Biology subjects

Irving, S.

Publications and source records attributed to Irving, S..

6 recordsLinked to original sources

bioRxiv2023

EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites through Endothelial Fatty Acid Uptake

BackgroundAtherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, but its involvement in atherosclerosis remains unexplored. This study investigates the potential interplay between EPAS1, obesity, and atherosclerosis. MethodsResponses to shear stress were analysed using cultured porcine aortic EC exposed to flow in vitro coupled with metabolic and molecular analyses, and by en face immunostaining of murine aortic EC exposed to disturbed flow in vivo. Obesity and dyslipidemia were induced in mice via exposure to high-fat diet or through Leptin gene deletion. The role of Epas1 in atherosclerosis was evaluated by inducible endothelial Epas1 deletion, followed by hypercholesterolemia induction (AAV-PCSK9; high-fat diet). ResultsEn face staining revealed EPAS1 enrichment at sites of disturbed blood flow that are prone to atherosclerosis initiation. Obese mice exhibited substantial reduction in endothelial EPAS1 expression, correlating with hyperlipidaemia. Sulforaphane, a compound with known atheroprotective effects, restored EPAS1 expression and concurrently reduced plasma triglyceride levels in obese mice. Consistently, triglyceride derivatives (free fatty acids) suppressed EPAS1 in cultured EC by upregulating the negative regulator PHD3. Clinical observations revealed that reduced plasma EPAS1 correlated with increased endothelial PHD3 in obese individuals. Functionally, endothelial EPAS1 deletion increased lesion formation in hypercholesterolemic mice, indicating an atheroprotective function. Mechanistic insights revealed that EPAS1 protects arteries by maintaining endothelial proliferation by positively regulating CD36 and LIPG expression to increase fatty acid beta-oxidation. ConclusionsEndothelial EPAS1 attenuates atherosclerosis at sites of disturbed flow by maintaining EC proliferative via fatty acid uptake and metabolism. This endothelial repair pathway is inhibited in obesity, suggesting a novel triglyceride-PHD3 modulation pathway suppressing EPAS1 expression. These findings have implications for therapeutic strategies addressing vascular dysfunction in obesity.

physiology↗

bioRxiv2021

Pain and the Emotional Brain: Affective Rather than Cognitive Processes Drive the Cortical Encoding of Pain

BackgroundThe experience of pain has been dissociated into two interwoven aspects: a sensory-discriminative aspect and an affective-motivational aspect. We aimed to explore which of the pain descriptors is more deeply rooted in the human brain. FindingsParticipants were asked to evaluate applied cold pain. The majority of the trials showed distinct ratings: some were rated higher for unpleasantness and others for intensity. We compared the relationship between functional data recorded from 7 tesla MRI with unpleasantness and intensity ratings and revealed a stronger relationship between cortical data and unpleasantness ratings. ConclusionsThe present study underlines the importance of the emotional-affective aspects of pain-related cortical processes in the brain. The findings corroborate previous studies showing a higher sensitivity to pain unpleasantness compared to ratings of pain intensity. For the processing of pain in healthy subjects, this effect may reflect the more direct and intuitive evaluation of emotional aspects of the pain system, which is to prevent harm and to preserve the physical integrity of the body.

neuroscience↗

bioRxiv2021

Intrinsic Network Activity Reflects the Ongoing Experience of Chronic Pain

Analyses of intrinsic network activity have been instrumental in revealing cortical processes that are altered in chronic pain patients. However, such studies have not accounted for variable time courses of network activity and subjective pain experience. In a novel approach, we aimed to elucidate how intrinsic functional networks evolve in regard to the fluctuating intensity of the experience of chronic pain. In a longitudinal study with 156 fMRI sessions, 20 chronic back pain patients and 20 chronic migraine patients were asked to continuously rate the intensity of their endogenous pain. Using group independent component analysis and dual-regression, we extracted the time courses of 100 independent components separately for chronic back pain and chronic migraine. We investigated the relationship between the fluctuation of intrinsic network activity with the time course of subjective pain ratings. For chronic back pain, we found increased cortical network activity for the salience network and a local pontine network, as well as decreased network activity in the anterior and posterior default mode network for higher pain intensities. Higher pain intensities in chronic migraine were accompanied with lower activity in a prefrontal cortical network. By taking the perspective of the individual, we focused on the processes that matter for each patient, which are phases of relatively low pain and more straining phases of relatively high pain. The present design of ongoing assessment of the endogenous pain can be a powerful and promising tool to assess the signature of a patients endogenous pain encoding over weeks and months.

neuroscience↗

bioRxiv2020

A Novel Tool for the Removal of Muscle Artefacts from EEG: Improving Data Quality in the Gamma Frequency Range

BackgroundThe past two decades have seen a particular focus towards high-frequency neural activity in the gamma band (>30Hz). However, gamma band activity shares frequency range with unwanted artefacts from muscular activity. New MethodWe developed a novel approach to remove muscle artefacts from neurophysiological data. We re-analysed existing EEG data that were decomposed by a blind source separation method (independent component analysis, ICA), which helped to better spatially and temporally separate single muscle spikes. We then applied an adapting algorithm that detects these singled-out muscle spikes. ResultsWe obtained data almost free from muscle artefacts; we needed to remove significantly fewer artefact components from the ICA and we included more trials for the statistical analysis compared to standard ICA artefact removal. All pain-related cortical effects in the gamma band have been preserved, which underlines the high efficacy and precision of this algorithm. ConclusionsOur results show a significant improvement of data quality by preserving task-relevant gamma oscillations of cortical origin. We were able to precisely detect, gauge, and carve out single muscle spikes from the time course of neurophysiological measures. We advocate the application of the tool for studies investigating gamma activity that contain a rather low number of trials, as well as for data that are highly contaminated with muscle artefacts. This validation of our tool allows for the application on event-free continuous EEG, for which the artefact removal is more challenging.

neuroscience↗

bioRxiv2020

Migraine Attacks as a Result of Hypothalamic Loss of Control

To assess the natural trajectory of brain activity over the migraine cycle, we assessed (1) the cerebral perfusion and (2) the hypothalamic connectivity during spontaneous headache attacks with follow-up recordings towards the next migraine attack. Using pseudo-continuous arterial spin labelling and resting-state functional magnetic resonance imaging, 12 migraine patients were examined in 82 sessions. We detected cyclic changes of brain perfusion in the limbic circuit (insula, hippocampus, and nucleus accumbens), with the highest perfusion during headache attacks. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval, then collapsing during the headache. Our data provide strong evidence for the predominant role of the hypothalamus as a zeitgeber for generating migraine attacks. Our findings suggest that migraine attacks are the result of the hypothalamus losing control over the limbic system.

neuroscience↗

bioRxiv2019

Ultra-high field imaging reveals increased whole brain connectivity underpins cognitive strategies that attenuate pain

We investigate how the attenuation of pain with cognitive interventions affects the strength of cortical connections by pursuing a whole brain approach. While receiving tonic cold pain, 20 healthy participants were asked to utilise three different pain attenuation strategies. During a 7T fMRI recording, participants were asked to rate their pain after each single trial. We related the trial-by-trial variability of the attenuation performance to the trial-by-trial functional connectivity of the cortical data. Across all conditions, we found that a higher performance of pain attenuation was predominantly associated with higher functional connectivity. Of note, we observed an association between low pain and high connectivity for regions that belong to the core areas of pain processing, i.e. the insular and cingulate cortices. For one of the cognitive strategies (safe place), the performance of pain attenuation was explained by diffusion tensor imaging metrics of increased white matter integrity. Impact StatementIn a single trial analysis, the more effective attempts to attenuate pain in three different conditions are associated with general higher functional connectivity across the entire brain.

neuroscience↗