Biology subjects

Gandini Wheeler-Kingshott, C. A. M.

Publications and source records attributed to Gandini Wheeler-Kingshott, C. A. M..

16 recordsLinked to original sources

bioRxiv2026

Virtual Brain Modelling Reveals Altered Network Dynamics and Predicts Symptom Severity in Schizophrenia: Relevance to Antipsychotic Treatment Response and Resistance.

Background: Schizophrenia (SZ) is a heterogeneous disorder characterized by positive, negative, cognitive and disorganisation symptoms, with pleomorphic phenotype and poorly understood aetiology. Dopamine dysregulation represents the most replicated in vivo pathophysiology finding. However, accumulating evidence suggests altered large-scale brain connectivity and excitation/inhibition balance disruption. While quantifying these alterations would help clarify SZ neurophysiology and guide therapy, single-patient identification remains impractical. This is particularly relevant for treatment-resistant SZ (TRS) whose pathophysiology remains unclear. Methods: Using virtual brain modelling, we simulated large-scale brain dynamics from functional and structural MRI data in 43 healthy controls and 33 SZ patients, stratified into TRS and non-TRS. We used the Wong-Wang model to derive four network parameters reflecting GABAergic and NMDA receptor-mediated glutamatergic transmission: global coupling (G), local inhibitory (Ji) and excitatory (JNMDA) coupling, and recurrent excitation (w+). We performed simulations in the whole brain and in resting-state networks, compared model parameters between groups and tested their association with Positive and Negative Syndrome Scale (PANSS) scores. Results: Compared to non-TRS, TRS patients showed increased JNMDA and decreased w+ at the whole-brain level, increased JNMDA and G in the dorsal attention network, lower G in the limbic network and increased w+ in the visual network. Moreover, Ji in the default mode network predicted negative symptom severity while JNMDA in the limbic and ventral attention networks predicted total PANSS scores and disorganisation. Conclusions: These findings suggest that TRS is characterized by network-specific alterations in excitation/inhibition profiles and support the use of personalised multiscale modelling to identify symptom biomarkers.

neuroscience↗

bioRxiv2026

Directed Human Structural Connectome Reveals Hierarchical Organization and Shapes Large-Scale Brain Dynamics

The human structural connectome, most commonly derived from diffusion-weighted imaging (DWI) and tractography, provides a macroscopic description of whole-brain wiring and serves as the structural foundation of network neuroscience, large-scale brain simulations, and personalized digital brain twins. However, tractography-derived connectomes are fundamentally limited by their inability to distinguish afferent from efferent connections, yielding networks that are undirected and therefore blind to the hierarchical organization imposed by the directionality of anatomical connections. In this study, we introduce a directed human structural connectome (DHSC) by transferring tracer-derived projection patterns from macaque to human using cross-species connectivity blueprints. Topological analysis of the DHSC manifests biological plausibility, a small-world network organization, and a directionality-based hierarchy, which offer the hierarchical organization of human brain networks. In the context of brain dynamics, the introduction of directionality reshapes the propagation and persistence of sensory inputs. DHSC also best captures the empirical spatiotemporal dynamics of stimulus-evoked brain activity. The findings demonstrate that anatomical directionality is a critical determinant of large-scale brain organization and dynamics. This provides evidence that directed connectome may offer potential advantages in large-scale simulations of the human brain. The resulting DHSC, along with all related analyses and data are openly available.

neuroscience↗

bioRxiv2026

Automated derivation of mean field models from spiking neural networks for the simulation of brain dynamics

A mean field model (MFM) is a mesoscopic description of neuronal population dynamics that can reduce the complexity of neural microcircuits into equations preserving key functional properties. The generation of a MFM is a complex mathematical process that starts with the incorporation of single neuron input/output relationships and local connectivity. Once neuron electroresponsiveness and synaptic properties are defined, in principle, the process can be automatized. Here we develop a tool for automatic MFM derivation from biophysically grounded spiking networks (Auto-MFM) by performing micro-to-mesoscale parameter remapping, estimating input/output relationships specific for different neuronal populations (i.e., transfer functions), and optimizing transfer function parameters. Auto-MFM was tested using a spiking cerebellar circuit as a generative model. The cerebellar MFM derived with Auto-MFM accurately reproduced cerebellar population dynamics of the corresponding spiking network, matching mean and time-varying firing rates across a wide range of stimulation patterns. Auto-MFM allowed us to model and explore physiological and pathological circuit variants; indeed, it was used to map ataxia-related structural connectivity alterations of the cerebellar network, in which Purkinje cells with simplified dendritic structure altered the cerebellar connectivity. Furthermore, Auto-MFM was used to create a library of cerebellar MFMs by sweeping the level of the excitatory conductance at mossy fiber - granule cell synapse, which is altered in several neuropathologies. Auto-MFM is thus proving a flexible and powerful tool to generate region-specific MFMs of healthy and pathological brain networks to be embedded in brain digital models.

neuroscience↗

bioRxiv2025

Causal inference and functional dynamics of a visuomotor network demonstrate excitatory/inhibitory alterations in Multiple Sclerosis

Balanced excitation and inhibition are essential for brain dynamics, and their disruption can lead to network dysfunction in neurological diseases. Here, we present a conceptually unified multiscale brain modelling framework combining Dynamic Causal Modelling (DCM) applied to task and resting-state functional Magnetic Resonance Imaging (fMRI) data and The Virtual Brain (TVB) to characterise the excitatory/inhibitory balance of the brain. We applied the framework to a visuomotor brain subnetwork in a cohort of 9 healthy controls and 17 people with multiple sclerosis (pwMS). Acquired data included an event-related task fMRI experiment with variable grip force, resting-state fMRI, and diffusion-weighted imaging. The visuomotor network comprised the bilateral primary visual cortex (V1), left primary motor cortex (M1), supplementary motor and premotor cortex (SMAPMC), cingulate cortex (CC), superior parietal lobule (SPL), and right cerebellar lobule VI (CR). Results from DCM showed that while the overall network architecture was preserved in MS, there were significant alterations in the excitatory/inhibitory nature of effective connectivity: at rest, a statistical change was observed in CR-to-V1 connectivity, which was inhibitory in healthy volunteers but excitatory in MS. During task, effective connectivity feedback, including cerebellar self-connection, was positive in healthy volunteers but negative in MS and became increasingly dysregulated with higher motor demand. Alterations in functional and effective connectivity were associated with behavioural performance (task reaction time) and clinical measures (disability severity). At the overall group level, TVB parameters linked reduced NMDA-mediated excitatory gain to slower task responses. Moreover, integrating DCM and TVB demonstrated that higher global excitatory gain was associated with stronger task-engaged effective connectivity across sensorimotor and visuomotor pathways, linking network-level excitability captured by TVB to context-dependent reconfiguration of directed interactions and to connection-level strength revealed by DCM.

neuroscience↗

bioRxiv2025

Region-specific mean field models enhance simulations of local and global brain dynamics

Brain dynamics can be simulated using virtual brain models, in which a standard mathematical representation of oscillatory activity is usually adopted for all cortical and subcortical regions. However, some brain regions have specific microcircuit properties that are not recapitulated by standard oscillators. Moreover, magnetic resonance imaging (MRI)-based connectomes may not be able to capture local circuit connectivity. Region-specific models incorporating computational properties of local neurons and microcircuits have recently been generated using the mean field (MF) approach and proposed to impact large-scale brain dynamics. Here we have used a MF of the cerebellar cortex to generate a mesoscopic model of the whole cerebellum featuring a prewired connectivity of multiple cerebellar cortical areas with deep cerebellar nuclei. This multi-node cerebellar mean field model was then used to substitute the corresponding standard oscillators and build up a cerebellar mean field virtual brain (cMF-TVB), for a group of healthy human subjects. Simulations revealed that electrophysiological and fMRI signals generated by the cMF-TVB significantly improved the fitness of local and global dynamics with respect to a homogeneous model made solely of standard oscillators. The cMF-TVB reproduced the rhythmic oscillations and coherence typical of the cerebellar circuit and allowed to correlate electrophysiological and functional MRI signals to specific neuronal populations. In aggregate, region-specific models based on MF technology and pre-wired circuit connectivity can significantly improve virtual brain simulations fostering the generation of effective brain digital twins that could be used for physiological studies and clinical applications.

bioengineering↗

bioRxiv2024

Cerebellar control over inter-regional excitatory/inhibitory dynamics discriminates execution from observation of an action

The motor learning theory anticipates that cerebro-cerebellar loops perform sensorimotor prediction thereby regulating motor control. This operation has been identified during action execution (AE) and observation (AO) but the causal interaction between the cerebellum and cerebral cortex remained unclear. Here we used Dynamic Causal Modelling (DCM) to study functional MRI (fMRI) data obtained during a squeeze ball task in either the AE or AO conditions. In both cases, active regions included bilateral primary visual cortex (V1), left primary motor cortex (M1), left supplementary motor and premotor cortex (SMAPMC), left cingulate cortex (CC), left superior parietal lobule (SPL), and right cerebellum (CRBL). AE and AO networks showed the same fixed effective connectivity, with pathways between V1, CRBL, SMAPMC and CC wired in a closed loop. However, the cerebellar communication towards the cerebral cortex switched from excitatory in AE to inhibitory in AO. Moreover, in AE only, signal modulation was non-linear from SMAPMC to CRBL and within the CRBL self-connection, supporting the role of the CRBL in elaborating motor plans received from SMAPMC. Thus, the need for motor planning and the presence of a sensorimotor feedback in AE discriminate the modality of forward control operated by the CRBL on SMAPMC. While the underlying circuit mechanisms remain to be determined, these results reveal that the CRBL differentially controls the excitatory/inhibitory dynamics of inter-regional effective connectivity depending on its functional engagement, opening new prospective for the design of artificial sensorimotor controllers and for the investigation of neurological diseases.

neuroscience↗

bioRxiv2024

Body size interacts with the structure of the central nervous system: A multi-center in vivo neuroimaging study

Clinical research emphasizes the implementation of rigorous and reproducible study designs that rely on between-group matching or controlling for sources of biological variation such as subjects sex and age. However, corrections for body size (i.e. height and weight) are mostly lacking in clinical neuroimaging designs. This study investigates the importance of body size parameters in their relationship with spinal cord (SC) and brain magnetic resonance imaging (MRI) metrics. Data were derived from a cosmopolitan population of 267 healthy human adults (age 30.1{+/-}6.6 years old, 125 females). We show that body height correlated strongly or moderately with brain gray matter (GM) volume, cortical GM volume, total cerebellar volume, brainstem volume, and cross-sectional area (CSA) of cervical SC white matter (CSA-WM; 0.44[≤]r[≤]0.62). In comparison, age correlated weakly with cortical GM volume, precentral GM volume, and cortical thickness (-0.21[≥]r[≥]-0.27). Body weight correlated weakly with magnetization transfer ratio in the SC WM, dorsal columns, and lateral corticospinal tracts (-0.20[≥]r[≥]-0.23). Body weight further correlated weakly with the mean diffusivity derived from diffusion tensor imaging (DTI) in SC WM (r=-0.20) and dorsal columns (-0.21), but only in males. CSA-WM correlated strongly or moderately with brain volumes (0.39[≤]r[≤]0.64), and weakly with precentral gyrus thickness and DTI-based fractional anisotropy in SC dorsal columns and SC lateral corticospinal tracts (-0.22[≥]r[≥]-0.25). Linear mixture of sex and age explained 26{+/-}10% of data variance in brain volumetry and SC CSA. The amount of explained variance increased at 33{+/-}11% when body height was added into the mixture model. Age itself explained only 2{+/-}2% of such variance. In conclusion, body size is a significant biological variable. Along with sex and age, body size should therefore be included as a mandatory variable in the design of clinical neuroimaging studies examining SC and brain structure.

neuroscience↗

bioRxiv2022

A multi-layer mean-field model for the cerebellar cortex: design, validation, and prediction

Mean-field (MF) models can be used to summarize in a few statistical parameters the salient properties of an inter-wired neuronal network incorporating different types of neurons and synapses along with their topological organization. MF are crucial to efficiently implement the modules of large-scale brain models maintaining the specificity of local microcircuits. While MFs have been generated for the isocortex, they are still missing for other parts of the brain. Here we have designed and simulated a multi-layer MF of the cerebellar network (including Granule Cells, Golgi Cells, Molecular Layer Interneurons, and Purkinje Cells) and validated it against experimental data and the corresponding spiking neural network (SNN) microcircuit model. The cerebellar MF was built using a system of equations, where properties of neuronal populations and topological parameters are embedded in inter-dependent transfer functions. The model time constant was optimised using local field potentials recorded experimentally from acute mouse cerebellar slices as a template. The MF satisfactorily reproduced the average dynamics of the different neuronal populations in response to various input patterns and predicted the modulation of Purkinje Cells firing depending on cortical plasticity, which drives learning in associative tasks, and the level of feedforward inhibition. The cerebellar MF provides a computationally efficient tool that will allow to investigate the causal relationship between microscopic neuronal properties and ensemble brain activity in virtual brain models addressing both physiological and pathological conditions.

bioengineering↗

bioRxiv2022

Parallel processing relies on a distributed, low-dimensional cortico-cerebellar architecture

A characteristic feature of human cognition is our ability to multi-task - performing two or more tasks in parallel - particularly when one task is well-learned. How the brain supports this capacity remains poorly understood. Most past studies have focussed on identifying the areas of the brain - typically the dorsolateral prefrontal cortex - that are required to navigate information processing bottlenecks. In contrast, we take a systems neuroscience approach to test the hypothesis that the capacity to conduct effective parallel processing relies on a distributed architecture that interconnects the cerebral cortex with the cerebellum. The latter structure contains over half of the neurons in the adult human brain, and is well-suited to support the fast, effective, dynamic sequences required to perform tasks relatively automatically. By delegating stereotyped within-task computations to the cerebellum, the cerebral cortex can be freed up to focus on the more challenging aspects of performing the tasks in parallel. To test this hypothesis, we analysed task-based fMRI data from 50 participants who performed a task in which they either balanced an avatar on a screen ( Balance), performed serial-7 subtractions ( Calculation) or performed both in parallel ( Dual-Task). Using a set of approaches that include dimensionality reduction, structure-function coupling and time-varying functional connectivity, we provide robust evidence in support of our hypothesis. We conclude that distributed interactions between the cerebral cortex and cerebellum are crucially involved in parallel processing in the human brain.

neuroscience↗

bioRxiv2021

Subject-specific features of excitation/inhibition profiles in neurodegenerative diseases

Brain pathologies are based on microscopic changes in neurons and synapses that reverberate into large scale networks altering brain dynamics and functional states. An important yet unresolved issue concerns the impact of patients excitation/inhibition profiles on neurodegenerative diseases including Alzheimers disease, Frontotemporal Dementia and Amyotrophic Lateral Sclerosis. In this work we used a simulation platform, The Virtual Brain, to simulate brain dynamics in healthy controls and in Alzheimers disease, Frontotemporal Dementia and Amyotrophic Lateral Sclerosis patients. The brain connectome and functional connectivity were extracted from 3T-MRI scans and The Virtual Brain nodes were represented by a Wong-Wang neural mass model endowing an explicit representation of the excitatory/inhibitory balance. The integration of cerebro-cerebellar loops improved the correlation between experimental and simulated functional connectivity, and hence The Virtual Brain predictive power, in all pathological conditions. The Virtual Brain biophysical parameters differed between clinical phenotypes, predicting higher global coupling and inhibition in Alzheimers disease and stronger NMDA (N-methyl-D-aspartate) receptor-dependent excitation in Amyotrophic Lateral Sclerosis. These physio-pathological parameters allowed an advanced analysis of patients state. In backward regressions, The Virtual Brain parameters significantly contributed to explain the variation of neuropsychological scores and, in discriminant analysis, the combination of The Virtual Brain parameters and neuropsychological scores significantly improved discriminative power between clinical conditions. Eventually, cluster analysis provided a unique description of the excitatory/inhibitory balance in individual patients. In aggregate, The Virtual Brain simulations reveal differences in the excitatory/inhibitory balance of individual patients that, combined with cognitive assessment, can promote the personalized diagnosis and therapy of neurodegenerative diseases.

neuroscience↗

bioRxiv2021

Non-linear frequency-dependence of neurovascular coupling in the cerebellar cortex implies vasodilation-vasoconstriction competition

Neurovascular coupling (NVC) is the process associating local cerebral blood flow (CBF) to neuronal activity (NA). Although NVC provides the basis for the blood-oxygen-level-dependent (BOLD) effect used in functional MRI (fMRI), the relationship between NVC and NA is still unclear. Since recent studies reported cerebellar non-linearities in BOLD signals during motor tasks execution, we investigated the NVC/NA relationship using a range of input frequencies in acute mouse cerebellar slices of vermis and hemisphere. The capillary diameter increased in response to mossy fiber activation in the 6-300Hz range, with a marked inflection around 50Hz (vermis) and 100Hz (hemisphere). The corresponding NA was recorded using high-density multi-electrode arrays and correlated to capillary dynamics through a computational model dissecting the main components of granular layer activity. Here, NVC is known to involve a balance between the NMDAR-NO pathway driving vasodilation and the mGluRs-20HETE pathway driving vasoconstriction. Simulations showed that the NMDAR-mediated component of NA was sufficient to explain the time-course of the capillary dilation but not its non-linear frequency-dependence, suggesting that the mGluRs-20HETE pathway plays a role at intermediate frequencies. These parallel control pathways imply a vasodilation-vasoconstriction competition hypothesis that could adapt local hemodynamics at the microscale bearing implications for fMRI signals interpretation.

neuroscience↗

bioRxiv2020

Deep learning model fitting for diffusion-relaxometry: a comparative study

Quantitative Magnetic Resonance Imaging (qMRI) signal model fitting is traditionally performed via non-linear least square (NLLS) estimation. NLLS is slow and its performance can be affected by the presence of different local minima in the fitting objective function. Recently, machine learning techniques, including deep neural networks (DNNs), have been proposed as robust alternatives to NLLS. Here we present a deep learning implementation of qMRI model fitting, which uses DNNs to perform the inversion of the forward signal model. We compare two DNN training strategies, based on two alternative definitions of the loss function, since at present it is not known which definition leads to the most accurate, precise and robust parameter estimation. In strategy 1 we define the loss as the l2-norm of tissue parameter prediction errors, while in strategy 2 as the l2-norm of MRI signal prediction errors. We compare the two approaches on synthetic and 3T in vivo saturation inversion recovery (SIR) diffusion-weighted (DW) MRI data, using a model for joint diffusion-T1 mapping. Strategy 1 leads to lower tissue parameter root mean squared errors (RMSEs) when realistic noise distributions are considered (e.g. Rician vs Gaussian). However, strategy 2 offers lower signal reconstruction RMSE, and allows training to be performed on both synthetic and actual in vivo MRI measurements. In conclusion, both strategies are valid choices for DNN-based fitting. Strategy 2 is more practical, as it does not require pre-computation of reference tissue parameters, but may lead to worse parameter estimation.

neuroscience↗

bioRxiv2020

BOLD response to multiple grip forces in MS: going beyond the main effect of movement in BA 4a and BA 4p

This study highlights the importance of looking beyond the main effect of movement to study alterations in functional response in the presence of central nervous system pathologies such as multiple sclerosis (MS). Data show that MS selectively affects regional BOLD (Blood Oxygenation Level Dependent) responses to variable grip forces (GF). It is known that the anterior and posterior BA 4 areas (BA 4a and BA 4p) are anatomically and functionally distinct. It has also been shown in Healthy volunteers that there are linear (1st order, typical of BA 4a) and non-linear (2nd-4th order, typical of BA 4p) BOLD responses to different levels of GF applied during a dynamic motor paradigm. After modelling the BOLD response with a polynomial expansion of the applied GFs, the particular case of BA 4a and BA 4p were investigated in Healthy Volunteers (HV) and MS subjects. The main effect of movement (0th order) analysis showed that the BOLD signal is greater in MS compared to healthy volunteers within both BA 4 sub-regions. At higher order, BOLD-GF responses were similar in BA 4a but showed a marked alteration in BA 4p of MS subjects, with those with greatest disability showing the greatest deviations from the healthy response profile. Therefore, the different behaviour in HV and MS could only be uncovered through a polynomial analysis looking beyond the main effect of movement into the two BA 4 sub-regions. Future studies will investigate the source of this pathophysiology, combining the present fMRI paradigm with blood perfusion and non-linear neuronal response analysis.

neuroscience↗

bioRxiv2020

Automatic segmentation of dentate nuclei for microstructure assessment: example of application to temporal lobe epilepsy patients

Dentate nuclei (DNs) segmentation is helpful for assessing their potential involvement in neurological diseases. Once DNs have been segmented, it becomes possible to investigate whether DNs they are microstructurally affected, through analysis of quantitative MRI parameters, such as the ones derived from diffusion weighted imaging (DWI). This study, therefore, aimed to develop a fully automated segmentation method using the non-DWI (b0) images from a DWI dataset to obtain DN masks inherently registered with parameter maps. Three different automatic methods were applied to healthy subjects in order to segment the DNs: registration to SUIT (a spatially unbiased atlas template of the cerebellum and brainstem), OPAL (Optimized Patch Match for Label fusion) and CNN (Convolutional Neural Network). DNs manual segmentation was considered the gold standard. Results show that the segmentation obtained with SUIT has an average Dice Similarity Coefficient (DSC) of 0.4907{+/-}0.0793 between the automatic SUIT masks and the gold standard. A comparison with manual masks was also performed for OPAL (DSC = 0.7624 {+/-} 0.1786) and CNN (DSC = 0.8658 {+/-} 0.0255), showing a better performance when using CNN. OPAL and CNN were optimised on heathy subjects data with high spatial resolution from the Human Connectome Project. The three methods were further used to segment the DNs of a subset of subjects affected by Temporal Lobe Epilepsy (TLE). This subset was derived from a 3T MRI research study which included DWI data acquired with a coarser resolution. In TLE dataset, SUIT performed similarly to using the HCP dataset, with a DSC = 0.4145 {+/-} 0.1023. Using TLE data, OPAL performed worse than using HCP data: after changing the probability threshold the DSC was 0.4522 {+/-} 0.1178. CNN was able to extract the DNs using the TLE data without need for retraining and with a good DSC = 0.7368 {+/-} 0.0799. Statistical comparison of quantitative parameters derived from DWI analysis, as well as volumes of each DN, revealed altered and lateralised changes in TLE patients compared to healthy controls. The proposed CNN is therefore a viable option for accurate extraction of DNs from b0 images of DWI data with different resolutions and acquired at different sites.

bioengineering↗

bioRxiv2019

Multi-parametric quantitative spinal cord MRI with unified signal readout and image denoising

Multi-parametric quantitative MRI (qMRI) of the spinal cord is a promising non-invasive tool to probe early microstructural damage in neurological disorders. It is usually performed by combining acquisitions with multiple signal readouts, which exhibit different thermal noise levels, geometrical distortions and susceptibility to physiological noise. This ultimately hinders joint multi-contrast modelling and makes the geometric correspondence of parametric maps challenging. We propose an approach to overcome these limitations, by implementing state-of-the-art microstructural MRI of the spinal cord with a unified signal readout. We base our acquisition on single-shot echo planar imaging with reduced field-of-view, and obtain data from two different vendors (vendor 1: Philips Achieva; vendor 2: Siemens Prisma). Importantly, the unified acquisition allows us to compare signal and noise across contrasts, thus enabling overall quality enhancement via Marchenko-Pastur (MP) Principal Component Analysis (PCA) denoising. MP-PCA is a recent method relying on redundant acquisitions, i.e. such that the number of measurements is much larger than the number of informative principal components. Here we used in vivo and synthetic data to test whether a unified readout enables more efficient denoising of less redundant acquisitions, since these can be denoised jointly with more redundant ones. We demonstrate that a unified readout provides robust multi-parametric maps, including diffusion and kurtosis tensors from diffusion MRI, myelin metrics from two-pool magnetisation transfer, and T1 and T2 from relaxometry. Moreover, we show that MP-PCA improves the quality of our multi-contrast acquisitions, since it reduces the coefficient of variation (i.e. variability) by up to 15% for mean kurtosis, 8% for bound pool fraction (BPF, myelin-sensitive), and 13% for T1, while enabling more efficient denoising of modalities limited in redundancy (e.g. relaxometry). In conclusion, multi-parametric spinal cord qMRI with unified readout is feasible and provides robust microstructural metrics with matched resolution and distortions, whose quality benefits from MP-PCA denoising, a useful pre-processing tool for spinal cord MRI.

neuroscience↗

bioRxiv2019

Cervical spinal cord atrophy and Alzheimer’s disease

ObjectiveBrain atrophy is an established biomarker for dementia, yet spinal cord involvement has not been investigated to date. As the spinal cord is relaying sensorimotor control signals from the cortex to the peripheral nervous system and viceversa, it is indeed a very interesting question to assess whether it is affected by atrophy in a disease that is known for its involvement of cognitive domains first and foremost, with motor symptoms being clinically assessed too. We therefore hypothesize that Alzheimer Disease severe atrophy can affect the spinal cord too and that spinal cord atrophy is indeed an important in vivo imaging biomarker contributing to understanding neurodegeneration associated with dementia.\n\nMethods3DT1 images of 31 Alzheimers disease (AD) and 35 healthy control (HC) subjects were processed to calculate volumes of brain structures and cross-sectional area (CSA) and volume (CSV) of the cervical cord (per vertebra as well as the C2-C3 pair (CSA23 and CSV23)). Correlated features ({rho}>0.7) were removed, and best subset identified for patients classification with the Random Forest algorithm. General linear model regression was used to find significant differences between groups (p<=0.05). Linear regression was implemented to assess the explained variance of the Mini Mental State Examination (MMSE) score as dependent variable with best features as predictors.\n\nResultsSpinal cord features were significantly reduced in AD, independently of brain volumes. Patients classification reached 76% accuracy when including CSA23 together with volumes of hippocampi, left amygdala, white and grey matter, with 74% sensitivity and 78% specificity. CSA23 alone explained 13% of MMSE variance.\n\nDiscussionOur findings reveal that C2-C3 spinal cord atrophy contributes to discriminate AD from HC, together with more established features. Results show that CSA23, calculated form the same 3DT1 scan as all other brain volumes (including right and left hippocampi), has a considerable weight in classification tasks warranting further investigations. Together with recent studies revealing that AD atrophy is spread beyond the temporal lobes, our result adds the spinal cord to a number of unsuspected regions involved in the disease. Interestingly, spinal cord atrophy explains also cognitive scores, which could significantly impact how we model sensorimotor control in degenerative diseases with a primary cognitive domain involvement. Prospective studies should be purposely designed to understand the mechanisms of atrophy and the role of the spinal cord in AD.

neuroscience↗