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The neural mechanisms responsible for the initiation and expression of migraines remain unknown. Though there is growing evidence of changes in brainstem anatomy and function between attacks, very little is known about brainstem function and structure in the period immediately prior to a migraine. The aim of this investigation is to use brainstem-specific analyses of diffusion weighted images to determine if the brainstem pain processing regions display altered structure in individuals with migraine across the migraine cycle, and in particular immediately prior to a migraine. Diffusion tensor images (29 controls, 36 migraineurs) were used to assess brainstem anatomy in migraineurs compared with controls. We found that during the interictal phase, migraineurs displayed greater mean diffusivity in the region of the spinal trigeminal nucleus, dorsomedial/dorsolateral pons and midbrain periaqueductal gray matter/cuneiform nucleus. Remarkably, the mean diffusivity returned to controls levels during the 24-hour period immediately prior to a migraine, only to increase again within the three following days. Additionally, fractional anisotropy was significantly elevated in the region of the medial lemniscus/ventral trigeminal thalamic tract in migraineurs compared with controls over the entire migraine cycle. These data show that regional brainstem anatomy changes over the migraine cycle, with specific anatomical changes occurring in the 24 hours prior to onset. These changes may contribute to the activation of the ascending trigeminal pathway by either an increase in basal traffic or by sensitising the trigeminal nuclei to external triggers, with activation ultimately resulting in perception of head pain during a migraine attack. It has been hypothesised that modulation of brainstem pain pathways may be critical for the initiation of migraine attacks. There is some evidence that altered brainstem function, possibly involving increased astrocyte activation, occurs immediately prior to a migraine attack. We sought to obtain evidence to support this theory. Using diffusion tensor imaging, we found that immediately prior to a migraine, mean diffusivity decreased in the spinal trigeminal nucleus, dorsomedial/dorsolateral pons and midbrain periaqueductal gray matter/nucleus cuneiform. Mean diffusivity then increased again immediately following the migraine attack. Decreased mean diffusivity before a migraine is consistent with increased astrocyte activation, since astrocyte processes enlarge during activation. These changes may underlie changes in brainstem function that are essential for the generation of a migraine.
Learn More >Epidemiological studies have to a little extent addressed the potential fluctuations of chronic pain over time, and there is a lack of information about the long-term course of pain using repeated measurements. We wanted to identify different trajectories of pain during eight waves of follow-up over four years among individuals in the general population reporting pain lasting at least six months at baseline. Secondarily, we wanted to investigate whether biopsychosocial factors at baseline were associated with the different pain trajectories. Longitudinal Latent Class Analysis (LLCA) was performed to classify 1905 random participants from a larger population-based study (HUNT3) into groups based on their longitudinal pain severity reporting. A five-class solution gave the best fit. The terms chosen to describe the pain trajectories were: "fluctuating" (n = 586 [31 %]), "persistent mild" (n = 449 [24 %]), "persistent moderate" (n = 414 [22 %]), "persistent severe" (n = 251 [13 %]), and "gradual improvement" (n = 205 [11 %]). In a multinomial logistic regression model using "gradual improvement" as the reference category, the "persistent moderate", "persistent severe", and "fluctuating" pain groups were associated with chronic widespread pain (CWP), elevated levels of catastrophizing, and poorer mental health. The "persistent mild" group was associated with sleep difficulties only. This study finds that although most individuals have a stable pain course, individuals in the largest distinct trajectory reports pain that fluctuate between mild and moderate levels, thus fluctuating under and above the chronic pain definition using moderate pain or more as a criterion. Perspective: When examining the long-term course of chronic pain in the general population, five trajectories emerge. Although most individuals have stable pain, the largest distinct trajectory fluctuated under and above the chronic pain cut-off, using moderate pain or more as a criterion. A dichotomous categorization of chronic pain may be overly simplistic.
Learn More >Specific components of physical activity, such as vigorous exercise and heavy occupational work, are known to increase the risk of chronic low back pain (CLBP) and knee pain (CKP), but impacts of other components are less known. This study aimed to assess the relationship between total physical activity and risk of CLBP and CKP from a public health perspective.
Learn More >Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-G signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and G coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.
Learn More >To investigate the outcomes 1 year after multimodal rehabilitation programmes in primary care for patients with chronic pain, both as a whole and for men and women separately. A second aim was to identify predictive factors for not being on sickness absence at follow-up after 1 year.
Learn More >Migraine with aura (MwA) is associated with increased brain hyper-responsiveness to visual stimuli and increased visual network connectivity relative to migraine without aura (MwoA). Despite this, prior studies have provided conflicting results regarding whether MwA is associated with higher photophobia symptom scores compared to MwoA. The relationships between MwA and other types of sensory hypersensitivity, such as phonophobia and cutaneous allodynia (CA), have not been previously investigated. The purpose of this cross-sectional observational study was to investigate whether MwA is associated with greater symptoms of photophobia, phonophobia, and CA compared to MwoA.
Learn More >Intense or sustained activation of peripheral nociceptors can induce central sensitization. This enhanced responsiveness to nociceptive input of the central nervous system primarily manifests as an increased sensitivity to painful mechanical pinprick stimuli extending beyond the site of injury (secondary mechanical hyperalgesia) and is thought to be a key mechanism in the development of chronic pain, such as persistent post-operative pain. It is increasingly recognized that emotional and cognitive factors can strongly influence the pain experience. Furthermore, through their potential effects on pain modulation circuits including descending pathways to the spinal cord, it has been hypothesized that these emotional and cognitive factors could constitute risk factors for the susceptibility to develop chronic pain. Here, we tested whether, in healthy volunteers, the experimental induction of central sensitization by peripheral nociceptive input can be modulated by selective spatial attention. While participants performed a somatosensory detection task that required focusing attention towards one of the forearms, secondary hyperalgesia was induced at both forearms using bilateral and simultaneous high-frequency electrical stimulation (HFS) of the skin. HFS induced an increased sensitivity to mechanical pinprick stimuli at both forearms, directly (T1) and 20 min (T2) after HFS, confirming the successful induction of secondary hyperalgesia at both forearms. Most importantly, at T2, the HFS-induced increase in pinprick sensitivity as well as the area of secondary hyperalgesia was greater at the attended arm as compared to the non-attended arm. This indicates that top-down attentional factors can modulate the development of central sensitization by peripheral nociceptive input, and that the focus of spatial attention, besides its modulatory effects on perception, can affect activity-dependent neuroplasticity.
Learn More >Benefits of primary care provider (PCP) participation in pain management telementoring have been reported; however, no studies have examined within-patient changes in dose or discontinuation of long-term opioid therapy (LOT). The objectives of this nonrandomized study were to evaluate the relationship between telementoring participation and 1) LOT dose reduction and 2) LOT discontinuation and to 3) explore the relationship between LOT dose changes and patient-reported outcomes.
Learn More >The opioid-related behaviours in treatment (ORBIT) scale are a measure of recent indicators of potential extra-medical opioid use. Indicators of potential extra-medical opioid use are divergent practices among people prescribed opioids that may place them at risk of harm. This study aimed to examine the correlates of indicators of potential extra-medical opioid use in people prescribed opioids for chronic non-cancer pain (CNCP).
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