Biology subjects

Zelaya, F.

Publications and source records attributed to Zelaya, F..

11 recordsLinked to original sources

bioRxiv2026

Multimodal imaging suggests potential immune-vascular contributions to altered regional brain perfusion and oxygen metabolism in Post-COVID-19 Syndrome

Post-COVID-19 Syndrome (PCS) frequently presents with persistent fatigue, cognitive impairment, and emotional symptoms. Although structural brain changes remain subtle, growing evidence implicates functional and metabolic disruptions in ongoing symptomatology. We used multimodal MRI to investigate cerebral perfusion and oxygen metabolism in PCS and examined their associations with cognitive function and peripheral biomarkers. We enrolled 40 individuals with prior mild SARS-CoV-2 infection, including 20 with persistent fatigue and 20 recovered controls matched for age, sex, BMI, and acute COVID-19 severity. Participants underwent structural MRI, arterial spin labelling (ASL) to quantify regional cerebral blood flow (CBF), and asymmetric spin echo imaging to estimate oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO{square}). We assessed cognition using an online battery and measured serum levels of TNF-, IL-6, IL-8, IL-13, IFN-{gamma}, GFAP, and S100{beta}, alongside blood routine tests. We performed ANCOVAs on predefined regions of interest (hippocampus, anterior cingulate cortex [ACC], insula, amygdala, striatum), followed by Bayesian inference and exploratory whole-brain analyses. PCS participants showed increased CMRO{square} in the hippocampus and decreased CMRO{square} in the ACC. Subfield analysis revealed elevated OEF and CMRO{square} across most hippocampal regions, excluding the entorhinal cortex. Whole-brain analyses identified increased perfusion in salience-related regions (insula, ACC, thalamus) and decreased perfusion in posterior cortical and cerebellar areas, in the absence of grey matter volume differences. Higher hippocampal metabolism positively correlated with cognitive performance, suggesting compensatory adaptation to sustain function. In contrast, lower ACC CMRO{square} correlated with depressive symptoms, reduced motivation, and elevated TNF- and GFAP, consistent with neurovascular uncoupling possibly driven by immune-glial activation. These findings reveal distinct physiological disruptions in PCS, with potential implications for stratified, metabolism-focused interventions.

neuroscience↗

bioRxiv2024

Transcriptional and neurochemical signatures of cerebral blood flow alterations in schizophrenia and the clinical high-risk state for psychosis

The brain integrates multiple scales of description, from the level of cells and molecules to large-scale networks and behaviour, and understanding the relationships between these layers may be fundamental to advancing our understanding of how the brain works in health and disease. Recent neuroimaging research has shown that alterations in brain function that are associated with schizophrenia spectrum disorders (SSD) are already present in young adults at clinical high-risk for psychosis (CHR-P), yet the cellular and molecular determinants of these alterations are not well understood. Here, combining regional cerebral blood flow (rCBF) data with existing transcriptomic and neurotransmitter data, we show that cell-types involved in stress response and inflammation, as well as the dopamine, acetylcholine, GABAA and NMDA receptor systems, align as shared and distinct cellular and neurochemical signatures of rCBF phenotypes in people with SSD and those at CHR-P. Decoding the biological pathways involved in neuroimaging-based psychosis phenotypes may provide a basis for the development of novel interventions.

neuroscience↗

bioRxiv2023

Anhedonia severity mediates the relationship between attentional networks recruitment and emotional blunting during music listening

Recent studies have reported atypical emotional processing in individuals with greater levels of anhedonic depressive symptoms. However, the relationship between brain networks dynamics and moment-to-moment affective responses to naturalistic paradigms, as emotions are unfolding, remains unclear. In this study, we used the unique temporal characteristics of music to investigate behavioural and brain network dynamics as a function of anhedonic depressive symptoms severity in healthy adults during an emotionally provocative music listening task. Thirty-one neurotypical participants aged 18-30 years were required to continuously rate happy, neutral and sad pieces of music whilst undergoing MRI scanning. They were also asked to fill in questionnaires assessing their levels of anhedonic depressive symptoms. Using a novel fMRI analysis method called Leading Eigenvector Dynamics Analysis (LEiDA), we found an increased probability of occurrence of attentional networks and a blunted emotional response to both happy and sad pieces of music in participants with greater levels of anhedonic depressive symptoms. More specifically, anhedonic depressive symptoms mediated the relationship between attentional networks recruitment and emotional blunting. Furthermore, the elevated recruitment of attentional networks during emotional pieces of music carried over into subsequent neutral music. Future studies are needed to investigate whether these findings could be generalised to a clinical population (i.e., Major Depressive Disorder).

neuroscience↗

bioRxiv2022

The effects of acute Methylene Blue administration on cerebral blood flow and metabolism in humans and rats

Methylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the haemodynamic and metabolic effects of MB in the human brain. We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p=0.02) and rats (F(1,5)26.04, p=0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p=0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t=2.6(16) p=0.018). This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MBs hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MBs ability to enhance cerebral metabolism might be limited.

neuroscience↗

bioRxiv2022

Molecular-enriched functional connectivity in the human brain using multiband multi-echo simultaneous ASL/BOLD fMRI

Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) is a novel analytical strategy that enriches functional connectivity (FC) information from functional MRI (fMRI) with molecular information on the neurotransmitter distribution density in the human brain, providing a biological basis to the FC analysis. So far, this integrative approach has been used in blood oxygen level-dependent (BOLD) fMRI studies only, providing new insights into the brain mechanisms underlying specific disorders and its response to pharmacological challenges. In this study, we demonstrate that the application of REACT can be further extended to arterial spin labelling (ASL) fMRI. Some of the advantages of this extension include the combination of neurotransmitter specific information provided by molecular imaging with a quantitative marker of neuronal activity, the suitability of ASL for pharmacological MRI (phMRI) studies assessing drug effects on baseline brain function, and the possibility to acquire images that are not affected by susceptibility artifacts in the regions linked to major neurotransmitter systems. In this work, we tested the feasibility of applying REACT to resting state ASL fMRI and compared the molecular-enriched FC maps derived from ASL data with those derived from BOLD data. We applied REACT to high-resolution, whole-brain simultaneous ASL/BOLD resting-state fMRI data of 29 healthy subjects and estimated the ASL- and BOLD-based FC maps related to six molecular systems, including the transporters of dopamine, noradrenaline, serotonin and vesicular acetylcholine, and the GABA-A and mGlu5 receptors. We then compared the ASL and BOLD FC maps in terms of spatial similarity, using the Dice Similarity Index and the voxel-wise spatial correlation. On a data subsample (N=19) we also evaluated the test-retest reproducibility of each modality using the regional intraclass correlation coefficient, and compared the two modalities. Our results showed robust spatial patterns of molecular-enriched functional connectivity for both modalities, moderate to high similarity between BOLD- and ASL-derived FC maps and mixed results in terms of reproducibility (i.e., none of the modalities outperformed the other). Overall, our findings show that the ASL signal is as informative as BOLD in detecting functional circuits associated with specific molecular pathways, and that the two modalities may provide complementary information related to these circuits. Considering the more direct link of ASL imaging with neuronal acrivity compared to BOLD and its suitability for phMRI studies, this new integrative approach could become a valuable asset in clinical studies investigating functional alterations in patients with brain disorders, or in pharmacological studies investigating the effects of new or existing compounds on the brain.

neuroscience↗

bioRxiv2021

Less is more: a dose-response mechanistic account of intranasal oxytocin pharmacodynamics in the human brain

Intranasal oxytocin is receiving increasing research attention as a potential treatment for several brain disorders due to promising preclinical results. However, translating these findings to humans has been hampered by remaining uncertainties about its pharmacodynamics and the methods used to probe its effects in the human brain. Using a dose-response design (9, 18 and 36 IU) and a novel administration device, we demonstrate that oxytocin-induced physiological changes in the amygdala at rest, a key-hub of the brain oxytocin system, follow a dose-response curve with maximal effects for lower doses. Yet, the effects of oxytocin vary by amygdala subdivision, highlighting the need to qualify dose-response curves within subregion. We further link physiological changes with the density of the oxytocin receptor gene mRNA across brain regions, strengthening our confidence in intranasal oxytocin as a valid approach to engage central targets. Finally, we demonstrate that intranasal oxytocin does not disrupt cerebrovascular reactivity; the absence of major vascular confounds corroborates the validity of haemodynamic neuroimaging to probe the effects of intranasal oxytocin in the human brain.

neuroscience↗

bioRxiv2020

Investigating resting brain perfusion abnormalities and target-engagement by intranasal oxytocin in women with bulimia nervosa and binge-eating disorder and healthy controls

Advances in the treatment of bulimia nervosa and binge eating disorder (BN/BED) have been marred by our limited understanding of the underpinning neurobiology. Here we measured regional cerebral blood flow (rCBF) to map resting perfusion abnormalities in women with BN/BED compared to healthy controls and investigate if intranasal oxytocin (OT), proposed as a potential treatment, can restore perfusion in disorder-related brain circuits. Twenty-four women with BN/BED and 23 healthy women participated in a randomised, double-blind, crossover, placebo-controlled study. We used arterial spin labelling MRI to measure rCBF and the effects of an acute dose of intranasal OT (40IU) or placebo over 18-26 minutes post-dosing, as we have previously shown robust OT-induced changes in resting rCBF in men 15-36min post-dosing. We tested for effects of treatment, diagnosis and their interaction on extracted rCBF values in anatomical regions-of-interest previously implicated in BN/BED by other neuroimaging modalities, and conducted exploratory whole-brain analyses to investigate previously unidentified brain regions. We demonstrated that women with BN/BED presented increased resting rCBF in key neural circuits previously implicated in BN/BED pathophysiology, namely the medial prefrontal and orbitofrontal cortices, anterior cingulate gyrus, posterior insula and middle/inferior temporal gyri bilaterally. Hyperperfusion in these areas specifically correlated with eating symptoms severity in patients. Our data did not support a normalizing effect of 40IU intranasal OT on perfusion abnormalities in these patients 18-26 minutes post-dosing. Our findings enhance our understanding of resting brain abnormalities in BN/BED and identify resting rCBF as a non-invasive potential biomarker for disease-related changes and treatment monitoring.

neuroscience↗

bioRxiv2019

ExploreASL: an image processing pipeline for multi-center ASL perfusion MRI studies

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners. The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. The toolbox adheres to previously defined international standards for data structure, provenance, and best analysis practice. ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow. ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts to increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

neuroscience↗

bioRxiv2019

Do direct nose-to-brain pathways underlie intranasal oxytocin-induced changes in regional cerebral blood flow in humans?

Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.

neuroscience↗

bioRxiv2018

Increased Cerebral Blood Flow after single dose of antipsychotics in healthy volunteers depends on dopamine D2 receptor density profiles.

As a result of neuro-vascular coupling, the functional effects of antipsychotics in human brain have been investigated in both healthy and clinical populations using haemodynamic markers such as regional Cerebral Blood Flow (rCBF). However, the relationship between observed haemodynamic effects and the pharmacological action of these drugs has not been fully established. Here, we analysed MRI-based rCBF data from a placebo-controlled study in healthy volunteers, who received a single dose of three different D2 receptor antagonists and tested the association of the main effects of the drugs on rCBF against normative population maps of D2R protein density and gene-expression data. In particular, we correlated CBF changes after antipsychotic administration with non-displaceable binding potential (BPND) template maps of the high affinity D2-antagonist Positron Emission Tomography (PET) ligand [18F]Fallypride and brain post-mortem microarray mRNA expression data for the DRD2 gene. For all antipsychotics, rCBF changes were directly proportional to brain D2R densities and DRD2 mRNA expression measures, although PET BPND spatial profiles explained more variance as compared with mRNA profiles (PET R2 range= 0.20-0.60, mRNA PET R2 range 0.04-0.20, pairwise-comparisons all p<0.05). In addition, the spatial coupling between {Delta}CBF and D2R profiles varied between the different antipsychotics tested, possibly reflecting differential affinities. Overall, these results indicate that the functional effects of antipsychotics as measured with rCBF are tightly correlated with the distribution of their target receptors in striatal and extra-striatal regions. Our results further demonstrate the link between neurotransmitter targets and haemodynamic changes reinforcing rCBF as a robust in-vivo marker of drug effects. This work is important in bridging the gap between pharmacokinetic and pharmacodynamics of novel and existing compounds.

pharmacology and toxicology↗

bioRxiv2017

Cerebral blood flow predicts differential neurotransmitter activity

Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.

neuroscience↗