in basic, clinical, and social science that captures how critical developmental stages for both sex and gender can affect children's health and longer-term outcomes. The literature on pediatric chronic pain is used as a worked example of how the framework can be applied to understanding different chronic conditions.

Weak Relationships Between Psychological Factors and Experimental Pain Outcomes in Pain-Free Individuals: An Aggregate Analysis of 8 Studies.

Although psychological factors such as anxiety, depression, and pain catastrophizing are known to influence pain outcomes in chronic pain populations, there are mixed results regarding whether they influence experimental pain outcomes in pain-free individuals. The objectives of this study were to determine the associations between psychological factors and experimental pain outcomes in pain-free adolescents and adults. Relationships between anxiety, depression, and pain catastrophizing and experimental pain outcomes across 8 different studies (total N = 595) were examined in different populations of pain-free adult and adolescent participants. Analyses were conducted with and without controlling for sex, age, and race. Studies were analyzed separately and as part of an aggregate analysis. Individual study analyses resulted in 136 regression models. Of these, only 8 models revealed a significant association between psychological factors and pain outcomes. The significant results were small and likely due to Type 1 error. Controlling for demographic factors had minimal effect on the results. The aggregate analyses revealed weak relationships between anxiety and pressure pain threshold (Fisher's z = -.10 [-.19, -.01]), anxiety and cold pain intensity ratings (Fisher's z = .18 [.04, .32]), and pain catastrophizing and pressure pain threshold (Fisher's z = -.14 [-.26, -.02]). Sample size calculations based on the aggregate analyses indicated that several hundred participants would be required to detect true relationships between these psychological factors and pain measures. The overall negative findings suggest that in pain-free individuals, anxiety, depression, and pain catastrophizing are not meaningfully related to experimental pain outcomes. PERSPECTIVE: Psychological variables have been shown to predict pain outcomes in chronic pain populations but these relationships may not generalize to pain-free populations. An analysis of 595 pain-free individuals across 8 studies in our lab revealed that anxiety, depression, and pain catastrophizing were not meaningfully related to experimental pain outcomes.

Harnessing the conditioned pain modulation response in migraine diagnosis, outcome prediction, and treatment-A narrative review.

OBJECTIVE: To present the potential use and relevance of the conditioned pain modulation (CPM) response to migraine diagnosis, outcome prediction, and treatment. BACKGROUND: The CPM response is a widely used laboratory test to examine inhibitory pain modulation capabilities. METHODS: This narrative review summarizes and synthesizes the findings on the CPM response in patients with migraine. RESULTS: For diagnosis, we summarized the studies comparing CPM responses between patients with migraine and individuals without migraine or with other headache syndromes, as well as between patients with subtypes of migraine. For prediction, we summarized the studies utilizing the CPM response to predict migraine outcome, such as response to interventions. For treatment, we described a device that utilizes the CPM response for acute and preventative migraine treatment. In addition, we suggest the requirements needed for the CPM response to be used for migraine diagnosis, outcome prediction, and treatment. CONCLUSIONS: Although more research is needed, the CPM response could be a useful tool for improving migraine management.

Communication of pain intensity and unpleasantness through magnitude ratings: Influence of scale type, but not gender of the participant.

BACKGROUND: A critical aspect for most human pain research is the ability of participants to communicate their first-person, experiential perspective to a third-person observer. This communication is frequently accomplished via pain ratings. The scale type can influence the communication of pain experiences and can contribute to gender differences in pain. This study examined the role of gender on pain ratings using noxious and innocuous stimuli across two types of rating scales. METHODS: Healthy participants (n = 46) underwent noxious heat, auditory and visual stimulation paradigms. Pain intensity and unpleasantness ratings were collected using the visual analogue scale (VAS) and numerical rating scale (NRS). To determine if one rating scale allows a better report of small differences between different stimulus intensities, the sensitivity to small differences was calculated. RESULTS: Significant effects for rating scale were found for all stimulus modalities (noxious heat, auditory and visual, p < 0.001) with higher intensity and unpleasantness ratings for the NRS compared to the VAS. Overall, no effects of gender or interactions with gender were found. No differences in rating scale and gender were detected for sensitivity to small differences between stimuli. CONCLUSIONS: These findings confirm differences in rating scale usage; however, the different usage might not contribute significantly to gender differences in pain. SIGNIFICANCE: There are differences in the usage of rating scales in which ratings for auditory, visual and noxious somatosensory stimuli are higher with NRS compared to VAS. Choosing a rating scale for research or clinical use should take this different item functioning into account.

Alterations in pain during adolescence and puberty.

During adolescence and puberty, alterations in pain, both experimental and clinical, are observed. In addition, adolescents undergo extensive biopsychosocial changes as they transition from childhood to adulthood. However, a better understanding of how the biopsychosocial changes during adolescence impact pain is needed to improve pain management and develop targeted pain interventions for adolescents. This review synthesizes the literature on alterations in pain during adolescence in humans, describes the potential biopsychosocial factors impacting pain during adolescence, and suggests future research directions to advance the understanding of the impact of adolescent development on pain.

Bridging the gap between preclinical scientists, clinical researchers, and clinicians: From animal research to clinical practice.

BACKGROUND: Collaborations amongst researchers and clinicians with complementary areas of expertise enhance knowledge for everyone and can lead to new discoveries. To facilitate these interactions, shared language and a general understanding of how colleagues in different subfields of headache and headache research approach their work are needed. METHODS: This narrative review focuses on research methods applied in animal studies, human studies including clinical trials, and provides an overview of clinical practice. RESULTS: For animal studies, we describe concepts needed to evaluate the quality and relevance of preclinical studies. For human research, fundamental concepts of neuroimaging, quantitative sensory testing, genetic and epidemiological research methods, and clinical research methodology that are commonly used in headache research are summarized. In addition, we provide an understanding of what guides headache clinicians, and summarize the practical approach to migraine management in adults and children. CONCLUSIONS: It is hoped that this review facilitates further dialogue between clinicians and researchers that will help guide future research efforts and implementation of research findings into clinical practice.

Neural mechanisms underlying the conditioned pain modulation response: a narrative review of neuroimaging studies.

ABSTRACT: Processing spatially distributed nociceptive information is critical for survival. The conditioned pain modulation (CPM) response has become a common psychophysical test to examine pain modulation capabilities related to spatial filtering of nociceptive information. Neuroimaging studies have been conducted to elucidate the neural mechanisms underlying the CPM response in health and chronic pain states, yet their findings have not been critically reviewed and synthesized before. This narrative review presents a simplified overview of MRI methodology in relation to CPM assessments and summarizes the findings of neuroimaging studies on the CPM response. The summary includes functional MRI studies assessing CPM responses during scanning as well as functional and structural MRI studies correlating indices with CPM responses assessed outside of the scanner. The findings are discussed in relation to the suggested mechanisms for the CPM response. A better understanding of neural mechanisms underlying spatial processing of nociceptive information could advance both pain research and clinical use of the CPM response as a marker or a treatment target.

Disentangling the roles of circadian rhythms and sleep drive in experimental pain sensitivity.

Differentiating between circadian rhythm and sleep's effect on pain is challenging, as these two systems can be tightly coupled. A recent study by Daguet et al. found that circadian rhythm, rather than sleep drive, significantly contributed to the variability of experimental heat pain sensitivity in humans. These results support chrono-pharmacological approaches to pain management.

To Calibrate or not to Calibrate? A Methodological Dilemma in Experimental Pain Research.

To calibrate or not to calibrate? This question is raised by almost everyone designing an experimental pain study with supra-threshold stimulation. The dilemma is whether to individualize stimulus intensity to the pain threshold / supra-threshold pain level of each participant or whether to provide the noxious stimulus at a fixed intensity so that everyone receives the identical input. Each approach has unique pros and cons which need to be considered to i) accurately design an experiment, ii) enhance statistical inference in the given data and, iii) reduce bias and the influence of confounding factors in the individual study e.g., body composition, differences in energy absorption and previous experience. Individualization requires calibration, a procedure already irritating the nociceptive system but allowing to match the pain level across individuals. It leads to a higher variability of the stimulus intensity, thereby influencing the encoding of "noxiousness" by the central nervous system. Results might be less influenced by statistical phenomena such as ceiling/floor effects and the approach does not seem to rise ethical concerns. On the other hand, applying a fixed (standardized) intensity reduces the problem of intensity encoding leading to a large between-subjects variability in pain responses. Fixed stimulation intensities do not require pre-exposure. It can be proposed that one method is not preferable over another, however the choice depends on the study aim and the desired level of external validity. This paper discusses considerations for choosing the optimal approach for experimental pain studies and provides recommendations for different study designs. PERSPECTIVE: To calibrate pain or not? This dilemma is related to almost every experimental pain research. The decision is a trade-off between statistical power and greater control of stimulus encoding. The article decomposes both approaches and presents the pros and cons of either approach supported by data and simulation experiment.

New insight into the neural mechanisms of migraine in adolescents: Relationships with sleep.

OBJECTIVE: This case-control study examines if measures of subjective and objective (actigraphic) sleep difficulties mediate alterations in amygdalar connectivity in adolescents with migraine compared to healthy adolescents. BACKGROUND: Adolescents with migraine have different functional connectivity of the amygdala compared to individuals without migraine. Sleep is often disturbed in adolescents with migraine, and could contribute to the alterations in functional connectivity. METHODS: Twenty adolescents with migraine and 20 healthy controls were recruited from Cincinnati Children's Hospital. Participants completed surveys about their headaches and overall sleep quality, sleep hygiene, and perceived sleep difficulties (Insomnia Severity Scale [ISI]); completed wrist-worn actigraphy; and underwent a magnetic resonance imaging scan. RESULTS: Adolescents with migraine differed from healthy controls only in perceived difficulty in sleep initiation and maintenance (ISI: 8.5 ± 4.7 and 4.5 ± 3.7 [mean ± standard deviation], -4.00 [95% confidence: -6.7 to -1.3], p = 0.005) and had greater functional connectivity between the amygdala and the posterior cingulate cortex, precuneus, dorsolateral prefrontal, sensorimotor, and the occipital cortexes. The differences in functional connectivity of the amygdala were not mediated by the subjective/objective sleep measures (ISI/wake minutes after sleep onset). CONCLUSIONS: Adolescents with migraine have greater connectivity between the amygdala and areas involved in sensory, affective, and cognitive aspects of pain. These alterations may not be due to higher levels of sleep difficulties in adolescents with migraine, suggesting that both amygdala and sleep alterations may play an independent role in migraine pathophysiology. This advances the understanding of the mechanisms underlying pediatric migraine and can potentially advance migraine management.

Amygdalar functional connectivity during resting and evoked pain in youth with functional abdominal pain disorders.

ABSTRACT: Pediatric functional abdominal pain disorders (FAPD) are highly prevalent, difficult to diagnose, and challenging to treat. The brain systems supporting FAPD remain poorly understood. This investigation examined the neuromechanisms of FAPD during a well-tolerated visceral pain induction task, the water load symptom provocation task (WL-SPT). Youth between the ages of 11 and 17 years participated. Functional connectivity (FC) was examined through the blood oxygenation level-dependent effect using the left and right amygdala (AMY) as seed regions. Relationships of the time courses within these seeds with voxels across the whole brain were evaluated. Arterial spin labeling was used to assess regional brain activation by examining cerebral blood flow. Increased FC between the left AMY with regions associated with nociceptive processing (eg, thalamus) and right AMY FC changes with areas associated with cognitive functioning (dorsolateral prefrontal cortex) and the default mode network (DMN; parietal lobe) were observed in youth with FAPD after the WL-SPT. These changes were related to changes in pain unpleasantness. Amygdala FC changes post-WL-SPT were also related to changes in pain intensity. Amygdala FC with the DMN in youth with FAPD also differed from healthy controls. Global cerebral blood flow changes were also noted between FAPD and healthy controls, but no significant differences in grey matter were detected either between groups or during the WL-SPT in youth with FAPD. Findings confirm youth with FAPD undergo changes in brain systems that could support the development of biomarkers to enhance understanding of the mechanisms of pain and treatment response.

Pain sensitivity does not differ between obese and healthy weight individuals.

INTRODUCTION: There is emerging evidence suggesting a relationship between obesity and chronic pain. OBJECTIVES: The aim of this study was to determine whether pain-free obese individuals display altered pain responses to acute noxious stimuli, thus raising the possibility of greater pain sensitivity and potential susceptibility for chronic pain development. METHODS: Psychophysical and anthropometric data were collected from 38 individuals with an obese body mass index (BMI) classification (BMI ≥ 30) and 41 age/sex-matched individuals of a healthy BMI (BMI < 24.9). Because BMI may be an inaccurate index of obesity, additional anthropometric parameters of central adiposity and percent body fat were examined. Pain responses to suprathreshold noxious heat and cold stimuli were examined. Subjects provided pain intensity and unpleasantness ratings to noxious heat (49°C) applied at varying durations and locations (ventral forearm/lower leg). Cold pain ratings, thresholds, and tolerances were obtained after immersion of the hand in a cold-water bath (0-2°C). Between-group differences in pain responses, as well as relationships between pain responses and obesity parameters, were examined. Importantly, confounds that may influence pain such as anxiety, depression, impulsivity, sleepiness, and quality of life were assessed. RESULTS: No between-group differences in pain sensitivity to noxious heat and cold stimuli were found. No relationships were found between central adiposity or body fat (percentage or distribution) and pain responses to noxious heat or cold stimuli. CONCLUSIONS: Obesity has minimal influence on pain sensitivity. Accordingly, it is unlikely that obesity alone increases susceptibility for chronic pain development through amplification of nociceptive processes.

Identification of neural and psychophysical predictors of headache reduction after cognitive behavioral therapy in adolescents with migraine.

ABSTRACT: Cognitive behavioral therapy (CBT) is a psychological intervention that involves development of coping strategies to reduce the experience of pain. Although CBT is a promising intervention to reduce headache days in patients with migraine, it may not be effective for all patients. Thus, there is a need to identify markers that could predict which patients will respond to CBT. We aimed to determine whether baseline brain function and amygdalar connectivity, assessed by functional magnetic resonance imaging, or pain modulation capacities, assessed by the conditioned pain modulation (CPM) response, can predict a reduction in headache days after CBT in adolescents with migraine. Patients with migraine (n = 20; age range 10-17 years) completed 8 weekly CBT sessions. The CPM response was examined in the trapezius and the leg. Headache days significantly decreased after CBT (P < 0.001). Greater functional connectivity before CBT between the right amygdala and frontal gyrus, anterior cingulate cortex, and precentral gyrus was related to greater headache reduction after CBT. Greater reduction in headache days after CBT was related with less efficient CPM response before CBT at the trapezius (r = -0.492, P = 0.028) but not at the leg. This study found that headache reduction after CBT was related to right amygdala connectivity with frontal and sensorimotor regions at baseline as well as baseline pain modulation capacities. These findings suggest that individual differences in brain function and pain modulation can be associated with clinical improvements and help with determination of CBT responsiveness.

Spatial aspects of pain modulation are not disrupted in adolescents with migraine.

OBJECTIVE: To compare spatial pain modulation capabilities between adolescents with and without migraine. BACKGROUND: Conditioned pain modulation (CPM) responses at the leg are similar in adolescents with versus without migraine. However, the anatomical region of testing may affect spatial pain modulation capabilities as differences in nociceptive processing between patients with migraine and healthy controls are found in local areas that are near the site of clinical pain but not in nonlocal areas. This study aimed to examine spatial pain modulation capabilities tested by the CPM paradigm using test stimulus applied to a local body area. METHODS: Nineteen adolescents with migraine (age 14.9 ± 2.3, mean ± SD; 16 female) and 20 healthy adolescents (age 13.8 ± 2.5, mean ± SD; 16 female) completed this case-control study at Cincinnati Children's Hospital Medical Center. Pressure pain thresholds (PPT) were assessed at the trapezius before and during immersion of the foot in a cold water bath (8°C). RESULTS: In the migraine group (146.0 ± 79.1, mean ± SD), compared to healthy controls (248.0 ± 145.5, mean ± SD), significantly lower PPT (kilopascal) values were found (estimate = 124.28, 95% CI: 58.98, 189.59, p < 0.001; effect size: d = 1.40). No differences between the groups were found for pain intensity and unpleasantness ratings of cold-water immersion nor the CPM response. CONCLUSIONS: This study found altered ascending nociceptive processing of mechanical stimuli at the neck in adolescents with migraine. However, endogenous pain modulatory mechanisms were functional and not altered. In light of other studies, impairments in inhibitory control may not be involved in migraine pathophysiology in pediatric patients regardless of stimulus location.

Alterations in Brain Function After Cognitive Behavioral Therapy for Migraine in Children and Adolescents.

OBJECTIVES: This basic mechanistic study examined the changes in brain activation and resting-state connectivity after 8 weeks of CBT in youth with migraine. BACKGROUND: Cognitive behavioral therapy (CBT) is a psychological intervention that is effective in reducing pain in migraine patients. However, the neural mechanisms underlying CBT in adolescents with migraine are not yet known. METHODS: Eighteen adolescents with migraine (15 females, age 15.1 ± 2.1 years [mean ± SD]) completed 8 weekly CBT sessions. Before the first and after the final CBT session, participants underwent structural and resting-state blood-oxygen-level-dependent contrast MRI scans. Arterial spin labeling was also used to examine brain activation during the resting state. For connectivity analyses, the right and left amygdala were chosen as seed regions. Relationships of the time courses within these seeds with voxels across the whole brain were evaluated. RESULTS: Headache frequency decreased from 15 ± 7.4 headaches per month before CBT to 10 ± 7.4 after CBT (P < .001). After CBT, greater brain activations in frontal regions involved in cognitive regulation of pain were found. In addition, after CBT increased connectivity between the amygdala and frontal regions was observed. Associations between brain activation and amygdalar connectivity with a reduction in headache frequency were also observed. CONCLUSIONS: Alterations in brain function and amygdalar connectivity with areas involved in nociceptive processing, cognitive function, and emotional regulation may underlie the ability of CBT to aid in the prevention of headaches in migraine patients.