Mapping connectivity in the developing brain

Recently, there has been a wealth of research into structural and functional brain connectivity, and how they change over development. While we are far from a complete understanding, these studies have yielded important insights into human brain development. There is an ever growing variety of methods for assessing connectivity, each with its own advantages. Here we review research on the development of structural and/or functional brain connectivity in both typically developing subjects and subjects with neurodevelopmental disorders. Space limitations preclude an exhaustive review of brain connectivity across all developmental disorders, so we review a representative selection of recent findings on brain connectivity in autism, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Turner syndrome, and ADHD. Major strides have been made in understanding the developmental trajectory of the human connectome, offering insight into characteristic features of brain development and biological processes involved in developmental brain disorders. We also discuss some common themes, including hemispheric specialization – or asymmetry – and sex differences. We conclude by discussing some promising future directions in connectomics, including the merger of imaging and genetics, and a deeper investigation of the relationships between structural and functional connectivity.     

Typical and atypical brain development: a review of neuroimaging studies

In the course of development, the brain undergoes a remarkable process of restructuring as it adapts to the environment and becomes more efficient in processing information. A variety of brain imaging methods can be used to probe how anatomy, connectivity, and function change in the developing brain. Here we review recent discoveries regarding these brain changes in both typically developing individuals and individuals with neurodevelopmental disorders. We begin with typical development, summarizing research on changes in regional brain volume and tissue density, cortical thickness, white matter integrity, and functional connectivity. Space limits preclude the coverage of all neurodevelopmental disorders; instead, we cover a representative selection of studies examining neural correlates of autism, attention deficit/hyperactivity disorder, Fragile X, 22q11.2 deletion syndrome, Williams syndrome, Down syndrome, and Turner syndrome. Where possible, we focus on studies that identify an age by diagnosis interaction, suggesting an altered developmental trajectory. The studies we review generally cover the developmental period from infancy to early adulthood. Great progress has been made over the last 20 years in mapping how the brain matures with MR technology. With ever-improving technology, we expect this progress to accelerate, offering a deeper understanding of brain development, and more effective interventions for neurodevelopmental disorders.     

Structural control energy of resting‐state functional brain states reveals less cost‐effective brain dynamics in psychosis vulnerability

How the brain''s white‐matter anatomy constrains brain activity is an open question that might give insights into the mechanisms that underlie mental disorders such as schizophrenia. Chromosome 22q11.2 deletion syndrome (22q11DS) is a neurodevelopmental disorder with an extremely high risk for psychosis providing a test case to study developmental aspects of schizophrenia. In this study, we used principles from network control theory to probe the implications of aberrant structural connectivity for the brain''s functional dynamics in 22q11DS. We retrieved brain states from resting‐state functional magnetic resonance images of 78 patients with 22q11DS and 85 healthy controls. Then, we compared them in terms of persistence control energy; that is, the control energy that would be required to persist in each of these states based on individual structural connectivity and a dynamic model. Persistence control energy was altered in a broad pattern of brain states including both energetically more demanding and less demanding brain states in 22q11DS. Further, we found a negative relationship between persistence control energy and resting‐state activation time, which suggests that the brain reduces energy by spending less time in energetically demanding brain states. In patients with 22q11DS, this behavior was less pronounced, suggesting a deficiency in the ability to reduce energy through brain activation. In summary, our results provide initial insights into the functional implications of altered structural connectivity in 22q11DS, which might improve our understanding of the mechanisms underlying the disease.     

Connectivity dynamics in typical development and its relationship to autistic traits and autism spectrum disorder

Recent advances in neuroimaging techniques have provided significant insights into developmental trajectories of human brain function. Characterizations of typical neurodevelopment provide a framework for understanding altered neurodevelopment, including differences in brain function related to developmental disorders and psychopathology. Historically, most functional connectivity studies of typical and atypical development operate under the assumption that connectivity remains static over time. We hypothesized that relaxing stationarity assumptions would reveal novel features of both typical brain development related to children on the autism spectrum. We employed a “chronnectomic” (recurring, time‐varying patterns of connectivity) approach to evaluate transient states of connectivity using resting‐state functional MRI in a population‐based sample of 774 6‐ to 10‐year‐old children. Dynamic connectivity was evaluated using a sliding‐window approach, and revealed four transient states. Internetwork connectivity increased with age in modularized dynamic states, illustrating an important pattern of connectivity in the developing brain. Furthermore, we demonstrated that higher levels of autistic traits and ASD diagnosis were associated with longer dwell times in a globally disconnected state. These results provide a roadmap to the chronnectomic organization of the developing brain and suggest that characteristics of functional brain connectivity are related to children on the autism spectrum.     

A Comprehensive Review of Brain Connectomics and Imaging to Improve Deep Brain Stimulation Outcomes

DBS is an effective neuromodulatory therapy that has been applied in various conditions, including PD, essential tremor, dystonia, Tourette syndrome, and other movement disorders. There have also been recent examples of applications in epilepsy, chronic pain, and neuropsychiatric conditions. Innovations in neuroimaging technology have been driving connectomics, an emerging whole-brain network approach to neuroscience. Two rising techniques are functional connectivity profiling and structural connectivity profiling. Functional connectivity profiling explores the operational relationships between multiple regions of the brain with respect to time and stimuli. Structural connectivity profiling approximates physical connections between different brain regions through reconstruction of axonal fibers. Through these techniques, complex relationships can be described in various disease states, such as PD, as well as in response to therapy, such as DBS. These advances have expanded our understanding of human brain function and have provided a partial in vivo glimpse into the underlying brain circuits underpinning movement and other disorders. This comprehensive review will highlight the contemporary concepts in brain connectivity as applied to DBS, as well as introduce emerging considerations in movement disorders. © 2020 International Parkinson and Movement Disorder Society     

Short-range connections in the developmental connectome during typical and atypical brain maturation

The human brain is remarkably complex with connectivity constituting its basic organizing principle. Although long-range connectivity has been focused on in most research, short-range connectivity is characterized by unique and spatiotemporally heterogeneous dynamics from infancy to adulthood. Alterations in the maturational dynamics of short-range connectivity has been associated with neuropsychiatric disorders, such as autism and schizophrenia. Recent advances in neuroimaging techniques, especially diffusion magnetic resonance imaging (dMRI), resting-state functional MRI (rs-fMRI), electroencephalography (EEG) and magnetoencephalography (MEG), have made quantification of short-range connectivity possible in pediatric populations. This review summarizes findings on the development of short-range functional and structural connections at the macroscale. These findings suggest an inverted U-shaped pattern of maturation from primary to higher-order brain regions, and possible “hyper-” and “hypo-” short-range connections in autism and schizophrenia, respectively. The precisely balanced short- and long-range connections contribute to the integration and segregation of the connectome during development. The mechanistic relationship among short-range connectivity maturation, the developmental connectome and emerging brain functions needs further investigation, including the refinement of methodological approaches.     

Sex steroids and connectivity in the human brain: a review of neuroimaging studies

Our brain operates by the way of interconnected networks. Connections between brain regions have been extensively studied at a functional and structural level, and impaired connectivity has been postulated as an important pathophysiological mechanism underlying several neuropsychiatric disorders. Yet the neurobiological mechanisms contributing to the development of functional and structural brain connections remain to be poorly understood. Interestingly, animal research has convincingly shown that sex steroid hormones (estrogens, progesterone and testosterone) are critically involved in myelination, forming the basis of white matter connectivity in the central nervous system. To get insights, we reviewed studies into the relation between sex steroid hormones, white matter and functional connectivity in the human brain, measured with neuroimaging. Results suggest that sex hormones organize structural connections, and activate the brain areas they connect. These processes could underlie a better integration of structural and functional communication between brain regions with age. Specifically, ovarian hormones (estradiol and progesterone) may enhance both cortico-cortical and subcortico-cortical functional connectivity, whereas androgens (testosterone) may decrease subcortico-cortical functional connectivity but increase functional connectivity between subcortical brain areas. Therefore, when examining healthy brain development and aging or when investigating possible biological mechanisms of 'brain connectivity' diseases, the contribution of sex steroids should not be ignored.     

Toward dysfunctional connectivity: a review of neuroimaging findings in pediatric major depressive disorder

Child and adolescent psychiatric neuroimaging research typically lags behind similar advances in adult disorders. While the pediatric depression imaging literature is less developed, a recent surge in interest has created the need for a synthetic review of this work. Major findings from pediatric volumetric and functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and resting state functional connectivity studies converge to implicate a corticolimbic network of key areas that work together to mediate the task of emotion regulation. Imaging the brain of children and adolescents with unipolar depression began with volumetric studies of isolated brain regions that served to identify key prefrontal, cingulate and limbic nodes of depression-related circuitry elucidated from more recent advances in DTI and functional connectivity imaging. Systematic review of these studies preliminarily suggests developmental differences between findings in youth and adults, including prodromal neurobiological features, along with some continuity across development.     

The developing brain: from theory to neuroimaging and back

Surprisingly little headway has been made towards understanding how brain growth maps onto mental growth during child development. This review aims at bridging and integrating recent human neuroscientific brain maturation findings with the conceptual thinking of theorists in the behavioural tradition of studying cognitive development. Developmental research in the field of internal control and self-regulation serves as a reference point for understanding the relation between brain maturation and mental growth. Using several recent neuroimaging findings as points in case, we show how a deeper appreciation of structural and functional neural development can be obtained from considering the traditional conceptual frameworks, and vice versa. We conclude that paradigmatic progress in developmental neuroscience can rely more on knowledge from developmental experimental psychology, and that developmental models of cognitive development can be constrained and articulated with more precision on the basis of knowledge of differential structural and functional brain maturation.     

Postnatal development of the primate hippocampal formation

The hippocampal formation is a multicomponent region of the medial temporal lobe preferentially involved in declarative and relational memory processing. Behavioral studies have suggested a protracted functional maturation of these structures in primates, and postnatal developmental abnormalities in the hippocampal formation are thought to contribute to neurodevelopmental disorders, such as autism, schizophrenia, epilepsy and Down syndrome. Despite all that we know about the functional organization of the adult hippocampal formation, notably absent is a systematic study of its postnatal maturation in primates. In this article, we review current knowledge of the structural development of the primate hippocampal formation and present new data on its postnatal neuroanatomical development. We summarize what is known about the neurobiological processes, such as the addition of new neurons, the establishment and elaboration of connectivity, and the neurochemical changes, that underlie the structural development and functional maturation of the primate hippocampal formation. We conclude that there is yet insufficient information to identify distinct developmental windows during which different hippocampal regions undergo specific maturational processes. For this reason, it is currently impossible to determine the ages at which specific hippocampal circuits become structurally mature and potentially capable of supporting defined, age-specific functional processes. Together with work in rodents, systematic studies of the structural development and functional maturation of the monkey hippocampal formation will be necessary to gain insight not only into the types of information processing that it subserves, but also into the specific maturational processes that might be affected in human neurodevelopmental disorders.     

Imaging structural and functional connectivity: towards a unified definition of human brain organization?

PURPOSE OF REVIEW: Diffusion tractography and functional/effective connectivity MRI provide a better understanding of the structural and functional human brain connectivity. This review will underline the major recent methodological developments and their exceptional respective contributions to physiological and pathophysiological studies in vivo. We will also emphasize the benefits provided by computational models of complex networks such as graph theory. RECENT FINDINGS: Imaging structural and functional brain connectivity has revealed the complex brain organization into large-scale networks. Such an organization not only permits the complex information segregation and integration during high cognitive processes but also determines the clinical consequences of alterations encountered in development, ageing, or neurological diseases. Recently, it has also been demonstrated that human brain networks shared topological properties with the so-called 'small-world' mathematical model, allowing a maximal efficiency with a minimal energy and wiring cost. SUMMARY: Separately, magnetic resonance tractography and functional MRI connectivity have both brought new insights into brain organization and the impact of injuries. The small-world topology of structural and functional human brain networks offers a common framework to merge structural and functional imaging as well as dynamical data from electrophysiology that might allow a comprehensive definition of the brain organization and plasticity.     

Alterations of Functional Connectivity in Patients With Restless Legs Syndrome

Restless legs syndrome (RLS) is a common neurological illness marked by a strong desire to move one’s legs, usually in association with uncomfortable sensations. Recent studies have investigated brain networks and connectivity in RLS. The advent of network analysis has greatly improved our understanding of the brain and various neurological disorders. A few studies have investigated alterations in functional connectivity in patients with RLS. This article reviews functional connectivity studies of patients with RLS, which have identified significant alterations relative to healthy controls in several brain networks including thalamic, salience, default-mode, and small-world networks. In addition, network changes related to RLS treatment have been found, including to repetitive transcranial magnetic stimulation, transcutaneous spinal cord direct-current stimulation, and dopaminergic drugs. These findings suggest that the underlying pathogenesis of RLS includes alterations in the functional connectivity in the brain and that RLS is a network disorder.     

Control of cortical synapse development and plasticity by MET receptor tyrosine kinase,a genetic risk factor for autism

The key developmental milestone events of the human brain, such as neurogenesis, synapse formation, maturation, and plasticity, are determined by a myriad of molecular signaling events, including those mediated by a number of receptor tyrosine kinases (RTKs) and their cognate ligands. Aberrant or mistimed brain development and plasticity can lead to maladaptive changes, such as dysregulated synaptic connectivity and breakdown of circuit functions necessary for cognition and adaptive behaviors, which are hypothesized pathophysiologies of many neurodevelopmental and neuropsychiatric disorders. Here we review recent literature that supports autism spectrum disorder as a likely result of aberrant synapse development due to mistimed maturation and plasticity. We focus on MET RTK, a prominent genetic risk factor for autism, and discuss how a pleiotropic molecular signaling system engaged by MET exemplifies a genetic program that controls cortical circuit development and plasticity by modulating the anatomical and functional connectivity of cortical circuits, thus conferring genetic risk for neurodevelopmental disorders.     

Graph theoretical analysis of human brain structural networks

There is a growing interest in exploring the connectivity patterns of the human brain. Specifically, the utility of noninvasive neuroimaging data and graph theoretical analysis have provided important insights into the anatomical connections and topological pattern of human brain structural networks in vivo. This review focuses on recent methodological and application studies, utilizing graph theoretical approaches, on brain structural networks with structural magnetic resonance imaging (MRI) and diffusion MRI. These studies showed many nonrandom properties of structural brain networks, such as small-worldness, modularity, and highly connected hubs. Importantly, topological organization of the networks shows changes during normal development, aging, and neuropsychiatric diseases. Network structures have also been found to correlate with behavioral or cognitive functions, which imply their associations with functional dynamics. These advances not only help us to understand how the healthy human brain is structurally organized, but also provide a novel insight into the biological mechanisms of brain disorders. Future studies will involve the combination of structural/diffusion MRI and functional MRI, to realize how the structural connectivity patterns of the brain underlie its functional states, and will explore whether graph theoretical analysis of structural brain networks could serve as potential imaging biomarkers for disease diagnosis and treatment.     

Magnetic Resonance Imaging in Paediatric Psychoneuroendocrinology: A New Frontier for Understanding the Impact of Hormones on Emotion and Cognition

Mounting magnetic resonance imaging (MRI) research is characterising the neurobiological trajectories of healthy human brain development. In parallel, studies increasingly acknowledge the relevance of perturbations of these trajectories for adolescent and adult psychopathology. Although an influence of steroid hormones on mood and anxiety disorders has been demonstrated in adults, very little is known about how steroid hormones alter human brain development and contribute to adolescent psychopathology. This review focuses on recent evidence obtained from structural and functional MRI in children and adolescents with genetic endocrine disorders and with characteristic fluctuations in androgen or oestrogen levels (familial male precocious puberty, congenital adrenal hyperplasia, Klinefelter syndrome and Turner syndrome). It aims to highlight how neurobiological findings from these paediatric endocrine disorders can provide insight into the contribution of sex steroids with respect to the development of neurocircuitry involved in affective processing (amygdala, hippocampus) and cognitive control (prefrontal cortex, inferior frontal gyrus, striatum). In addition, findings from these populations may also provide important information on aberrant psychological processes relevant for the clinical care and management of these populations. Finally, the findings are discussed within the context of current frameworks in animal models, such as the organisational–activational hypothesis or the aromatisation hypothesis. The review ends with a discussion of open questions for future enquiry with the goal of integrating translational models with current knowledge of endocrine disorders and developmental studies in healthy populations.     

Mobile EEG in research on neurodevelopmental disorders: Opportunities and challenges

Mobile electroencephalography (mobile EEG) represents a next-generation neuroscientific technology – to study real-time brain activity – that is relatively inexpensive, non-invasive and portable. Mobile EEG leverages state-of-the-art hardware alongside established advantages of traditional EEG and recent advances in signal processing. In this review, we propose that mobile EEG could open unprecedented possibilities for studying neurodevelopmental disorders. We first present a brief overview of recent developments in mobile EEG technologies, emphasising the proliferation of studies in several neuroscientific domains. As these developments have yet to be exploited by neurodevelopmentalists, we then identify three research opportunities: 1) increase in the ease and flexibility of brain data acquisition in neurodevelopmental populations; 2) integration into powerful developmentally-informative research designs; 3) development of innovative non-stationary EEG-based paradigms. Critically, we address key challenges that should be considered to fully realise the potential of mobile EEG for neurodevelopmental research and for understanding developmental psychopathology more broadly, and suggest future research directions.     

Parcellation of the human hippocampus based on gray matter volume covariance: Replicable results on healthy young adults

The hippocampus is a key brain region that participates in a range of cognitive and affective functions, and is involved in the etiopathogenesis of numerous neuropsychiatric disorders. The structural complexity and functional diversity of the hippocampus suggest the existence of structural and functional subdivisions within this structure. For the first time, we parcellated the human hippocampus with two independent data sets, each of which consisted of 198 T1‐weighted structural magnetic resonance imaging (sMRI) images of healthy young subjects. The method was based on gray matter volume (GMV) covariance, which was quantified by a bivariate voxel‐to‐voxel linear correlation approach, as well as a multivariate masked independent component analysis approach. We subsequently interrogated the relationship between the GMV covariance patterns and the functional connectivity patterns of the hippocampal subregions using sMRI and resting‐state functional MRI (fMRI) data from the same participants. Seven distinct GMV covariance‐based subregions were identified for bilateral hippocampi, with robust reproducibility across the two data sets. We further demonstrated that the structural covariance patterns of the hippocampal subregions had a correspondence with the intrinsic functional connectivity patterns of these subregions. Together, our results provide a topographical configuration of the hippocampus with converging structural and functional support. The resulting subregions may improve our understanding of the hippocampal connectivity and functions at a subregional level, which provides useful parcellations and masks for future neuroscience and clinical research on the structural and/or functional connectivity of the hippocampus.     

Resting state EEG abnormalities in autism spectrum disorders

Autism spectrum disorders (ASD) are a group of complex and heterogeneous developmental disorders involving multiple neural system dysfunctions. In an effort to understand neurophysiological substrates, identify etiopathophysiologically distinct subgroups of patients, and track outcomes of novel treatments with translational biomarkers, EEG (electroencephalography) studies offer a promising research strategy in ASD. Resting-state EEG studies of ASD suggest a U-shaped profile of electrophysiological power alterations, with excessive power in low-frequency and high-frequency bands, abnormal functional connectivity, and enhanced power in the left hemisphere of the brain. In this review, we provide a summary of recent findings, discuss limitations in available research that may contribute to inconsistencies in the literature, and offer suggestions for future research in this area for advancing the understanding of ASD.     

Degrees of functional connectome abnormality in disorders of consciousness

Understanding the neuronal basis of disorders of consciousness can help improve the accuracy of their diagnosis, indicate potential targets for therapeutic interventions, and provide insights into the organization of normal conscious information processing. Measurements of brain activity have been used to find associations of the levels of consciousness with brain complexity, topological features of functional connectomes, and disruption of resting‐state networks. However, obtainment of a detailed picture of activity patterns underlying the vegetative state/unresponsive wakefulness syndrome and the minimally conscious state remains a work in progress. We here aimed at finding the aspects of fMRI‐based functional connectivity that differentiate these states from each other and from the normal condition. A group of 22 patients was studied (9 minimally conscious state and 13 vegetative state/unresponsive wakefulness syndrome). Patients were shown to have reduced connectivity in most resting‐state networks and disrupted patterns of relative connection strengths as compared to healthy subjects. Differences between the unresponsive wakefulness syndrome and the minimally conscious state were found in the patterns formed by a relatively small number of strongest positive correlations selected by thresholding. These differences were captured by measures of functional connectivity disruption that integrate area‐specific abnormalities over the whole brain. The results suggest that the strong positive correlations between the functional activities of specific brain areas observed in healthy individuals may be critical for consciousness and be an important target of disruption in disorders of consciousness.