Accepted

Calcitonin gene related peptide (CGRP) plays a key role in the pathophysiology of migraine and is therefore considered a potential biomarker for primary headache disorders. The challenge remaining is establishing standardized protocols for its assessment in various extracellular compartments and identifying pathological situations associated with an increase in CGRP.

The cerebellum is associated with the biology of migraine in a variety of ways. Clinically, symptoms such as fatigue, motor weakness, vertigo, dizziness, difficulty concentrating and finding words, nausea, and visual disturbances are common in different types of migraine. The neural basis of these symptoms is complex, not completely known, and likely involve activation of both specific and shared circuits throughout the brain. Posterior circulation stroke, or neurosurgical removal of posterior fossa tumors, as well as anatomical tract tracing in animals, provided the first insights to theorize about cerebellar functions. Nowadays, with the addition of functional imaging, much progress has been done on cerebellar structure and function in health and disease, and, as a consequence, the theories refined. Accordingly, the cerebellum may be useful but not necessary for the execution of motor, sensory or cognitive tasks, but, rather, would participate as an efficiency facilitator of neurologic functions by improving speed and skill in performance of tasks produced by the cerebral area to which it is reciprocally connected. At the subcortical level, critical regions in these processes are the basal ganglia and thalamic nuclei. Altogether, a modulatory role of the cerebellum over multiple brain regions appears compelling, mainly by considering the complexity of its reciprocal connections to common neural networks involved in motor, vestibular, cognitive, affective, sensory, and autonomic processing-all functions affected at different phases and degrees across the migraine spectrum. Despite the many associations between cerebellum and migraine, it is not known whether this structure contributes to migraine initiation, symptoms generation or headache. Specific cerebellar dysfunction genetically driven excitatory/inhibitory imbalances, oligemia and/or increased risk to white matter lesions has been proposed as a critical contributor to migraine pathogenesis. Therefore, given that neural projections and functions of many brainstem, midbrain and forebrain areas are shared between the cerebellum and migraine trigeminovascular pathways, this review will provide a synopsis on cerebellar structure and function, its role in trigeminal pain, and an updated overview of relevant clinical and preclinical literature on the potential role of cerebellar networks in migraine pathophysiology.

Fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain condition characterized by widespread pain, sleep problems (i.e., insomnia and unrefreshing sleep), fatigue, cognitive, and emotional difficulties. Although pain has been proposed the factor mostly impacting in the FMS patients' function, emotional and psychological FMS-associated factors are also known to exert a negative impact in quality of life and functional capacity. Nonetheless, the relationship between these factors and functional limitations in FMS patients is considered to be complex and not clearly defined. Therefore, the present study is aimed at assessing the associations between FMS functional capacity, FMS symptoms (pain, fatigue, insomnia, depression, and state and trait anxiety), and associated psychological factors such as pain catastrophizing, as well as the possible mediating role of these latter in the relationship between pain and FMS functional capacity.

A role of the immune system in the pathophysiology of pain and hyperalgesia has received growing attention, especially in the context of visceral pain and the gut-brain axis. While acute experimental inflammation can induce visceral hyperalgesia as part of sickness behavior in healthy individuals, it remains unclear if normal plasma levels of circulating pro-inflammatory cytokines contribute to interindividual variability in visceral sensitivity. We herein compiled data from a tightly screened and well-characterized sample of healthy volunteers ( = 98) allowing us to assess associations between visceral sensitivity and gastrointestinal symptoms, and plasma concentrations of three selected pro-inflammatory cytokines (i.e., TNF-α, IL-6, and IL-8), along with cortisol and stress-related psychological variables. For analyses, we compared subgroups created to have distinct pro-inflammatory cytokine profiles, modelling healthy individuals at putative risk or resilience, respectively, for symptoms of the gut-brain axis, and compared them with respect to rectal sensory and pain thresholds and subclinical GI symptoms. Secondly, we computed multiple regression analyses to test if circulating pro-inflammatory markers predict visceral sensitivity in the whole sample. Despite pronounced subgroup differences in pro-inflammatory cytokine and cortisol concentrations, we observed no differences in measures of visceroception. In regression analyses, cytokines did not emerge as predictors. The pain threshold was predicted by emotional state and trait variables, especially state anxiety, together explaining 10.9% of the variance. These negative results do not support the hypothesis that systemic cytokine levels contribute to normal interindividual variability in visceroception in healthy individuals. Trajectories to visceral hyperalgesia as key marker in disorders of gut-brain interactions likely involve complex interactions of biological and psychological factors in keeping with a psychosocial model. Normal variations in systemic cytokines do not appear to constitute a vulnerability factor in otherwise healthy individuals, calling for prospective studies in at risk populations.