Biology subjects

Brammerloh, M.

Publications and source records attributed to Brammerloh, M..

9 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

OCTOPUS: A versatile open-source tool creating realistic numericalbrain cells

Brain cell morphology plays a crucial role in function and pathology. Biophysical models of diffusion MRI (dMRI) quantify cell morphology in vivo, enabling the design of novel biomarkers. These models represent cells by simplified geometries, such as spheres and randomly oriented cylinders, for which analytical signal expressions exist. However, dMRI signals are sensitive to morphological features, such as branching, tapering, undulation, beading, and protrusions, unaccounted for in most models, as they often render analytical solutions impossible. Simulations of the dMRI signal in synthetically generated cells offer a powerful tool to explore how microstructural morphology impacts the dMRI signal. Nevertheless, no tool to generate digital replicas of brain cells is available openly. To address this gap, we introduce the OCTOPUS toolbox, which generates cells featuring all geometrical features described above. OCTOPUS, provided via the Python interface OCTOpool, enables accessible, efficient creation of cells with complex geometries. We recreated histologically reconstructed neuronal and glial cells, including pyramidal, GABAergic and glutamatergic neurons, and astro- and microglia. To illustrate the plausibility of OCTOPUS-generated cells, we reproduced established properties of dMRI signals from brain tissue, such as the signatures of short-range disorder, branching and protrusions, and a high-b-value power law. By comparing the geometries and dMRI signals of generated and original cells, we found different growth strategies adequate for more isotropic and more anisotropic cells. We anticipate that realistic cell substrates created by OCTOPUS will help validate biophysical models, design dMRI sequences sensitive to fine-grained cell morphology beyond analytical models, and generate realistic numerical substrates of brain tissue.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

bioRxiv2026

Multimodal imaging reveals no evidence for magnetite-based magnetoreceptors in the mole-rat eye

Magnetoreception, the ability to perceive the geomagnetic field, is widespread across animals. The underlying sensory mechanism remains elusive, but a long-standing hypothesis proposes single-domain magnetite linked to mechanosensitive ion channels. The Ansells mole-rat (Fukomys anselli) is a subterranean rodent with a magnetic sense, and published behavioral and histological data are consistent with magnetite-based magnetoreceptors in the cornea or retina. Here, we systematically screened for magnetite in the mole-rat eye, combining iron detection via enhanced Prussian blue staining and synchrotron X-ray fluorescence microscopy (XFM) with magnetic detection via MRI quantitative susceptibility mapping (MRI-QSM) and quantum-diamond microscopy (QDM). This revealed only a few iron particles in the retina and cornea, which predominantly overlapped with titanium or chromium, indicating a non-biogenic origin. XFM showed iron-enriched lines in the cornea, but these did not show ferrimagnetic signals. Focusing on other ocular tissues, MRI-QSM revealed the highest susceptibility in the ciliary body, where iron-rich pigmented cells were identified. A TEM-screen, however, failed to detect single-domain magnetite particles in these cells. We conclude that our high-sensitivity multimodal screen provides no evidence for magnetite-based magnetoreceptors in the mole-rat eye, suggesting that mole-rat magnetoreceptors either do not reside in the eye or are based on different physical principles.

neuroscience↗

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.

neuroscience↗

bioRxiv2026

Validating Neurite EXchange Imaging (NEXI) using diffusion Monte Carlo simulations in realistic numerical gray matter substrates

NEXI is a gray matter (GM) microstructural model designed to probe brain tissue microstructure in vivo using diffusion MRI. NEXI describes GM as two exchanging Gaussian compartments - neurites, modeled as randomly oriented, infinitely long sticks, and the extracellular space - allowing the estimation of biophysically interpretable parameters related to neurite microstructure and intercompartmental exchange. While modeling cell processes as sticks and each compartment as Gaussian are common assumptions for brain biophysical models of diffusion, neurite structural irregularities and the presence of somas, particularly in GM, may violate them and bias NEXI parameter estimates. Furthermore, the barrier-limited exchange assumed in the Karger model that underlies NEXI may also be violated in realistic conditions. Therefore, in this work, we evaluate NEXIs accuracy in numerical substrates that incorporate realistic GM features and membrane permeability. To this end, we generated several GM-like substrates with neurite beading, undulation, orientation dispersion, and somas across a range of membrane permeabilities. Diffusion signals were generated with Monte Carlo simulations of water diffusion and subsequently fitted with NEXI. Overall, NEXI accurately recovered exchange times across permeability levels and successfully disentangled exchange effects from other microstructural features, showing only minor bias in estimates from the realistic geometries. These results support its potential for in vivo GM microstructure mapping and studies of brain disorders.

neuroscience↗

bioRxiv2025

CATERPillar: A Flexible Framework for Generating White Matter Numerical Substrates with incorporated Glial Cells

Monte Carlo diffusion simulations in numerical substrates are valuable for exploring the sensitivity and specificity of the diffusion MRI (dMRI) signal to realistic cell microstructure features. A crucial component of such simulations is the use of numerical phantoms that accurately represent the target tissue, which is in this case, cerebral white matter (WM). This study introduces CATERPillar (Computational Axonal Threading Engine for Realistic Proliferation), a novel method that simulates the mechanic of axonal growth using overlapping spheres as elementary units. CATERPillar facilitates parallel axon development while preventing collisions, offering user control over key structural parameters such as cellular density, undulation, beading and myelination. Its uniqueness lies in its ability to generate not only realistic axonal structures but also realistic glial cells, enhancing the biological fidelity of simulations. We showed that our grown substrates feature distributions of key morphological parameters that agree with those from histological studies. The structural realism of the astrocytic components was quantitatively validated using Sholl analysis. Furthermore, the time-dependent diffusion in the extra- and intra-axonal compartments accurately reflected expected characteristics of short-range disorder, as predicted by theoretical models. CATERPillar is open source and can be used to (a) develop new acquisition schemes that sensitise the MRI signal to unique tissue microstructure features, (b) test the accuracy of a broad range of analytical models, and (c) build a set of substrates to train machine learning models on. HighlightsO_LICATERPillar generates realistic synthetic voxels of white matter containing packed axons and glial cells. C_LIO_LISynthetic axons had similar morphologies to those segmented from human electron microscopy in previous works. C_LIO_LIThe morphological features of synthetic astrocytes closely matched those observed in histology. C_LIO_LIThe functional form of diffusion and kurtosis time-dependence in the intraand extra-axonal spaces agreed with experimentally observed disorder power laws in voxels composed of synthetic axons. C_LI

neuroscience↗

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.

neuroscience↗