Biology subjects

Ranft, A.

Publications and source records attributed to Ranft, A..

11 recordsLinked to original sources

bioRxiv2026

The blueprint of human functional architecture shifts from cognition to anatomy during perturbations of consciousness

Consciousness and cognition arise from the ongoing interactions between brain regions. Synchronous fluctuations of fMRI signals may indicate that two brain regions perform similar cognitive functions, but neural interactions are also constrained by anatomical connectivity and regions molecular, cytoarchitectonic, and metabolic profiles. Here we disentangle the respective contributions of ongoing cognition and multimodal neurobiological constraints in shaping functional connectivity. We jointly contextualise haemodynamic FC against eight distinct multimodal representations of the human connectome: (i) structural connectivity from diffusion tractography; (ii) spatial embedding; (iii) similarity of transcriptional profiles from gene expression; (iv) similarity of receptor profiles from Positron Emission Tomography; (v) laminar profile similarity from histology; (vi) correlated electrophysiological activity from magnetoencephalography; (vii) correlated metabolic activity from PET glucose uptake; (viii) coordinated activation across 123 cognitive operations from the NeuroSynth meta-analytic engine. We demonstrate that cognitive co-activation is the dominant predictor of inter-regional fMRI synchrony in the awake human brain, even when quantified using intracranial electrical stimulation. Crucially, this predominance of cognitive co-activation for shaping functional connectivity is systematically obliterated across five datasets of pharmacological and pathological perturbations of consciousness (chronic disorders of consciousness; anaesthesia with sevoflurane, propofol, or ketamine) when cognition is disconnected from the environment or altogether abolished. Altogether, we show that multimodal predictors of functional architecture shift away from cognitive co-activation and toward anatomicalmolecular constraints during pharmacological and pathological perturbations of consciousness.

neuroscience↗

bioRxiv2026

Directed cortical connectivity inferred from neural energy metabolism

Complex cognition depends on directed communication between brain regions. Yet, resting functional MRI resolves only undirected associations, and inferring the direction of signalling has proven difficult across the whole brain. Because synaptic transmission is metabolically asymmetric, with the postsynaptic neuron bearing most of the energetic cost, regional energy demand carries a physical signature of the direction of communication. Here, we show that this signature organizes the human cortex into a reproducible directed hierarchy, in which sensory and attentional systems preferentially drive higher-order networks, while the default mode and control networks act as principal receivers. Critically, the inferred directionality is independently predicted by two cellular markers of neuronal energy demand, regional mitochondrial density and laminar cytoarchitecture, linking macroscale information flow to its cellular substrate. The directed architecture recapitulates the known feedforward and feedback organization of visual pathways and, using an average CMRGlc template, extends to functional MRI acquired without PET. By grounding communication direction in energy metabolism, Metabolic Connectivity Mapping bridges correlative and effective connectivity and offers a scalable, biologically interpretable framework for mapping directed communication across the human brain.

neuroscience↗

bioRxiv2025

Comprehensive profiling of anaesthetised brain dynamics across phylogeny

Intrinsic dynamics of neuronal circuits shape information processing. Combining neuroimaging with causal perturbation offers the opportunity to understand how local dynamics mediate the link between neurobiology and functional repertoire. We compile a unique dataset of multi-scale neural activity during wakefulness and anaesthetic-induced suppression of information processing encompassing human, macaque, marmoset, mouse, zebrafish and nematode. Applying massive feature extraction, we comprehensively characterise local neural dynamics across >6,000 time-series features. Using dynamics as a common space for cross-species comparison reveals a conserved dynamical profile of anaesthesia across species, characterised by shorter intrinsic timescales of neural activity and dampened interregional synchrony. This dynamical regime is experimentally reversed in vivo by deep-brain stimulation of the macaque centromedian thalamus, restoring behavioural responsiveness. Spatially, this conserved dynamical phenotype covaries with conserved transcriptional profiles of excitatory and inhibitory neurotransmission across human, macaque, marmoset and mouse cortex. Biophysical modelling provides a mechanistic link between the macroscale dynamical phenotype of anaesthesia, and microscale effects of key molecular targets on the timescales of synaptic excitation and inhibition. Altogether, comprehensive dynamical phenotyping reveals a shared neural endpoint of anaesthesia: across species and scales, anaesthetics induce spatio-temporal isolation of local neural activity.

neuroscience↗

bioRxiv2024

Simultaneous quantification of oxygen and glucose consumption during visual stimulation in the human cortex

The brain is fueled by oxidative glucose metabolism, yet activation may uncouple oxygen and glucose consumption. Because the two have never been measured simultaneously in humans across conditions, we combined multiparametric quantitative BOLD (mqBOLD) imaging with functional PET (fPET) during rest and visual stimulation. Participants (n = 12 with complete data) were scanned on an integrated PET/MR system during alternating six-minute blocks of checkerboard stimulation and fixation, with continuous arterial sampling. Cerebral metabolic rates of oxygen (CMRO2) and glucose (CMRglc), and cerebral blood flow (CBF) were quantified per condition and combined into the oxygen-to-glucose index (OGI = CMRO2/CMRglc), where six indicates fully oxidative glucose use. At rest, OGI was 4.6-5.0 in task-responsive visual regions and 4.9 elsewhere. Stimulation increased CMRglc (12-26%) and CBF (10-22%) more than CMRO2; (3-10%, not significant), lowering OGI by 12% in metabolically defined visual regions. Beyond the visual cortex, OGI fell 8%, significantly in 47% of cortical regions. The mechanisms differed, however: glycolytic upregulation in visual cortex (CBF, CMRglc up) versus oxidative downregulation elsewhere (CBF, CMRO2; down; CMRglc unchanged). Simultaneous imaging thus shows that focal activation shifts metabolism toward glycolysis across the cortex, with consequences for interpreting metabolic contrasts outside engaged regions.

neuroscience↗

bioRxiv2023

General anaesthesia reduces the uniqueness of brain connectivity across individuals and across species

The human brain is characterised by idiosyncratic patterns of spontaneous thought, rendering each brain uniquely identifiable from its neural activity. However, deep general anaesthesia suppresses subjective experience. Does it also suppress what makes each brain unique? Here we used functional MRI under the effects of the general anaesthetics sevoflurane and propofol to determine whether anaesthetic-induced unconsciousness diminishes the uniqueness of the human brain: both with respect to the brains of other individuals, and the brains of another species. We report that under anaesthesia individual brains become less self-similar and less distinguishable from each other. Loss of distinctiveness is highly organised: it co-localises with the archetypal sensory-association axis, correlating with genetic and morphometric markers of phylogenetic differences between humans and other primates. This effect is more evident at greater anaesthetic depths, reproducible across sevoflurane and propofol, and reversed upon recovery. Providing convergent evidence, we show that under anaesthesia the functional connectivity of the human brain becomes more similar to the macaque brain. Finally, anaesthesia diminishes the match between spontaneous brain activity and meta-analytic brain patterns aggregated from the NeuroSynth engine. Collectively, the present results reveal that anaesthetised human brains are not only less distinguishable from each other, but also less distinguishable from the brains of other primates, with specifically human-expanded regions being the most affected by anaesthesia.

neuroscience↗

bioRxiv2023

An energy costly architecture of neuromodulators for human brain evolution and cognition

Humans spend more energy on the brain than any other species. However, the high energy demand cannot be fully explained by brain size scaling alone. We hypothesized that energy-demanding signaling strategies may have contributed to human cognitive development. We measured the energy distribution along signaling pathways using multimodal brain imaging and found that evolutionarily novel connections have up to 67% higher energetic costs of signaling than sensory-motor pathways. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an upregulation of signaling at G-protein coupled receptors in energy-demanding regions. We found that neuromodulators are predominantly involved in complex cognition such as reading or memory processing. Our study suggests that the upregulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.

neuroscience↗

bioRxiv2023

Global neuronal activity drives cerebrospinal fluid motion mediated by brain blood volume changes in humans

In the mammalian brain, the directed motion of cerebrospinal fluid (CSF-flux) is instrumental in the distribution and removal of solutes. Changes in total cerebral blood volume (CBV) have been hypothesized to drive CSF-flux. We tested this hypothesis in two multi-modal brain imaging experiments in healthy humans, in which we drove large changes in total CBV by neuronal burst-suppression under anesthesia, or by transient global vasodilation in a hypercapnic challenge. We developed a technique to monitor CBV changes based on associated changes in total brain volume by functional MRI (fMRI) and measured cerebral blood flow by arterial spin-labeling. Relating CBV-sensitive signals to fMRI-derived measures of macroscopic CSF flow across the basal cisternae, we demonstrate that increasing total CBV extrudes CSF from the skull and decreasing CBV allows its influx. Moreover, CSF largely stagnates when CBV is stable. Together, our results establish the direct coupling between total CBV changes and CSF-flux.

neuroscience↗

bioRxiv2022

Mapping Pharmacologically-induced Functional Reorganisation onto the Brain's Neurotransmitter Landscape

To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brains rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically-induced macroscale functional reorganisation, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from Positron Emission Tomography, and the regional changes in functional MRI connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, LSD, psilocybin, DMT, ayahuasca, MDMA, modafinil, and methylphenidate. Our results reveal that psychoactive drugs exert their effects on brain function by engaging multiple neurotransmitter systems. The effects of both anaesthetics and psychedelics on brain function are organised along hierarchical gradients of brain structure and function. Finally, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganisation of the brains functional architecture.

neuroscience↗

bioRxiv2021

Spatial signatures of anesthesia-induced burst-suppression differ between primates and rodents

During deep anesthesia, the electroencephalographic (EEG) signal of the brain alternates between bursts of activity and periods of relative silence (suppressions). The origin of burst-suppression and its distribution across the brain remain matters of debate. In this work, we used functional magnetic resonance imaging (fMRI) to map the brain areas involved in anesthesia-induced burst-suppression across four mammalian species: humans, long-tailed macaques, common marmosets, and rats. At first, we determined the fMRI signatures of burst-suppression in human EEG-fMRI data. Applying this method to animal fMRI datasets, we found distinct burst-suppression signatures in all species. The burst-suppression maps revealed a marked inter-species difference: in rats the entire neocortex engaged in burst-suppression, while in primates most sensory areas were excluded--predominantly the primary visual cortex. We anticipate that the identified species-specific fMRI signatures and whole-brain maps will guide future targeted studies investigating the cellular and molecular mechanisms of burst-suppression in unconscious states.

neuroscience↗

bioRxiv2021

Translational evidence for RRM2 as a prognostic biomarker and therapeutic target in Ewing sarcoma

PurposeEwing sarcoma (EwS) is a highly aggressive bone- or soft tissue-associated malignancy mostly affecting children, adolescents, and young adults. Although multimodal therapies have strongly improved patients overall survival over the past decades, the development of prognostic biomarkers for risk-based patient stratification and more effective therapies with less adverse effects is stagnating. Thus, new personalized medicine approaches are urgently required. Experimental designGene expression data of EwS and normal tissues were crossed with survival data to identify highly overexpressed, prognostically relevant, and actionable potential targets. RNA-interference and dose-response assays as well as tissue-microarray analyses were carried out to explore the functional role and druggability of a prominent candidate gene in vitro and in vivo, and to validate its suitability as a prognostic biomarker. ResultsEmploying a multilayered screening approach, we discover ribonucleotide reductase regulatory subunit M2 (RRM2) as a promising therapeutic target and prognostic biomarker in EwS. Through analysis of two independent EwS patient cohorts, we show that RRM2 mRNA and protein overexpression is associated with an aggressive clinical phenotype and poor patients overall survival. In agreement, RRM2 silencing as well as pharmacological inhibition by the specific inhibitor triapine (3-AP) significantly reduces EwS growth in vitro and in vivo. Furthermore, we present evidence that pharmacological RRM2 inhibition by triapine can overcome chemoresistance against doxorubicin or gemcitabine, and synergize with cell cycle checkpoint inhibitors (CHEK1 or WEE1). ConclusionsBased on the aggressive phenotype mediated by and the druggability of RRM2 our results provide a translational rationale for exploiting RRM2 as a novel therapeutic target in EwS and prompt further clinical investigations.

cancer biology↗

bioRxiv2018

SOX2 expression identifies Ewing sarcoma patients with high risk for tumor relapse and poor survival

Purpose: Up to 30-40% of Ewing sarcoma (EwS) patients with non-metastatic disease develop local or metastatic relapse within a time range of 2-10 years. This is in part caused by the absence of prognostic biomarkers that can identify high-risk patients to assign them to risk-adapted monitoring and treatment regimens. Since cancer stemness has been associated with tumor relapse and poor outcome, we investigated in the current study the prognostic potential SOX2 (sex determining region Y box 2) - a major transcription factor involved in development and stemness - previously described to contribute to the undifferentiated phenotype of EwS. Methods: Two independent patient cohorts, one consisting of 189 retrospectively collected EwS tumors with corresponding mRNA expression data (test cohort) and the other of 141 prospectively collected formalin-fixed and paraffin embedded resected tumors (validation cohort), were employed to analyze SOX2 expression levels by DNA microarrays or immunohistochemistry, respectively, and to compare them with clinical parameters and patient outcome. Two methods were employed to test the validity of the results at both mRNA and protein levels. Results: Both cohorts showed that only a subset of EwS patients (16-20%) express high SOX2 mRNA or protein levels, which significantly correlated with poor overall survival. Multivariate analyses of our validation cohort revealed that high SOX2 expression represents a major risk factor for survival (HR=3.19; P<0.01) that is independent from metastasis and other known clinical risk-factors at time of diagnosis. Univariate analysis demonstrated that SOX2-high expression correlated with tumor relapse (P=0.001). Median first relapse was at 14.7 months (range: 3.5-180.7). Conclusions: High SOX2 expression constitutes an independent prognostic biomarker for EwS patients with poor outcome, which may help to identify patients with localized disease who are at high risk for tumor relapse within the first two years after diagnosis.

pathology↗