Relationship between large-scale structural and functional brain connectivity in the human lifespan

The relationship between the anatomical structure of the brain and its functional organization is not straightforward and has not been elucidated yet, despite the growing interest this topic has received in the last decade. In particular, a new area of research has been defined in these years, called \u2019connectomics\u2019: this is the study of the different kinds of \u2019connections\u2019 existing among micro- and macro-areas of the brain, from structural connectivity \u2014 described by white matter fibre tracts physically linking cortical areas \u2014 to functional connectivity \u2014 defined as temporal correlation between electrical activity of different brain regions \u2014 to effective connectivity\u2014defining causal relationships between functional activity of different brain areas. Cortical areas of the brain physically linked by tracts of white matter fibres are known to exhibit a more coherent functional synchronization than areas which are not anatomically linked, but the absence of physical links between two areas does not imply a similar absence of functional correspondence. Development and ageing, but also structural modifications brought on by malformations or pathology, can modify the relation between structure and function. The aim of my PhD work has been to further investigate the existing relationship between structural and functional connectivity in the human brain at different ages of the human lifespan, in particular in healthy adults and both healthy and pathological neonates and children. These two \u2019categories\u2019 of subjects are very different in terms of the analysis techniques which can be applied for their study, due to the different characteristics of the data obtainable from them: in particular, while healthy adult data can be studied with the most advanced state-of-the-art methods, paediatric and neonatal subjects pose hard constraints to the acquisition methods applicable, and thus to the quality of the data which can be analysed. During this PhD I have studied this relation in healthy adult subjects by comparing structural connectivity from DWI data with functional connectivity from stereo-EEG recordings of epileptic patients implanted with intra-cerebral electrodes. I have then focused on the paediatric age, and in particular on the challenges posed by the paediatric clinical environment to the analysis of structural connectivity. In collaboration with the Neuroradiology Unit of the Giannina Gaslini Hospital in Genova, I have adapted and tested advanced DWI analysis methods for neonatal and paediatric data, which is commonly studied with less effective methods. We applied the same methods to the study of the effects of a specific brain malformation on the structural connectivity in 5 paediatric patients. While diffusion weighted imaging (DWI) is recognised as the best method to compute structural connectivity in the human brain, the most common methods for estimating functional connectivity data \u2014 functional MRI (fMRI) and electroencephalography (EEG) \u2014 suffer from different limitations: fMRI has good spatial resolution but low temporal resolution, while EEG has a better temporal resolution but the localisation of each signal\u2019s originating area is difficult and not always precise. Stereo-EEG (SEEG) combines strong spatial and temporal resolution with a high signal-to-noise ratio and allows to identify the source of each signal with precision, but is not used for studies on healthy subjects because of its invasiveness. Functional connectivity in children can be computed with either fMRI, EEG or SEEG, as in adult subjects. On the other hand, the study of structural connectivity in the paediatric age is met with obstacles posed by the specificity of this data, especially for the application of the advanced DWI analysis techniques commonly used in the adult age. Moreover, the clinical environment introduces even more constraints on the quality of the available data, both in children and adults, further limiting the possibility of applying advanced analysis methods for the investigation of connectivity in the paediatric age. Our results on adult subjects showed a positive correlation between structural and functional connectivity at different granularity levels, from global networks to community structures to single nodes, suggesting a correspondence between structural and functional organization which is maintained at different aggregation levels of brain units. In neonatal and paediatric subjects, we successfully adapted and applied the same advanced DWI analysis method used for the investigation in adults, obtaining white matter reconstructions more precise and anatomically plausible than with methods commonly used in paediatric clinical environments, and we were able to study the effects of a specific type of brain malformation on structural connectivity, explaining the different physical and functional manifestation of this malformation with respect to similar pathologies. This work further elucidates the relationship between structural and functional connectivity in the adult subject, and poses the basis for a corresponding work in the neonatal and paediatric subject in the clinical environment, allowing to study structural connectivity in the healthy and pathological child with clinical data

Long-range phase synchronization of high-gamma activity in human cortex

AbstractInter-areal synchronization of neuronal oscillations below 100 Hz is ubiquitous in cortical circuitry and thought to regulate neuronal communication. In contrast, faster activities are generally considered to be exclusively local-circuit phenomena. We show with human intracerebral recordings that 100–300 Hz high-gamma activity (HGA) may be synchronized between widely distributed regions. HGA synchronization was not attributable to artefacts or to epileptic pathophysiology. Instead, HGA synchronization exhibited a reliable cortical connectivity and community structures, and a laminar profile opposite to that of lower frequencies. Importantly, HGA synchronization among functional brain systems during non-REM sleep was distinct from that in resting state. Moreover, HGA synchronization was transiently enhanced for correctly inhibited responses in a Go/NoGo task. These findings show that HGA synchronization constitutes a new, functionally significant form of neuronal spike-timing relationships in brain activity. We suggest that HGA synchronization reflects the temporal microstructure of spiking-based neuronal communication per se in cortical circuits

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Long-range phase synchronization of highfrequency oscillations in human cortex

Inter-areal synchronization of neuronal oscillations at frequencies below similar to 100Hz is a pervasive feature of neuronal activity and is thought to regulate communication in neuronal circuits. In contrast, faster activities and oscillations have been considered to be largely local-circuit-level phenomena without large-scale synchronization between brain regions. We show, using human intracerebral recordings, that 100-400Hz high-frequency oscillations (HFOs) may be synchronized between widely distributed brain regions. HFO synchronization expresses individual frequency peaks and exhibits reliable connectivity patterns that show stable community structuring. HFO synchronization is also characterized by a laminar profile opposite to that of lower frequencies. Importantly, HFO synchronization is both transiently enhanced and suppressed in separate frequency bands during a response-inhibition task. These findings show that HFO synchronization constitutes a functionally significant form of neuronal spike-timing relationships in brain activity and thus a mesoscopic indication of neuronal communication per se.Peer reviewe

The influence of inter-regional delays in generating large-scale brain networks of phase synchronization

Funding Information: The authors are grateful to the reviewers of this manuscript for their thoughtful comments, addressing which has substantively improved the manuscript. Further, we acknowledge Finnish centre for Artificial Intelligence (FCAI), Academy of Finland ( NW: 321542 , SK: 292334 , 956 319264 , MP: 253130 , 256472 , 281414 , 296304 , 266745 , SP: 266402 , 266745 , 303933 , 957 325404 ), Department of Science & Technology (DST), India and Sigrid Juselius Foundation , for providing funding for this project. The authors are grateful to Prof. Sitabhra Sinha, Dr. Chandrasekhar Kuyyamudi, Dr. Ayush Bharti, Dr. Henri Pesonen, Dr. Michael Gutmann and Antti Karvanen for invaluable discussions, and to Alex Aushev, Anirudh Jain, Diego Mesquita and Sophie Wharrie for comments on manuscript drafts. Most of all, we are very grateful to Jarno Rantaharju, Thomas Pfau, Richard Darst and Enrico Glerean from Aalto Scientific Computing, for facilitating use of computational resources provided by the Aalto Science-ITproject. Publisher Copyright: © 2023 The AuthorsLarge-scale networks of phase synchronization are considered to regulate the communication between brain regions fundamental to cognitive function, but the mapping to their structural substrates, i.e., the structure-function relationship, remains poorly understood. Biophysical Network Models (BNMs) have demonstrated the influences of local oscillatory activity and inter-regional anatomical connections in generating alpha-band (8–12 Hz) networks of phase synchronization observed with Electroencephalography (EEG) and Magnetoencephalography (MEG). Yet, the influence of inter-regional conduction delays remains unknown. In this study, we compared a BNM with standard “distance-dependent delays”, which assumes constant conduction velocity, to BNMs with delays specified by two alternative methods accounting for spatially varying conduction velocities, “isochronous delays” and “mixed delays”. We followed the Approximate Bayesian Computation (ABC) workflow, i) specifying neurophysiologically informed prior distributions of BNM parameters, ii) verifying the suitability of the prior distributions with Prior Predictive Checks, iii) fitting each of the three BNMs to alpha-band MEG resting-state data (N = 75) with Bayesian optimization for Likelihood-Free Inference (BOLFI), and iv) choosing between the fitted BNMs with ABC model comparison on a separate MEG dataset (N = 30). Prior Predictive Checks revealed the range of dynamics generated by each of the BNMs to encompass those seen in the MEG data, suggesting the suitability of the prior distributions. Fitting the models to MEG data yielded reliable posterior distributions of the parameters of each of the BNMs. Finally, model comparison revealed the BNM with “distance-dependent delays”, as the most probable to describe the generation of alpha-band networks of phase synchronization seen in MEG. These findings suggest that distance-dependent delays might contribute to the neocortical architecture of human alpha-band networks of phase synchronization. Hence, our study illuminates the role of inter-regional delays in generating the large-scale networks of phase synchronization that might subserve the communication between regions vital to cognition.Peer reviewe

SEEG assistant: A 3DSlicer extension to support epilepsy surgery

Background: In the evaluation of Stereo-Electroencephalography (SEEG) signals, the physicist's workflow involves several operations, including determining the position of individual electrode contacts in terms of both relationship to grey or white matter and location in specific brain regions. These operations are (i) generally carried out manually by experts with limited computer support, (ii) hugely time consuming, and (iii) often inaccurate, incomplete, and prone to errors. Results: In this paper we present SEEG Assistant, a set of tools integrated in a single 3DSlicer extension, which aims to assist neurosurgeons in the analysis of post-implant structural data and hence aid the neurophysiologist in the interpretation of SEEG data. SEEG Assistant consists of (i) a module to localize the electrode contact positions using imaging data from a thresholded post-implant CT, (ii) a module to determine the most probable cerebral location of the recorded activity, and (iii) a module to compute the Grey Matter Proximity Index, i.e. the distance of each contact from the cerebral cortex, in order to discriminate between white and grey matter location of contacts. Finally, exploiting 3DSlicer capabilities, SEEG Assistant offers a Graphical User Interface that simplifies the interaction between the user and the tools. SEEG Assistant has been tested on 40 patients segmenting 555 electrodes, and it has been used to identify the neuroanatomical loci and to compute the distance to the nearest cerebral cortex for 9626 contacts. We also performed manual segmentation and compared the results between the proposed tool and gold-standard clinical practice. As a result, the use of SEEG Assistant decreases the post implant processing time by more than 2 orders of magnitude, improves the quality of results and decreases, if not eliminates, errors in post implant processing. Conclusions: The SEEG Assistant Framework for the first time supports physicists by providing a set of open-source tools for post-implant processing of SEEG data. Furthermore, SEEG Assistant has been integrated into 3D Slicer, a software platform for the analysis and visualization of medical images, overcoming limitations of command-line tools

Improvement in White Matter Tract Reconstruction with Constrained Spherical Deconvolution and Track Density Mapping in Low Angular Resolution Data: A Pediatric Study and Literature Review

IntroductionDiffusion-weighted magnetic resonance imaging (DW-MRI) allows noninvasive investigation of brain structure in vivo. Diffusion tensor imaging (DTI) is a frequently used application of DW-MRI that assumes a single main diffusion direction per voxel, and is therefore not well suited for reconstructing crossing fiber tracts. Among the solutions developed to overcome this problem, constrained spherical deconvolution with probabilistic tractography (CSD-PT) has provided superior quality results in clinical settings on adult subjects; however, it requires particular acquisition parameters and long sequences, which may limit clinical usage in the pediatric age group. The aim of this work was to compare the results of DTI with those of track density imaging (TDI) maps and CSD-PT on data from neonates and children, acquired with low angular resolution and low b-value diffusion sequences commonly used in pediatric clinical MRI examinations.Materials and methodsWe analyzed DW-MRI studies of 50 children (eight neonates aged 3–28 days, 20 infants aged 1–8 months, and 22 children aged 2–17 years) acquired on a 1.5 T Philips scanner using 34 gradient directions and a b-value of 1,000 s/mm2. Other sequence parameters included 60 axial slices; acquisition matrix, 128 × 128; average scan time, 5:34 min; voxel size, 1.75 mm × 1.75 mm × 2 mm; one b = 0 image. For each subject, we computed principal eigenvector (EV) maps and directionally encoded color TDI maps (DEC-TDI maps) from whole-brain tractograms obtained with CSD-PT; the cerebellar-thalamic, corticopontocerebellar, and corticospinal tracts were reconstructed using both CSD-PT and DTI. Results were compared by two neuroradiologists using a 5-point qualitative score.ResultsThe DEC-TDI maps obtained presented higher anatomical detail than EV maps, as assessed by visual inspection. In all subjects, white matter (WM) tracts were successfully reconstructed using both tractography methodologies. The mean qualitative scores of all tracts obtained with CSD-PT were significantly higher than those obtained with DTI (p-value < 0.05 for all comparisons).ConclusionCSD-PT can be successfully applied to DW-MRI studies acquired at 1.5 T with acquisition parameters adapted for pediatric subjects, thus providing TDI maps with greater anatomical detail. This methodology yields satisfactory results for clinical purposes in the pediatric age group