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The study of brain connectivity, both functional and structural, can inform us on the development of psychopathology. The use of multimodal MRI methods allows us to study associations between structural and functional connectivity, and how this relates to psychopathology. This may be especially useful during childhood and adolescence, a period where most forms of psychopathology manifest for the first time. The current paper explores structure-function coupling, measured through diffusion and resting-state functional MRI, and quantified as the correlation between structural and functional connectivity matrices. We investigate associations between psychopathology and coupling in a transdiagnostic group of adolescents, including many treatment-seeking youth with relatively high levels of symptoms ( n = 72, M age = 13.3). We used a bifactor model to extract our main outcome measure, Negative Affectivity, from anxiety and irritability ratings. This provided the principal measure of psychopathology. Supplementary analyses investigated 'domain-specific' factors of anxiety and irritability. Findings indicate a positive association between negative affectivity and structure-function coupling between the default mode and the fronto-parietal control networks. Higher structure-function coupling may indicate heightened structural constraints on function, which limit functional network reorganization during adolescence required for healthy psychological outcomes., Competing Interests: Declaration of Interest: the authors have nothing to declare. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Neural consequences of social disparities are not yet rigorously investigated. How socioeconomic conditions influence children's connectome development remains unknown. This paper endeavors to gauge how precisely the connectome structure of the brain can predict an individual's social environment, thereby inversely assessing how social influences are engraved in the neural development of the Adolescent brain. Utilizing Adolescent Brain and Cognition Development (ABCD) data (9099 children residing in the United States), we found that social conditions both at the household and neighborhood levels are significantly associated with specific neural connections. Solely with brain connectome data, we train a linear support vector machine (SVM) to predict socio-economic conditions of those adolescents. The classification performance generally improves when the thresholds of the advantageous and disadvantageous environments compartmentalize the extreme cases. Among the tested thresholds, the 20th and 80th percentile thresholds using the dual combination of household income and neighborhood education yielded the highest Area Under the Precision-Recall Curve (AUPRC) of 0.8224. We identified 8 significant connections that critically contribute to predicting social environments in the parietal lobe and frontal lobe. Insights into social factors that contribute to early brain connectome development is critical to mitigate the disadvantages of children growing up in unfavorable neighborhoods., (© 2024. The Author(s).)

Large-scale diffusion MRI tractography remains a significant challenge. Users must orchestrate a complex sequence of instructions that requires many software packages with complex dependencies and high computational costs. We developed MaPPeRTrac, an edge-centric tractography pipeline that simplifies and accelerates this process in a wide range of high-performance computing (HPC) environments. It fully automates either probabilistic or deterministic tractography, starting from a subject's magnetic resonance imaging (MRI) data, including structural and diffusion MRI images, to the edge density image (EDI) of their structural connectomes. Dependencies are containerized with Singularity (now called Apptainer) and decoupled from code to enable rapid prototyping and modification. Data derivatives are organized with the Brain Imaging Data Structure (BIDS) to ensure that they are findable, accessible, interoperable, and reusable following FAIR principles. The pipeline takes full advantage of HPC resources using the Parsl parallel programming framework, resulting in the creation of connectome datasets of unprecedented size. MaPPeRTrac is publicly available and tested on commercial and scientific hardware, so it can accelerate brain connectome research for a broader user community. MaPPeRTrac is available at: https://github.com/LLNL/mappertrac ., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Mean-field models have been developed to replicate key features of epileptic seizure dynamics. However, the precise mechanisms and the role of the brain area responsible for seizure onset and propagation remain incompletely understood. In this study, we employ computational methods within The Virtual Brain framework and the Epileptor model to explore how the location and connectivity of an Epileptogenic Zone (EZ) in a mouse brain are related to focal seizures (seizures that start in one brain area and may or may not remain localized), with a specific focus on the hippocampal region known for its association with epileptic seizures. We then devise computational strategies to confine seizures (prevent widespread propagation), simulating medical-like treatments such as tissue resection and the application of an anti-seizure drugs or neurostimulation to suppress hyperexcitability. Through selectively removing (blocking) specific connections informed by the structural connectome and graph network measurements or by locally reducing outgoing connection weights of EZ areas, we demonstrate that seizures can be kept constrained around the EZ region. We successfully identified the minimal connections necessary to prevent widespread seizures, with a particular focus on minimizing surgical or medical intervention while simultaneously preserving the original structural connectivity and maximizing brain functionality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Courson, Quoy, Timofeeva and Manos.)

Rasmussen's encephalitis is an immune-mediated brain disorder characterised by progressive unilateral cerebral atrophy, neuroinflammation, drug-resistant seizures and cognitive decline. However, volumetric changes and epileptiform EEG activity were also observed in the contralateral hemisphere, raising questions about the aetiology of contralateral involvement. In this study, we aim to investigate alterations of white matter integrity, structural network topology and network efficiency in Rasmussen's encephalitis using diffusion-tensor imaging. Fourteen individuals with Rasmussen's encephalitis (11 female, median onset 6 years, range 4-22, median disease duration at MRI 5 years, range 0-42) and 20 healthy control subjects were included. All subjects underwent T1-weighted structural and diffusion-tensor imaging. Diffusion-tensor images were analysed using the fixel-based analysis framework included in the MRtrix3 toolbox. Fibre density and cross-section served as a quantitative measure for microstructural white matter integrity. T1-weighted structural images were processed using FreeSurfer, subcortical segmentations and cortical parcellations using the Desikan-Killiany atlas served as nodes in a structural network model, edge weights were determined based on streamline count between pairs of nodes and compared using network-based statistics. Global efficiency was used to quantify network integration on an intrahemispheric level. All metrics were compared cross-sectionally between individuals with Rasmussen's encephalitis and healthy control subjects using sex and age as regressors and within the Rasmussen's encephalitis group using linear regression including age at onset and disease duration as independent variables. Relative to healthy control subjects, individuals with Rasmussen's encephalitis showed significantly (family-wise-error-corrected P < 0.05) lower fibre density and cross-section as well as edge weights in intrahemispheric connections within the ipsilesional hemisphere and in interhemispheric connections. Lower edge weights were noted in the contralesional hemisphere and in interhemispheric connections, with the latter being mainly affected within the first 2 years after disease onset. With longer disease duration, fibre density and cross-section significantly (uncorrected P < 0.01) decreased in both hemispheres. In the contralesional corticospinal tract, fibre density and cross-section significantly (uncorrected P < 0.01) increased with disease duration. Intrahemispheric edge weights (uncorrected P < 0.01) and global efficiency significantly increased with disease duration in both hemispheres (ipsilesional r = 0.74, P = 0.001; contralesional r = 0.67, P = 0.012). Early disease onset was significantly (uncorrected P < 0.01) negatively correlated with lower fibre density and cross-section bilaterally. Our results show that the disease process of Rasmussen's encephalitis is not limited to the cortex of the lesioned hemisphere but should be regarded as a network disease affecting white matter across the entire brain and causing degenerative as well as compensatory changes on a network level., Competing Interests: C.Ho. reports personal fees from Eisai. A.R. has received fees as speaker or served on the advisory board of Bayer, Bracco, GE, Guerbet. C.He. has received fees as speaker or served on the advisory board of Eisai. R.S. has received fees as speaker or served on the advisory board of Angelini, Arvelle, Bial, Eisai, Livanova, Novartis, Janssen-Cilag GmbH, Novartis, Precisis GmbH, UCB Pharma, UnEEG and Zogenix. T.R. has received fees as a speaker from Eisai. These activities were not related to the content of this manuscript., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The relationship between brain functional connectivity and structural connectivity has caught extensive attention of the neuroscience community, commonly inferred using mathematical modeling. Among many modeling approaches, spectral graph model (SGM) is distinctive as it has a closed-form solution of the wide-band frequency spectra of brain oscillations, requiring only global biophysically interpretable parameters. While SGM is parsimonious in parameters, the determination of SGM parameters is non-trivial. Prior works on SGM determine the parameters through a computational intensive annealing algorithm, which only provides a point estimate with no confidence intervals for parameter estimates. To fill this gap, we incorporate the simulation-based inference (SBI) algorithm and develop a Bayesian procedure for inferring the posterior distribution of the SGM parameters. Furthermore, using SBI dramatically reduces the computational burden for inferring the SGM parameters. We evaluate the proposed SBI-SGM framework on the resting-state magnetoencephalography recordings from healthy subjects and show that the proposed procedure has similar performance to the annealing algorithm in recovering power spectra and the spatial distribution of the alpha frequency band. In addition, we also analyze the correlations among the parameters and their uncertainty with the posterior distribution which cannot be done with annealing inference. These analyses provide a richer understanding of the interactions among biophysical parameters of the SGM. In general, the use of simulation-based Bayesian inference enables robust and efficient computations of generative model parameter uncertainties and may pave the way for the use of generative models in clinical translation applications., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Attention deficit hyperactivity disorder (ADHD) is a prevalent childhood neurodevelopmental disorder. Given the profound brain changes that occur during childhood and adolescence, it is important to examine longitudinal changes of both functional and structural brain connectivity across development in ADHD. This study aimed to examine the development of functional and structural connectivity in children with ADHD compared to controls using graph metrics. One hundred and seventy five individuals (91 children with ADHD and 84 non-ADHD controls) participated in a longitudinal neuroimaging study with up to three waves. Graph metrics were derived from 370 resting state fMRI (197 Control, 173 ADHD) and 297 diffusion weighted imaging data (152 Control, 145 ADHD) acquired between the ages of 9 and 14. For functional connectivity, children with ADHD (compared to typically developing children) showed lower degree, local efficiency and betweenness centrality predominantly in parietal, temporal and visual cortices and higher degree, local efficiency and betweenness centrality in frontal, parietal, and temporal cortices. For structural connectivity, children with ADHD had lower local efficiency in parietal and temporal cortices and, higher degree and betweenness centrality in frontal, parietal and temporal cortices. Further, differential developmental trajectories of functional and structural connectivity for graph measures were observed in higher-order cognitive and sensory regions. Our findings show that topology of functional and structural connectomes matures differently between typically developing controls and children with ADHD during childhood and adolescence. Specifically, functional and structural neural circuits associated with sensory and various higher order cognitive functions are altered in children with ADHD., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: Subthalamic nucleus (STN)-deep brain stimulation (DBS) in Parkinson's disease (PD) patients affects not just focused target areas but also diffuse brain networks. The effect of this network modulation on nonmotor DBS effects is not fully understood. By concentrating on the sleep domain, the authors comprehensively determined the influence of electrode location and related structural/functional connections on changes in probable rapid eye movement (REM) sleep behavior disorder (pRBD) symptoms after STN-DBS, which has been reported to ameliorate, deteriorate, or remain constant., Methods: Preoperative and postoperative pRBD symptoms were documented in 60 PD patients. The volumes of tissue activated (VTAs) were assessed on the basis of individual electrode reconstructions and merged with normative connectome data to identify structural/functional connections associated with VTAs. The entire cohort was used to construct connection models that explained changes in pRBD symptoms, as well as to perform cross-validations., Results: Structural/functional connectivity was associated with pRBD symptom changes during STN-DBS. Changes in pRBD symptoms were predicted using an ideal structural connection map. Prefrontal connection was related with improved pRBD symptoms, whereas sensorimotor connectivity was associated with deterioration., Conclusions: Recovery of pRBD symptoms was predicted on the basis of the fibers connecting the STN electrode to prefrontal regions. These findings implied that the placement of STN-DBS leads influences the fibers to prefrontal regions and may be used to enhance treatment of pRBD symptoms; however, further prospective studies are needed to validate these findings.

We explore the stability and dynamic properties of a hierarchical, linearized, and analytic spectral graph model for neural oscillations that integrates the structural wiring of the brain. Previously, we have shown that this model can accurately capture the frequency spectra and the spatial patterns of the alpha and beta frequency bands obtained from magnetoencephalography recordings without regionally varying parameters. Here, we show that this macroscopic model based on long-range excitatory connections exhibits dynamic oscillations with a frequency in the alpha band even without any oscillations implemented at the mesoscopic level. We show that depending on the parameters, the model can exhibit combinations of damped oscillations, limit cycles, or unstable oscillations. We determined bounds on model parameters that ensure stability of the oscillations simulated by the model. Finally, we estimated time-varying model parameters to capture the temporal fluctuations in magnetoencephalography activity. We show that a dynamic spectral graph modeling framework with a parsimonious set of biophysically interpretable model parameters can thereby be employed to capture oscillatory fluctuations observed in electrophysiological data in various brain states and diseases., (© 2022 Massachusetts Institute of Technology.)

Traumatic brain injury (TBI) is a major public health problem. Caused by external mechanical forces, a major characteristic of TBI is the shearing of axons across the white matter, which causes structural connectivity disruptions between brain regions. This diffuse injury leads to cognitive deficits, frequently requiring rehabilitation. Heterogeneity is another characteristic of TBI as severity and cognitive sequelae of the disease have a wide variation across patients, posing a big challenge for treatment. Thus, measures assessing network-wide structural connectivity disruptions in TBI are necessary to quantify injury burden of individuals, which would help in achieving personalized treatment, patient monitoring, and rehabilitation planning. Despite TBI being a disconnectivity syndrome, connectomic assessment of structural disconnectivity has been relatively limited. In this study, we propose a novel connectomic measure that we call network normality score (NNS) to capture the integrity of structural connectivity in TBI patients by leveraging two major characteristics of the disease: diffuseness of axonal injury and heterogeneity of the disease. Over a longitudinal cohort of moderate-to-severe TBI patients, we demonstrate that structural network topology of patients is more heterogeneous and significantly different than that of healthy controls at 3 months postinjury, where dissimilarity further increases up to 12 months. We also show that NNS captures injury burden as quantified by posttraumatic amnesia and that alterations in the structural brain network is not related to cognitive recovery. Finally, we compare NNS to major graph theory measures used in TBI literature and demonstrate the superiority of NNS in characterizing the disease., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The diversity of the diprotodontids provides an excellent opportunity to study how a basic marsupial cortical plan has been modified for the needs of the mammals living in different habitats. Very little is known about the connections of the cerebral cortex with the deep brain structures (basal ganglia and thalamus) in this evolutionarily significant group of mammals. In this study, we performed mapping of brain regions and connections in a diprotodontid marsupial from data obtained from an excised brain scanned in high-field (9.4 T) microstructural magnetic resonance imaging (MRI) instrument. The analysis was based on two MRI methodologies. First, high-resolution structural scans were used to map MRI visible brain regions from T1w and T2w images. Second, extensive diffusion tensor imaging (DTI) data were obtained to elucidate connectivity between brain areas using deterministic diffusion tracking of neuronal brain fibers. From the data, we were able to identify corticostriate connections between the frontal association and dorsomedial isocortex and the head of the caudate, and between the lateral somatosensory cortex and the putamen. We were also able to follow the olfactory and limbic connections by tracing fibers in the fornix, cingulum, intrabulbar part of the anterior commissure, and lateral olfactory tract. There was segregation of fibers in the anterior commissure such that olfactory connections passed through the rostroventral part and successively more dorsal cortical areas connected through more dorsal parts of the commissure. Our findings confirm a common pattern of cortical connectivity in therian mammals, even where brain expansion has occurred independently in diverse groups., (© 2022 Wiley Periodicals LLC.)

The anatomic validity of structural connectomes remains a significant uncertainty in neuroimaging. Edge-centric tractography reconstructs streamlines in bundles between each pair of cortical or subcortical regions. Although edge bundles provides a stronger anatomic embedding than traditional connectomes, calculating them for each region-pair requires exponentially greater computation. We observe that major speedup can be achieved by reducing the number of streamlines used by probabilistic tractography algorithms. To ensure this does not degrade connectome quality, we calculate the identifiability of edge-centric connectomes between test and re-test sessions as a proxy for information content. We find that running PROBTRACKX2 with as few as 1 streamline per voxel per region-pair has no significant impact on identifiability. Variation in identifiability caused by streamline count is overshadowed by variation due to subject demographics. This finding even holds true in an entirely different tractography algorithm using MRTrix. Incidentally, we observe that Jaccard similarity is more effective than Pearson correlation in calculating identifiability for our subject population., Competing Interests: GM discloses grants from the United States Department of Defense—TBI Endpoints Development Initiative (Grant #W81XWH-14-2-0176), TRACK-TBI Precision Medicine (Grant #W81XWH-18-2-0042), and TRACK-TBI NETWORK (Grant #W81XWH-15-9-0001); NIH-NINDS—TRACK-TBI (Grant #U01NS086090); and the National Football League (NFL) Scientific Advisory Board—TRACK-TBI LONGITUDINAL. The United States Department of Energy supports GM for a precision medicine collaboration. One Mind has provided funding for TRACK-TBI patients stipends and support to clinical sites. He has received an unrestricted gift from the NFL to the UCSF Foundation to support research efforts of the TRACK-TBI NETWORK. He has also received funding from NeuroTruama Sciences LLC to support TRACK-TBI data curation efforts. Additionally, Abbott Laboratories has provided funding for add-in TRACK-TBI clinical studies. AM receives funding from the Department of Defense TBI Endpoints Development Initiative (Grant #W81XWH-14-2-0176) and TRACK-TBI NETWORK (Grant #W81XWH-15-9-0001). She also receives salary support from the United States Department of Energy precision medicine collaboration and the philanthropic organization, One Mind. JM and P-TB are employed by Lawrence Livermore National Security, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Moon, Mukherjee, Madduri, Markowitz, Cai, Palacios, Manley and Bremer.)

Mathematical modeling of the relationship between the functional activity and the structural wiring of the brain has largely been undertaken using non-linear and biophysically detailed mathematical models with regionally varying parameters. While this approach provides us a rich repertoire of multistable dynamics that can be displayed by the brain, it is computationally demanding. Moreover, although neuronal dynamics at the microscopic level are nonlinear and chaotic, it is unclear if such detailed nonlinear models are required to capture the emergent meso-(regional population ensemble) and macro-scale (whole brain) behavior, which is largely deterministic and reproducible across individuals. Indeed, recent modeling effort based on spectral graph theory has shown that an analytical model without regionally varying parameters and without multistable dynamics can capture the empirical magnetoencephalography frequency spectra and the spatial patterns of the alpha and beta frequency bands accurately. In this work, we demonstrate an improved hierarchical, linearized, and analytic spectral graph theory-based model that can capture the frequency spectra obtained from magnetoencephalography recordings of resting healthy subjects. We reformulated the spectral graph theory model in line with classical neural mass models, therefore providing more biologically interpretable parameters, especially at the local scale. We demonstrated that this model performs better than the original model when comparing the spectral correlation of modeled frequency spectra and that obtained from the magnetoencephalography recordings. This model also performs equally well in predicting the spatial patterns of the empirical alpha and beta frequency bands., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Biological neuronal networks (BNNs) are a source of inspiration and analogy making for researchers that focus on artificial neuronal networks (ANNs). Moreover, neuroscientists increasingly use ANNs as a model for the brain. Despite certain similarities between these two types of networks, important differences can be discerned. First, biological neural networks are sculpted by evolution and the constraints that it entails, whereas artificial neural networks are engineered to solve particular tasks. Second, the network topology of these systems, apart from some analogies that can be drawn, exhibits pronounced differences. Here, we examine strategies to construct recurrent neural networks (RNNs) that instantiate the network topology of brains of different species. We refer to such RNNs as bio-instantiated. We investigate the performance of bio-instantiated RNNs in terms of: (i) the prediction performance itself, that is, the capacity of the network to minimize the cost function at hand in test data, and (ii) speed of training, that is, how fast during training the network reaches its optimal performance. We examine bio-instantiated RNNs in working memory tasks where task-relevant information must be tracked as a sequence of events unfolds in time. We highlight the strategies that can be used to construct RNNs with the network topology found in BNNs, without sacrificing performance. Despite that we observe no enhancement of performance when compared to randomly wired RNNs, our approach demonstrates how empirical neural network data can be used for constructing RNNs, thus, facilitating further experimentation with biologically realistic network topologies, in contexts where such aspect is desired., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Since the pioneering work of Ramón y Cajal, scientists have sought to unravel the complexities of axon development underlying neural circuit formation. Micrometer-scale axonal growth cones navigate to targets that are often centimeters away. To reach their targets, growth cones react to dynamic environmental cues that change in the order of seconds to days. Proper axon growth and guidance are essential to circuit formation, and progress in imaging has been integral to studying these processes. In particular, advances in high- and super-resolution microscopy provide the spatial and temporal resolution required for studying developing axons. In this Review, we describe how improved microscopy has revolutionized our understanding of axonal development. We discuss how novel technologies, specifically light-sheet and super-resolution microscopy, led to new discoveries at the cellular scale by imaging axon outgrowth and circuit wiring with extreme precision. We next examine how advanced microscopy broadened our understanding of the subcellular dynamics driving axon growth and guidance. We finally assess the current challenges that the field of axonal biology still faces for imaging axons, and examine how future technology could meet these needs., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

The human brain constitutes one of the most advanced networks produced by nature, consisting of billions of neurons communicating with each other. However, this communication is not in real-time, with different communication or time-delays occurring between neurons in different brain areas. Here, we investigate the impacts of these delays by modeling large interacting neural circuits as neural-field systems which model the bulk activity of populations of neurons. By using a Master Stability Function analysis combined with numerical simulations, we find that delays (1) may actually stabilize brain dynamics by temporarily preventing the onset to oscillatory and pathologically synchronized dynamics and (2) may enhance or diminish synchronization depending on the underlying eigenvalue spectrum of the connectivity matrix. Real eigenvalues with large magnitudes result in increased synchronizability while complex eigenvalues with large magnitudes and positive real parts yield a decrease in synchronizability in the delay vs. instantaneously coupled case. This result applies to networks with fixed, constant delays, and was robust to networks with heterogeneous delays. In the case of real brain networks, where the eigenvalues are predominantly real, owing to the nearly symmetric nature of these weight matrices, biologically plausible, small delays, are likely to increase synchronization, rather than decreasing it., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Al-Darabsah, Chen, Nicola and Campbell.)

Human brain connectome studies aim to both explore healthy brains, and extract and analyze relevant features associated with pathologies of interest. Usually this consists of modeling the brain connectome as a graph and using graph metrics as features. A fine brain description requires graph metrics computation at the node level. Given the relatively reduced number of patients in standard cohorts, such data analysis problems fall in the high-dimension, low-sample-size framework. In this context, our goal is to provide a machine learning technique that exhibits flexibility, gives the investigator an understanding of the features and covariates, allows visualization and exploration, and yields insight into the data and the biological phenomena at stake. The retained approach is dimension reduction in a manifold learning methodology; the originality is that the investigator chooses one (or several) reduced variables. The proposed method is illustrated in two studies. The first one addresses comatose patients; the second one compares young and elderly populations. The method sheds light on the differences between brain connectivity graphs using graph metrics and potential clinical interpretations of these differences., Competing Interests: Competing Interests: The authors have declared that no competing interests exist., (© 2020 Massachusetts Institute of Technology.)

The nematode Caenorhabditis elegans ( C. elegans ) is a prevailing model which is commonly utilized in a variety of biomedical research arenas, including neuroscience. Due to its transparency and simplicity, it is becoming a choice model organism for conducting imaging and behavioral assessment crucial to understanding the intricacies of the nervous system. Here, the methods required for neuronal characterization using fluorescent proteins and behavioral tasks are described. These are simplified protocols using fluorescent microscopy and behavioral assays to examine neuronal connections and associated neurotransmitter systems involved in normal physiology and aberrant pathology of the nervous system. Our aim is to make available to readers some streamlined and replicable procedures using C. elegans models as well as highlighting some of the limitations.

The relationship between the brain's structural wiring and the functional patterns of neural activity is of fundamental interest in computational neuroscience. We examine a hierarchical, linear graph spectral model of brain activity at mesoscopic and macroscopic scales. The model formulation yields an elegant closed-form solution for the structure-function problem, specified by the graph spectrum of the structural connectome's Laplacian, with simple, universal rules of dynamics specified by a minimal set of global parameters. The resulting parsimonious and analytical solution stands in contrast to complex numerical simulations of high dimensional coupled nonlinear neural field models. This spectral graph model accurately predicts spatial and spectral features of neural oscillatory activity across the brain and was successful in simultaneously reproducing empirically observed spatial and spectral patterns of alpha-band (8-12 Hz) and beta-band (15-30 Hz) activity estimated from source localized magnetoencephalography (MEG). This spectral graph model demonstrates that certain brain oscillations are emergent properties of the graph structure of the structural connectome and provides important insights towards understanding the fundamental relationship between network topology and macroscopic whole-brain dynamics. ., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Methods have been developed to allow quantitative connectivity of the whole fixed mouse brain by means of magnetic resonance imaging (MRI). We have translated what we have learned in clinical imaging to the very special domain of the mouse brain. Diffusion tensor imaging (DTI) of perfusion fixed specimens can now be performed with spatial resolution of 45 μm 3 , that is, voxels that are 21,000 times smaller than the human connectome protocol. Specimen preparation has been optimized through an active staining protocol using a Gd chelate. Compressed sensing has been integrated into high performance reconstruction and post processing pipelines allowing acquisition of a whole mouse brain connectome in <12 hr. The methods have been validated against retroviral tracer studies. False positive tracts, which are especially problematic in clinical studies, have been reduced substantially to ~28%. The methods have been streamlined to provide high-fidelity, whole mouse brain connectomes as a routine study. The data package provides holistic insight into the mouse brain with anatomic definition at the meso-scale, quantitative volumes of subfields, scalar DTI metrics, and quantitative tractography., (© 2018 Wiley Periodicals, Inc.)

Connectome-based lesion symptom mapping (CLSM) can be used to relate disruptions of brain network connectivity with clinical measures. We present a novel method that extends current CLSM approaches by introducing a fast reliable and accurate way for computing disconnectomes, i.e. identifying damaged or lesioned connections. We introduce a new algorithm that finds the maximally disconnected subgraph containing regions and region pairs with the greatest shared connectivity loss. After normalizing a stroke patient's segmented MRI lesion into template space, probability weighted structural connectivity matrices are constructed from shortest paths found in white matter voxel graphs of 210 subjects from the Human Connectome Project. Percent connectivity loss matrices are constructed by measuring the proportion of shortest-path probability weighted connections that are lost because of an intersection with the patient's lesion. Maximally disconnected subgraphs of the overall connectivity loss matrix are then derived using a computationally fast greedy algorithm that closely approximates the exact solution. We illustrate the approach in eleven stroke patients with hemiparesis by identifying expected disconnections of the corticospinal tract (CST) with cortical sensorimotor regions. Major disconnections are found in the thalamus, basal ganglia, and inferior parietal cortex. Moreover, the size of the maximally disconnected subgraph quantifies the extent of cortical disconnection and strongly correlates with multiple clinical measures. The methods provide a fast, reliable approach for both visualizing and quantifying the disconnected portion of a patient's structural connectome based on their routine clinical MRI, without reliance on concomitant diffusion weighted imaging. The method can be extended to large databases of stroke patients, multiple sclerosis or other diseases causing focal white matter injuries helping to better characterize clinically relevant white matter lesions and to identify biomarkers for the recovery potential of individual patients., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

To facilitate the comparison of white matter morphologic connectivity across target populations, it is invaluable to map the data to a standardized neuroanatomical space. Here, we evaluated direct streamline normalization (DSN), where the warping was applied directly to the streamlines, with two publically available approaches that spatially normalize the diffusion data and then reconstruct the streamlines. Prior work has shown that streamlines generated after normalization from reoriented diffusion data do not reliably match the streamlines generated in native space. To test the impact of these different normalization methods on quantitative tractography measures, we compared the reproducibility of the resulting normalized connectivity matrices and network metrics with those originally obtained in native space. The two methods that reconstruct streamlines after normalization led to significant differences in network metrics with large to huge standardized effect sizes, reflecting a dramatic alteration of the same subject's native connectivity. In contrast, after normalizing with DSN we found no significant difference in network metrics compared with native space with only very small-to-small standardized effect sizes. DSN readily outperformed the other methods at preserving native space connectivity and introduced novel opportunities to define connectome networks without relying on gray matter parcellations., Competing Interests: Competing Interests: The authors have declared that no competing interests exist.

Brain parcellation divides the brain's spatial domain into small regions, which are represented by nodes within the network analysis framework. While template-based parcellations are widely used, the parcels on the template do not necessarily match individual's functional nodes. A new method is developed to overcome the inconsistent network analysis results by by-passing the difficulties of parcellating the brain into functionally meaningful areas. First, roughly equal-sized parcellations are obtained. Second, these random parcellations are applied to individual subjects multiple times and a pseudo-bootstrap (PBS) of the network is obtained for statistical inferences. It was found that the variation of mean global network metrics from PBS sampling is smaller compared with inter-subject variation or within-subject variation between two diffusion MRI scans. Using the mean global network metrics from PBS sampling, the intra-class correlation is always higher than the average obtained from using a single random parcellation. As one application, the PBS method was tested on the Human Connectome Project resting state dataset to identify individuals across scan sessions based on the mean functional connectivity (FC)-a trivial network property that has little information about the connectivity between nodes. An accuracy rate of ∼90% was achieved by simply finding the maximum correlation of mean FC of PBS samples between two scan sessions.

See Lytton (doi:10.1093/awx018) for a scientific commentary on this article.Neural network oscillations are a fundamental mechanism for cognition, perception and consciousness. Consequently, perturbations of network activity play an important role in the pathophysiology of brain disorders. When structural information from non-invasive brain imaging is merged with mathematical modelling, then generative brain network models constitute personalized in silico platforms for the exploration of causal mechanisms of brain function and clinical hypothesis testing. We here demonstrate with the example of drug-resistant epilepsy that patient-specific virtual brain models derived from diffusion magnetic resonance imaging have sufficient predictive power to improve diagnosis and surgery outcome. In partial epilepsy, seizures originate in a local network, the so-called epileptogenic zone, before recruiting other close or distant brain regions. We create personalized large-scale brain networks for 15 patients and simulate the individual seizure propagation patterns. Model validation is performed against the presurgical stereotactic electroencephalography data and the standard-of-care clinical evaluation. We demonstrate that the individual brain models account for the patient seizure propagation patterns, explain the variability in postsurgical success, but do not reliably augment with the use of patient-specific connectivity. Our results show that connectome-based brain network models have the capacity to explain changes in the organization of brain activity as observed in some brain disorders, thus opening up avenues towards discovery of novel clinical interventions., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

This paper develops object-oriented data analysis (OODA) statistical methods that are novel and complementary to existing methods of analysis of human brain scan connectomes, defined as graphs representing brain anatomical or functional connectivity. OODA is an emerging field where classical statistical approaches (e.g., hypothesis testing, regression, estimation, and confidence intervals) are applied to data objects such as graphs or functions. By analyzing data objects directly we avoid loss of information that occurs when data objects are transformed into numerical summary statistics. By providing statistical tools that analyze sets of connectomes without loss of information, new insights into neurology and medicine may be achieved. In this paper we derive the formula for statistical model fitting, regression, and mixture models; test their performance in simulation experiments; and apply them to connectomes from fMRI brain scans collected during a serial reaction time task study. Software for fitting graphical object-oriented data analysis is provided., (Copyright © 2015 John Wiley & Sons, Ltd.)