Neurobiologic Features of Fibromyalgia Are Also Present Among Rheumatoid Arthritis Patients

Funding: The study recieved support from Pfizer. The funder had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript. The content is solely the responsibility of the authors. Funding Information Pfizer Aptinyx Cerephex ACKNOWLEDGEMENTS: The authors wish to thank all of the patient volunteers. We also thank Mariella D’Allesandro for supporting recruitment and data collection.Peer reviewedPostprin

Minireviews Fibromyalgia Syndrome in Need of Effective Treatments

ABSTRACT Fibromyalgia syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain, affecting primarily women. It is clinically characterized by chronic, nonarticular pain and a heightened response to pressure along with sleep disturbances, fatigue, bowel and bladder abnormalities, and cognitive dysfunction. The diagnostic criteria have changed repeatedly, and there is neither a definitive pathogenesis nor reliable diagnostic or prognostic biomarkers. Clinical and laboratory studies have provided evidence of altered central pain pathways. Recent evidence suggests the involvement of neuroinflammation with stress peptides triggering the release of neurosenzitizing mediators. The management of FMS requires a multidimensional approach including patient education, behavioral therapy, exercise, and pain management. Here we review recent data on the pathogenesis and propose new directions for research and treatment

Exercising the brain in pain : using fMRI to investigate intrinsic connectivity, cognition and pain regulation in fibromyalgia and how this is affected by physical exercise

The aims of the studies of this thesis were to use functional magnetic resonance imaging (fMRI) to investigate cerebral activation patterns in fibromyalgia (FM) patients and healthy controls (HC) at rest, when performing the stroop colour word test (SCWT) and during pressure pain provocation. Distraction induced analgesia (DIA), performance on the SCWT and pressure pain sensitivity was investigated on the behavioural and psychophysical level. Lastly studies III and IV investigated the effects of a 15-week resistance exercise training intervention on SCWT and pain processing. The main finding in study I was that FM was associated with decreased connectivity between pain related and sensorimotor brain areas, more specifically between insula and primary sensorimotor areas (S1/M1). Furthermore increased pain sensitivity in both groups correlated to increased connectivity between the insula and thalamus with the default mode network (DMN). Study II utilised the SCWT were participants are given colour words written in either congruent or incongruent colours. To induce DIA, participants were given two versions of the test, one with congruent words and one with incongruent words, this in order to investigate the impact of cognitive load on pain perception. In the scanner, the stimuli were mixed and presented in an eventrelated fMRI paradigm. The study revealed that DIA functioned the same in FM as it did in HC, and analgesia was not dependant on cognitive load. Performance on the SCWT showed that both groups were slower on the more cognitively demanding task, but interference disrupted performance more in the FM group than in the HC. The fMRI results yielded less activation of the caudate nucleus and hippocampus during SCWT in FM patients. These regions are implicated in learning and reward, suggesting that impaired learning mechanisms can contribute to the cognitive dysfunction often reported by FM patients. In study III, the SCWT assessments were repeated following the physical exercise intervention. Performance on the SCWT was improved in both groups, in the HC speed of processing had improved significantly, but a specific improvement of cognitive ability was only found in the FM patients. The latter was accompanied by an increased activation of the amygdala following the intervention in the FM group. Regarding DIA, no effects of exercise were found. Lastly, in study IV fMRI was used to assess pressure pain processing in FM patients and HC before and following the exercise intervention. FM patients were more pain sensitive than HC at both times, but following the intervention pressure pain sensitivity was significantly reduced in the FM group. We found no evidence that the exercise intervention had an effect on cerebral processing of evoked pain in either group. Our data suggest that the reduced pain sensitivity following exercise in FM patients was caused by peripheral mechanisms. Taken together the results of the four studies all demonstrated aberrations in cerebral activation in FM patients compared to controls, as well as poorer cognitive performance and increased pain sensitivity. However, interestingly, normal function of DIA was found in FM patients. Studies three and four showed that physical exercise was beneficial to FM patients, both regarding cognitive ability and by reducing pain sensitivity

An Examination of Brain Network Organization and the Analgesic Mechanisms of a Non-Pharmacological Treatment in Chronic Centralized Pain

Chronic pain is a global public health challenge, affecting nearly one third of adults worldwide. Current treatments are inadequate, especially since some of the mainstay therapies (e.g. opioids, NSAIDs) are often ineffective and/or associated with significant toxicity. The solution to these problems requires an improved understanding of chronic pain pathology, particularly the role that the brain plays in causing or amplifying pain perception, and how analgesic intervention might target these brain-based mechanisms. This dissertation aims to identify brain network alterations in fibromyalgia (FM), a common and canonical chronic pain condition with presumed CNS pathology, and determine how non-invasive brain stimulation may target aberrant brain network connectivity to promote analgesia. Across a wide range of diverse neurological disorders, hubs (i.e. highly connected brain regions) appear to be disrupted and the character of this disruption can yield insights into the pathophysiology of these disorders. In Chapter 2, we describe the application of a brain network based approach to examine hub topology in FM patients compared to healthy volunteers. We identified significant disruptions in hub rank order in FM patients. In FM, but not controls, the anterior insula was a hub with significantly higher inter-modular connectivity and membership in the rich club (a functional backbone of connectivity formed by highly interconnected hubs). Among FM patients, rich club membership varied with the intensity of clinical pain: the posterior insula, primary somatosensory and motor cortices belonged to the rich club only in FM patients with the highest pain. Further, we found that the eigenvector centrality (a measure of how connected a brain region is to other highly connected regions) of the posterior insula positively correlated with clinical pain, and mediated the relationship between levels of glutamate + glutamine within this structure and the patient’s subjective clinical pain report. Together, these findings demonstrate an altered hub topology in FM and are the first to suggest that disruptions in the excitatory tone within the insula could alter the strength of the insula as a hub and subsequently lead to increased clinical pain. Transcranial direct current stimulation (tDCS) has emerged as an attractive noninvasive treatment for pain, given its ability to target specific cortical regions with relatively few side effects. Motor cortex (M1) tDCS relieves pain in FM, but the analgesic mechanism remains unknown. In Chapter 3, we measured changes in resting state functional connectivity after sham and real M1 tDCS in twelve FM patients and examined if these changes were related to subsequent analgesia. M1 tDCS (compared to sham) reduced pro-nociceptive functional connectivity, specifically between the motor and sensory nuclei of the thalamus and multiple cortical regions, including primary motor and somatosensory areas. Interestingly, decreased connectivity between the thalamus and posterior insula, M1 and somatosensory cortices correlated with reductions in clinical pain after both sham and active treatment. These results suggest that while there may be a placebo response common to both sham and real tDCS, repetitive M1 tDCS causes distinct changes in functional connectivity that last beyond the stimulation period and may produce analgesia by inhibiting pro-nociceptive thalamic connectivity. This research offers new insight into the neurobiology of chronic centralized pain conditions and contributes to the understanding of how non-invasive brain stimulation causes analgesia. This knowledge could lead to more informed stimulation sites and personalized treatment based on network connectivity in each individual patient.PHDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/143930/1/chelsmar_1.pd

Intrinsic brain activity in health and disease

The main part of the brain’s energy need is to support housekeeping functions and internal information processing, regardless of external tasks. Cognitive brain imaging, aimed at relating mental phenomena to neurophysiological processes, has conventionally investigated the brain activity induced by external stimuli. In contrast, resting state functional Magnetic Resonance Imaging (rs-fMRI) aims to characterize the spatiotemporal properties of the ongoing baseline brain activity. In the projects constituting the current thesis, we have used rs-fMRI to investigate effects of neuropharamcological administrations, long-term physical exercise and to characterize central pain processing in rheumatic pain conditions. Study I is a randomized, cross sectional placebo study, in which healthy subjects were administered Parkinson medications (L-dopa), anxiolytics (oxazepam), or placebo. Our a priori hypothesis of preferential modulations of connectivity of brain regions with high density of target receptors was not confirmed. Instead, oxazepam was associated with increased connectivity of cardinal hubs within the default mode network, and interestingly, a decoupling of the amygdala. L-dopa, on the other hand, primarily decreased connectivity, particularly between amygdala and bilateral prefrontal gyri. In studies II-IV we investigated rheumatic pain patients. In study II we compared a fibromyalgia (FM) cohort and healthy controls (HC) with regard to functional brain connectivity of particularly cerebral pain regions. Conducting both data driven independent component analysis (ICA) and seed correlation analysis (SCA), we observed a weaker coupling between pain regions and sensorimotor brain areas in the FM group. Across groups, pain sensitivity correlated with e.g. increased connectivity between insula and the posterior cingulate cortex. Physical exercise is a potent reliever of FM symptoms. In study III, we investigated the effects a three months physical training intervention for FM patients. Following exercise, patients reported decreased symptom gravity, and the FM associated hyper-connectivity identified at baseline was partly normalized. In study IV, we investigated the extent to which exposure to chronic pain for patients with rheumatoid arthritis (RA) was reflected in functional connectivity of pain regions. Overall, RA patients had elevated connectivity, particularly between frontal midline areas and bilateral sensorimotor cortex. Taken together, we have shown that short-term neuropharmachological interventions, a three months physical exercise intervention as well as long-term rheumatic pain exposure, all are accompanied by changes in intrinsic brain activity. Although the functional significance of the observed group differences in connectivity warrants further investigations, the evidences presented here support the notion that rs-fMRI could prove useful for diagnosing neuropsychiatric conditions and evaluating interventions in the future

Fibromialgia: Enfoque en terapia

La fibromialgia es una patología que cursa con dolor crónico, su diagnóstico es clínico y se basa en el dolor generalizado o difuso y la presencia de a la presión de 11 de 18 puntos localizados en sitios especificados. Para el tratamiento de la misma, muchos pacientes recurren a diversos tratamientos para aliviar el dolor y mejorar la calidad de vida. La fisioterapia pasiva puede ser un tratamiento efectivo a nivel sintomático, siendo algunas técnicas más indicadas que otras según los síntomas de mayor severidad en los pacientes.Fibromyalgia is a pathology that presents with chronic pain, its diagnosis is clinical and is based on generalized or diffuse pain and the presence of pressure at 11 of 18 points located at specified sites. For the treatment of it, many patients resort to various treatments to relieve pain and improve the quality of life. The passive physiotherapy can be an effective treatment at a symptomatic level, being some techniques, more indicated than others according to the symptoms of greater severity in the patients. However, it should be noted that the treatment must be multidisciplinary and that all of them complement each other in order to have a successful outcome in the patient

Actividad eléctrica cerebral asociada al funcionamiento cognitivo en pacientes con fibromialgia

La fibromialgia es una enfermedad de dolor crónico que cursa con disfunción cognitiva. Sin embargo, la investigación existente sobre la disfunción cognitiva es muy escasa. En el presente trabajo analizamos la actividad eléctrica cerebral de pacientes con fibromialgia y controles sanos durante la realización de una tarea de inhibición motora, una tarea de memoria de trabajo y una tarea de control cognitivo. No se observaron alteraciones en la ejecución conductual ni la actividad eléctrica cerebral relacionada con la inhibición motora, sin embargo si que encontramos una menor activación eléctrica global en las pacientes. Durante la tarea de memoria de trabajo tampoco se observaron alteraciones conductuales, aunque las pacientes mostraron menor modulación de la potencia de theta y alfa, y una menor sincronización de la fase de theta. Finalmente, durante la tarea de control cognitivo, las pacientes mostraron peores tiempos de reacción, menor modulación de la potencia de theta y alfa, menor sincronización de fase de theta y un mayor nivel de ruido neural. Estos resultados sugieren que las pacientes muestran déficits en la movilización de recursos neurales durante la realización de tareas cognitivas. Además, el mayor nivel ruido neural puede explicar porqué la fibromialgia se relaciona con problemas cognitivos