Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome

Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure (BP) and heart rate (HR). In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring. We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS. Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter. Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations. This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions

Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process—Multi-Cohort Multi-Modal Evidence

Differential axonal myelination synchronises signalling over different axon lengths. The consequences of myelination processes described at the cellular level for the regulation of myelination at the macroscopic level are unknown. We analysed multiple cohorts of myelin-sensitive brain MRI. Our aim was to (i) confirm a previous report of anti-correlation between myelination in subcortical and sensorimotor areas in healthy subjects, (ii) and thereby test our hypothesis for a regulatory interaction between them. We analysed nine image-sets across three different human cohorts using six MRI modalities. Each image-set contained healthy controls (HC) and ME/CFS subjects. Subcortical and Sensorimotor regions of interest (ROI) were optimised for the detection of anti-correlations and the same ROIs were used to test the HC in all image-sets. For each cohort, median MRI values were computed in both regions for each subject and their correlation across the cohort was computed. We confirmed negative correlations in healthy controls between subcortical and sensorimotor regions in six image-sets: three T1wSE (p = 5 × 10−8, 5 × 10−7, 0.002), T2wSE (p =2 × 10−6), MTC (p = 0.01), and WM volume (p = 0.02). T1/T2 was the exception with a positive correlation (p = 0.01). This myelin regulation study is novel in several aspects: human subjects, cross-sectional design, ROI optimization, spin-echo MRI and reproducible across multiple independent image-sets. In multiple independent image-sets we confirmed an anti-correlation between subcortical and sensorimotor myelination which supports a previously unreported regulatory interaction. The subcortical region contained the brain’s primary regulatory nuclei. We suggest a mechanism has evolved whereby relatively low subcortical myelination in an individual is compensated by upregulated sensorimotor myelination to maintain adequate sensorimotor performance

Caveolin-1 Regulates Store-Operated Ca\u3csup\u3e2+\u3c/sup\u3e Influx By Binding of Its Scaffolding Domain to Transient Receptor Potential Channel-1 in Endothelial Cells

Caveolin-1 associates with store-operated cation channels (SOC) in endothelial cells. We examined the role of the caveolin-1 scaffolding domain (CSD) in regulating the SOC [i.e., transient receptor potential channel-1 (TRPC1)] in human pulmonary artery endothelial cells (HPAECs). We used the cellpermeant antennapedia (AP)-conjugated CSD peptide, which competes for protein binding partners with caveolin-1, to assess the interactions of caveolin-1 with TRPC1 and its consequences on thrombin-induced Ca2+ influx. We observed that AP-CSD peptide markedly reduced thrombin-induced Ca2+ influx via SOC in HPAECs in contrast to control peptide. AP-CSD also suppressed thapsigargin-induced Ca2+influx. Streptavidin-bead pull-down assay indicated strong binding of biotin-labeled AP-CSD peptide to TRPC1. Immunoprecipitation studies demonstrated an interaction between endogenous TRPC1 and ectopically expressed hemagglutinin-tagged CSD. Analysis of the deduced TRPC1 amino acid sequence revealed the presence of CSD binding consensus sequence in the TRPC1 C terminus. We also observed that an AP-TRPC1 peptide containing the CSD binding sequence markedly reduced the thrombin-induced Ca2+ influx. We identified the interaction between biotin-labeled AP-TRPC1 C terminus peptide and caveolin-1. Thus, these results demonstrate a crucial role of caveolin-1 scaffolding domain interaction with TRPC1 in regulating Ca2+ influx via SOC