Nikolaus Weiskopf

Axon caliber determines signal conduction velocity and varies within and across the bundles that form the brain’s wiring. Our knowledge of this organization derives largely from 2D histology, assuming cylindrical axons whose calibers are described by their radius. However, recent 3D histology reveals substantial along-axon variability in radius, calling into question 2D-derived insights into axon radius and conduction velocity. We show in 450,000 3D axon reconstructions from male rats that—despite this individual variation—axon bundles possess stable radius distributions at the ensemble level. These distributions are faithfully captured by 2D cross-sections and yield robust conduction velocity predictions, as along-axon variability has only a modest effect. Conduction in large axons is particularly stable, supporting 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 show how axonal organization gives rise to stable ensemble statistics and conduction, explaining and reinforcing decades of 2D histology-based research.

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 aging UHF qMRI MP2RAGEME-based dataset with two different multiparameter mapping (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 previously published 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 in the pooled dataset 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% of the lifespan mean in the pooled dataset. Subcortical structure volume change is on the order of 5–26%. 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.

Sensory experience is critical for cortical maturation, but the cellular consequences of its absence remain poorly understood in humans. Using in vivo sub-millimeter 3 T and 7 T MRI and ultra-high-gradient diffusion MRI, we investigated the effects of congenital blindness on the human early visual cortex. Blind individuals showed reduced R ₂ ^* and MT _sat —markers of iron and myelin—along with increased diffusivity, orientation dispersion, and reduced neurite density in the gray and superficial white matter. Cortical thickness was increased in blind individuals and associated with lower myelin and iron, questioning the long-standing assumption that increased thickness primarily reflects disrupted pruning. Our results provide no direct evidence for disrupted pruning. However, they suggest reduced myelination and oligodendrogenesis as key effects of congenital blindness and highlight the critical role of sensory input in shaping and stabilizing cortical circuits.

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.

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 Parkinson’s 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.

NG101 is a recombinant antibody that neutralizes the nerve growth inhibitor Nogo-A, promoting neural repair and improving upper extremity motor function in spinal cord injury (SCI). This study evaluated spinal cord MRI biomarkers to detect treatment-related structural changes and enhance patient stratification using data from 106 participants with acute cervical SCI in the phase 2b NISCI trial. We assessed lesion volume, tissue bridges, and remote changes in cross-sectional cord area (CSA), and tract-specific myelin-sensitive magnetization transfer saturation (MTsat) over six months. Compared to placebo, NG101-treated participants exhibited faster lesion volume reduction and a slower decline of CSA and MTsat in the corticospinal tracts and dorsal columns. Crucially, multimodal stratification incorporating MRI and electrophysiological measures substantially enhanced the detection of clinical treatment effects. These findings suggest NG101 slows trauma-induced progressive macro- and microstructural degeneration or promotes fiber sprouting. Combining MRI with electrophysiology enables sensitive detection of treatment effects and efficient trial designs. ClinicalTrials.gov identifier: NCT03935321.

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 Parkinson’s 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 atlas’s 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.

Axons are the brain’s 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 brain’s 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.

Understanding how the injured nervous system adapts to training is key to advancing rehabilitation across neurological disorders. Using spinal cord injury (SCI) as a model of severe motor-sensory disruption, we investigate whether training-induced structural plasticity in the brain is preserved despite ongoing neurodegeneration. Thirty-two healthy controls and 17 chronic SCI patients (SCI > 6 months) undergo training in a bimanual-bipedal computer-controlled motion game for one hour, four times a week, over one month, with longitudinal microstructural MRI at 3 T, including multiparameter mapping and diffusion MRI. All SCI patients exhibit performance improvements over the training period. These improvements are accompanied by spatially and temporally distributed changes in both gray and white matter, encompassing alterations in volumetric and myelin-sensitive MRI markers. SCI patients demonstrate trajectories of training-induced neuroplasticity that are comparable to, and in some cases greater than, those of healthy controls. Our findings highlight a fundamental capacity of the injured nervous system to adapt through rehabilitation, with evidence from SCI patients showing that—despite severe motor and sensory deficits—the brain can undergo learning-related structural changes. These results suggest that the mechanisms of training-induced plasticity observed in SCI may generalize to rehabilitation across a broad spectrum of neurological disorders.

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.