Pain-related Processes Research Articles

Potential role of remimazolam in alleviating bone cancer pain in mice via modulation of translocator protein in spinal astrocytes

Bone cancer pain (BCP) is a complex clinical challenge, with current treatments often falling short of providing adequate relief. Remimazolam, a benzodiazepine receptor agonist recognized for its anxiolytic effects, has emerged as a potential agent in managing BCP. This study explores the analgesic properties of remimazolam and its interaction with the translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, in spinal astrocytes. In the context of BCP, previous research has indicated that TSPO expression in spinal astrocytes may serve a protective regulatory function in neuropathic pain models. Building on this, the BCP mice received various doses of remimazolam on the 15th day post-inoculation, and pain behavior was assessed over time. The results showed that BCP induced an upregulation of TSPO and astrocyte activation in the spinal dorsal horn, alongside increased extracellular signal-regulated kinase (ERK) signaling and inflammatory cytokine expression. Remimazolam administration resulted in a dose-dependent reduction of pain behaviors, which corresponded with a decrease in both ERK pathway activation and inflammatory factor expression. This suggests that remimazolam's analgesic effects are mediated through its action as a TSPO agonist, leading to the attenuation of neuroinflammation and pain signaling pathways. Importantly, the analgesic effects of remimazolam were reversed by the TSPO antagonist PK11195, underscoring the pivotal role of TSPO in the drug's mechanism of action. This reversal also reinstated the heightened levels of ERK activity and inflammatory mediators, further confirming the involvement of TSPO in the modulation of these pain-related processes. These findings open new avenues for the therapeutic management of bone cancer pain, positioning remimazolam as a promising candidate for further investigation and development.

Placebo effects contribute to brief online mindfulness interventions for chronic pain: results from an online randomized sham-controlled trial.

Mindfulness apps are becoming popular treatments for chronic pain and mental health, despite mixed evidence supporting their efficacy. Furthermore, it is unclear whether improvements in pain are due to mindfulness-specific effects or placebo effects because no trials have compared mindfulness against a sham control. The objective of this study was to compare mindfulness against 2 sham conditions with differing proximity to mindfulness to characterize the relative contributions of mindfulness-specific and nonspecific processes on chronic pain. We assessed changes in pain intensity and unpleasantness and mindfulness-specific and nonspecific pain-related processes in 169 adults with chronic or recurrent pain randomized to receive a single 20-minute online session of mindfulness, specific sham mindfulness, general sham mindfulness, or audiobook control. Mindfulness was not superior to shams for reducing pain intensity or unpleasantness, and no differential engagement of theorized mindfulness-specific processes was observed. However, mindfulness and both shams reduced pain unpleasantness relative to audiobook control, with expectancy most strongly associated with this effect. Sham specificity had no influence on expectancy or credibility ratings, pain catastrophizing, or pain effects. These findings suggest that improvements in chronic pain unpleasantness following a single session of online-delivered mindfulness meditation may be driven by placebo effects. Nonspecific treatment effects including placebo expectancy and pain catastrophizing may drive immediate pain attenuation rather than theorized mindfulness-specific processes themselves. Further research is needed to understand whether mindfulness-specific effects emerge after longer durations of online training.

Effect of stimulation intensity of a differential target multiplexed SCS program in an animal model of neuropathic pain.

Spinal cord stimulation (SCS) has been proven to be an effective treatment for patients suffering from intractable chronic neuropathic pain. Recent advances in the field include the utilization of programs that multiplex various signals to target different neural structures in the dorsal spinal cord associated with the painful area. Preclinical studies have been fundamental in understanding the mechanism by which this differential target multiplexed programming (DTMP) SCS approach works. Transcriptomic- and proteomic-based studies demonstrated that DTMP can modulate expression levels of genes and proteins involved in pain-related processes that have been affected by a neuropathic pain model. This work studied the effect of the intensity of DTMP signals on mechanical hypersensitivity and cell-specific transcriptomes. The spared nerve injury model (SNI) of neuropathic pain was induced in 20 animals which were 1:1 randomized into two SCS groups in which the intensity of the DTMP was adjusted to either 70% or 40% of the motor threshold (MT). SCS was applied continuously for 48 h via a quadripolar lead implanted in the dorsal epidural space of animals. Controls, which included a group of implanted SNI animals that received no SCS and a group of animals naive to the SNI, were assessed in parallel to the SCS groups. Mechanical hypersensitivity was assessed before SNI, before SCS, and at 48 h of SCS. At the end of SCS, the stimulated segment of the dorsal spinal cord was dissected and subjected to RNA sequencing to quantify expression levels in all experimental groups. Differential effects were assessed via fold-change comparisons of SCS and naive groups versus the no-SCS group for transcriptomes specific to neurons and glial cells. Standard statistical analyses were employed to assess significance of the comparisons (p < 0.05). SCS treatments provided significant improvement in mechanical sensitivity relative to no SCS treatment. However, the change in the intensity did not provide a significant difference in the improvement of mechanical sensitivity. DTMP regulated expression levels back toward those found in the naive group in the cell-specific transcriptomes analyzed. There were no significant differences related to the intensity of the stimulation in terms of the percentage of genes in each transcriptome in which expression levels were reversed toward the naive state. DTMP when applied at either 40% MT or 70% MT provided similar reduction of pain-like behavior in rats and similar effects in neuron- and glia-specific transcriptomes.

ID:16469 Transcriptomics of Differential Target Multiplexed SCS Using Reduced Energy in a Model of Neuropathic Pain

Spinal cord stimulation (SCS) utilizing differential target multiplexed programming (DTM SCS) has demonstrated significant improvements in pain-like behavior (mechanical and thermal hypersensitivity) in animal models of neuropathic pain1. DTM SCS has also modulated expression levels of genes associated with pain-related processes toward levels in naïve animals2-4. Preclinical work has been translated successfully to the clinic in patients with chronic neuropathic pain5,6. Although energy demands are well covered by non-rechargeable devices, there are patients that may benefit from reduced energy derivatives of DTM SCS (DTM-RE). The transcriptomics of DTM-RE are presented here.

The Role of Posttraumatic Stress Symptoms on Pain Catastrophizing among Acutely Injured Patients

Posttraumatic symptom severity (PTSS) conveys amplified vulnerability to the development of chronic pain-related processes after physical injury, namely pain catastrophizing (PC) (e.g., magnification of threat, helplessness, and rumination). Yet, early relationships between PTSS and PC in the aftermath of injury remain relatively unexplored. We examined the role of PTSS on PC among emergency department (ED) patients following motor vehicle crash (MVC). Sixty-three injured patients (63% female; 57% nonwhite; average age = 37) with moderate pain (≥ 4 out of 10) were recruited in the EDs of two Level-1 trauma centers within 24 hours post-MVC. In the ED, participants completed assessments regarding pre-injury PTSS and PC (T1PC); acute PTSS stemming from the injury was assessed at 30-days post-injury (T2) and PC was assessed again at 90-days post-injury (T3PC). This study represents secondary data analysis of a randomized clinical trial (NCT03247179) testing whether a smartphone app ("PTSD Coach") may prevent post-injury PTSS; we controlled for group assignment (PTSD Coach vs. standard of care) in all analyses. Most participants (84.1%) had mild injuries and did not require hospitalization. T3PC was higher among non-White versus White subjects. After adjusting for race, sex, group assignment, baseline pain and T1PC, pre-injury PTSS uniquely predicted higher levels of total T3PC (β = 0.50; p < 0.001) and T3PC subscales (magnification of threat, helplessness, and rumination) (ps < 0.01). Similarly, acute PTSS stemming from the MVC uniquely predicted total and subscale T3PC scores (β = 0.64; p < 0.001), even beyond controlling for pre-injury PTSS. These findings extend prior work by highlighting that both pre-injury and acute PTSS are robust predictors of post-injury PC. PTSS can be briefly assessed in the ED to identify high-risk patients, and both PTSS and PC are amenable to intervention; these findings inform early intervention strategies to improve recovery. This work was supported by the Virginia Kaufman Endowment Fund and the University of Pittsburgh Clinical and Translational Science Institute (The Pain Research Challenge Award 2017), and the National Institute of Arthritis and Musculoskeletal Skin Diseases (1 K01 AR073300-01A1).

Effects of spatial attention and limb position on the cortical interaction of bilateral noxious inputs.

Bilateral noxious inputs interact in the brain to provide a better representation of physical threat. In the present study, we investigated the effects of spatial attention and limb position on this interaction. Painful laser stimuli were applied randomly on the right hand or on both hands, while varying spatial attention (focal or overall) and limb position (hands near or far from each other). Pain perception and laser-evoked potentials (N1, N2, P2) were compared between conditions in 27 healthy volunteers. Compared with unilateral stimulation, bilateral stimulation increased pain (p=.004), the N2 (p=.0015) and P2 (p<.001) amplitude. The effects on pain and the P2 were greater when hands were in the near compared with the far position (p<.05). The effect on pain was also greater for overall compared with focal pain rating (p=.003). In addition, the N1 amplitude was greater for bilateral stimulation when hands were in the far compared with the near position (p=.01). These results show that increased brain responses and pain for bilateral compared with unilateral noxious stimulation are modulated differentially by spatial attention and limb position. This suggests that the integration of noxious inputs occurs through partially independent pain-related processes, that it is modulated by limb position, and that it is partially independent of pain perception. We propose that this is necessary to produce coordinated, flexible and adapted defensive responses.

Dysregulated anterior insula reactivity as robust functional biomarker for chronic pain-Meta-analytic evidence from neuroimaging studies.

Neurobiological pain models propose that chronic pain is accompanied by neurofunctional changes that mediate pain processing dysfunctions. In contrast, meta‐analyses of neuroimaging studies in chronic pain conditions have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta‐analysis combined three different meta‐analytic approaches with stringent study selection criteria for case–control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders. Convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex. Seed‐based resting‐state functional connectivity based on a large publicly available dataset combined with a meta‐analytic task‐based approach identified the anterior insular region as a key node of an extended bilateral insula‐fronto‐cingular network, resembling the salience network. Moreover, the meta‐analytic decoding showed that this region presents a high probability to be specifically activated during pain‐related processes, although we cannot exclude an involvement in autonomic processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.

Chronic jaw pain attenuates neural oscillations during motor-evoked pain

Motor- and pain-related processes separately induce a reduction in alpha and beta power. When movement and pain occur simultaneously but are independent of each other, the effects on alpha and beta power are additive. It is not clear whether this additive effect is evident during motor-evoked pain in individuals with chronic pain. We combined highdensity electroencephalography (EEG) with a paradigm in which motor-evoked pain was induced during a jaw force task. Participants with chronic jaw pain and pain-free controls produced jaw force at 2% and 15% of their maximum voluntary contraction. The chronic jaw pain group showed exacerbated motor-evoked pain as force amplitude increased and showed increased motor variability and motor error irrespective of force amplitude. The chronic jaw pain group had an attenuated decrease in power in alpha and lower-beta frequencies in the occipital cortex during the anticipation and experience of motor-evoked pain. Rather than being additive, motor-evoked pain attenuated the modulation of alpha and beta power, and this was most evident in occipital cortex. Our findings provide the first evidence of changes in neural oscillations in the cortex during motor-evoked jaw pain.

Impact of the Sensory and Sympathetic Nervous System on Fracture Healing in Ovariectomized Mice.

The peripheral nervous system modulates bone repair under physiological and pathophysiological conditions. Previously, we reported an essential role for sensory neuropeptide substance P (SP) and sympathetic nerve fibers (SNF) for proper fracture healing and bone structure in a murine tibial fracture model. A similar distortion of bone microarchitecture has been described for mice lacking the sensory neuropeptide α-calcitonin gene-related peptide (α-CGRP). Here, we hypothesize that loss of SP, α-CGRP, and SNF modulates inflammatory and pain-related processes and also affects bone regeneration during fracture healing under postmenopausal conditions. Intramedullary fixed femoral fractures were set to 28 days after bilateral ovariectomy (OVX) in female wild type (WT), SP-, α-CGRP-deficient, and sympathectomized (SYX) mice. Locomotion, paw withdrawal threshold, fracture callus maturation and numbers of TRAP-, CD4-, CD8-, F4/80-, iNos-, and Arg1-positive cells within the callus were analyzed. Nightly locomotion was reduced in unfractured SP-deficient and SYX mice after fracture. Resistance to pressure was increased for the fractured leg in SP-deficient mice during the later stages of fracture healing, but was decreased in α-CGRP-deficient mice. Hypertrophic cartilage area was increased nine days after fracture in SP-deficient mice. Bony callus maturation was delayed in SYX mice during the later healing stages. In addition, the number of CD 4-positive cells was reduced after five days and the number of CD 8-positive cells was additionally reduced after 21 days in SYX mice. The number of Arg1-positive M2 macrophages was higher in α-CGRP-deficient mice five days after fracture. The alkaline phosphatase level was increased in SYX mice 16 days after fracture. Absence of α-CGRP appears to promote M2 macrophage polarization and reduces the pain threshold, but has no effect on callus tissue maturation. Absence of SP reduces locomotion, increases the pain-threshold, and accelerates hypertrophic callus tissue remodeling. Destruction of SNF reduces locomotion after fracture and influences bony callus tissue remodeling during the later stages of fracture repair, whereas pain-related processes are not affected.

Modulation of neuroglial interactions using differential target multiplexed spinal cord stimulation in an animal model of neuropathic pain.

The development and maintenance of chronic neuropathic pain involves distorted neuroglial interactions, which result in prolonged perturbations of immune and inflammatory response, as well as disrupted synapses and cellular interactions. Spinal cord stimulation (SCS) has proven effective and safe for more than 40 years, but comprehensive understanding of its mode of action remains elusive. Previous work in our laboratory provided evidence that conventional SCS parameters modulate biological processes associated with neuropathic pain in animals. This inspired the development of differential target multiplexed programming (DTMP) in which multiple electrical signals are used for modulating glial cells and neurons in order to rebalance their interactions. This work compares DTMP with both low rate and high rate programming using an animal model of neuropathic pain. The spared nerve injury model was implemented in 48 rats equally randomized into four experimental groups: No-SCS, DTMP, low rate, and high rate. Naive animals (N = 7) served as a reference control. SCS was applied continuously for 48 h and pain-related behavior assessed before and after SCS. RNA from the spinal cord exposed to SCS was sequenced to determine changes in gene expression as a result of injury (No-SCS vs. naïve) and as a result of SCS (SCS vs. No-SCS). Bioinformatics tools (Weighted Gene Co-expression Network Analysis and Gene Ontology Enrichment Analysis) were used to evaluate the significance of the results. All three therapies significantly reduced mechanical hypersensitivity, although DTMP provided statistically better results overall. DTMP also reduced thermal hypersensitivity significantly. RNA-sequencing corroborated the complex effects of nerve injury on the transcriptome. In addition, DTMP provided significantly more effective modulation of genes associated with pain-related processes in returning their expression toward levels observed in naïve, noninjured animals. DTMP provides a more effective way of modulating the expression of genes involved in pain-relevant biological processes associated with neuroglial interactions.

Abstract #4303 Pain-related learning and memory processes are distinctly altered in patients with functional and inflammatory abdominal pain

Abstract #4303 Pain-related learning and memory processes are distinctly altered in patients with functional and inflammatory abdominal pain

Development of a Stimulator for the Characterization of Mechanical-Evoked Pain-Related Supra-Spinal Processing Using BOLD-fMRI in Rodents.

Investigation of pain-related brain processing in animal models is often performed with unspecific stimuli that are not representative of clinically relevant pain phenomena such as punctate hyperalgesia or pressure pain. In order to explore cerebral processing of mechanically evoked pain with functional Magnetic Resonance Imaging (fMRI), a MRI-compatible spatially- and strength-specific mechanical stimulator incorporating either von-Frey filaments or an air-puff system was developed. With this device, mechanical stimuli can be applied to various aspects on the rat hind paw (HP). The mechanical stimulator consists of an electro-pneumatic unit connected to the part delivering the mechanical stimulation (MS) via a non-magnetic spring for punctate MS (using a von-Frey filament) or via a Lure-lock unit for pressure pain (air-puffs). The strengths of stimuli were calibrated against the delivered air pressure and weight exerted on a pressure pad or in vivo. BOLD fMRI was performed in a 9.4T MRI scanner during calibrated MS at increasing air pressure. We observed a linear relationship between air pressure and force. These calibrations provided quantitative, adjustable, precise and reproducible sub- and supra-threshold MS. Changes in brain activation were investigated up to a force of 154g using von-Frey filaments, while the maximum force was 30.9 g for air-puffs. Stimulation demonstrated a significant difference between the two types of MS. Unilateral suprathreshold MS induced strong bilateral brain activation in the areas related to pain processing for both types of MS. However, the patterns of brain activity in subcortical areas evoked by von-Frey MS were different from that evoked by air-puffs. The precise delivery of calibrated and reproducible punctate and static MS allows for the specific assessment of clinically relevant supra-spinal correlates of pain-related processes using BOLD fMRI. A novel device for clinically relevant MS in BOLD fMRI pain studies in rats, providing results that may be directly translated to human pain research.

Synchrony vs. pain in males and females: an examination of differential effects on social bonding in a naturally occurring ritual

ABSTRACT Rituals are thought to bind individuals together. Rituals that are perceived high in pain and behavioral synchrony increase social bonding, but the relative contribution of perceived pain vs. synchrony is unexplored. In addition, gender differences are rarely investigated in experimental studies of ritual, despite known gender differences in ritual participation, emotional processing, social bonding and pain processing. The current study uses data from 137 participants in a naturally occurring high ordeal ritual lasting 10 days. Because all individuals participated in multiple rituals varying in perceived pain and synchrony, it was possible to separate the unique and joint effects in a natural context. We found strong bonding effects for rituals perceived as painful, but not for synchrony. Rituals rated as higher in level of pain (involving cuts, piercings and burns) were associated with greater self-reported social bonding. Gender moderated these effects: Women reported stronger bonding after participating in non-synchronous rituals perceived higher in pain, whereas men reported greater bonding after synchronous activities with more perceived pain. These findings suggest that pain-related processes are a more potent social bonding mechanism than synchrony in naturally occurring high ordeal rituals, but that perceived pain may have different signaling functions depending on the gender of performers.

Acceptance: a factor to consider in persistent pain after neck trauma.

Studies on the interaction between acceptance and pain-related processes after neck trauma are to our knowledge sparse and such treatment strategies are rarely incorporated in management and treatment of posttraumatic neck pain. Thus, the aim of the present study is to investigate how acceptance relates to persistent pain in patients after neck trauma, when controlling for the influence of other psychological factors, trauma characteristics and demographic variables. Consecutive patients with persistent pain and disability after neck trauma (n = 565) were assessed by a multi-professional team at a specialized pain rehabilitation clinic. Separate regression analyses were conducted with three outcomes: pain distribution, pain interference, and pain severity. Predictors were age, sex, education, time since trauma, type of trauma, anxiety, depression, and acceptance. Acceptance was the only factor associated with all outcomes, and patients with lower acceptance displayed more widespread pain and greater interference and severity of pain. The results also showed that higher depression was associated with worse pain interference and severity, whilst anxiety only mattered significantly for pain severity and not for pain interference. Female sex was related to more widespread pain and greater pain interference. Overall acceptance stood out as the most important factor for the different outcomes and lower acceptance was associated with more widespread pain distribution and greater pain interference and severity. The findings of this study add to a growing body of literature confirming that the development of chronicity after neck trauma should be understood as a multidimensional process, best described by a biopsychosocial model. The results also suggest that psychological factors and especially acceptance might be important processes with implications for enhanced recovery after neck trauma.

Some Physiological Mechanisms Functioning in Models of Pain-Related Processes

Psychophysiological sensing of pain is formed due to the activity of a number of neuronal mechanisms. Among the pain-related processes, nociception per se, peripheral sensitization, synaptic plasticity, central sensitization, forming of abnormal excitability, structural reorganization in the respective neuronal networks, modulation of recurrent suppression, and a few other phenomena/processes can be mentioned. Nociception includes the processes of transduction, transmission, spreading, and perception of the pain signals. Transduction of the pain influences is a process of transformation of excessively strong and/or (sometimes) long-lasting mechanical, thermal, or chemical stimuli in electrical spike activity generated in peripheral processes of primary nociceptive sensory neurons. This process is mediated by specific receptor-channel complexes that are expressed exclusively in the nociceptive units; it also includes synaptic transmission to secondary and higher-order neurons of the nociception system and modulation of this transmission in neuron-to-neuron synapses in the nociception ascending pathways. The abnormal excitability, structural reorganization, and modulation of recurrent suppression are especially typical of neuropathic pain. Central sensitization is a phenomenon typical of inflammation-related pain, neuropathic pain, and “functional” pain. Different mechanisms responsible for the formation of pain can be targets for analgesic agents; naturally, elucidation of the mechanisms of antinociceptive effects is critically important. Some aspects of the nociception and antinociception events can, in many cases, be examined only in model experiments on animals. In this review, we describe the classification of the types of pain, mention some particular experimental models of pain, analyze the respective physiological mechanisms acting in such models, and also discussed some advantages and limitations of different experimental approaches used in these models.

Nociceptive Biology of Molluscs and Arthropods: Evolutionary Clues About Functions and Mechanisms Potentially Related to Pain.

Important insights into the selection pressures and core molecular modules contributing to the evolution of pain-related processes have come from studies of nociceptive systems in several molluscan and arthropod species. These phyla, and the chordates that include humans, last shared a common ancestor approximately 550 million years ago. Since then, animals in these phyla have continued to be subject to traumatic injury, often from predators, which has led to similar adaptive behaviors (e.g., withdrawal, escape, recuperative behavior) and physiological responses to injury in each group. Comparisons across these taxa provide clues about the contributions of convergent evolution and of conservation of ancient adaptive mechanisms to general nociceptive and pain-related functions. Primary nociceptors have been investigated extensively in a few molluscan and arthropod species, with studies of long-lasting nociceptive sensitization in the gastropod, Aplysia, and the insect, Drosophila, being especially fruitful. In Aplysia, nociceptive sensitization has been investigated as a model for aversive memory and for hyperalgesia. Neuromodulator-induced, activity-dependent, and axotomy-induced plasticity mechanisms have been defined in synapses, cell bodies, and axons of Aplysia primary nociceptors. Studies of nociceptive sensitization in Drosophila larvae have revealed numerous molecular contributors in primary nociceptors and interacting cells. Interestingly, molecular contributors examined thus far in Aplysia and Drosophila are largely different, but both sets overlap extensively with those in mammalian pain-related pathways. In contrast to results from Aplysia and Drosophila, nociceptive sensitization examined in moth larvae (Manduca) disclosed central hyperactivity but no obvious peripheral sensitization of nociceptive responses. Squid (Doryteuthis) show injury-induced sensitization manifested as behavioral hypersensitivity to tactile and especially visual stimuli, and as hypersensitivity and spontaneous activity in nociceptor terminals. Temporary blockade of nociceptor activity during injury subsequently increased mortality when injured squid were exposed to fish predators, providing the first demonstration in any animal of the adaptiveness of nociceptive sensitization. Immediate responses to noxious stimulation and nociceptive sensitization have also been examined behaviorally and physiologically in a snail (Helix), octopus (Adopus), crayfish (Astacus), hermit crab (Pagurus), and shore crab (Hemigrapsus). Molluscs and arthropods have systems that suppress nociceptive responses, but whether opioid systems play antinociceptive roles in these phyla is uncertain.

Functional Neuroimaging of Nociceptive and Pain-Related Activity in the Spinal Cord and Brain: Insights From Neurovascular Coupling Studies.

Spinal cord and brain processes underlie pain perception, which produces systemic cardiovascular changes. In turn, the autonomic nervous system regulates vascular function in the spinal cord and brain in order to adapt to these systemic changes, while neuronal activity induces local vascular changes. Thus, autonomic regulation and pain processes in the brain and spinal cord are tightly linked and interrelated. The objective of this topical review is to discuss work on neurovascular coupling during nociceptive processing in order to highlight supporting evidence and limitations for the use of cerebral and spinal fMRI to investigate pain mechanisms and spinal nociceptive processes. Work on functional neuroimaging of pain is presented and discussed in relation to available neurovascular coupling studies and related issues. Perspectives on future work are also discussed with an emphasis on differences between the brain and the spinal cord and on different approaches that may be useful to improve current methods, data analyses and interpretation. In summary, this review highlights the lack of data on neurovascular coupling during nociceptive stimulation and indicates that hemodynamic and BOLD responses measured with fMRI may be biased by nonspecific vascular changes. Future neuroimaging studies on nociceptive and pain-related processes would gain further understanding of neurovascular coupling in the brain and spinal cord and should take into account the effects of systemic vascular changes that may affect hemodynamic responses. Anat Rec, 301:1585-1595, 2018. © 2018 Wiley Periodicals, Inc.

Grey matter alterations in migraine: A systematic review and meta-analysis.

ObjectivesTo summarize and meta-analyze studies on changes in grey matter (GM) in patients with migraine. We aimed to determine whether there are concordant structural changes in the foci, whether structural changes are concordant with functional changes, and provide further understanding of the anatomy and biology of migraine.MethodsWe searched PubMed and Embase for relevant articles published between January 1985 and November 2015, and examined the references within relevant primary articles. Following exclusion of unsuitable studies, meta-analysis were performed using activation likelihood estimation (ALE).ResultsEight clinical studies were analyzed for structural changes, containing a total of 390 subjects (191 patients and 199 controls). Five functional studies were enrolled, containing 93 patients and 96 controls. ALE showed that the migraineurs had concordant decreases in the GM volume (GMV) in the bilateral inferior frontal gyri, the right precentral gyrus, the left middle frontal gyrus and the left cingulate gyrus. GMV decreases in right claustrum, left cingulated gyrus, right anterior cingulate, amygdala and left parahippocampal gyrus are related to estimated frequency of headache attack. Activation was found in the somatosensory, cingulate, limbic lobe, basal ganglia and midbrain in migraine patients.ConclusionGM changes in migraineurs may indicate the mechanism of pain processing and associated symptoms. Changes in the frontal gyrus may predispose a person to pain conditions. The limbic regions may be accumulated damage due to the repetitive occurrence of pain-related processes. Increased activation in precentral gyrus and cingulate opposed to GMV decrease might suggest increased effort duo to disorganization of these areas and/or the use of compensatory strategies involving pain processing in migraine. Knowledge of these structural and functional changes may be useful for monitoring disease progression as well as for therapeutic interventions.

Systemic blood pressure alters cortical blood flow and neurovascular coupling during nociceptive processing in the primary somatosensory cortex of the rat

Inference on nociceptive and pain-related processes from functional magnetic resonance imaging is made with the assumption that the coupling of neuronal activity and cerebral hemodynamic changes is stable. However, since nociceptive stimulation is associated with increases in systemic arterial pressure, it is essential to determine whether this coupling remains the same during different levels of nociception and pain. The main objective of the present study was to compare the amplitude of local field potentials (LFP) and cerebral blood flow (CBF) changes in the primary somatosensory cortex during nociceptive electrical stimulation of the contralateral or ipsilateral forepaw in isoflurane-anesthetized rats, while manipulating mean arterial pressure (MAP). MAP changes induced by nociceptive stimulation were manipulated by transecting the spinal cord at the upper thoracic segments (T1–T2), which interrupts sympathetic pathways and prevents nociception-related MAP increases, while sensory pathways between the forepaws and the brain remain intact. Intensity-dependent increases in MAP and CBF were observed and these effects were abolished or significantly decreased after spinal transection (p<0.001 and p<0.05, respectively). In contrast, the intensity-dependent changes in LFP amplitude were decreased for the contralateral stimulation but increased for the ipsilateral stimulation after spinal transection (p<0.05). Thus, neurovascular coupling was altered differently by stimulus-induced MAP changes, depending on stimulus intensity and location. This demonstrates that CBF changes evoked by nociceptive processing do not always match neuronal activity, which may lead to inaccurate estimation of neuronal activity from hemodynamic changes. These results have important implications for neuroimaging of nociceptive and pain-related processes.

Pain-Related Suppression of Beta Oscillations Facilitates Voluntary Movement.

Increased beta oscillations over sensorimotor cortex are antikinetic. Motor- and pain-related processes separately suppress beta oscillations over sensorimotor cortex leading to the prediction that ongoing pain should facilitate movement. In the current study, we used a paradigm in which voluntary movements were executed during an ongoing pain-eliciting stimulus to test the hypothesis that a pain-related suppression of beta oscillations would facilitate the initiation of a subsequent voluntary movement. Using kinematic measures, electromyography, and high-density electroencephalography, we demonstrate that ongoing pain leads to shorter reaction times without affecting the kinematics or accuracy of movement. Reaction time was positively correlated with beta power prior to movement in contralateral premotor areas. Our findings corroborate the view that beta-band oscillations are antikinetic and provide new evidence that pain primes the motor system for action. Our observations provide the first evidence that a pain-related suppression of beta oscillations over contralateral premotor areas leads to shorter reaction times for voluntary movement.