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Background: In people with low back pain (LBP), altered motor control has been related to reorganization of the primary motor cortex (M1). Sensory impairments in LBP have also been suggested to be associated with reorganization of M1. Little is known about reorganization of M1 over time in people with LBP, and whether it relates to changes in motor control and sensory impairments and recovery. This study aims to investigate 1) differences in organization of M1 of trunk muscles between people with and without LBP, and whether the organization of M1 relates to motor control and sensory impairments (cross-sectional component) and 2) reorganization of M1 over time and its relation with changes in motor control and sensory impairments and experienced recovery (longitudinal component). Methods: A case-control study with a cross-sectional and five-week longitudinal component is conducted in participants with LBP (N = 25) and participants without LBP (N = 25). Participants with LBP received usual care physiotherapy. Various tests were administered at baseline and follow-up. Following an anatomical MRI, organization of M1 (Center of Gravity and Area of the cortical representation of trunk muscles) was determined using transcranial magnetic stimulation. Quantitative sensory testing, a spiral-tracking motor control test, graphesthesia, two-point discrimination threshold and various self-reported questionnaires were also assessed. Multivariate multilevel analysis will be used for statistical analysis. Conclusion: We will address the gaps in knowledge about the association between reorganization of M1 and motor control and sensory tests during the clinical course of LBP. This study is registered at DOI 10.17605/OSF.IO/5C8ZG.
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BACKGROUND: HSPB1 belongs to the family of small heat shock proteins (sHSP) that have importance in protection against unfolded protein stress, in cancer cells for escaping drug toxicity stress and in neurons for suppression of protein aggregates. sHSPs have a conserved α-crystalline domain (ACD), flanked by variable N- and C-termini, whose functions are not fully understood. Dominant missense variants in HSPB1, locating mostly to the ACD, have been linked to inherited neuropathy. METHODS: Patients underwent detailed clinical and neurophysiologic characterization. Disease causing variants were identified by exome or gene panel sequencing. Primary patient fibroblasts were used to investigate the effects of the dominant defective HSPB1 proteins. RESULTS: Frameshift variant predicting ablation of the entire C-terminus p.(Met169Cfs2*) of HSPB1 and a missense variant p.(Arg127Leu) were identified in patients with dominantly inherited motor-predominant axonal Charcot-Marie-Tooth neuropathy. We show that the truncated protein is stable and binds wild type HSPB1. Both mutations impaired the heat stress tolerance of the fibroblasts. This effect was particularly pronounced for the cells with the truncating variant, independent of heat-induced nuclear translocation and induction of global transcriptional heat response. Furthermore, the truncated HSPB1 increased cellular sensitivity to protein misfolding. CONCLUSION: Our results suggest that truncation of the non-conserved C-terminus impairs the function of HSPB1 in cellular stress response. GENERAL SIGNIFICANCE: sHSPs have important roles in prevention of protein aggregates that induce toxicity. We showed that C-terminal part of HSPB1 is critical for tolerance of unfolded protein stress, and when lacking causes axonal neuropathy in patients.
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Fibromyalgia is a chronic pain syndrome characterized by widespread pain, fatigue, and memory and mood disturbances. Despite advances in our understanding of the underlying pathophysiology, treatment is often challenging. New research indicates that changes in functional connectivity between brain regions, as can be measured by magnetic resonance imaging (fcMRI) of the resting state, may underlie the pathogenesis of this and other chronic pain states. As such, this parameter may be able to be used to monitor changes in brain function associated with pharmacological treatment, and might also be able to predict treatment response. We performed a resting state fcMRI trial using a randomized, placebo-controlled, cross-over design to investigate mechanisms of action of milnacipran (MLN), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in fibromyalgia patients. Our aim was to identify functional connectivity patterns at baseline that would differentially predict treatment response to MLN as compared to placebo. Since preclinical studies of MLN suggest that this medication works by augmenting antinociceptive processes, we specifically investigated brain regions known to be involved in pain inhibition. 15 fibromyalgia patients completed the study, consisting of 6 weeks of drug and placebo intake (order counterbalanced) with an interspersed 2 week wash out period. As a main finding we report that reductions in clinical pain scores during MLN were associated with decreased functional connectivity between pro-nociceptive regions and antinociceptive pain regions at baseline, specifically between the rostral part of the anterior cingulate cortex (ACC) and the insular cortex (IC), as well as between the periaqueductal gray (PAG) and the IC: patients with lower preexisting functional connectivity had the greatest reduction in clinical pain. This pattern was not observed for the placebo period. However a more robust placebo response was associated with lower baseline functional connectivity between the ACC and the dorsolateral prefrontal cortex. This study indicates that ACC-IC connectivity might play a role in the mechanism of action of MLN, and perhaps more importantly fcMRI might be a useful tool to predict pharmacological treatment response.