The development of human cognition results from the emergence of coordinated activity between distant brain areas. Network science, combined with non-invasive functional imaging, has generated ...unprecedented insights regarding the adult brain's functional organization, and promises to help elucidate the development of functional architectures supporting complex behavior. Here we review what is known about functional network development from birth until adulthood, particularly as understood through the use of resting-state functional connectivity MRI (rs-fcMRI). We attempt to synthesize rs-fcMRI findings with other functional imaging techniques, with macro-scale structural connectivity, and with knowledge regarding the development of micro-scale structure. We highlight a number of outstanding conceptual and technical barriers that need to be addressed, as well as previous developmental findings that may need to be revisited. Finally, we discuss key areas ripe for future research in order to (1) better characterize normative developmental trajectories, (2) link these trajectories to biologic mechanistic events, as well as component behaviors and (3) better understand the clinical implications and pathophysiological basis of aberrant network development.
•Reviews development of functional connectivity networks from birth until adulthood.•Reviews trends in resting-state functional MR imaging (rs-fMRI) and network analysis.•Synthesizes developmental rs-fMRI findings with structural connectivity and EEG/MEG.•Suggests strategies to overcome limitations of rs-fMRI in developmental studies.•Suggests approaches to interrogate neurodevelopmental disorders.
The vast majority of mental illnesses can be conceptualized as developmental disorders of neural interactions within the connectome, or developmental miswiring. The recent maturation of pediatric ...in vivo brain imaging is bringing the identification of clinically meaningful brain-based biomarkers of developmental disorders within reach. Even more auspicious is the ability to study the evolving connectome throughout life, beginning in utero, which promises to move the field from topological phenomenology to etiological nosology. Here, we scope advances in pediatric imaging of the brain connectome as the field faces the challenge of unraveling developmental miswiring. We highlight promises while also providing a pragmatic review of the many obstacles ahead that must be overcome to significantly impact public health.
In this Perspective, Di Martino et al. discuss recent advances in pediatric imaging of the developing brain connectome as well as challenges in using pediatric in vivo imaging to identify brain-based biomarkers of developmental disorders.
•We developed a cross-species alignment that enables comparing and quantifying the functional homology between species.•We proposed a functional-based homology index that reflects the gradient of ...unimodal-transmodal hierarchy.•We characterized the cross-species similarity that follows the local hierarchies and supports the tethering hypothesis.•We suggest that the default mode network has changed in a complex manner during human evolution – even within subnetworks.
Evolution provides an important window into how cortical organization shapes function and vice versa. The complex mosaic of changes in brain morphology and functional organization that have shaped the mammalian cortex during evolution, complicates attempts to chart cortical differences across species. It limits our ability to fully appreciate how evolution has shaped our brain, especially in systems associated with unique human cognitive capabilities that lack anatomical homologues in other species. Here, we develop a function-based method for cross-species alignment that enables the quantification of homologous regions between humans and rhesus macaques, even when their location is decoupled from anatomical landmarks. Critically, we find cross-species similarity in functional organization reflects a gradient of evolutionary change that decreases from unimodal systems and culminates with the most pronounced changes in posterior regions of the default mode network (angular gyrus, posterior cingulate and middle temporal cortices). Our findings suggest that the establishment of the default mode network, as the apex of a cognitive hierarchy, has changed in a complex manner during human evolution – even within subnetworks.
The widely acknowledged homogeneity assumption limits progress in refining clinical diagnosis, understanding mechanisms, and developing new treatments for mental health disorders. This homogeneity ...assumption drives both a comorbidity and a heterogeneity problem, where two different approaches tackle the problems. One, a unifying approach, tackles the comorbidity problem by assuming that a single general psychopathology factor underlies multiple disorders. Another, a multifactorial approach, tackles the heterogeneity problem by assuming that disorders comprise multiple subtypes driven by multiple discrete factors. We show how each of these approaches can make useful contributions to mental health–related research and clinical practice. For example, the unifying approach can develop a rapid assessment tool that may be clinically valuable for triaging cases. The multifactorial approach can reveal subtypes that are differentially responsive to treatments and highlight distinct mechanisms leading to similar phenotypes. Because both approaches tackle different problems, both have different limitations. We describe the statistical frameworks that incorporate and adjudicate between both approaches (e.g., the bifactor model, normative modeling, and the functional random forest). Such frameworks can identify whether sets of disorders are more affected by heterogeneity or comorbidity. Therefore, future studies that incorporate such frameworks can provide further insight into the nature of psychopathology.
Recent studies using Magnetic Resonance Imaging (MRI) have proposed that the brain's white matter is organized as a rich club, whereby the most highly connected regions of the brain are also highly ...connected to each other. Here we use both functional and diffusion-weighted MRI in the human brain to investigate whether the rich club phenomena is present with functional connectivity, and how this organization relates to the structural phenomena. We also examine whether rich club regions serve to integrate information between distinct brain systems, and conclude with a brief investigation of the developmental trajectory of rich-club phenomena. In agreement with prior work, both adults and children showed robust structural rich club organization, comprising regions of the superior medial frontal/dACC, medial parietal/PCC, insula, and inferior temporal cortex. We also show that these regions were highly integrated across the brain's major networks. Functional brain networks were found to have rich club phenomena in a similar spatial layout, but a high level of segregation between systems. While no significant differences between adults and children were found structurally, adults showed significantly greater functional rich club organization. This difference appeared to be driven by a specific set of connections between superior parietal, insula, and supramarginal cortex. In sum, this work highlights the existence of both a structural and functional rich club in adult and child populations with some functional changes over development. It also offers a potential target in examining atypical network organization in common developmental brain disorders, such as ADHD and Autism.
Cognitive abilities, such as working memory, differ among people; however, individuals also vary in their own day-to-day cognitive performance. One potential source of cognitive variability may be ...fluctuations in the functional organization of neural systems. The degree to which the organization of these functional networks is optimized may relate to the effective cognitive functioning of the individual. Here we specifically examine how changes in the organization of large-scale networks measured via resting state functional connectivity MRI and graph theory track changes in working memory capacity.
Twenty-two participants performed a test of working memory capacity and then underwent resting-state fMRI. Seventeen subjects repeated the protocol three weeks later. We applied graph theoretic techniques to measure network organization on 34 brain regions of interest (ROI). Network modularity, which measures the level of integration and segregation across sub-networks, and small-worldness, which measures global network connection efficiency, both predicted individual differences in memory capacity; however, only modularity predicted intra-individual variation across the two sessions. Partial correlations controlling for the component of working memory that was stable across sessions revealed that modularity was almost entirely associated with the variability of working memory at each session. Analyses of specific sub-networks and individual circuits were unable to consistently account for working memory capacity variability.
The results suggest that the intrinsic functional organization of an a priori defined cognitive control network measured at rest provides substantial information about actual cognitive performance. The association of network modularity to the variability in an individual's working memory capacity suggests that the organization of this network into high connectivity within modules and sparse connections between modules may reflect effective signaling across brain regions, perhaps through the modulation of signal or the suppression of the propagation of noise.
The mature human brain is organized into a collection of specialized functional networks that flexibly interact to support various cognitive functions. Studies of development often attempt to ...identify the organizing principles that guide the maturation of these functional networks. In this report, we combine resting state functional connectivity MRI (rs-fcMRI), graph analysis, community detection, and spring-embedding visualization techniques to analyze four separate networks defined in earlier studies. As we have previously reported, we find, across development, a trend toward 'segregation' (a general decrease in correlation strength) between regions close in anatomical space and 'integration' (an increased correlation strength) between selected regions distant in space. The generalization of these earlier trends across multiple networks suggests that this is a general developmental principle for changes in functional connectivity that would extend to large-scale graph theoretic analyses of large-scale brain networks. Communities in children are predominantly arranged by anatomical proximity, while communities in adults predominantly reflect functional relationships, as defined from adult fMRI studies. In sum, over development, the organization of multiple functional networks shifts from a local anatomical emphasis in children to a more "distributed" architecture in young adults. We argue that this "local to distributed" developmental characterization has important implications for understanding the development of neural systems underlying cognition. Further, graph metrics (e.g., clustering coefficients and average path lengths) are similar in child and adult graphs, with both showing "small-world"-like properties, while community detection by modularity optimization reveals stable communities within the graphs that are clearly different between young children and young adults. These observations suggest that early school age children and adults both have relatively efficient systems that may solve similar information processing problems in divergent ways.
The imprecise nature of psychiatric nosology restricts progress towards characterizing and treating mental health disorders. One issue is the ‘heterogeneity problem’: different causal mechanisms may ...relate to the same disorder, and multiple outcomes of interest can occur within one individual. Our review tackles this heterogeneity problem, providing considerations, concepts, and approaches for investigators examining human cognition and mental health. We highlight the difficulty of pure dimensional approaches due to ‘the curse of dimensionality’. Computationally, we consider supervised and unsupervised statistical approaches to identify putative subtypes within a population. However, we emphasize that subtype identification should be linked to a particular outcome or question. We conclude with novel hybrid approaches that can identify subtypes tied to outcomes, and may help advance precision diagnostic and treatment tools.
The heterogeneity problem limits efforts to characterize typical and atypical cognitive phenomenon.Multidimensional approaches to overcome the heterogeneity problem are promising, but also limited by the curse of dimensionality.Identification of subpopulations through supervised and unsupervised methods offers an alternative approach toward characterizing heterogeneity.Supervised and unsupervised approaches toward characterizing heterogeneity are limited in that subpopulations are not tied to specific questions of interest.Hybrid methods that combine both supervised and unsupervised methods, such as FRF and SVA, are able to identify subpopulations tied to specific questions of interest (e.g., cognitive performance or treatment outcome), and may ultimately help refine psychiatric nosology.
A better characterization of how an individual's brain is functionally organized will likely bring dramatic advances to many fields of study. Here we show a model-based approach toward characterizing ...resting state functional connectivity MRI (rs-fcMRI) that is capable of identifying a so-called "connectotype", or functional fingerprint in individual participants. The approach rests on a simple linear model that proposes the activity of a given brain region can be described by the weighted sum of its functional neighboring regions. The resulting coefficients correspond to a personalized model-based connectivity matrix that is capable of predicting the timeseries of each subject. Importantly, the model itself is subject specific and has the ability to predict an individual at a later date using a limited number of non-sequential frames. While we show that there is a significant amount of shared variance between models across subjects, the model's ability to discriminate an individual is driven by unique connections in higher order control regions in frontal and parietal cortices. Furthermore, we show that the connectotype is present in non-human primates as well, highlighting the translational potential of the approach.
Freezing of gait (FoG) is a transient inability to initiate or maintain stepping that often accompanies advanced Parkinson's disease (PD) and significantly impairs mobility. The current study uses a ...multimodal neuroimaging approach to assess differences in the functional and structural locomotor neural network in PD patients with and without FoG and relates these findings to measures of FoG severity. Twenty-six PD patients and fifteen age-matched controls underwent resting-state functional magnetic resonance imaging and diffusion tensor imaging along with self-reported and clinical assessments of FoG. After stringent movement correction, fifteen PD patients and fourteen control participants were available for analysis. We assessed functional connectivity strength between the supplementary motor area (SMA) and the following locomotor hubs: 1) subthalamic nucleus (STN), 2) mesencephalic and 3) cerebellar locomotor region (MLR and CLR, respectively) within each hemisphere. Additionally, we quantified structural connectivity strength between locomotor hubs and assessed relationships with metrics of FoG. FoG+ patients showed greater functional connectivity between the SMA and bilateral MLR and between the SMA and left CLR compared to both FoG- and controls. Importantly, greater functional connectivity between the SMA and MLR was positively correlated with i) clinical, ii) self-reported and iii) objective ratings of freezing severity in FoG+, potentially reflecting a maladaptive neural compensation. The current findings demonstrate a re-organization of functional communication within the locomotor network in FoG+ patients whereby the higher-order motor cortex (SMA) responsible for gait initiation communicates with the MLR and CLR to a greater extent than in FoG- patients and controls. The observed pattern of altered connectivity in FoG+ may indicate a failed attempt by the CNS to compensate for the loss of connectivity between the STN and SMA and may reflect a loss of lower-order, automatic control of gait by the basal ganglia.
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