A multicomponent physical activity home-based intervention for fibromyalgia patients: effects on clinical and skin biopsy features.

OBJECTIVES: Adapted physical activity (APA) has been recommended for fibromyalgia (FM) treatment as an essential component of a biopsychosocial therapeutic approach for patients. Previous studies report that aerobic and resistance training are the most effective programs in improving the quality of life and psycho-physical well-being. Patients with FM are frequently affected by an impairment of small fibers innervation, which is evident in the proximal somatic districts. Therefore, this pilot randomised controlled not pharmacological trial aimed to investigate if a 12-week home-based multicomponent (aerobic and resistance training and mobility) physical activity (PA) intervention was effective in improving pain perception, FM-related disability, and IntraEpidermal Nerve Fibers Density (IENFD) in adult FM patients. METHODS: Thirty-four female subjects with a fibromyalgia diagnosis (51.5±11.88 years) were randomly assigned to an experimental group (n=17) that received a supervised home-based multicomponent PA intervention twice a week and a control group (n=17) that received a generic program of aerobic exercise. Skin biopsy was performed before the physical program and after 18 months with constant execution of the supervised PA intervention or generic aerobic exercise. Both groups assumed pharmacological treatment with duloxetine and/or pregabalin. RESULTS: We found that the group performing physical activity in a supervised and regular way showed a significant improvement in the Fibromyalgia-linked invalidity questionnaire (FIQ) as well as epidermal fibers density at proximal and distal sites. CONCLUSIONS: Physical activity could improve FM outcomes, with a possible beneficial impact on peripheral factors contributing to pain-related disability.

Outcome of small fibre pathology in fibromyalgia: a real life longitudinal observational study.

OBJECTIVES: Small fibre pathology is frequently described in fibromyalgia (FM), but its evolution and its role in clinical outcome of the disease are unclear. This longitudinal observational real-life study aimed to monitor the evolution of skin nerve fibre density in FM, in view of the clinical data. METHODS: Sixty-two FM patients were controlled by means of skin biopsy and clinical assessment after 18 months of follow-up. RESULTS: At T0 intraepidermal nerve fibre density (IENFD) was normal in 10 patients, reduced at thigh-proximal-site in 46 cases and decreased at proximal and foot-distal-site in 6 patients. At follow up-T1-the IENFD was unchanged, while Brief Pain Inventory-BPI-pain sub score, DN4 and fatigue were improved. Reduced IENFD at proximal and distal sites, together with fatigue and BPI-motor and work sub scores were predictors of more severe disability measured with Fibromyalgia Impact Questionnaire (FIQ) at T1. Reduced IENFD influenced a minor effect of drugs-antiepileptics and/or antidepressants, and physical exercise on fatigue. CONCLUSIONS: Small fibre impairment seems stable in medium term in FM. A possible influence of small fibre dysfunction on motor performance could have a role in FM evolution. The beneficial effect of physical exercise could be limited in patients with reduced IENFD.

Central effects of galcanezumab in migraine: a pilot study on Steady State Visual Evoked Potentials and occipital hemodynamic response in migraine patients.

BACKGROUND: The discovery of the prominent action of Calcitonin Gene Related Peptide -CGRP- on trigeminal afferents and meningeal vessels, opened a new era in migraine treatment. However, how the block of nociceptive afferents could act on central mechanisms of migraine is still not clear. In this pilot study we aimed to test the effect of 3 months Galcanezumab (CGA) therapy on occipital visual reactivity in migraine patients, using the Steady State Visual Evoked Potentials-SSVEPs and Functional Near Infrared Spectroscopy -fNIRS. METHOD: Thirteen migraine patients underwent clinical and neurophysiological examination in basal condition (T0), 1 h after GCA injection (T1) and after 3 months of GCA treatment (T2). Ten healthy volunteers were also evaluated. RESULTS: At T2, there was a reduction of headache frequency and disability. At T2, the EEG power significantly diminished as compared to T0 and T1 at occipital sites, and the topographical analysis confirmed a restoration of SSVEPs within normal values. The Oxyhemoglobin levels in occipital cortex, which were basically increased during visual stimulation in migraine patients, reverted to normal values at T2. CONCLUSIONS: The present pilot study indicates that Galcanezumab could act on cortical targets located beyond the pain network, restoring the abnormal occipital reactivity. This effect could indicate the possible disease modifying properties of CGRP related monoclonal antibodies.

Laser evoked potentials in fibromyalgia with peripheral small fiber involvement.

OBJECTIVE: To evaluate multichannel laser evoked potentials (LEPs) in patients with fibromyalgia (FM) and small fiber impairment. METHODS: We recorded LEPs using 65 electrodes in 22 patients with FM and proximal denervation, 18 with normal skin biopsy, and 7 with proximal and distal intraepidermal nerve fiber density (IENFD) reduction. We considered the amplitude and topographical distribution of N1, N2 and P2 components, and habituation of N2 and P2 waves. The sLORETA dipolar analysis was also applied. We evaluated 15 healthy subjects as controls. RESULTS: We observed reduced amplitude of the P2 component in FM group, without a topographic correspondence with the prevalent site of denervation. Decreased habituation of P2 prevailed in patients with reduced IENFD. The cingulate cortex and prefrontal cortex, were activated in the FM group, without correlation between the degree of denervation and the strength of late wave dipoles. A correlation was noted between anxiety, depression, fibromyalgia invalidity, and pain diffusion. CONCLUSIONS: The amplitude and topography of LEPs were not coherent with epidermal nerve fiber density loss. They supposedly reflected the clinical expression of pain and psychopathological factors. SIGNIFICANCE: Multichannel LEPs are not the expression of small fiber impairment in FM. Rather, they reflect the complexity of the disease.

Magnetoencephalography and High-Density Electroencephalography Study of Acoustic Event Related Potentials in Early Stage of Multiple Sclerosis: A Pilot Study on Cognitive Impairment and Fatigue.

Cognitive impairment (CI) is a common and disabling symptom of Multiple Sclerosis (MS) with a negative impact on daily living. In this pilot study, we applied magnetoencephalography (MEG) and high density (hd) electroencephalography (EEG) study to evaluate acoustic P300 features in a cohort of early MS. Sixteen MS patients (pwMS) and 19 healthy controls (HCs) matched for age and gender underwent an MEG-/(hd)-EEG-co-recording, using 306-channel Vectorview and 64 scalp electrodes. CI was assessed using Rao's Brief Repeatable Battery (BRB). Moreover, we performed psychometric tests to assess depression and fatigue. In pwMS, we observed a slight latency prolongation of P300 peak compared to HCs, while P300 amplitude and scalp distribution were similar in the two groups. pwMS did not show an amplitude reduction and different scalp distribution of Event-Related Potentials (ERPs) and Event Related Fields (ERFs) related to an acoustic oddball paradigm. We found an inverse correlation between P300 amplitude and fatigue (r Spearman = -0.4; p = 0.019). In pwMS, phenomena of cortical adaptation to early dysfunction could preserve the cognitive performance of the P300 acoustic task, while the development of fatigue could prospectively lead to amplitude decline of P300, suggesting its possible role as a biomarker.

Pain-Related Brain Connectivity Changes in Migraine: A Narrative Review and Proof of Concept about Possible Novel Treatments Interference.

A neuronal dysfunction based on the imbalance between excitatory and inhibitory cortical-subcortical neurotransmission seems at the basis of migraine. Intercritical neuronal abnormal excitability can culminate in the bioelectrical phenomenon of Cortical Spreading Depression (CSD) with secondary involvement of the vascular system and release of inflammatory mediators, modulating in turn neuronal activity. Neuronal dysfunction encompasses the altered connectivity between the brain areas implicated in the genesis, maintenance and chronic evolution of migraine. Advanced neuroimaging techniques allow to identify changes in functional connectivity (FC) between brain areas involved in pain processes. Through a narrative review, we re-searched case-control studies on FC in migraine, between 2015 and 2020, by inserting the words migraine, fMRI, EEG, MEG, connectivity, pain in Pubmed. Studies on FC have shown that cortical processes, in the neurolimbic pain network, are likely to be prevalent for triggering attacks, in response to predisposing factors, and that these lead to a demodulation of the subcortical areas, at the basis of migraine maintenance. The link between brain dysfunction and peripheral interactions through the inhibition of CGRP, the main mediator of sterile migraine inflammation needs to be further investigated. Preliminary evidence could suggest that peripheral nerves inference at somatic and trigeminal levels, appears to change brain FC.

Effect of single dose Erenumab on cortical responses evoked by cutaneous a-delta fibers: A pilot study in migraine patients.

BACKGROUND: Erenumab is a monoclonal antibody against calcitonin gene-related peptide receptors, which showed efficacy in migraine attack prevention. The aims of the present pilot study were to i) evaluate the effect of single dose of Erenumab 70 mg on laser evoked potentials from trigeminal and brachial stimulation in a cohort of migraine patients; ii) correlate the neurophysiological changes with clinical outcome after 3 months' treatment. METHODS: Laser evoked potentials were recorded by 61 electroencephalogram channels before (T0), 1 h (T1) and 7 days after (T2) Erenumab 70 mg injection, stimulating the left and right forehead and the right hand. Laser evoked potential control 1 h after the injection served as placebo session. RESULTS: Seventeen migraine patients were evaluated. The N1 and N2 component obtained from the right and left trigeminal stimulation diminished in amplitude at T2, compared to T0 and T1 conditions. N2 habituation reduction slightly recovered at T2. Laser evoked potential changes did not correlate with clinical improvement after 3 months of Erenumab treatment. CONCLUSIONS: A single dose of Erenumab has a mild inhibitory effect on cortical responses evoked from trigeminal cutaneous a-delta fibers. Though this phenomenon was not predictive of the clinical outcome, it confirms a wide representation of calcitonin gene-related peptide receptors on trigeminal afferents.