Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Univariate and multivariate pattern analysis of preterm subjects: a multimodal neuroimaging study

Background: Widespread lasting functional connectivity (FC) and brain volume changes in cortices and subcortices after premature birth have been researched in recent studies. However, the relationship remains unclear between spontaneously slow blood oxygen dependent level (BOLD) fluctuations and gray matter volume (GMV) changes in specific brain areas, such as temporal insular cortices, and whether classification methods based on MRI could be successfully applied to the identification of preterm individuals. In this thesis I hypothesized that in prematurely born adults 1. Ongoing neural excitability and brain activity, as estimated by regional functional connectivity of resting state functional MRI (rs-fMRI) is accompanied with altered low-frequency fluctuations and neonatal complications; 2. Altered regional functional connectivity is connected with superimposed cerebral structural reductions; and 3. multivariate neuroanatomical and functional brain patterns could be treated as features to identify preterm subjects from term subjects individually. Methods: To investigate these hypotheses, the principal results of structural alterations were measured with voxel-based morphometry (VBM), while rs-fMRI outcomes were estimated with amplitude of low-frequency fluctuations (ALFF) in analysis with ninety-four very preterm/very low birth weight (VP/VLBW) and ninety-two full-term (FT) born young adults. Results: The results of the thesis support the hypotheses by showing that, in univariate results, first in VP/VLBW grownups, ALFF was decreased in the left lateral temporal cortices no matter with global signal regression, and this reduction was closely associated with neonatal complications and cognitive variables. Second overlapped brain regions were found between reduced ALFF and reduced brain volumes in the left temporal cortices, and positively associated with each other, demonstrating a potential relationship between VBM and ALFF in this brain area. In multimodal multivariate pattern recognition analysis (MVPA), the gray matter volume (GMV) classifier displayed a higher accuracy (80.7%) contrast with the ALFF classifier (77.4%). The late fusion of GMV and ALFF did not outperform single GMV modality classification by reaching 80.4% accuracy. Moderator analysis from both rs-fMRI and structural MRI (sMRI) uncovered that the neuro-prematurity performance was predominantly determined by neonatal complications. Conclusions: In conclusion, these outcomes exhibit the long term effects of premature labour on lateral temporal cortices, which changed in both ongoing BOLD fluctuations and decreased cerebral structural volumes. This thesis further provided evidence that multivariate pattern analysis such as support vector machine (SVM) may identify imaging-based biomarkers and reliably detect signatures of preterm birth

Typical and atypical development of the brain’s functional network architecture

The human brain is a complex organ that gives rise to many behaviors. Specialized neural regions cooperate as functional networks that form an intricate functional architecture. Development provides a unique window into how brain functioning and human thinking are affected if the necessary neural features and connections are not fully formed. Similarly, developmental disorders can shed light on atypical trajectories of neural systems that may lead to or be a consequence of symptomatic behavior. A description of the typical and atypical development of functional networks is essential to identify the features of brain organization critical for mature human thinking and to provide better diagnosis, treatment, and prognosis in neurodevelopmental disorders. Recently, resting state functional MRI has been found to illuminate functionally related regions, giving access to functional networks and the organization of brain’s functional architecture. This thesis aims to harness resting-state functional connectivity to explore how functional networks coordinate over the course of development. First, I present our work investigating the organizing principles of typical developmental patterns in functional networks (Chapter 2). Then, I apply these approaches to the atypical development of functional networks in Tourette syndrome (TS), a developmental disorder characterized by motor and vocal tics. In this work, we tested whether the patterns in functional networks that distinguish individuals with TS from controls differ between children and adults and alter the typical developmental pattern of functional networks (Chapter 3). Lastly, I present our work to identify and describe the coordination of specific functional networks that develop atypically in TS (Chapter 4)

Development of Large-Scale Functional Brain Networks in Children

Large-scale rewiring of brain circuits in children leads to emergence of hierarchical organization in the mature adult brain

A Baseline for the Multivariate Comparison of Resting-State Networks

As the size of functional and structural MRI datasets expands, it becomes increasingly important to establish a baseline from which diagnostic relevance may be determined, a processing strategy that efficiently prepares data for analysis, and a statistical approach that identifies important effects in a manner that is both robust and reproducible. In this paper, we introduce a multivariate analytic approach that optimizes sensitivity and reduces unnecessary testing. We demonstrate the utility of this mega-analytic approach by identifying the effects of age and gender on the resting-state networks (RSNs) of 603 healthy adolescents and adults (mean age: 23.4 years, range: 12–71 years). Data were collected on the same scanner, preprocessed using an automated analysis pipeline based in SPM, and studied using group independent component analysis. RSNs were identified and evaluated in terms of three primary outcome measures: time course spectral power, spatial map intensity, and functional network connectivity. Results revealed robust effects of age on all three outcome measures, largely indicating decreases in network coherence and connectivity with increasing age. Gender effects were of smaller magnitude but suggested stronger intra-network connectivity in females and more inter-network connectivity in males, particularly with regard to sensorimotor networks. These findings, along with the analysis approach and statistical framework described here, provide a useful baseline for future investigations of brain networks in health and disease

Anomalous morphology in left hemisphere motor and premotor cortex of children who stutter

Stuttering is a neurodevelopmental disorder that affects the smooth flow of speech production. Stuttering onset occurs during a dynamic period of development when children first start learning to formulate sentences. Although most children grow out of stuttering naturally, ∼1% of all children develop persistent stuttering that can lead to significant psychosocial consequences throughout one’s life. To date, few studies have examined neural bases of stuttering in children who stutter, and even fewer have examined the basis for natural recovery versus persistence of stuttering. Here we report the first study to conduct surface-based analysis of the brain morphometric measures in children who stutter. We used FreeSurfer to extract cortical size and shape measures from structural MRI scans collected from the initial year of a longitudinal study involving 70 children (36 stuttering, 34 controls) in the 3–10-year range. The stuttering group was further divided into two groups: persistent and recovered, based on their later longitudinal visits that allowed determination of their eventual clinical outcome. A region of interest analysis that focused on the left hemisphere speech network and a whole-brain exploratory analysis were conducted to examine group differences and group × age interaction effects. We found that the persistent group could be differentiated from the control and recovered groups by reduced cortical thickness in left motor and lateral premotor cortical regions. The recovered group showed an age-related decrease in local gyrification in the left medial premotor cortex (supplementary motor area and and pre-supplementary motor area). These results provide strong evidence of a primary deficit in the left hemisphere speech network, specifically involving lateral premotor cortex and primary motor cortex, in persistent developmental stuttering. Results further point to a possible compensatory mechanism involving left medial premotor cortex in those who recover from childhood stuttering.This study was supported by Award Numbers R01DC011277 (SC) and R01DC007683 (FG) from the National Institute on Deafness and other Communication Disorders (NIDCD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIDCD or the National Institutes of Health. (R01DC011277 - National Institute on Deafness and other Communication Disorders (NIDCD); R01DC007683 - National Institute on Deafness and other Communication Disorders (NIDCD))Accepted manuscrip

Altered Cortico-Striatal Connectivity in Offspring of Schizophrenia Patients Relative to Offspring of Bipolar Patients and Controls

Schizophrenia (SZ) and bipolar disorder (BD) share clinical features, genetic risk factors and neuroimaging abnormalities. There is evidence of disrupted connectivity in resting state networks in patients with SZ and BD and their unaffected relatives. Resting state networks are known to undergo reorganization during youth coinciding with the period of increased incidence for both disorders. We therefore focused on characterizing resting state network connectivity in youth at familial risk for SZ or BD to identify alterations arising during this period. We measured resting-state functional connectivity in a sample of 106 youth, aged 7-19 years, comprising offspring of patients with SZ (N = 27), offspring of patients with BD (N = 39) and offspring of community control parents (N = 40). We used Independent Component Analysis to assess functional connectivity within the default mode, executive control, salience and basal ganglia networks and define their relationship to grey matter volume, clinical and cognitive measures. There was no difference in connectivity within any of the networks examined between offspring of patients with BD and offspring of community controls. In contrast, offspring of patients with SZ showed reduced connectivity within the left basal ganglia network compared to control offspring, and they showed a positive correlation between connectivity in this network and grey matter volume in the left caudate. Our findings suggest that dysconnectivity in the basal ganglia network is a robust correlate of familial risk for SZ and can be detected during childhood and adolescence

Influence of age and cognitive performance on resting-state functional connectivity of dopaminergic and noradrenergic centers

Aging is associated with structural and functional changes in the brain, with a decline in cognitive functions observed as its inevitable concomitant. The body of literature suggests dopamine and noradrenaline as prominent candidate neuromodulators to mediate these effects; however, knowledge regarding the underlying mechanisms is scarce. To fill this gap, we compared resting-state functional connectivity (FC) patterns of ventral tegmental area (VTA), substantia nigra pars compacta (SNc) and locus coeruleus (LC) in healthy young (20–35 years; N = 37) and older adults (55–80 years; N = 27). Additionally, we sought FC patterns of these structures associated with performance in tasks probing executive, attentional and reward functioning, and we compared the functional coupling of the bilateral SNc. The results showed that individual SNc had stronger coupling with ipsilateral cortical and subcortical areas along with the contralateral cerebellum in the whole sample, and that the strength of connections of this structure with angular gyrus and lateral orbitofrontal cortex predicted visuomotor search abilities. In turn, older age was associated with greater local synchronization within VTA, its lower FC with caudate, mediodorsal thalamus, and SNc, as well as higher FC of both midbrain dopaminergic seeds with red nuclei. LC functional coupling showed no differences between the groups and was not associated with any of the behavioral functions. To the best of our knowledge, this work is the first to report the age-related effects on VTA local synchronization and its connectivity with key recipients of dopaminergic innervation, such as striatum and mediodorsal thalamus

Sex differences in functional connectivity between resting state brain networks in Autism Spectrum Disorder

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Functional brain connectivity (FBC) has previously been examined in autism spectrum disorder (ASD) between-resting-state networks (RSNs) using a highly sensitive and reproducible hypothesis-free approach. However, results have been inconsistent and sex differences have only recently been taken into consideration using this approach. We estimated main effects of diagnosis and sex and a diagnosis by sex interaction on between-RSNs FBC in 83 ASD (40 females/43 males) and 85 typically developing controls (TC; 43 females/42 males). We found increased connectivity between the default mode (DM) and (a) the executive control networks in ASD (vs. TC); (b) the cerebellum networks in males (vs. females); and (c) female-specific altered connectivity involving visual, language and basal ganglia (BG) networks in ASD-in suggestive compatibility with ASD cognitive and neuroscientific theories.VT received support from Fundação Ciência e Tecnologia (FCT) PhD fellowship (PD/BD/114460/2016) and paid by FCT DSAIPA/DS/0065/2018 Grant. DP was supported by the European Commission Seventh Framework Programme Marie Curie Career Integration Grant FP7-PEOPLE-2013-CIG-631952, the 2016 Bial Foundation Psychophysiology Grant Ref. 292/16, and the IF/00787/2014, LISBOA-01-0145-FEDER-030907 and DSAIPA/DS/0065/2018 FCT Grants, and the iMM Lisboa Director’s Fund Breakthrough Idea Grant 2016; and is co-founder and shareholder of the neuroimaging research services company NeuroPsyAI, Ltd. MA was supported by FCT Grant UID/MAT/00006/2013.info:eu-repo/semantics/publishedVersio