Individual Connectomes Research Articles

A generative model of the connectome with dynamic axon growth

Abstract Connectome generative models, otherwise known as generative network models, provide insight into the wiring principles underpinning brain network organization. While these models can approximate numerous statistical properties of empirical networks, they typically fail to explicitly characterize an important contributor to brain organization - axonal growth. Emulating the chemoaffinity guided axonal growth, we provide a novel generative model in which axons dynamically steer the direction of propagation based on distance-dependent chemoattractive forces acting on their growth cones. This simple dynamic growth mechanism, despite being solely geometry-dependent, is shown to generate axonal fiber bundles with brain-like geometry and features of complex network architecture consistent with the human brain, including lognormally distributed connectivity weights, scale-free nodal degrees, small-worldness, and modularity. We demonstrate that our model parameters can be fitted to individual connectomes, enabling connectome dimensionality reduction and comparison of parameters between groups. Our work offers an opportunity to bridge studies of axon guidance and connectome development, providing new avenues for understanding neural development from a computational perspective.

Enhancing the network specific individual characteristics in rs‐fMRI functional connectivity by dictionary learning

Most fMRI inferences are based on analyzing the scans of a cohort. Thus, the individual variability of a subject is often overlooked in these studies. Recently, there has been a growing interest in individual differences in brain connectivity also known as individual connectome. Various studies have demonstrated the individual specific component of functional connectivity (FC), which has enormous potential to identify participants across consecutive testing sessions. Many machine learning and dictionary learning-based approaches have been used to extract these subject-specific components either from the blood oxygen level dependent (BOLD) signal or from the FC. In addition, several studies have reported that some resting-state networks have more individual-specific information than others. This study compares four different dictionary-learning algorithms that compute the individual variability from the network-specific FC computed from resting-state functional Magnetic Resonance Imaging (rs-fMRI) data having 10 scans per subject. The study also compares the effect of two FC normalization techniques, namely, Fisher Z normalization and degree normalization on the extracted subject-specific components. To quantitatively evaluate the extracted subject-specific component, a metric named is proposed, and it is used in combination with the existing differential identifiability metric. It is based on the hypothesis that the subject-specific FC vectors should be similar within the same subject and different across different subjects. Results indicate that Fisher Z transformed subject-specific fronto-parietal and default mode network extracted using Common Orthogonal Basis Extraction (COBE) dictionary learning have the best features to identify a participant.

Identifying covariate-related subnetworks for whole-brain connectome analysis.

Whole-brain connectome data characterize the connections among distributed neural populations as a set of edges in a large network, and neuroscience research aims to systematically investigate associations between brain connectome and clinical or experimental conditions as covariates. A covariate is often related to a number of edges connecting multiple brain areas in an organized structure. However, in practice, neither the covariate-related edges nor the structure is known. Therefore, the understanding of underlying neural mechanisms relies on statistical methods that are capable of simultaneously identifying covariate-related connections and recognizing their network topological structures. The task can be challenging because of false-positive noise and almost infinite possibilities of edges combining into subnetworks. To address these challenges, we propose a new statistical approach to handle multivariate edge variables as outcomes and output covariate-related subnetworks. We first study the graph properties of covariate-related subnetworks from a graph and combinatorics perspective and accordingly bridge the inference for individual connectome edges and covariate-related subnetworks. Next, we develop efficient algorithms to exact covariate-related subnetworks from the whole-brain connectome data with an $\ell_0$ norm penalty. We validate the proposed methods based on an extensive simulation study, and we benchmark our performance against existing methods. Using our proposed method, we analyze two separate resting-state functional magnetic resonance imaging data sets for schizophrenia research and obtain highly replicable disease-related subnetworks.

Parameter estimation for connectome generative models: Accuracy, reliability, and a fast parameter fitting method

Generative models of the human connectome enable in silico generation of brain networks based on probabilistic wiring rules. These wiring rules are governed by a small number of parameters that are typically fitted to individual connectomes and quantify the extent to which geometry and topology shape the generative process. A significant shortcoming of generative modeling in large cohort studies is that parameter estimation is computationally burdensome, and the accuracy and reliability of current estimation methods remain untested. Here, we propose a fast, reliable, and accurate parameter estimation method for connectome generative models that is scalable to large sample sizes. Our method achieves improved estimation accuracy and reliability and reduces computational cost by orders of magnitude, compared to established methods. We demonstrate an inherent tradeoff between accuracy, reliability, and computational expense in parameter estimation and provide recommendations for leveraging this tradeoff. To enable power analyses in future studies, we empirically approximate the minimum sample size required to detect between-group differences in generative model parameters. While we focus on the classic two-parameter generative model based on connection length and the topological matching index, our method can be generalized to other growth-based generative models. Our work provides a statistical and practical guide to parameter estimation for connectome generative models.

Connectomics and the neural basis of behaviour.

Methods to acquire and process synaptic-resolution electron-microscopy datasets have progressed very rapidly, allowing production and annotation of larger, more complete connectomes. More accurate neuronal matching techniques are enriching cell type data with gene expression, neuron activity, behaviour and developmental information, providing ways to test hypotheses of circuit function. In a variety of behaviours such as learned and innate olfaction, navigation and sexual behaviour, connectomics has already revealed interconnected modules with a hierarchical structure, recurrence and integration of sensory streams. Comparing individual connectomes to determine which circuit features are robust and which are variable is one key research area; new work in comparative connectomics across development, experience, sex and species will establish strong links between neuronal connectivity and brain function.

Predicting multilingual effects on executive function and individual connectomes in children: An ABCD study

While there is a substantial amount of work studying multilingualism's effect on cognitive functions, little is known about how the multilingual experience modulates the brain as a whole. In this study, we analyzed data of over 1,000 children from the Adolescent Brain Cognitive Development (ABCD) Study to examine whether monolinguals and multilinguals differ in executive function, functional brain connectivity, and brain-behavior associations. We observed significantly better performance from multilingual children than monolinguals in working-memory tasks. In one finding, we were able to classify multilinguals from monolinguals using only their whole-brain functional connectome at rest and during an emotional n-back task. Compared to monolinguals, the multilingual group had different functional connectivity mainly in the occipital lobe and subcortical areas during the emotional n-back task and in the occipital lobe and prefrontal cortex at rest. In contrast, we did not find any differences in behavioral performance and functional connectivity when performing a stop-signal task. As a second finding, we investigated the degree to which behavior is reflected in the brain by implementing a connectome-based behavior prediction approach. The multilingual group showed a significant correlation between observed and connectome-predicted individual working-memory performance scores, while the monolingual group did not show any correlations. Overall, our observations suggest that multilingualism enhances executive function and reliably modulates the corresponding brain functional connectome, distinguishing multilinguals from monolinguals even at the developmental stage.

Nodal Memberships to Communities of Functional Brain Networks Reveal Functional Flexibility and Individualized Connectome

Abstract Human brain network is organized as interconnected communities for supporting cognition and behavior. Despite studies on the nonoverlapping communities of brain network, overlapping community structure and its relationship to brain function remain largely unknown. With this consideration, we employed the Bayesian nonnegative matrix factorization to decompose the functional brain networks constructed from resting-state fMRI data into overlapping communities with interdigitated mapping to functional subnetworks. By examining the heterogeneous nodal membership to communities, we classified nodes into three classes: Most nodes in somatomotor and limbic subnetworks were affiliated with one dominant community and classified as unimodule nodes; most nodes in attention and frontoparietal subnetworks were affiliated with more than two communities and classified as multimodule nodes; and the remaining nodes affiliated with two communities were classified as bimodule nodes. This three-class paradigm was highly reproducible across sessions and subjects. Furthermore, the more likely a node was classified as multimodule node, the more flexible it will be engaged in multiple tasks. Finally, the FC feature vector associated with multimodule nodes could serve as connectome “fingerprinting” to gain high subject discriminability. Together, our findings offer new insights on the flexible spatial overlapping communities that related to task-based functional flexibility and individual connectome “fingerprinting.”

Clinical connectome fingerprints of cognitive decline

Brain connectome fingerprinting is rapidly rising as a novel influential field in brain network analysis. Yet, it is still unclear whether connectivity fingerprints could be effectively used for mapping and predicting disease progression from human brain data. We hypothesize that dysregulation of brain activity in disease would reflect in worse subject identification. We propose a novel framework, Clinical Connectome Fingerprinting, to detect individual connectome features from clinical populations. We show that “clinical fingerprints” can map individual variations between elderly healthy subjects and patients with mild cognitive impairment in functional connectomes extracted from magnetoencephalography data. We find that identifiability is reduced in patients as compared to controls, and show that these connectivity features are predictive of the individual Mini-Mental State Examination (MMSE) score in patients. We hope that the proposed methodology can help in bridging the gap between connectivity features and biomarkers of brain dysfunction in large-scale brain networks.

Functional connectome fingerprinting: Identifying individuals and predicting cognitive functions via autoencoder.

Functional network connectivity has been widely acknowledged to characterize brain functions, which can be regarded as “brain fingerprinting” to identify an individual from a pool of subjects. Both common and unique information has been shown to exist in the connectomes across individuals. However, very little is known about whether and how this information can be used to predict the individual variability of the brain. In this paper, we propose to enhance the uniqueness of individual connectome based on an autoencoder network. Specifically, we hypothesize that the common neural activities shared across individuals may reduce the individual identification. By removing contributions from shared activities, inter‐subject variability can be enhanced. Our experimental results on HCP data show that the refined connectomes obtained by utilizing autoencoder with sparse dictionary learning can distinguish an individual from the remaining participants with high accuracy (up to 99.5% for the rest–rest pair). Furthermore, high‐level cognitive behaviors (e.g., fluid intelligence, executive function, and language comprehension) can also be better predicted with the obtained refined connectomes. We also find that high‐order association cortices contribute more to both individual discrimination and behavior prediction. In summary, our proposed framework provides a promising way to leverage functional connectivity networks for cognition and behavior study, in addition to a better understanding of brain functions.

Application of Structural and Functional Connectome Mismatch for Classification and Individualized Therapy in Alzheimer Disease.

While machine learning approaches to analyzing Alzheimer disease connectome neuroimaging data have been studied, many have limited ability to provide insight in individual patterns of disease and lack the ability to provide actionable information about where in the brain a specific patient's disease is located. We studied a cohort of patients with Alzheimer disease who underwent resting state functional magnetic resonance imaging and diffusion tractography imaging. These images were processed, and a structural and functional connectivity matrix was generated using the HCP cortical and subcortical atlas. By generating a machine learning model, individual-level structural and functional anomalies detection and characterization were explored in this study. Our study found that structural disease burden in Alzheimer's patients is mainly focused in the subcortical structures and the Default mode network (DMN). Interestingly, functional anomalies were less consistent between individuals and less common in general in these patients. More intriguing was that some structural anomalies were noted in all patients in the study, namely a reduction in fibers involving parcellations in the right anterior cingulate. Alternately, the functional consequences of connectivity loss were cortical and variable. Integrated structural/functional connectomics might provide a useful tool for assessing AD progression, while few concerns have been made for analyzing the mismatch between these two. We performed a preliminary exploration into a set of Alzheimer disease data, intending to improve a personalized approach to understanding individual connectomes in an actionable manner. Specifically, we found that there were consistent patterns of white matter fiber loss, mainly focused around the DMN and deep subcortical structures, which were present in nearly all patients with clinical AD. Functional magnetic resonance imaging shows abnormal functional connectivity different within the patients, which may be used as the individual target for further therapeutic strategies making, like non-invasive stimulation technology.

Functional reorganization of brain networks across the human menstrual cycle

The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone production that occurs in most mammalian species. In rodents and nonhuman primates, estrogen and progesterone’s impact on the brain is evident across a range of spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain networks at rest in a woman who underwent brain imaging and venipuncture for 30 consecutive days. Standardized regression analyses illustrate estrogen and progesterone’s widespread associations with functional connectivity. Time-lagged analyses examined the temporal directionality of these relationships and suggest that cortical network dynamics (particularly in the Default Mode and Dorsal Attention Networks, whose hubs are densely populated with estrogen receptors) are preceded—and perhaps driven—by hormonal fluctuations. A similar pattern of associations was observed in a follow-up study one year later. Together, these results reveal the rhythmic nature in which brain networks reorganize across the human menstrual cycle. Neuroimaging studies that densely sample the individual connectome have begun to transform our understanding of the brain’s functional organization. As these results indicate, taking endocrine factors into account is critical for fully understanding the intrinsic dynamics of the human brain.

Aging-Sensitive Networks Within the Human Structural Connectome Are Implicated in Late-Life Cognitive Declines

BackgroundAging-related cognitive decline is a primary risk factor for Alzheimer’s disease and related dementias. More precise identification of the neurobiological bases of cognitive decline in aging populations may provide critical insights into the precursors of late-life dementias. MethodsUsing structural and diffusion brain magnetic resonance imaging data from the UK Biobank (n = 8185; age range, 45–78 years), we examined aging of regional gray matter volumes (nodes) and white matter structural connectivity (edges) within 9 well-characterized networks of interest in the human brain connectome. In the independent Lothian Birth Cohort 1936 (n = 534; all 73 years of age), we tested whether aging-sensitive connectome elements are enriched for key domains of cognitive function before and after controlling for early-life cognitive ability. ResultsIn the UK Biobank, age differences in individual connectome elements corresponded closely with principal component loadings reflecting connectome-wide integrity (|rnodes| = .420; |redges| = .583), suggesting that connectome aging occurs on broad dimensions of variation in brain architecture. In the Lothian Birth Cohort 1936, composite indices of node integrity were predictive of all domains of cognitive function, whereas composite indices of edge integrity were associated specifically with processing speed. Elements within the central executive network were disproportionately predictive of late-life cognitive function relative to the network’s small size. Associations with processing speed and visuospatial ability remained after controlling for childhood cognitive ability. ConclusionsThese results implicate global dimensions of variation in the human structural connectome in aging-related cognitive decline. The central executive network may demarcate a constellation of elements that are centrally important to age-related cognitive impairments.

Measuring Cognitive Flexibility with the Flexible Item Selection Task: From fMRI Adaptation to Individual Connectome Mapping.

Cognitive flexibility, the ability to appropriately adjust behavior in a changing environment, has been challenging to operationalize and validate in cognitive neuroscience studies. Here, we investigate neural activation and directed functional connectivity underlying cognitive flexibility using an fMRI-adapted version of the Flexible Item Selection Task (FIST) in adults (n = 32, ages 19-46 years). The fMRI-adapted FIST was reliable, showed comparable performance to the computer-based version of the task, and produced robust activation in frontoparietal, anterior cingulate, insular, and subcortical regions. During flexibility trials, participants directly engaged the left inferior frontal junction, which influenced activity in other cortical and subcortical regions. The strength of intrinsic functional connectivity between select brain regions was related to individual differences in performance on the FIST, but there was also significant individual variability in functional network topography supporting cognitive flexibility. Taken together, these results suggest that the FIST is a valid measure of cognitive flexibility, which relies on computations within a broad corticosubcortical network driven by inferior frontal junction engagement.

Graph Matching Based Connectomic Biomarker with Learning for Brain Disorders.

Advances in neuroimaging techniques such as diffusion MRI and functional MRI enabled evaluation of the brain as an information processing network that is called connectome. Connectomic analysis has led to numerous findings on the organization of the brain its pathological changes with diseases, providing imaging-based biomarkers that help in diagnosis and prognosis. A large majority of connectomic biomarkers benefit either from graph-theoretical measures that evaluate brain's network structure, or use standard metrics such as Euclidean distance or Pearson's correlation to show between-connectomes relations. However, such methods are limited in diagnostic evaluation of diseases, because they do not simultaneously measure the difference between individual connectomes, incorporate disease-specific patterns, and utilize network structure information. To address these limitations, we propose a graph matching based method to quantify connectomic similarity, which can be trained for diseases at functional systems level to provide a subject-specific biomarker assessing the disease. We validate our measure on a dataset of patients with traumatic brain injury and demonstrate that our measure achieves better separation between patients and controls compared to commonly used connectomic similarity measures. We further evaluate the vulnerability of the functional systems to the disease by utilizing the parameter tuning aspect of our method. We finally show that our similarity score correlates with clinical scores, highlighting its potential as a subject-specific biomarker for the disease.

Parsing Heterogeneity in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder with Individual Connectome Mapping.

Traditional diagnostic systems for neurodevelopmental disorders define diagnostic categories that are heterogeneous in behavior and underlying neurobiological alterations. The goal of this study was to parse heterogeneity in a core executive function (EF), cognitive flexibility, in children with a range of abilities (N = 132; children with autism spectrum disorder, attention-deficit/hyperactivity disorder [ADHD], and typically developing children) using directed functional connectivity profiles derived from resting-state functional magnetic resonance imaging data. Brain regions activated in response to a cognitive flexibility task in adults were used to guide region-of-interest selection to estimate individual connectivity profiles in this study. We expected to find subgroups of children who differed in their network connectivity metrics and symptom measures. Unexpectedly, we did not find a stable or valid subgrouping solution, which suggests that categorical models of the neural substrates of cognitive flexibility in children may be invalid. Exploratory analyses revealed dimensional associations between network connectivity metrics and ADHD symptomatology and EF ability across the entire sample. Results shed light on the validity of conceptualizing the neural substrates of cognitive flexibility categorically in children. Ultimately, this work may provide a foundation for the development of a revised nosology focused on neurobiological substrates as an alternative to traditional symptom-based classification systems.

Dissociating individual connectome traits using low-rank learning

Intrinsic functional connectivity (FC) exhibits high variability across individuals, which may account for the diversity of cognitive and behavioural ability. This variability in connectivity could be attributed to individual-specific trait and inter-session state differences (intra-subject differences), as well as a small amount of noise. However, it is still a challenge to perform accurate identification of connectivity traits from FC. Here, we introduced a novel low-rank learning model to solve this problem with a new constraint item that could reduce intra-subject differences. The model could dissociate FC into a substrate (substrate) that delineates functional characteristics common across the population and connectivity traits that are expected to account for individual behavioural differences. Subsequently, we performed a sparse dictionary learning algorithm on the extracted connectivity traits and obtained a dictionary matrix, named connectivity dictionary. We could then predict cognitive behaviours, including fluid intelligence, oral reading recognition, grip strength and anger-aggression, more accurately using the connectivity dictionary than the original FC. The results reflect that we captured individual connectivity traits that more effectively represent cognitive behaviour. Moreover, we found that the functional substrate is significantly correlated with large-scale anatomical brain architecture, and individual differences in connectivity traits are constrained by the connectivity substrate. Our findings may advance our understanding of the relationships among anatomy, function, and behaviour.

Whole-brain structural connectivity in dyskinetic cerebral palsy and its association with motor and cognitive function.

Dyskinetic cerebral palsy (CP) has long been associated with basal ganglia and thalamus lesions. Recent evidence further points at white matter (WM) damage. This study aims to identify altered WM pathways in dyskinetic CP from a standardized, connectome-based approach, and to assess structure-function relationship in WM pathways for clinical outcomes. Individual connectome maps of 25 subjects with dyskinetic CP and 24 healthy controls were obtained combining a structural parcellation scheme with whole-brain deterministic tractography. Graph theoretical metrics and the network-based statistic were applied to compare groups and to correlate WM state with motor and cognitive performance. Results showed a widespread reduction of WM volume in CP subjects compared to controls and a more localized decrease in degree (number of links per node) and fractional anisotropy (FA), comprising parieto-occipital regions and the hippocampus. However, supramarginal gyrus showed a significantly higher degree. At the network level, CP subjects showed a bilateral pathway with reduced FA, comprising sensorimotor, intraparietal and fronto-parietal connections. Gross and fine motor functions correlated with FA in a pathway comprising the sensorimotor system, but gross motor also correlated with prefrontal, temporal and occipital connections. Intelligence correlated with FA in a network with fronto-striatal and parieto-frontal connections, and visuoperception was related to right occipital connections. These findings demonstrate a disruption in structural brain connectivity in dyskinetic CP, revealing general involvement of posterior brain regions with relative preservation of prefrontal areas. We identified pathways in which WM integrity is related to clinical features, including but not limited to the sensorimotor system. Hum Brain Mapp 38:4594-4612, 2017. © 2017 Wiley Periodicals, Inc.

Abstract WP163: Post-stroke Aphasia Severity is Determined by the Disorganization of Residual White Matter Networks

Introduction: Many stroke survivors who suffer from aphasia in the acute period experience spontaneous recovery within the first six months post-stroke. About 20% sustain permanent and disabling language problems and the factors that drive incomplete recovery are not clear. Cortical dysfunction may occur in areas seemingly spared by the stroke due to changes to metabolism as well as loss of white matter connectivity and disruption of cortical and subcortical network integrity. We hypothesized that residual white matter connectivity could provide a personalized predictor of the severity of chronic aphasia. Methods: We reconstructed the individual structural whole-brain connectome from 90 right handed participants with a single left hemisphere ischemic or hemorrhagic stroke. All participants underwent language assessment using the Western Aphasia Battery (WAB-AQ). Data analysis was performed on each subject’s individual connectome, a weighted adjacency matrix M of size 189 x 189. We measured comprehensive white matter topological network organization using Newman’s modularity algorithm and calculated the probability of brain regions clustering together though a community affiliation index, which was used to determine the structural fragmentation of white matter networks in the left hemisphere relative to right hemisphere, expressed by a fragmentation index. Results: Patients with greater post-stroke left hemisphere network fragmentation and higher modularity index had more severe chronic aphasia, controlling for the size of the stroke lesion. Modularity and fragmentation index significantly increased with aphasia severity (r = -0.42), and (r = -0.43) respectively. Even when the left hemisphere was relatively spared, patients with disorganized community structure had significantly worse aphasia. Conclusion: Our findings confirm that residual white matter integrity and disorganization of neuronal networks are important determinants of chronic aphasia severity. Furthermore, the assessment of residual connectome white matter organization through modularity provides a comprehensive and personalized measurement that may be used as a marker for clinical staging and aphasia treatment planning.

A Connectome Computation System for discovery science of brain

Much like genomics, brain connectomics has rapidly become a core component of most national brain projects around the world. Beyond the ambitious aims of these projects, a fundamental challenge is the need for an efficient, robust, reliable and easy-to-use pipeline to mine such large neuroscience datasets. Here, we introduce a computational pipeline—namely the Connectome Computation System (CCS)—for discovery science of human brain connectomes at the macroscale with multimodal magnetic resonance imaging technologies. The CCS is designed with a three-level hierarchical structure that includes data cleaning and preprocessing, individual connectome mapping and connectome mining, and knowledge discovery. Several functional modules are embedded into this hierarchy to implement quality control procedures, reliability analysis and connectome visualization. We demonstrate the utility of the CCS based upon a publicly available dataset, the NKI–Rockland Sample, to delineate the normative trajectories of well-known large-scale neural networks across the natural life span (6–85 years of age). The CCS has been made freely available to the public via GitHub (https://github.com/zuoxinian/CCS) and our laboratory’s Web site (http://lfcd.psych.ac.cn/ccs.html) to facilitate progress in discovery science in the field of human brain connectomics.

Assessing the Clinical Effect of Residual Cortical Disconnection After Ischemic Strokes

Studies assessing the relationship between chronic poststroke language impairment (aphasia) and ischemic brain damage usually rely on measuring the extent of brain necrosis observed on MRI. Nonetheless, clinical observation suggests that patients can exhibit deficits that are more severe than what would be expected based on lesion location and size. This phenomenon is commonly explained as being the result of cortical disconnection. To understand whether disconnection contributes to clinical symptoms, we assessed the relationship between language impairments and structural brain connectivity (the connectome) in patients with chronic aphasia after a stroke. Thirty-nine patients with chronic aphasia underwent language assessment and MRI scanning. Relying on MRI data, we reconstructed the individual connectome from T1-weighted and diffusion tensor imaging. Deterministic fiber tractography was used to assess connectivity between each possible pair of cortical Brodmann areas. Multiple linear regression analyses were performed to evaluate the relationship between language performance and cortical necrosis and cortical disconnection. We observed that structural disconnection of Brodmann area 45 (spared by the necrotic tissue) was independently associated with naming performance, controlling for the extent of Brodmann area 45 necrosis (F=4.62; P<0.01; necrosis: β=0.43; P=0.03; disconnection β=1.21; P<0.001). We suggest that cortical disconnection, as measured by the structural connectome, is an independent predictor of naming impairment in patients with chronic aphasia. The full extent of clinically relevant brain damage after an ischemic stroke may be underappreciated by visual inspection of cortical necrosis alone.