Biology subjects

Kirilina, E.

Publications and source records attributed to Kirilina, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Selective nigrosome vulnerability in Parkinson's disease revealed by histology-anchored ultra-high-field quantitative MRI

Selective vulnerability is a hallmark of Parkinson's disease (PD): post-mortem, dopamine-containing cell loss in the substantia nigra first and most severely affects calbindin-poor compartments termed nigrosomes. Testing this in vivo has been limited by circularity, as MRI studies have delineated nigrosomes from the same disease-related contrast they then measure. Here, we warp histology-derived, calbindin-validated probabilistic masks of nigrosomes 1-5 into a cohort-specific multimodal 7 Tesla quantitative MRI template, providing a degeneration-independent anatomical scaffold, in 28 patients with PD and 28 age- and sex-matched controls. In controls, nigrosomes differ from the surrounding nigral matrix in magnetic susceptibility and R1. PD shifts nigrosomal values upward relative to the matrix in susceptibility, R2*, and R1, concentrated in nigrosomes 1, 2, and 4, whereas whole-nigra analysis shows no group difference. Within the matrix, disease effects are largest caudally and emerge dorsally from the ventral tier, and susceptibility alterations in nigrosomes 1 and 4 track contralateral motor symptoms asymmetry. The multimodal pattern suggests that the detectable signal reflects predominantly secondary, iron-associated glial processes rather than neuronal loss itself. These findings recover the post-mortem spatial pattern of nigral vulnerability in vivo and establish a degeneration-independent framework for subregional nigral imaging in PD.

neuroscience↗

bioRxiv2026

Evolution of the motor cortex microstructure and its lateralization: a comparative study of chimpanzees and humans

Human hand coordination exceeds that of other species, including great apes, and is marked by pronounced right-hand dominance. This specialization parallels an expansion of its cortical representation, forming the hand-knob in the motor cortex. In humans, this region shows high myelination on quantitative MRI (qMRI), but whether this feature is shared with great apes remains unclear. It is also unknown whether increased right-hand dominance in humans is mirrored by greater hemispheric asymmetry in cortical microstructure. Using high-resolution qMRI, we compared motor cortex subdivisions controlling the leg, hand, and face in humans and chimpanzees. We found consistently higher myelin and iron content in the hand-knob in both species, suggesting an evolutionarily conserved role. However, only humans showed enhanced rightward lateralization. These results highlight both conserved and species-specific features of the motor cortex, offering insights into the evolution of manual dexterity and handedness.

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bioRxiv2026

Single-cell quantification of the iron-neuromelanin balance in dopaminergic neurons across the lifespan

Dopaminergic neurons in the substantia nigra depend on iron for dopamine synthesis but are vulnerable to iron-induced oxidative stress. Many of these neurons synthesize neuromelanin, an iron-chelating pigment that accumulates across the lifespan and makes them vulnerable in Parkinsons disease. It remains unclear whether their selective vulnerability arises from neuromelanin overload or from the release of toxic labile iron from the oversaturated pigment. We quantified iron and neuromelanin at the single-cell level across the lifespan of chimpanzees, a species closely resembling humans in pigment and iron accumulation. Combining quantitative MRI, X-ray fluorescence imaging, and microscopic colorimetry, we found that the iron-to-neuromelanin ratio remains stable with age across large neuronal populations. Chemical equilibrium modeling of the iron binding in neuromelanin indicated that cytosolic labile iron concentrations remain low throughout adulthood. We have found no evidence for neuromelanin saturation or increased iron-mediated toxicity with age. This finding challenges the hypothesis that neuromelanin saturation drives age-related dopaminergic vulnerability. The presented method provides a quantitative framework for studying iron homeostasis in these neurons.

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bioRxiv2026

Giving you five: A neuroimaging atlas of the nigrosomes in the substantia nigra based on 3D histology

Nigrosomes are formed by clusters of pigmented dopaminergic cells in the substantia nigra that critically contribute to dopaminergic function. The ever-increasing resolution of ultra-high-field MRI brings clinical imaging of these clusters into reach, promising unprecedented insight into the functional role of the nigrosomes and their early degeneration in Parkinsons disease. However, due to the nigrosomes small extents and intricate shapes, they are not included in current MRI brain atlases, preventing nigrosome-specific MRI data analysis. We provide a comprehensive 3D histological atlas of the five nigrosomes co-aligned to the widely-used MNI152 2009b space. This atlas is based on 3D-reconstructed, ultra-high-resolution block-face images and gold-standard nigrosome delineations in calbindin-D28K immunohistochemistry. We validated the atlass accuracy using the multimodal ultra-high-resolution post mortem BigBrain dataset and demonstrated its consistency with qualitative nigrosome atlases based on classical 2D histology. We provide detailed usage instructions for applying our atlas to ultra-high-resolution and -field MRI data. The openly available atlas enables neuroimaging studies of the nigrosomes, opening a new avenue toward understanding the differential involvement of the nigrosomes in the healthy and diseased brain and the development of neuroimaging biomarkers of dopaminergic neurodegeneration.

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bioRxiv2026

Inter- and intra-individual variability in structure-function coupling in human brain

Microstructure shapes functional brain dynamics. Yet this notion has remained largely untested for human brain signals measured with electroencephalography and magnetoencephalography (EEG/MEG). In this study, we related functional activity variance to microstructural variance across brain regions and across participants. Across regions, we used multiple independent datasets: EEG (n=209), MEG (n=507), high-resolution MRI (n=10), and the human post-mortem brain. Across participants, we used a multimodal dataset including MEG and high-resolution MRI (n=31). Between regions, alpha power correlated positively with layer IV thickness and with myelin and iron estimates at mid-cortical depth. By contrast, between participants, alpha power correlated negatively with mid-cortical myelin and iron estimates. Using computational modeling, we demonstrated that regional effects are consistent with excitatory changes, whereas inter-individual effects may be driven by inhibitory influence. This dissociation reveals distinct underlying mechanisms and indicates that different factors influence intra-versus inter-individual variations in alpha activity.

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bioRxiv2026

A precise atlas of the human subcortex

Clinical interventions and neuroimaging in the subcortex require anatomical definitions that exceed the resolution and anatomical detail of currently available deformable brain atlases. Here, we introduce a high-resolution human brain atlas comprising 95 manually segmented grey and white matter structures as well as 82 white matter tracts compiled from a multitude of resources including ex-vivo MRI, histology, fibre dissections, and neuroanatomy textbooks. The atlas is defined at an isotropic resolution of 100 m and can be precisely deformed to individual subject brain anatomy. By providing precise definitions of both grey and white matter structures within and around the basal ganglia, thalamus, subthalamus, midbrain and cerebellum, the atlas provides a foundational resource for stereotactic surgery and subcortical brain imaging research, as well as for development of next-generation neuromodulation strategies.

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bioRxiv2026

Longitudinal whole-human-brain quantitative MRI study on autolysis, fixation, rehydration, and shrinkage effects

Postmortem MRI links in vivo MRI contrast to microstructure measured with ex vivo histology, yet fixation systematically alters relevant physical MRI parameters. We quantified these effects by longitudinally characterizing multi-parametric mapping (MPM) measures - longitudinal (R1) and effective transverse (R2*) relaxation rates, normalized proton density proxy (NA), and magnetization transfer saturation (MTsat) - and tissue-volume change in five whole human brains scanned unfixed ex vivo in situ, during formaldehyde immersion fixation, and, when available, after transfer to phosphate buffered saline solution. We included an independent in vivo cohort of 25 younger healthy participants to provide a qualitative in vivo reference. The largest changes were found for R1 during fixation relative to in situ values (up to 351% in dGM), followed by R2* (up to 60% in WM). NA was largely unchanged during fixation. Although MTsat decreased by up to 25% in gray matter from in vivo to in situ, it largely preserved tissue contrast during fixation and PBS immersion, making it an ideal candidate for longitudinal registration across tissue conditions. Phenomenological models characterized fixation-induced parameter changes and relative tissue-volume change. R1 and fixation-associated volume loss evolved under broadly similar timescales, consistent with a contribution from fixation-related water loss or redistribution. This densely sampled dataset and analyses provide a resource for linking in vivo MRI to postmortem fixed-tissue MRI and ex vivo histology under a standardized immersion-fixation protocol.

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bioRxiv2026

Pooling quantitative MRI data: A multi-protocol study of healthy subcortical ageing

Quantitative MRI (qMRI) measures relaxation rates, exchange rates and proton densities that reflect biophysical properties of tissue and are ideally free from protocol- and scanner-dependence. In practice, qMRI has not yet achieved this level of independence from sequence and hardware choice, and quantitative estimates often differ across sites and acquisition schemes. At the same time pooling data across different sources can be beneficial to statistical power of longitudinal, cross-sectional or case-control studies. Here we investigate how protocol and hardware differences can affect pooling data from different sources in large ultra high field (UHF) qMRI studies in the context of healthy aging. We combine the openly available ageing UHF qMRI MP2RAGEME-based dataset with two different MPM-based sets of qMRI data. We evaluate how pooling affects age dependence of qMRI parameters and investigate protocol-related biases, with a particular focus on subcortical structures. We focus the analysis, first, on replication and expansion of the reference qMRI dataset on normative aging, second, the examination of the protocol influence on the estimated qMRI values, and third, on detecting the protocol effect on the age dependence inferred from the data. We find that the age-related changes for R1 measure around 4-17% of the lifespan mean in different structures. Similarly, age-related R2* variation in different structures constitutes around 6-30%. Subcortical structure volume change is on the order of 5-27%. We further observe larger relative difference between protocols for R1 and volume, while R2* remains more consistent for most regions. We show how pooling the UHF qMRI data from different sites and collected with different quantitative protocols can be both detrimental and beneficial for the analysis outcomes.

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bioRxiv2025

Unraveling the mesoscale functional connectivity of the human primary visual cortex using high-resolution functional MRI.

Despite their importance for visual perception, functional connectivity between ocular dominance columns (ODCs)in the human primary visual cortex (V1) remains largely unknown. Using high- resolution functional MRI (fMRI), we localized ODCs and assessed their resting-state functional connectivity (rs-FC) in 12 human adults. Consistent with anatomical studies in animals, we found stronger rs-FC in the middle compared to deep and superficial cortical depths and selectively stronger rs- FC between ODCs with alike compared to unalike ocular polarity. Beyond what was known from animal models, and consistent with human perceptual biases, intra- and interhemispheric rs-FC was stronger in peripheral (compared to central) and in dorsal (compared to ventral) V1 subregions. Lastly, rs-FC patterns correlated with ODC maps, suggesting that ODC maps can be predicted from rs-FC patterns within V1. These results highlight the heterogeneity in rs-FC between ODCs across cortical depths and V1 subfields, underscoring their likely association with human perceptual features.

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bioRxiv2024

Lifespan trajectory of chimpanzee brains characterized by magnetic resonance imaging histology

Chimpanzee brain maturation provides an invaluable framework for understanding the evolution of the human brain. We performed ultra-high resolution quantitative magnetic resonance imaging (qMRI) with histological validation on post mortem brains from captive and wild chimpanzees with a broad age range. We mapped developmental myelination and age-related iron accumulation across regions and layers of the neocortex. Compared to humans, chimpanzees showed more myelination and iron deposition in motor and premotor cortices, while the auditory cortex was more strongly myelinated in humans. Our model suggests that chimpanzees cortical myelination was largely completed by the age of nine years, while iron accumulation continued throughout the lifespan. The regions with highest adult levels of myelin and iron took the longest to mature, challenging the widespread assumption that highly myelinated regions complete their development first. The reported maps and developmental curves provide a foundation for comparative neuroscience research and understanding of human brain evolution.

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bioRxiv2024

Human short association fibers are thinner and less myelinated than long fibers

The size and complexity of the human brain requires optimally sized and myelinated fibers. White matter fibers facilitate fast communication between distant areas, but also connect adjacent cortical regions via short association fibers. The fundamental questions of i) how thick these fibers are and ii) how strongly they are myelinated, however, remain unanswered. We present a comprehensive analysis of [~]400,000 fibers of human white matter regions with long (corpus callosum) and short fibers (superficial white matter). We demonstrate a substantially smaller fiber diameter and lower myelination in superficial white matter than in the corpus callosum. Surprisingly, we do not find a difference in the ratio between axon diameter and myelin thickness (g-ratio), which is close to the theoretically optimal value of [~]0.6 in both areas. For the first time, to our knowledge, we shed light on a fundamental principle of brain organization that will be essential to understand the human brain.

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bioRxiv2024

Connectivity at fine scale: mapping structural connective fields by tractography of short association fibres in vivo

The extraordinary number of short association fibres (SAF) connecting neighbouring cortical areas is a prominent feature of the large gyrified human brain. The contribution of SAF to the human connectome is largely unknown because of methodological challenges in mapping them. We present a method to characterise cortico-cortical connectivity mediated by SAF in topologically organised cortical areas. We introduce the structural connective fields (sCF) metric which specifically quantifies neuronal signal propagation and integration mediated by SAF. This new metric complements functional connective field metrics integrating across contributions from short- and long-range white matter and intracortical fibres. Applying the method in the human early visual processing stream, we show that SAF preserve cortical functional topology. Retinotopic maps of V2 and V3 could be predicted from retinotopy in V1 and SAF connectivity. The sCF sizes increased along the cortical hierarchy and were smaller than their functional counterparts, in line with the latter being additionally broadened by long-range and intracortical connections. In vivo sCF mapping provides insights into short-range cortico- cortical connectivity in humans comparable to tract tracing studies in animal research and is an essential step towards creating a complete human connectome. HighlightsO_LINon-invasive mapping of Short Association Fibre (SAF) connectivity via diffusion-weighted MRI-based probabilistic tractography accurately predicted cortical functional neuroanatomy. C_LIO_LIThe novel structural Connective Fields (sCF) concept provides a quantitative measure of cortico-cortical integration facilitated by SAF, complementing the existing functional Connective Field (CF) concept. C_LIO_LISub-millimeter resolution diffusion-weighted MRI enables tractography and connective field modeling of SAF, unlocking applications previously restricted to invasive tract tracing in animal studies. C_LI

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bioRxiv2023

Neuroinfectiology of an atypical anthrax-causing pathogen in wild chimpanzees

Bacillus cereus biovar anthracis (Bcbva) is an atypical anthrax-causing bacterium, inflicting wildlife fatalities across African rainforest ecosystems. The pathogens virulence in one of our closest living relatives, the chimpanzee, together with human serological evidence, suggests Bcbva is zoonotic. While classical B. anthracis-induced anthrax has been described to affect the central nervous system at a progressive disease-state, the neuroinfectiology of Bcbva is yet unknown. Here we characterised the pathogens neuro-invasiveness via gross pathological assessment, ultra-high resolution quantitative Magnetic Resonance Imaging and histological analysis on four brains, which were extracted from naturally deceased wild chimpanzees in Tai National Park, Cote dIvoire. Based on macroscopically evident pial vessel congestion and haemorrhages as well as cortical siderosis detected via MRI, we concluded that Bcbva induced meningitis analogous to B. anthracis. Further, histological visualisation of bacteria and leukocytes in the subarachnoid space evidenced the bacteriums capability to breach the arachnoid barrier. Bcbva was detected in the brain parenchyma of all four cases. This indicates a higher ability to transgress the glia limitans and therefore exhibits a higher neuroinvasiveness compared to B. anthracis that predominantly stays confined to the meninges. Heightened glial fibrillary acidic protein (GFAP) expression but little morphological gliosis suggest a rapid disease progression leading to host-death within hours to a few days after central nervous system invasion. Overall our results reveal Bcbvas ability to breach blood-brain barriers which results in a pronounced neuropathogenicity. Bcbva causes extensive damage to the meninges and the brain parenchyma, as well as rapid and massive digestion of brain extracellular matrix in chimpanzees and potentially so in humans in case of zoonotic spillover.

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bioRxiv2023

Flicker light stimulation induces thalamocortical hyperconnectivity with LGN and higher-order thalamic nuclei

The thalamus is primarily known as a relay for sensory information; however, it also critically contributes to higher-order cortical processing and coordination. Thalamocortical hyperconnectivity is associated with hallucinatory phenomena that occur in various psychopathologies (e.g., psychosis, migraine aura) and altered states of consciousness (ASC, e.g., induced by psychedelic drugs). However, the exact functional contribution of thalamocortical hyperconnectivity in forming hallucinatory experiences is unclear. Flicker light stimulation (FLS) can be used as an experimental tool to induce transient visual hallucinatory phenomena in healthy participants. Here, we use FLS in combination with fMRI to test how FLS modulates thalamocortical connectivity between specific thalamic nuclei and visual areas. We show that FLS induces thalamocortical hyperconnectivity between LGN, early visual areas and proximal upstream areas of ventral and dorsal visual streams (e.g., hV4, VO1, V3a). Further, an exploratory analysis indicates specific higher-order thalamic nuclei, such as anterior and mediodorsal nuclei, to be strongly affected by FLS. Here, the connectivity changes to upstream cortical visual areas directly reflect a frequency-dependent increase in experienced visual phenomena. Together these findings contribute to the identification of specific thalamocortical interactions in the emergence of visual hallucinations. HighlightsO_LIFlicker light stimulation (FLS) induces thalamocortical hyperconnectivity between the first-order thalamic LGN and early visual cortices, likely due to entrainment. C_LIO_LIThalamocortical connectivity between LGN and upstream visual areas, but not V1, is associated with the intensity of visual hallucinations. C_LIO_LIThalamocortical connectivity changes with higher-order thalamic nuclei, such as anterior and mediodorsal nuclei, show strongest modulation by flicker frequency, which corresponds to the intensity of visual hallucinations. C_LI

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bioRxiv2022

B1+-correction of MT saturation maps optimized for 7T postmortem MRI of the brain

PurposeMagnetization transfer saturation (MTsat) is a useful marker to probe tissue macromolecular content and myelination in the brain. The increased [Formula] -inhomogeneity at [≥] 7T and significantly larger saturation pulse flip angles which are often used for postmortem studies exceed the limits where previous MTsat [Formula] correction methods are applicable. Here, we develop a calibration-based correction model and procedure, and validate and evaluate it in postmortem 7T data of whole chimpanzee brains. TheoryThe [Formula] dependence of MTsat was investigated by varying the off-resonance saturation pulse flip angle. For the range of saturation pulse flip angles applied in typical experiments on postmortem tissue, the dependence was close to linear. A linear model with a single calibration constant C is proposed to correct bias in MTsat by mapping it to the reference value of the saturation pulse flip angle. MethodsC was estimated voxel-wise in five postmortem chimpanzee brains. "Individual-based global parameters" were obtained by calculating the mean C within individual specimen brains and "group-based global parameters" by calculating the means of the individual-based global parameters across the five brains. ResultsThe linear calibration model described the data well, though C was not entirely independent of the underlying tissue and [Formula]. Individual-based and group-based global correction parameters (C = 1.2) led to visible, quantifiable reductions of [Formula]-biases in high resolution MTsat maps. ConclusionThe presented model and calibration approach effectively corrects for [Formula] in-homogeneities in postmortem 7T data.

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bioRxiv2020

A novel approach for assessing hypoperfusion in stroke using spatial independent component analysis of resting-state fMRI data

Individualized treatment of acute stroke depends on the timely detection of ischemia and potentially salvageable tissue in the brain. Using functional MRI (fMRI), it is possible to characterize cerebral blood flow from blood-oxygen-level-dependent (BOLD) signals without the administration of exogenous contrast agents. In this study, we applied spatial independent component analysis to resting-state fMRI data of 37 stroke patients scanned within 24 hours of symptom onset, 17 of whom received follow-up scans the next day. Our analysis revealed "Hypoperfusion spatially-Independent Components" (HICs) whose spatial patterns of BOLD signal resembled regions of delayed perfusion depicted by dynamic susceptibility contrast MRI. These HICs were detected even in the presence of excessive patient motion, and disappeared following successful tissue reperfusion. The unique spatial and temporal features of HICs allowed them to be distinguished with high accuracy from other components in a user-independent manner (AUC = 0.95, accuracy = 0.96, sensitivity = 1.00, specificity = 0.96). Our study therefore presents a new, non-invasive method for assessing blood flow in acute stroke that minimizes interpretative subjectivity and is robust to severe patient motion.

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bioRxiv2020

Measuring the iron content of dopaminergic neurons in substantia nigra with MRI relaxometry

In Parkinsons disease, the depletion of iron-rich dopaminergic neurons in substantia nigras nigrosome 1 precedes first motor symptoms by two decades. Monitoring this neuronal depletion at an early disease stage is needed for diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is particularly suitable for this task due to its sensitivity to tissue iron. However, the mechanisms of MRI contrast in substantia nigra are not well understood, hindering the development of specific biomarkers. We showed that the dominant contribution to the effective transverse MRI relaxation rate [Formula] in nigrosome 1 originates from iron accumulated in the neuromelanin of dopaminergic neurons. We linked [Formula] quantitatively to the product of cell density and local iron concentration in dopaminergic neurons, combining quantitative 3D iron histology, biophysical modeling, and quantitative MRI on post mortem brain tissue. This knowledge opens an avenue for monitoring neuronal iron and density in vivo and may be applied to detect early neurodegeneration in Parkinsons disease.

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bioRxiv2019

Does higher sampling rate (Multiband + SENSE) benefit the detection of task correlated BOLD for cognitive neuroscience applications at 3T?

Multiband (MB) or Simultaneous multi-slice (SMS) acquisition schemes allow the acquisition of MRI signals from more than one spatial coordinate at a time. Commercial availability has brought this technique within the reach of many neuroscientists and psychologists. Most early evaluation of the performance of MB acquisition employed resting state fMRI or the most basic tasks. In this study, we tested whether the advantages of using MB acquisition schemes generalize to group analyses using a cognitive task more representative of typical cognitive neuroscience applications. Twenty-three subjects were scanned on a Philips 3T scanner using five sequences up to eight-fold acceleration with MB-factors 1 to 4, SENSE factors up to 2 and corresponding TRs of 2.45s down to 0.63s, while they viewed (i) movies showing complex actions with hand object interactions and (ii) control movies without hand object interaction. Using random effects group-level, voxel-wise analysis we found that all sequences were able to detect the basic action observation network known to be recruited by our task. The highest t-values were found for sequences with MB4 acceleration. For the MB1 sequence, a 50% bigger voxel volume was needed to reach comparable t-statistics. The group-level t-values for resting state networks (RSNs) were also highest for MB4 sequences. Here the MB1 sequence with larger voxel size did not perform comparable to the MB4 sequence. Altogether, we can thus recommend the use of MB4 (and SENSE 1.5 or 2) on a Philips scanner when aiming to perform group-level analyses using cognitive block design fMRI tasks and voxel sizes in the range of cortical thickness (e.g. 2.7mm isotropic). While results will not be dramatically changed by the use of multiband, our results suggest that MB will bring a moderate but significant benefit.

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