Biology subjects

Weiskopf, N.

Publications and source records attributed to Weiskopf, N..

At least 19 recordsLinked to original sources

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.

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

3D Histology Validates 2D Histology for Axon Radius Distributions and Conduction Velocities

Axons are the brains wiring, organized into bundles that connect nearby and distant regions. Axon caliber determines signal conduction velocity and varies both within and across bundles, reflecting the brains diverse functional demands. Much of what we know about this organization derives from 2D histology, assuming cylindrical axons whose calibers are described by their radius. Yet, recent 3D histology reveals that the radius varies along an individual axon--with implications for both characterizing axon caliber and potentially conduction velocity predictions. We show in 450,000 3D rat axon reconstructions that--despite this individual variation--axon bundles possess stable radius distributions at the ensemble level, which 2D cross-sections faithfully represent. This representativeness extends to conduction velocity predictions, as along-axon variation has only modest impact. In particular, large axons exhibit especially stable conduction, emphasizing their key role in time-critical signaling. With 2D sampling validated, we leverage 46 million human corpus callosum axons from 2D histology to determine sample size requirements across neuroscience applications. Our findings reinforce decades of 2D histology-based research on axon organization and its functional implications, while guiding future study design.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

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.

neuroscience↗

bioRxiv2025

Differences in LC integrity and fMRI activations in healthy aging and MCI associated with successful memory encoding

INTRODUCTIONWe examined whether the decline of delayed episodic memory in old age and MCI is related to structural integrity of the locus coeruleus (LC). We also tested whether LC integrity was associated with encoding-related brain activity, controlling for emotional salience. METHODSParticipants (28 young adults, 28 older adults, 25 MCI) memorized emotional and neutral images during fMRI. Delayed memory was tested four hours later and compared to immediate memory. LC integrity was measured with a neuromelanin-sensitive sequence. RESULTSMCI showed overall memory decline, independent of delay or emotional valence, and reduced LC integrity compared to older adults. Across participants, LC integrity correlated with delayed memory, but did not explain performance within OA or MCI. LC integrity was associated with lower activity related to encoding success and emotional salience. Groups remembered emotional better than neutral images, though memory was greatly impaired in MCI, matching with their reduce LC integrity. DISCUSSIONLC integrity was associated with lower brain activity during encoding and emotional salience processing, no clear relationship with delayed memory performance was observed in MCI.

neuroscience↗

bioRxiv2025

Spatial specificity of the functional gradient echo and spin echo BOLD signal across cortical depth at 7 T

Functional magnetic resonance imaging (fMRI) at high magnetic field strengths ([≥] 7 T) is a promising technique to study the functioning of the human brain at the spatial scale of cortical columns and layers. However, measurements most often rely on the blood oxygenation level dependent (BOLD) response sampled with a gradient echo (GE) sequence, which is known to be most sensitive to macrovascular contributions that limit their effective spatial resolution. Alternatively, a spin echo (SE) sequence can be used to increase the weighting toward the microvasculature and, therefore, the location of neural activation. In addition, due to the heterogeneous structure of the cortical cerebrovascular system, the effective spatial resolution can change across cortical depth. For high-resolution fMRI applications, it is hence important to know how much the effective spatial resolution varies across cortical depth. In this study, we used flickering rotating wedge stimuli to induce traveling waves with varying spatial frequencies in the retinotopically organized primary visual cortex (V1), which allowed us to infer the modulation transfer function (MTF) of the BOLD response that characterizes the spatial specificity of the measured signal. We acquired GE- and SE-BOLD data at 7 T and compared the MTF between acquisition techniques at different cortical depths. Our results show a small but consistent increase in spatial specificity when using SE-BOLD. But across cortical depth, both acquisition techniques generally show a similar decrease of specificity toward the pial surface demonstrating the dependence on macrovascular contributions, which needs to be carefully considered when interpreting the results of high-resolution fMRI studies.

neuroscience↗

bioRxiv2025

Ultra-high-field fMRI reveals layer-specific responses in the human spinal cord

Developments in functional magnetic resonance imaging (fMRI) at ultra-high field (UHF) now allow for insights into human brain function at mesoscopic scale. However, similar progress has not been achieved for the human spinal cord, despite its importance for reciprocal brain-body communication. Here, we therefore integrate substantial methodological improvements that enable previously unattainable high-resolution UHF spinal fMRI. Using a heat-pain paradigm in healthy volunteers, we investigate fMRI responses in the dorsal horn: we characterize their spatial pattern, establish their robustness and demonstrate that they can be reliably observed even for individual participants. Most importantly, we uncover two physiologically relevant spinal response components - phasic and tonic heat responses - that map differentially onto superficial and deep layers of the dorsal horn. Taken together, our novel UHF fMRI approach allows for differentiating responses across fundamental spinal processing units and will enable insights into human spinal cord function at mesoscopic scale in health and disease.

neuroscience↗

bioRxiv2025

Pupil dilation as a marker of attention/effort in aging and mild cognitive impairment

Pupil dilation (PD) can be easily measured and reflects responses to subjectively salient or cognitively demanding events. It therefore holds promise as a cognitive marker especially for individuals with mild cognitive impairment (MCI) or other neurodegenerative conditions with restricted abilities to respond in cognitive assessments. We assessed PD during two tasks, an oddball task for investigating attentional allocation and a Simon task which additionally allows for investigating cognitive effort in younger adults (YAs), older adults (OAs), and patients with MCI. PD is a useful marker for investigating attention and cognitive effort in MCI, as suggested by elevated PD to salient stimuli in particular of individuals with better attentional control in MCI patients, as well as YAs and OAs. Measurement of PD may serve as an easy-to-administer measure to assess changes in cognitive function in healthy aging and MCI.

neuroscience↗

bioRxiv2025

Layer-specific spatiotemporal dynamics of feedforward and feedback in human visual object perception

Visual object perception is mediated by information flow between regions of the ventral visual stream along feedforward and feedback anatomical connections. However, feedforward and feedback signals during naturalistic vision are rapid and overlapping, complicating their identification and precise functional specification. Here we recorded human layer-specific fMRI responses to naturalistic object images in early visual cortex (EVC) and lateral occipital complex (LOC) to isolate feedforward and feedback information signals spatially by their cortical layer-specific termination pattern. We combined these layer-specific fMRI responses with electroencephalography (EEG) responses for the same images to segregate feedforward and feedback signals in both time and space. Feedforward signals emerge early in the middle layers of EVC and LOC, followed by feedback signals in the superficial layer of LOC. Comparing the identified dynamics in LOC to a visual deep neural network (DNN), revealed that early feedforward signals in LOC encode medium-to-high complexity features, whereas later feedback signals increase the representational format to high complexity features. Together this specifies the spatiotemporal dynamics and functional role of feedforward and feedback information flow mediating visual object perception.

neuroscience↗

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.

neuroscience↗

bioRxiv2025

Challenges in replicating layer-specificity of working memory processes in human dlPFC

Although working memory reliably activates the dorsolateral prefrontal cortex (dlPFC), the functional contributions of its cortical layers in humans remain unclear. A seminal study reported a laminar dissociation in dlPFC--superficial layers engaged during working-memory manipulation and deeper layers during motor response execution. Like many current layer-resolved studies, that work relied on several manual and semi-manual processing steps, including the selection of regions of interest. We conducted a preregistered replication in 21 human participants using an automated and fully reproducible analysis pipeline. While we replicated the superficial-layer effect during manipulation, we found no evidence for preferential deep-layer activation during response execution. This biologically plausible result refines current models of laminar organization in the human prefrontal cortex and aligns human evidence with the more heterogeneous animal literature. By demonstrating reproducibility through preregistration and automation, this work establishes a benchmark for laminar analyses in cognitive neuroscience.

neuroscience↗

bioRxiv2025

Multi-center benchmarking of cervical spinal cord RF coils for 7 T MRI: A traveling spines study

PurposeThe depth within the body, small diameter, long length, and varying tissue surrounding the spinal cord impose specific considerations when designing radiofrequency coils. The optimal coil configuration for 7 T cervical spinal cord MRI is unknown and, currently, there are very few coil options. The purpose of this work was (1) to establish a quality control protocol for evaluating 7 T cervical spinal cord coils and (2) to use that protocol to evaluate the performance of 4 different coil designs. MethodsThree healthy volunteers and a custom anthropomorphic phantom (the traveling spines cohort) were scanned at seven 7 T imaging centers using a common protocol and each centers specific cervical spinal cord coil. Four different coil designs were tested (two in-house, one Rapid Biomedical, and one MRI.TOOLS design). ResultsThe Rapid Biomedical coil was found to have the highest B1+ efficiency, whereas one of the in-house designs (NeuroPoly Lab) had the highest SNR and the largest spinal cord coverage. The MRI.TOOLS coil had the most uniform B1+ profile along the cervical spinal cord; however, it was limited in its ability to provide the requested flip angles (especially for larger individuals). The latter was also the case for the second in-house coil (MSSM). ConclusionThe results of this study serve as a guide for the spinal cord MRI community in selecting the most suitable coil based on specific requirements and offer a standardized protocol for assessing future coils.

bioengineering↗

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.

neuroscience↗

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.

neuroscience↗

bioRxiv2024

Myelin-informed forward models for M/EEG source reconstruction

Magnetoencephalography (MEG) and Electroencephalography (EEG) provide direct electrophysiological measures at an excellent temporal resolution, but the spatial resolution of source-reconstructed current activity is limited to several millimetres. Here we show, using simulations of MEG signals and Bayesian model comparison, that non-invasive myelin estimates from high-resolution quantitative magnetic resonance imaging (MRI) can enhance MEG/EEG source reconstruction. Our approach assumes that MEG/EEG signals primarily arise from the synchronised activity of pyramidal cells, and since most of the myelin in the cortical sheet originates from these cells, myelin density can predict the strength of cortical sources measured by MEG/EEG. Leveraging recent advances in quantitative MRI, we exploit this structure-function relationship and scale the leadfields of the forward model according to the local myelin density estimates from in vivo quantitative MRI to inform MEG/EEG source reconstruction. Using Bayesian model comparison and dipole localisation errors (DLEs), we demonstrate that adapting local forward fields to reflect increased local myelination at the site of a simulated source explains the simulated data better than models without such leadfield scaling. Our model comparison framework proves sensitive to myelin changes in simulations with exact coregistration and moderate-to-high sensor-level signal-to-noise ratios ([≥]10 dB) for the multiple sparse priors (MSP) and empirical Bayesian beamformer (EBB) approaches. Furthermore, we sought to infer the microstructure giving rise to specific functional activation patterns by comparing the myelin-informed model which was used to generate the activation with a set of test forward models incorporating different myelination patterns. We found that the direction of myelin changes, however not their magnitude, can be inferred by Bayesian model comparison. Finally, we apply myelin-informed forward models to MEG data from a visuo-motor experiment. We demonstrate improved source reconstruction accuracy using myelin estimates from a quantitative longitudinal relaxation (R1) map and discuss the limitations of our approach. HighlightsO_LIWe use quantitative MRI to implement myelin-informed forward models for M/EEG C_LIO_LILocal myelin density was modelled by adapting the local leadfields C_LIO_LIMyelin-informed forward models can improve source reconstruction accuracy C_LIO_LIWe can infer the directionality of myelination patterns, but not their strength C_LIO_LIWe apply our approach to MEG data from a visuo-motor experiment C_LI

neuroscience↗