Neurobiology Underlying Fibromyalgia Symptoms

Fibromyalgia is characterized by chronic widespread pain, clinical symptoms that include cognitive and sleep disturbances, and other abnormalities such as increased sensitivity to painful stimuli, increased sensitivity to multiple sensory modalities, and altered pain modulatory mechanisms. Here we relate experimental findings of fibromyalgia symptoms to anatomical and functional brain changes. Neuroimaging studies show augmented sensory processing in pain-related areas, which, together with gray matter decreases and neurochemical abnormalities in areas related to pain modulation, supports the psychophysical evidence of altered pain perception and inhibition. Gray matter decreases in areas related to emotional decision making and working memory suggest that cognitive disturbances could be related to brain alterations. Altered levels of neurotransmitters involved in sleep regulation link disordered sleep to neurochemical abnormalities. Thus, current evidence supports the view that at least some fibromyalgia symptoms are associated with brain dysfunctions or alterations, giving the long-held “it is all in your head” view of the disorder a new meaning

Fibromyalgia and Depression

Fibromyalgia and depression might represent two manifestations of affective spectrum disorder. They share similar pathophysiology and are largely targeted by the same drugs with dual action on serotoninergic and noradrenergic systems. Here, we review evidence for genetic and environmental factors that predispose, precipitate, and perpetuate fibromyalgia and depression and include laboratory findings on the role of depression in fibromyalgia. Further, we comment on several aspects of fibromyalgia which support the development of reactive depression, substantially more so than in other chronic pain syndromes. However, while sharing many features with depression, fibromyalgia is associated with somatic comorbidities and absolutely defined by fluctuating spontaneous widespread pain. Fibromyalgia may, therefore, be more appropriately grouped together with other functional pain disorders, while psychologically distressed subgroups grouped additionally or solely with affective spectrum disorders

Dorsal premammillary projection to periaqueductal gray controls escape vigor from innate and conditioned threats

Escape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape vigor from innate and conditioned threats. Cholecystokinin (cck)-expressing cells in the hypothalamic dorsal premammillary nucleus (PMd) are necessary for initiating escape from innate threats via a projection to the dorsolateral periaqueductal gray (dlPAG). We now show that in mice PMd-cck cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Intriguingly, PMd-cck and dlPAG activity in mice showed higher mutual information during exposure to innate and conditioned threats. In parallel, human functional magnetic resonance imaging data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd-dlPAG circuit as a central node, controlling escape vigor elicited by both innate and conditioned threats. &nbsp;</p

A summary of new findings on the biological effects of selenium in selected animal species: a critical review.

Selenium is an essential trace element important for many physiological processes, especially for the functions of immune and reproductive systems, metabolism of thyroid hormones, as well as antioxidant defense. Selenium deficiency is usually manifested by an increased incidence of retention of placenta, metritis, mastitis, aborts, lowering fertility and increased susceptibility to infections. In calves, lambs and kids, the selenium deficiency demonstrates by WMD (white muscle disease), in foals and donkey foals, it is associated with incidence of WMD and yellow fat disease, and in pigs it causes VESD (vitamin E/selenium deficiency) syndrome. The prevention of these health disorders can be achieved by an adequate selenium supplementation to the diet. The review summarizes the survey of knowledge on selenium, its biological significance in the organism, the impact of its deficiency in mammalian livestock (comparison of ruminants vs. non-ruminants, herbivore vs. omnivore) and possibilities of its peroral administration. The databases employed were as follows: Web of Science, PubMed, MEDLINE and Google Scholar

The role of insula in somatosensory plasticity: MRI studies in human subjects

The insula is an important cortical processing area for thin fiber somatosensory input, including nociceptive and thermal input. This thesis desribes a series of studies focusing on the human insular cortex, in which structural and functional MRI, together with psychophysical testing, were used to explore the relationship between brain changes and alterations in somatosensory processing and regulation. In Study 1, we reported insular gray matter (GM) changes in a unique patient lacking large-fiber somatosensory input (proprioception, discriminative touch), but with intact thin-fiber input projecting into insular cortex. The patient had increased cortical thickness and resting state connectivity of the insula compared to matched controls. In Study 2, we reported increases in insular GM volume, and white matter (WM) integrity and connectivity in long-term yoga practitioners, who had heightened pain tolerance compared to matched controls. In addition, we observed a positive correlation between insular GM and individual pain tolerance across yoga practitioners and controls. In Study 3, which was part of a larger investigation of age-related GM changes in chronic pain (fibromyalgia) patients, we observed insular GM increase in younger patients compared to matched controls, and this GM increase was inversely related to patients' experimental pain sensitivity. Further, the anterior insula of younger patients had relative to matched controls decreased resting state connectivity to a cortical area involved in processing of the emotional salience of painful stimuli. This thesis provides three novel contributions to our understanding of the insula. Study 1 revealed insular structural and functional correlates of loss of specific somatosensory fibers in humans, Study 2 provided the first evidence for the effects of yoga practice on brain structure in general and on insular GM in particular, and related these effects to pain tolerance, and Study 3 was the first study to directly investigate age-related effects of chronic pain on brain GM, and in particular on insular GM structure and functional connectivity. We interpret the observed insular GM enhancements across all three studies as being suggestive of adaptive plasticity related to a) compensatory use of thin-fiber input – most notably temperature – in lieu of abolished large-fiber sensations b) pain regulation, likely via increased intra-insular processing and c) increased pain regulation, likely via functional disengagement from a cortical salience processing network. This work has improved our understanding of the insula in somatosensory and notably pain processing, and could thus help guide future studies aimed at developing treatments for chronic pain.L'insula est une aire corticale importante impliquée dans le traitement de l'input des fines fibres somato-sensorielles incluant l'input nociceptive et thermal. Cette thèse décrit une série d'études centrées sur le cortex insulaire humain dans lesquelles l'IRM structural et fonctionnel et l'évaluation psychophysique ont été utilisées pour explorer la relation entre les changements du cerveau et ceux liés au traitement somato-sensoriel et à sa régulation. Dans la première étude, nous décrivons les changements dans la matière grise (MG) de l'insula chez une patiente n'ayant pas d'input somato-sensoriel provenant des larges fibres (proprioception, touché discriminatif), mais ayant un input intact des fines fibres projetant au cortex insulaire. Lorsque comparée à un groupe apparié de sujets contrôle, cette patiente présentait une augmentation de l'épaisseur du cortex et de la connectivité insulaire à l'état de repos. Dans la deuxième étude, nous observons une augmentation du volume de MG insulaire ainsi que de l'intégrité et de la connectivité de la matière blanche (MB) insulaire chez des adeptes du yoga expérimentés présentant une augmentation de la tolérance à la douleur lorsque comparés au sujets d'un groupe contrôle apparié. Nous avons de plus observé une corrélation positive entre la MG insulaire et les résultats de tolérance à la douleur de l'ensemble des sujets (adeptes du yoga et groupe contrôle). Dans la troisième étude, qui représente l'examen des changements de MG liés à l'âge chez des patients souffrant de douleurs chronique (fibromyalgie), nous observons une augmentation de la MG insulaire chez les jeunes patientes comparativement aux sujets du groupe contrôle apparié. Cette augmentation de MG est inversement corrélée à la sensibilité des patientes à la douleur expérimentale. De plus, l'insula antérieure des jeunes patientes montre, lorsque comparée à celle des sujets du groupe contrôle, une diminution de la connectivité à l'état de repos à une aire corticale impliquée dans le traitement de l'aspect émotionnel des stimuli douloureux. Cette thèse apporte trois contributions nouvelles à notre compréhension de l'insula. L'étude 1 révèle les conséquences structurale et fonctionnelle liées à la perte de fibres nerveuses somato-sensorielles spécifiques chez l'humain. L'étude 2 apporte la première démonstration des effets de la pratique du yoga sur la MG insulaire et de sa relation avec la tolérance à la douleur et l'étude 3 est la première étude qui recherche directement les effets liés à l'âge de la douleur chronique sur la structure et la fonction de l'insula. Nous interprétons les augmentations observées de MG insulaire dans les trois études comme reflétant une plasticité d'adaptation liée a) à l'utilisation compensatoire de l'input des fines fibres nerveuses – notamment celles liées à la perception de la température – en remplacement des fibres de plus gros calibre; b) au contrôle de la douleur, probablement par l'augmentation du traitement intra-insulaire; et c) à l'augmentation du contrôle de la douleur, probablement via un désengagement fonctionnel d'un réseau cortical impliqué dans le traitement de la salliance. Ce travail a amélioré notre compréhension de l'implication de l'insula dans le traitement de l'information somato-sensorielle et douloureuse et pourrait aider à éclairer de futures études visant à développer des traitements contre la douleur chronique

Editorial: Pain in Early and late Life - A Call for Action

Chronic pain remains a leading cause of long-term disability (GBD 2016 Disease Injury Incidence Prevalence Collaborators, 2017), affects 20% of the world's population, imposes higher costs on the society than heart disease, cancer, and diabetes combined (GBD 2016 Disease Injury Incidence Prevalence Collaborators, 2017; Buchbinder et al., 2018), and is associated with increased mortality (Tesarz et al., 2019). Despite this global relevance, therapeutic options remain unsatisfactory to date (Williams et al., 2020). Consequently, in recent years, enormous efforts have been made to expand the knowledge about the development and maintenance of chronic pain disorders and to improve treatment options. The dramatic nature of the situation and the increasing global health burden due to chronic pain even culminated recently in a "global call for action" (Buchbinder et al., 2018)

Dopamine and pain sensitivity: neither sulpiride nor acute phenylalanine and tyrosine depletion have effects on thermal pain sensations in healthy volunteers.

Based on animal studies and some indirect clinical evidence, dopamine has been suggested to have anti-nociceptive effects. Here, we investigated directly the effects of increased and decreased availability of extracellular dopamine on pain perception in healthy volunteers. In Study 1, participants ingested, in separate sessions, a placebo and a low dose of the centrally acting D2-receptor antagonist sulpiride, intended to increase synaptic dopamine via predominant pre-synaptic blockade. No effects were seen on thermal pain thresholds, tolerance, or temporal summation. Study 2 used the acute phenylalanine and tyrosine depletion (APTD) method to transiently decrease dopamine availability. In one session participants ingested a mixture that depletes the dopamine amino acid precursors, phenylalanine and tyrosine. In the other session they ingested a nutritionally balanced control mixture. APTD led to a small mood-lowering response following aversive thermal stimulation, but had no effects on the perception of cold, warm, or pain stimuli. In both studies the experimental manipulation of dopaminergic neurotransmission was successful as indicated by manipulation checks. The results contradict proposals that dopamine has direct anti-nociceptive effects in acute experimental pain. Based on dopamine's well-known role in reward processing, we hypothesize that also in the context of pain, dopamine acts on stimulus salience and might play a role in the initiation of avoidance behavior rather than having direct antinociceptive effects in acute experimental pain

Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging

Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABAA receptor concentration, an indirect marker of neuronal integrity measured with [18F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABAA receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABAA receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABAA receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain. SIGNIFICANCE STATEMENT Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAA receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAA receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain

Overview of the time course of an experimental session of Study 1.

<p>All participants performed two sessions: in one session they ingested 600 mg sulpiride, in the other one a placebo. In each session, participants performed pre- and post-drug testing, separated by a 3.5h waiting period.</p

Fit-for-Purpose Quality Control System in Continuous Bioanalysis during Long-Term Pediatric Studies (vol 21, 104, 2019)

The LENA collaborator list below was not included in the original article.s.status: publishe