Heritability of human "directed" functional connectome

IntroductionThe functional connectivity patterns in the brain are highly heritable; however, it is unclear how genetic factors influence the directionality of such "information flows." Studying the "directionality" of the brain functional connectivity and assessing how heritability modulates it can improve our understanding of the human connectome. MethodsHere, we investigated the heritability of "directed" functional connections using a state-space formulation of Granger causality (GC), in conjunction with blind deconvolution methods accounting for local variability in the hemodynamic response function. Such GC implementation is ideal to explore the directionality of functional interactions across a large number of networks. Resting-state functional magnetic resonance imaging data were drawn from the Human Connectome Project (total n = 898 participants). To add robustness to our findings, the dataset was randomly split into a "discovery" and a "replication" sample (each with n = 449 participants). The two cohorts were carefully matched in terms of demographic variables and other confounding factors (e.g., education). The effect of shared environment was also modeled. ResultsThe parieto- and prefronto-cerebellar, parieto-prefrontal, and posterior-cingulate to hippocampus connections showed the highest and most replicable heritability effects with little influence by shared environment. In contrast, shared environmental factors significantly affected the visuo-parietal and sensory-motor directed connectivity. ConclusionWe suggest a robust role of heritability in influencing the directed connectivity of some cortico-subcortical circuits implicated in cognition. Further studies, for example using task-based fMRI and GC, are warranted to confirm the asymmetric effects of genetic factors on the functional connectivity within cognitive networks and their role in supporting executive functions and learning

An Interpretable Machine Learning Model to Predict Cortical Atrophy in Multiple Sclerosis

To date, the relationship between central hallmarks of multiple sclerosis (MS), such as white matter (WM)/cortical demyelinated lesions and cortical gray matter atrophy, remains unclear. We investigated the interplay between cortical atrophy and individual lesion-type patterns that have recently emerged as new radiological markers of MS disease progression. We employed a machine learning model to predict mean cortical thinning in whole-brain and single hemispheres in 150 cortical regions using demographic and lesion-related characteristics, evaluated via an ultrahigh field (7 Tesla) MRI. We found that (i) volume and rimless (i.e., without a "rim" of iron-laden immune cells) WM lesions, patient age, and volume of intracortical lesions have the most predictive power; (ii) WM lesions are more important for prediction when their load is small, while cortical lesion load becomes more important as it increases; (iii) WM lesions play a greater role in the progression of atrophy during the latest stages of the disease. Our results highlight the intricacy of MS pathology across the whole brain. In turn, this calls for multivariate statistical analyses and mechanistic modeling techniques to understand the etiopathogenesis of lesions

Latency correction in sparse neuronal spike trains

Background: In neurophysiological data, latency refers to a global shift of spikes from one spike train to the next, either caused by response onset fluctuations or by finite propagation speed. Such systematic shifts in spike timing lead to a spurious decrease in synchrony which needs to be corrected. New Method: We propose a new algorithm of multivariate latency correction suitable for sparse data for which the relevant information is not primarily in the rate but in the timing of each individual spike. The algorithm is designed to correct systematic delays while maintaining all other kinds of noisy disturbances. It consists of two steps, spike matching and distance minimization between the matched spikes using simulated annealing. Results: We show its effectiveness on simulated and real data: cortical propagation patterns recorded via calcium imaging from mice before and after stroke. Using simulations of these data we also establish criteria that can be evaluated beforehand in order to anticipate whether our algorithm is likely to yield a considerable improvement for a given dataset. Comparison with Existing Method(s): Existing methods of latency correction rely on adjusting peaks in rate profiles, an approach that is not feasible for spike trains with low firing in which the timing of individual spikes contains essential information. Conclusions: For any given dataset the criterion for applicability of the algorithm can be evaluated quickly and in case of a positive outcome the latency correction can be applied easily since the source codes of the algorithm are publicly available.Comment: 15 pages, 9 figure

Acute ischemic STROKE – from laboratory to the Patient’s BED (STROKELABED): A translational approach to reperfusion injury. Study Protocol

Cerebral edema (CE) and hemorrhagic transformation (HT) are frequent and unpredictable events in patients with acute ischemic stroke (AIS), even when an effective vessel recanalization has been achieved. These complications, related to blood-brain barrier (BBB) disruption, remain difficult to prevent or treat and may offset the beneficial effect of recanalization, and lead to poor outcomes. The aim of this translational study is to evaluate the association of circulating and imaging biomarkers with subsequent CE and HT in stroke patients with the dual purpose of investigating possible predictors as well as molecular dynamics underpinning those events and functional outcomes. Concurrently, the preclinical study will develop a new mouse model of middle cerebral artery (MCA) occlusion and recanalization to explore BBB alterations and their potentially harmful effects on tissue. The clinical section of the study is based on a single-center observational design enrolling consecutive patients with AIS in the anterior circulation territory, treated with recanalization therapies from October 1, 2015 to May 31, 2020. The study will employ an innovative evaluation of routine CT scans: in fact, we will assess and quantify the presence of CE and HT after stroke in CT scans at 24 h, through the quantification of anatomical distortion (AD), a measure of CE and HT. We will investigate the relationship of AD and several blood biomarkers of inflammation and extracellular matrix, with functional outcomes at 3 months. In parallel, we will employ a newly developed mouse model of stroke and recanalization, to investigate the emergence of BBB changes 24 h after the stroke onset. The close interaction between clinical and preclinical research can enhance our understanding of findings from each branch of research, enabling a deeper interpretation of the underlying mechanisms of reperfusion injury following recanalization treatment for AIS

A versatile clearing agent for multi-modal brain imaging

Extensive mapping of neuronal connections in the central nervous system requires high-throughput um-scale imaging of large volumes. In recent years, different approaches have been developed to overcome the limitations due to tissue light scattering. These methods are generally developed to improve the performance of a specific imaging modality, thus limiting comprehensive neuroanatomical exploration by multimodal optical techniques. Here, we introduce a versatile brain clearing agent (2,2'-thiodiethanol; TDE) suitable for various applications and imaging techniques. TDE is cost-efficient, water-soluble and low-viscous and, more importantly, it preserves fluorescence, is compatible with immunostaining and does not cause deformations at sub-cellular level. We demonstrate the effectiveness of this method in different applications: in fixed samples by imaging a whole mouse hippocampus with serial two-photon tomography; in combination with CLARITY by reconstructing an entire mouse brain with light sheet microscopy and in translational research by imaging immunostained human dysplastic brain tissue.Comment: in Scientific Reports 201

Back to the Past. The paleogeography as key to understand the Middle Palaeolithic peopling at Grotta dei Santi (Mt Argentario – Tuscany)

The mobility of hunter-gatherer groups is crucial in understanding Palaeolithic settlement dynamics. The concept of mobility cannot be separated from the space in which it occurs, including landscape components, localization of critical resources and of other sites, and routes between them. Nevertheless, the landscape is not constant in time due to the geomorphological changes that occurred in the long timescale of Prehistory. Here we present a paleogeographic reconstruction of the coastal area around Grotta dei Santi during the Neandertal occupation. A GIS-based approach, combining geological, bathymetric, and sea-level fluctuations data, allows us to reconstruct the landscape around the cave at about 45 ky BP. The cave today opens onto a cliff facing the sea. The Neandertal occupation occurred with a sea-level 74 m lower than present-day. Consequently, the cave faced a vast coastal plain, playing a strategic role due to its position, allowing both proximity and control of essential resources

Paleogeographic reconstruction of the Tuscan coastal area nearby Grotta dei Santi (Monte Argentario, Italy) during the Neandertal occupation

The mobility of hunter-gatherer groups is crucial in understanding Palaeolithic settlement dynamics. The concept of mobility cannot be separated from the space in which it occurs, including landscape components, localization of critical resources and of other sites, and routes between them. Nevertheless, the landscape is not constant in time due to the geomorphological changes that occurred in the long timescale of Prehistory. Here we present a paleogeographic reconstruction of the coastal area around Grotta dei Santi during the Neandertal occupation. A GIS-based approach, combining geological, bathymetric, and sea-level fluctuations data, allows us to reconstruct the landscape around the cave at about 45 ky BP. The cave today opens onto a cliff facing the sea. The Neandertal occupation occurred with a sea-level 74 m lower than present-day. Consequently, the cave faced a vast coastal plain, playing a strategic role due to its position, allowing both proximity and control of essential resources. © 2022 IMEKO TC-4 International Conference on Metrology for Archaeology and Cultural Heritage, MetroArchaeo 2022.All rights reserved

Preliminary Evidence of the Differential Expression of Human Endogenous Retroviruses in Kawasaki Disease and SARS-CoV-2-Associated Multisystem Inflammatory Syndrome in Children

Multisystem inflammatory syndrome in children (MIS-C) is a postinfectious sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some clinical features overlapping with Kawasaki disease (KD). Our research group and others have highlighted that the spike protein of SARS-CoV-2 can trigger the activation of human endogenous retroviruses (HERVs), which in turn induces inflammatory and immune reactions, suggesting HERVs as contributing factors in COVID-19 immunopathology. With the aim to identify new factors involved in the processes underlying KD and MIS-C, we analysed the transcriptional levels of HERVs, HERV-related genes, and immune mediators in children during the acute and subacute phases compared with COVID-19 paediatric patients and healthy controls. The results showed higher levels of HERV-W, HERV-K, Syn-1, and ASCT-1/2 in KD, MIS-C, and COV patients, while higher levels of Syn-2 and MFSD2A were found only in MIS-C patients. Moreover, KD and MIS-C shared the dysregulation of several inflammatory and regulatory cytokines. Interestingly, in MIS-C patients, negative correlations have been found between HERV-W and IL-10 and between Syn-2 and IL-10, while positive correlations have been found between HERV-K and IL-10. In addition, HERV-W expression positively correlated with the C-reactive protein. This pilot study supports the role of HERVs in inflammatory diseases, suggesting their interplay with the immune system in this setting. The elevated expression of Syn-2 and MFSD2A seems to be a distinctive trait of MIS-C patients, allowing to distinguish them from KD ones. The understanding of pathological mechanisms can lead to the best available treatment for these two diseases, limiting complications and serious outcomes

Multishell diffusion MRI reveals whole-brain white matter changes in HIV

Diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) have been previously used to explore white matter related to human immunodeficiency virus (HIV) infection. While DTI and DKI suffer from low specificity, the Combined Hindered and Restricted Model of Diffusion (CHARMED) provides additional microstructural specificity. We used these three models to evaluate microstructural differences between 35 HIV-positive patients without neurological impairment and 20 healthy controls who underwent diffusion-weighted imaging using three b-values. While significant group effects were found in all diffusion metrics, CHARMED and DKI analyses uncovered wider involvement (80% vs. 20%) of all white matter tracts in HIV infection compared with DTI. In restricted fraction (FR) analysis, we found significant differences in the left corticospinal tract, middle cerebellar peduncle, right inferior cerebellar peduncle, right corticospinal tract, splenium of the corpus callosum, left superior cerebellar peduncle, left superior cerebellar peduncle, pontine crossing tract, left posterior limb of the internal capsule, and left/right medial lemniscus. These are involved in language, motor, equilibrium, behavior, and proprioception, supporting the functional integration that is frequently impaired in HIV-positivity. Additionally, we employed a machine learning algorithm (XGBoost) to discriminate HIV-positive patients from healthy controls using DTI and CHARMED metrics on an ROIwise basis, and unique contributions to this discrimination were examined using Shapley Explanation values. The CHARMED and DKI estimates produced the best performance. Our results suggest that biophysical multishell imaging, combining additional sensitivity and built-in specificity, provides further information about the brain microstructural changes in multimodal areas involved in attentive, emotional and memory networks often impaired in HIV patients.This work is supported by: #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) (to NT)– A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022); by the MUR-PNRR M4C2I1.3 PE6 project PE00000019 Heal Italia (to NT); by the NATIONAL CENTRE FOR HPC, BIG DATA AND QUANTUM COMPUTING, within the spoke “Multiscale Modeling and Engineering Applications” (top NT); The European Innovation Council (Project CROSSBRAIN, Grant Agreement n. 101070908, Project BRAINSTORM, Grant Agreement 101099355); And by the Horizon 2020 research and innovation Programme (Project EXPERIENCE: Grant Agreement 101017727).Peer reviewe