Biology subjects

Haast, R. A.

Publications and source records attributed to Haast, R. A..

13 recordsLinked to original sources

bioRxiv2026

Higher-order interdependencies of the epileptogenic network in presurgical resting-state fMRI

Drug-resistant focal epilepsy (DRFE) is understood as a complex brain network disorder. As a result, conventional pair-wise functional connectivity may fail to capture the higher-order interactions between groups of epileptogenic regions. We applied multivariate information theory to stereotactic electroencephalography-defined networks in retrospective resting-state fMRI analysis to determine whether the overall strength and dominant type of interdependencies between three or more regions, represented by the S-information and O-information respectively, could offer clinically relevant insights prior to surgical intervention in DRFE. We found networks involving the epileptogenic zone to be mostly dominated by re-dundant information-sharing, which was predicted by stronger structural and functional connections between regions. Non-temporal lobe epilepsy patients demonstrated greater redundancy and stronger comparative interdependencies than temporal lobe epilepsy patients, in line with a more complex network architecture. Among non-temporal lobe cases with postoperative follow-up, not seizure-free patients displayed more positive O-information deviation scores than seizure-free patients, suggesting elevated redundancy in networks associated with poorer surgical outcomes. Our findings potentiate the S-information and O-information as complementary higher-order descriptors of the epileptogenic network within personalised presurgical assessments.

neuroscience↗

bioRxiv2026

An anatomically distinct dopaminergic cell population of the zona incerta as evidence for the human A13 nucleus

The zona incerta (ZI) is a functionally and molecularly diverse deep brain region increasingly recognized as an integrative hub. The rodent ZI contains the dopaminergic A13 nucleus, with studies supporting a central role in modulating sensorimotor integration, nociception, and confers resilience in models of neurodegeneration; however, to date, no clear human homologue has been identified. Here, we identified a tyrosine hydroxylase-positive subregion in the human ZI consistent with the A13, and refined its borders using ex vivo MRI and histology. We translate these findings to in vivo MRI, demonstrating the A13 is distinguishable from surrounding regions by elevated T1 and T2* values. We further revealed a principal rostral-caudal axis of molecular and structural connectivity variation in the ZI, and identified the A13 as a localized molecular specialization. Altogether, we report a distinct ZI subregion corresponding to the A13 nucleus, providing an anatomical foundation for further mechanistic and translational investigation.

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bioRxiv2025

Cholinergic synaptic plasticity shapes resilience and vulnerability to tau

Synaptic dysfunction is a hallmark of Alzheimers disease (AD). Yet due to their plasticity, synapses may also adapt to early AD pathology. Here, we demonstrate that cholinergic neurons mount a presynaptic response to tau pathology in the living human brain. Using multi-tracer positron emission tomography in cognitively normal older adults at risk for AD, we observe that cholinergic neurons increase presynaptic vesicular acetylcholine transporter (VAChT) protein levels when colocalized to tau, but not amyloid. Notably, stronger VAChT responses were associated with cognitive resilience over a decade. Whole-brain single-nucleus RNA sequencing in human and mouse tissue reveal that cholinergic neurons are enriched for a plasticity gene-network anchored to the microtubule-associated protein tau (MAPT) gene. In mice, forebrain-specific deletion of VAChT impairs cortical plasticity and hippocampal structural integrity. Overall, our findings identify cholinergic synaptic plasticity, and its failure, as a fundamental mechanism of resilience and vulnerability to tau in presymptomatic AD.

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bioRxiv2024

Mapping the topographic organization of the human zona incerta using diffusion MRI

The zona incerta (ZI) is a deep brain region originally described by Auguste Forel as an "immensely confusing area about which nothing can be said." Despite the elusive nature of this structure, mounting evidence supports the role of the ZI and surrounding regions across a diverse range of brain functions and as a candidate target for neuromodulatory therapies. Using in vivo diffusion MRI and data-driven connectivity, we identify a topographic organization between the ZI and neocortex. Specifically, our methods identify a rostral-caudal gradient predominantly connecting the frontopolar and ventral prefrontal cortices with the rostral ZI, and the primary sensorimotor cortices with the caudal ZI. Moreover, we demonstrate how clustering and gradient approaches build complementary evidence including facilitating the mapping of a central region of the ZI, connected with the dorsal prefrontal cortex. These results were shown to be replicable across multiple datasets and at the individual subject level, building evidence for the important role of the ZI in mediating frontal lobe-associated tasks, ranging from motor to cognitive to emotional control. Finally, we consider the impact of this topographic organization on the refinement of neuromodulatory targets. These results pave the way for an increasingly detailed understanding of ZI substructures, and considerations for in vivo targeting of the ZI for neuromodulation.

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bioRxiv2023

Novel insights into hippocampal perfusion using high-resolution, multi-modal 7T MRI

We present a comprehensive study on the non-invasive measurement of hippocampal perfusion. Using high-resolution 7 Tesla arterial spin labelling data, we generated robust perfusion maps and observed significant variations in perfusion among hippocampal subfields, with CA1 exhibiting the lowest perfusion levels. Notably, these perfusion differences were robust and detectable even within five minutes and just fifty perfusion-weighted images per subject. To understand the underlying factors, we examined the influence of image quality metrics, various tissue microstructure and morphometry properties, macrovasculature and cytoarchitecture. We observed higher perfusion in regions located closer to arteries, demonstrating the influence of vascular proximity on hippocampal perfusion. Moreover, ex vivo cytoarchitectonic features based on neuronal density differences appeared to correlate stronger with hippocampal perfusion than morphometric measures like gray matter thickness. These findings emphasize the interplay between microvasculature, macrovasculature, and metabolic demand in shaping hippocampal perfusion. Our study expands the current understanding of hippocampal physiology and its relevance to neurological disorders. By providing in vivo evidence of perfusion differences between hippocampal subfields, our findings have implications for diagnosis and potential therapeutic interventions. In conclusion, our study provides a valuable resource for extensively characterising hippocampal perfusion.

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bioRxiv2023

Multimodal gradients of human basal forebrain connectivity

The cholinergic innervation of the cortex originates almost entirely from populations of neurons in the basal forebrain (BF). Structurally, the ascending BF cholinergic projections are highly branched, with individual cells targeting multiple different cortical regions. However, it is not known whether the structural organization of basal forebrain projections reflects their functional integration with the cortex. We therefore used high-resolution 7T diffusion and resting state functional MRI in humans to examine multimodal gradients of BF cholinergic connectivity with the cortex. Moving from anteromedial to posterolateral BF, we observed reduced tethering between structural and functional connectivity gradients, with the most pronounced dissimilarity localized in the nucleus basalis of Meynert (NbM). The cortical expression of this structure-function gradient revealed progressively weaker tethering moving from unimodal to transmodal cortex, with the lowest tethering in midcingulo-insular cortex. We used human [18F] fluoroethoxy-benzovesamicol (FEOBV) PET to demonstrate that cortical areas with higher concentrations of cholinergic innervation tend to exhibit lower tethering between BF structural and functional connectivity, suggesting a pattern of increasingly diffuse axonal arborization. Anterograde viral tracing of cholinergic projections and [18F] FEOBV PET in mice confirmed a gradient of axonal arborization across individual BF cholinergic neurons. Like humans, cholinergic neurons with the highest arborization project to cingulo-insular areas of the mouse isocortex. Altogether, our findings reveal that BF cholinergic neurons vary in their branch complexity, with certain subpopulations exhibiting greater modularity and others greater diffusivity in the functional integration of their cortical targets.

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bioRxiv2022

Multi-scale structural alterations of basal ganglia in focal epilepsy as demonstrated by 7T MRI

Focal epilepsy is characterized by repeated spontaneous seizures that originate from cortical epileptogenic zone networks (EZN). More recently, analysis of intracerebral recordings showed that subcortical structures, and in particular the thalamus, play an important role in facilitating and/or propagating epileptic activity. This supports previously reported structural alterations of these structures. Nonetheless, between-patient differences in EZN (e.g., temporal vs. non-temporal lobe epilepsy) as well as other clinical features (e.g., number of epileptogenic regions) might impact the magnitude as well as spatial distribution of subcortical structural changes. Here we used 7 Tesla MRI T1 data to provide a comprehensive description of subcortical morphological (volume, tissue deformation, and shape) and longitudinal relaxation (T1) changes in focal epilepsy patients to evaluate the impact of the EZN and patient-specific clinical features. Our results showed widespread morphometric and T1 changes. Focusing on the thalamus, atrophy varied across nuclei but appeared most prominent for the TLE group and the ipsilateral side, while shortening of T1 was observed for the lateral thalamus, in particular. Multivariate analyses across thalamic nuclei and basal ganglia showed that volume acted as the dominant discriminator between patients and controls, while (posterolateral) thalamic T1 measures looked promising to further differentiate patients based on EZN. In particular, the observed differences in T1 changes between thalamic nuclei indicated differential involvement of thalamic nuclei based on EZN. Finally, the number of epileptogenic regions was found to best explain the observed variability between patients. To conclude, this work revealed multi-scale subcortical alterations in focal epilepsy as well as their dependence on several clinical characteristics. Our results provide a basis for further, in-depth investigations using (quantitative) MRI and SEEG data and warrant further personalization of intervention strategies, such as deep brain stimulation, for treating focal epilepsy patients.

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bioRxiv2022

Mapping the subcortical connectome using in vivo diffusion MRI: feasability and reliability

Tractography combined with regions of interest (ROIs) has been used to non-invasively study the structural connectivity of the cortex as well as to assess the reliability of these connections. However, the subcortical connectome (subcortex to subcortex) has not been comprehensively examined, in part due to the difficulty of performing tractography in this complex and compact region. In this study, we performed an in vivo investigation using tractography to assess the feasibility and reliability of mapping known connections between structures of the subcortex using the test-retest dataset from the Human Connectome Project (HCP). We further validated our observations using a separate unrelated subjects dataset from the HCP. Quantitative assessment was performed by computing tract densities and spatial overlap of identified connections between subcortical ROIs. Further, known connections between structures of the basal ganglia and thalamus were identified and visually inspected, comparing tractography reconstructed trajectories with descriptions from tract-tracing studies. Our observations demonstrate both the feasibility and reliability of using a data-driven tractography-based approach to map the subcortical connectome in vivo.

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bioRxiv2021

HippUnfold: Automated hippocampal unfolding, morphometry, and subfield segmentation

Like neocortical structures, the archicortical hippocampus differs in its folding patterns across individuals. Here, we present an automated and robust BIDS-App, HippUnfold, for defining and indexing individual-specific hippocampal folding in MRI, analogous to popular tools used in neocortical reconstruction. Such tailoring is critical for inter-individual alignment, with topology serving as the basis for homology. This topological framework enables qualitatively new analyses of morphological and laminar structure in the hippocampus or its subfields. It is critical for refining current neuroimaging analyses at a meso- as well as micro-scale. HippUnfold uses state-of-the-art deep learning combined with previously developed topological constraints to generate uniquely folded surfaces to fit a given subjects hippocampal conformation. It is designed to work with commonly employed sub-millimetric MRI acquisitions, with possible extension to microscopic resolution. In this paper we describe the power of HippUnfold in feature extraction, and highlight its unique value compared to several extant hippocampal subfield analysis methods.

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bioRxiv2021

The Role of the Temporal Pole in Temporal Lobe Epilepsy: A Diffusion Kurtosis Imaging Study

ObjectiveThis study aims to evaluate the use of diffusion kurtosis imaging (DKI) to detect microstructural abnormalities within the temporal pole (TP) in temporal lobe epilepsy (TLE) patients. MethodsDKI quantitative maps were obtained from fourteen lesional (MRI+) and ten non-lesional (MRI-) TLE patients, along with twenty-one healthy controls. This included mean (MK); radial (RK) and axial kurtosis (AK); mean diffusivity (MD) and axonal water fraction (AWF). Automated fiber quantification (AFQ) was used to quantify DKI measurements along the inferior longitudinal (ILF) and uncinate fasciculus (Unc). ILF and Unc tract profiles were compared between groups and tested for correlation with seizure duration. To characterize temporopolar cortex (TC) microstructure, DKI maps were sampled at varying depths from superficial white matter (WM) towards the pial surface. Each patient group was separated according to side ipsilateral to the epileptogenic temporal lobe and their AFQ results were used as input for statistical analyses. ResultsSignificant differences were observed between MRI+ and controls (p < 0.005), towards the most anterior of ILF and Unc proximal to the TP of the left (not right) ipsilateral temporal lobe for MK, RK, AWK and MD. Noticeable differences were also observed mostly towards the TP for MK, RK and AWK in the MRI-group. DKI measurements correlated with seizure duration, mostly towards the anterior segments of the WM bundles. Stronger differences in MK, RK and AWF within the TC were observed in the MRI+ and noticeable differences (except for MD) in MRI-groups compared to controls. SignificanceThe study demonstrates that DKI has potential to detect subtle microstructural alterations within the anterior segments of the ILF and Unc and the connected TC in TLE patients including MRI-subjects. This could aid our understanding of the extrahippocampal areas involved in seizure generation in TLE and might inform surgical planning, leading to better seizure outcomes.

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bioRxiv2021

Neurodegenerative and functional signatures of the cerebellar cortex in m.3243A>G patients

Mutations of the mitochondrial DNA are an important cause of inherited diseases that can severely affect the tissues homeostasis and integrity. The m.3243A>G mutation is the most commonly observed across mitochondrial disorders and is linked to multisystemic complications, including cognitive deficits. In line with in vitro experiments demonstrating the m.3243A>Gs negative impact on neuronal energy production and integrity, m.3243A>G patients show cerebral gray matter tissue changes. However, its impact on the most neuron-dense, and therefore energy-consuming brain structure - the cerebellum - remains elusive. In this work, we used high resolution structural and functional data acquired using 7 Tesla MRI to characterize the neurodegenerative and functional signatures of the cerebellar cortex in m.3243A>G patients. Our results reveal altered tissue integrity within distinct clusters across the cerebellar cortex, apparent by their significantly reduced volume and longitudinal relaxation rate compared to healthy controls, indicating macroscopic atrophy and microstructural pathology. Spatial characterization reveals that these changes occur especially in regions related to the frontoparietal brain network that is involved in information processing and selective attention. In addition, based on resting-state fMRI data, these clusters exhibit reduced functional connectivity to frontal and parietal cortical regions, especially in patients characterized by (i) a severe disease phenotype and (ii) reduced information processing speed and attention control. Combined with our previous work, these results provide insight into the neuropathological changes and a solid base to guide longitudinal studies aimed to track disease progression.

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bioRxiv2020

Direct visualization and characterization of the human zona incerta and surrounding structures

The zona incerta (ZI) is a small gray matter region of the deep brain first identified in the 19th century, yet direct in vivo visualization and characterization has remained elusive. Noninvasive detection of the ZI and surrounding region could be critical to further our understanding of this widely connected but poorly understood deep brain region and could contribute to the development and optimization of neuromodulatory therapies. We demonstrate that high resolution (submillimetric) longitudinal (T1) relaxometry measurements at high magnetic field strength (7 Tesla) can be used to delineate the ZI from surrounding white matter structures, specifically the fasciculus cerebellothalamicus, fields of Forel (fasciculus lenticularis, fasciculus thalamicus, field H), and medial lemniscus. Using this approach, we successfully derived in vivo estimates of the size, shape, location, and tissue characteristics of substructures in the ZI region, confirming observations only previously possible through histological evaluation that this region is not just a space between structures but contains distinct morphological entities that should be considered separately. Our findings pave the way for increasingly detailed in vivo study and provide a structural foundation for precise functional and neuromodulatory investigation.

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bioRxiv2020

Effects of MP2RAGE B1+ sensitivity on inter-site T1 reproducibility and morphometry at 7T

Most neuroanatomical studies are based on MR images, whose intensity profiles are not solely determined by the tissues longitudinal relaxation times (T1) but also affected by varying non-T1 contributions, hampering data reproducibility. In contrast, quantitative imaging using the MP2RAGE sequence, for example, allows direct characterization of the brain based on the tissue property of interest. Combined with 7 Tesla (7T) MRI, this offers unique opportunities to obtain robust high-resolution brain data characterized by a high reproducibility, sensitivity and specificity. However, specific MP2RAGE parameters choices - e.g., to emphasize intracortical myelin-dependent contrast variations - can substantially impact image quality and cortical analyses through remnants of B1+-related intensity variations, as illustrated in our previous work. To follow up on this: we (1) validate this protocol effect using a dataset acquired with a particularly B1+ insensitive set of MP2RAGE parameters combined with parallel transmission excitation; and (2) extend our analyses to evaluate the effects on hippocampal and subcortical morphometry. The latter remained unexplored initially but will provide important insights related to generalizability and reproducibility of neurodegenerative research using 7T MRI. We confirm that B1+ inhomogeneities have a considerably variable effect on cortical T1 and thickness estimates, as well as on hippocampal and subcortical morphometry depending on MP2RAGE setup. While T1 differed substantially across datasets initially, we show inter-site T1 comparability improves after correcting for the spatially varying B1+ field using a separately acquired Sa2RAGE B1+ map. Finally, as for cortical thickness, removal of B1+ residuals affects hippocampal and subcortical volumetry and boundary definitions, particularly near structures characterized by strong intensity changes (e.g. cerebral spinal fluid and arteries). Taken together, we show that the choice of MP2RAGE parameters can impact T1 comparability across sites and present evidence that hippocampal and subcortical segmentation results are modulated by B1+ inhomogeneities. This calls for careful (1) consideration of sequence parameters when setting acquisition protocols; as well as (2) interpretation of results focused on neuroanatomical changes due to disease. HighlightsO_LIPreviously observed effects of B1+ inhomogeneities on cortical T1 and thickness depend strongly on MP2RAGE parameters C_LIO_LIInter-site comparability of cortical T1 and thickness greatly improves after removal of B1+ residuals C_LIO_LIPost-hoc MP2RAGE B1+ correction affects hippocampal (and subcortical) size and shape analyses C_LIO_LINeuroradiological research would benefit from careful examination of imaging protocols and their impact on results, especially when B1+ maps are not acquired C_LI

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