Resting-state functional magnetic resonance imaging (fMRI) investigations have provided a view of the default network (DN) as composed of a specific set of frontal, parietal, and temporal cortical regions. This spatial topography is typically defined with reference to an influential network parcellation scheme that designated the DN as one of seven large-scale networks (Yeo et al., 2011). However, the precise functional organization of the DN is still under debate, with studies arguing for varying subnetwork configurations and the inclusion of subcortical regions. In this vein, the so-called limbic network-defined as a distinct large-scale network comprising the bilateral temporal poles, ventral anterior temporal lobes, and orbitofrontal cortex-is of particular interest. A large multi-modal and multi-species literature on the anatomical, functional, and cognitive properties of these regions suggests a close relationship to the DN. Notably, these regions have poor signal quality with conventional fMRI acquisition, likely obscuring their network affiliation in most studies. Here, we leverage a multi-echo fMRI dataset with high temporal signal-to-noise and whole-brain coverage, including orbitofrontal and anterior temporal regions, to examine the large-scale network resting-state functional connectivity of these regions and assess their associations with the DN. Consistent with our hypotheses, our results support the inclusion of the majority of the orbitofrontal and anterior temporal cortex as part of the DN and reveal significant heterogeneity in their functional connectivity. We observed that left-lateralized regions within the temporal poles and ventral anterior temporal lobes, as well as medial orbitofrontal regions, exhibited the greatest resting-state functional connectivity with the DN, with heterogeneity across DN subnetworks. Overall, our findings suggest that, rather than being a functionally distinct network, the orbitofrontal and anterior temporal regions comprise part of a larger, extended default network.

The global population is aging rapidly, and a research question of critical importance is why some older adults suffer tremendous cognitive decline while others are mostly spared. Past aging research has shown that older adults with spared cognitive ability have better local short-range information processing while global long-range processing is less efficient. We took this research a step further to investigate whether the underlying structural connections, measured in vivo using diffusion magnetic resonance imaging (dMRI), show a similar shift to support cognitive ability. We analyzed the structural connectivity streamline probability (representing the probability of connection between regions) and nodal efficiency and local efficiency regional graph theory metrics to determine whether age and cognitive ability are related to structural network differences. We found that the relationship between structural connectivity and cognitive ability with age was nuanced, with some differences with age that were associated with poorer cognitive outcomes, but other reorganizations that were associated with spared cognitive ability. These positive changes included strengthened local intrahemispheric connectivity and increased nodal efficiency of the ventral occipital-temporal stream, nucleus accumbens, and hippocampus for older adults, and widespread local efficiency primarily for middle-aged individuals.

Functional magnetic resonance imaging (fMRI) studies most commonly use cluster-based inference to detect local changes in brain activity. Insufficient statistical power and disproportionate false-positive rates reportedly hinder optimal inference. We propose a structural connectivity-guided clustering framework, called topological cluster statistic (TCS), that enhances sensitivity by leveraging white matter anatomical connectivity information. TCS harnesses multimodal information from diffusion tractography and functional imaging to improve task fMRI activation inference. Compared to conventional approaches, TCS consistently improves power over a wide range of effects. This improvement results in a 10%-50% increase in local sensitivity with the greatest gains for medium-sized effects. TCS additionally enables inspection of underlying anatomical networks and thus uncovers knowledge regarding the anatomical underpinnings of brain activation. This novel approach is made available in the PALM software to facilitate usability. Given the increasing recognition that activation reflects widespread, coordinated processes, TCS provides a way to integrate the known structure underlying widespread activations into neuroimaging analyses moving forward.

Representing data using time-resolved networks is valuable for analyzing functional data of the human brain. One commonly used method for constructing time-resolved networks from data is sliding window Pearson correlation (SWPC). One major limitation of SWPC is that it applies a high-pass filter to the activity time series. Therefore, if we select a short window (desirable to estimate rapid changes in connectivity), we will remove important low-frequency information. Here, we propose an approach based on single sideband modulation (SSB) in communication theory. This allows us to select shorter windows to capture rapid changes in the time-resolved functional network connectivity (trFNC). We use simulation and real resting-state functional magnetic resonance imaging (fMRI) data to demonstrate the superior performance of SSB+SWPC compared to SWPC. We also compare the recurring trFNC patterns between individuals with the first episode of psychosis (FEP) and typical controls (TC) and show that FEPs stay more in states that show weaker connectivity across the whole brain. A result exclusive to SSB+SWPC is that TCs stay more in a state with negative connectivity between subcortical and cortical regions. Based on all the results, we argue that SSB+SWPC is more sensitive for capturing temporal variation in trFNC.

Contemplative neuroscience has increasingly explored meditation using neuroimaging. However, the brain mechanisms underlying meditation remain elusive. Here, we implemented a mechanistic framework to explore the spatiotemporal dynamics of expert meditators during meditation and rest, and controls during rest. We first applied a model-free approach by defining a probabilistic metastable substate (PMS) space for each condition, consisting of different probabilities of occurrence from a repertoire of dynamic patterns. Moreover, we implemented a model-based approach by adjusting the PMS of each condition to a whole-brain model, which enabled us to explore perturbations to transition from resting-state to meditation and vice versa. Consequently, we assessed the sensitivity of different brain areas regarding their perturbability and their mechanistic local-global effects. Overall, our work reveals distinct whole-brain dynamics in meditation compared to rest, and how transitions can be induced with localized artificial perturbations. It motivates future work regarding meditation as a practice in health and as a potential therapy for brain disorders.

Promising evidence has suggested potential links between mind-wandering and Alzheimer's disease (AD). Yet, older adults with diagnosable neurocognitive disorders show reduced meta-awareness, thus questioning the validity of probe-assessed mind-wandering in older adults. In prior work, we employed response time variability as an objective, albeit indirect, marker of mind-wandering to identify patterns of functional connectivity that predicted mind-wandering. In the current study, we evaluated the association of this connectome-based, mind-wandering model with cerebral spinal fluid (CSF) p-tau/A ratio in 289 older adults from the Alzheimer's Disease NeuroImaging Initiative (ADNI). Moreover, we examined if this model was similarly associated with individual differences in composite measures of global cognition, episodic memory, and executive functioning. Edges from the high response time variability model were significantly associated with CSF p-tau/A ratio. Furthermore, connectivity strength within edges associated with high response time variability was negatively associated with global cognition and episodic memory functioning. This study provides the first empirical support for a link between an objective neuromarker of mind-wandering and AD pathophysiology. Given the observed association between mind-wandering and cognitive functioning in older adults, interventions targeted at reducing mind-wandering, particularly before the onset of AD pathogenesis, may make a significant contribution to the prevention of AD-related cognitive decline.

Spontaneous retinal wave activity shaping the visual system is a complex neurodevelopmental phenomenon. Retinal ganglion cells are the hubs through which activity diverges throughout the visual system. We consider how these divergent hubs emerge, using an adaptively rewiring neural network model. Adaptive rewiring models show in a principled way how brains could achieve their complex topologies. Modular small-world structures with rich-club effects and circuits of convergent-divergent units emerge as networks evolve, driven by their own spontaneous activity. Arbitrary nodes of an initially random model network were designated as retinal ganglion cells. They were intermittently exposed to the retinal waveform, as the network evolved through adaptive rewiring. A significant proportion of these nodes developed into divergent hubs within the characteristic complex network architecture. The proportion depends parametrically on the wave incidence rate. Higher rates increase the likelihood of hub formation, while increasing the potential of ganglion cell death. In addition, direct neighbors of designated ganglion cells differentiate like amacrine cells. The divergence observed in ganglion cells resulted in enhanced convergence downstream, suggesting that retinal waves control the formation of convergence in the lateral geniculate nuclei. We conclude that retinal waves stochastically control the distribution of converging and diverging activity in evolving complex networks.

Computational studies in network neuroscience build models of communication dynamics in the connectome that help us understand the structure-function relationships of the brain. In these models, the dynamics of cortical signal transmission in brain networks are approximated with simple propagation strategies such as random walks and shortest path routing. Furthermore, the signal transmission dynamics in brain networks can be associated with the switching architectures of engineered communication systems (e.g., message switching and packet switching). However, it has been unclear how propagation strategies and switching architectures are related in models of brain network communication. Here, we investigate the effects of the difference between packet switching and message switching (i.e., whether signals are packetized or not) on the transmission completion time of propagation strategies when simulating signal propagation in mammalian brain networks. The results show that packetization in the connectome with hubs increases the time of the random walk strategy and does not change that of the shortest path strategy, but decreases that of more plausible strategies for brain networks that balance between communication speed and information requirements. This finding suggests an advantage of packet-switched communication in the connectome and provides new insights into modeling the communication dynamics in brain networks.

One way to increase the statistical power and generalizability of neuroimaging studies is to collect data at multiple sites or merge multiple cohorts. However, this usually comes with site-related biases due to the heterogeneity of scanners and acquisition parameters, negatively impacting sensitivity. Brain structural connectomes are not an exception: Being derived from T1-weighted and diffusion-weighted magnetic resonance images, structural connectivity is impacted by differences in imaging protocol. Beyond minimizing acquisition parameter differences, removing bias with postprocessing is essential. In this work we create, from the exhaustive Human Connectome Project Young Adult dataset, a resampled dataset of different -values and spatial resolutions, modeling a cohort scanned across multiple sites. After demonstrating the statistical impact of acquisition parameters on connectivity, we propose a linear regression with explicit modeling of -value and spatial resolution, and validate its performance on separate datasets. We show that -value and spatial resolution affect connectivity in different ways and that acquisition bias can be reduced using a linear regression informed by the acquisition parameters while retaining interindividual differences and hence boosting fingerprinting performance. We also demonstrate the generative potential of our model, and its generalization capability in an independent dataset reflective of typical acquisition practices in clinical settings.

Emotion perception is essential to affective and cognitive development which involves distributed brain circuits. Emotion identification skills emerge in infancy and continue to develop throughout childhood and adolescence. Understanding the development of the brain's emotion circuitry may help us explain the emotional changes during adolescence. In this work, we aim to deepen our understanding of emotion-related functional connectivity (FC) from association to causation. We proposed a Bayesian incorporated linear non-Gaussian acyclic model (BiLiNGAM), which incorporated association model into the estimation pipeline. Simulation results indicated stable and accurate performance over various settings, especially when the sample size was small. We used fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC) to validate the approach. It included 855 individuals aged 8-22 years who were divided into five different adolescent stages. Our network analysis revealed the development of emotion-related intra- and intermodular connectivity and pinpointed several emotion-related hubs. We further categorized the hubs into two types: in-hubs and out-hubs, as the center of receiving and distributing information, respectively. In addition, several unique developmental hub structures and group-specific patterns were discovered. Our findings help provide a directed FC template of brain network organization underlying emotion processing during adolescence.

Machine learning algorithms are increasingly being utilized to identify brain connectivity biomarkers linked to behavioral and clinical outcomes. However, research often prioritizes prediction accuracy at the expense of biological interpretability, and inconsistent implementation of ML methods may hinder model accuracy. To address this, our paper introduces a network-level enrichment approach, which integrates brain system organization in the context of connectome-wide statistical analysis to reveal network-level links between brain connectivity and behavior. To demonstrate the efficacy of this approach, we used linear support vector regression (LSVR) models to examine the relationship between resting-state functional connectivity networks and chronological age. We compared network-level associations based on raw LSVR weights to those produced from the forward and inverse models. Results indicated that not accounting for shared family variance inflated prediction performance, the k-best feature selection via Pearson correlation reduced accuracy and reliability, and raw LSVR model weights produced network-level associations that deviated from the significant brain systems identified by forward and inverse models. Our findings offer crucial insights for applying machine learning to neuroimaging data, emphasizing the value of network enrichment for biological interpretation.

In response to a growing interest in refining brain connectivity assessments, this study focuses on integrating white matter fiber-specific microstructural properties into structural connectomes. Spanning ages 8-19 years in a developmental sample, it explores age-related patterns of microstructure-informed network properties at both local and global scales. First, the diffusion-weighted signal fraction associated with each tractography-reconstructed streamline was constructed. Subsequently, the convex optimization modeling for microstructure-informed tractography (COMMIT) approach was employed to generate microstructure-informed connectomes from diffusion MRI data. To complete the investigation, network characteristics within eight functionally defined networks (visual, somatomotor, dorsal attention, ventral attention, limbic, fronto-parietal, default mode, and subcortical networks) were evaluated. The findings underscore a consistent increase in global efficiency across child and adolescent development within the visual, somatomotor, and default mode networks ( < 0.005). Additionally, mean strength exhibits an upward trend in the somatomotor and visual networks ( < 0.001). Notably, nodes within the dorsal and ventral visual pathways manifest substantial age-dependent changes in local efficiency, aligning with existing evidence of extended maturation in these pathways. The outcomes strongly support the notion of a prolonged developmental trajectory for visual association cortices. This study contributes valuable insights into the nuanced dynamics of microstructure-informed brain connectivity throughout different developmental stages.

Identifying directed network models for multivariate time series is a ubiquitous problem in data science. Granger causality measure (GCM) and conditional GCM (cGCM) are widely used methods for identifying directed connections between time series. Both GCM and cGCM have frequency-domain formulations to characterize the dependence of time series in the spectral domain. However, the original methods were developed using a heuristic approach without rigorous theoretical explanations. To overcome the limitation, the minimum-entropy (ME) estimation approach was introduced in our previous work (Ning & Rathi, 2018) to generalize GCM and cGCM with more rigorous frequency-domain formulations. In this work, this information-theoretic framework is further generalized with three formulations for conditional causality analysis using techniques in control theory, such as state-space representations and spectral factorizations. The three conditional causal measures are developed based on different ME estimation procedures that are motivated by equivalent formulations of the classical minimum mean squared error estimation method. The relationship between the three formulations of conditional causality measures is analyzed theoretically. Their performance is evaluated using simulations and real neuroimaging data to analyze brain networks. The results show that the proposed methods provide more accurate network structures than the original approach.

Patients presenting with drug-resistant epilepsy are eligible for surgery aiming to remove the regions involved in the production of seizure activities, the so-called epileptogenic zone network (EZN). Thus the accurate estimation of the EZN is crucial. Data-driven, personalized virtual brain models derived from patient-specific anatomical and functional data are used in Virtual Epileptic Patient (VEP) to estimate the EZN via optimization methods from Bayesian inference. The Bayesian inference approach used in previous VEP integrates priors, based on the features of stereotactic-electroencephalography (SEEG) seizures' recordings. Here, we propose new priors, based on quantitative Na-MRI. The Na-MRI data were acquired at 7T and provided several features characterizing the sodium signal decay. The hypothesis is that the sodium features are biomarkers of neuronal excitability related to the EZN and will add additional information to VEP estimation. In this paper, we first proposed the mapping from Na-MRI features to predict the EZN via a machine learning approach. Then, we exploited these predictions as priors in the VEP pipeline. The statistical results demonstrated that compared with the results from current VEP, the result from VEP based on Na-MRI prior has better balanced accuracy, and the similar weighted harmonic mean of the precision and recall.

Generalized epileptic attacks, which exhibit widespread disruption of brain activity, are characterized by recurrent, spontaneous, and synchronized bursts of neural activity that self-initiate and self-terminate through critical transitions. Here we utilize the general framework of explosive synchronization (ES) from complex systems science to study the role of network structure and resource dynamics in the generation and propagation of seizures. We show that a combination of resource constraint and adaptive coupling in a Kuramoto network oscillator model can reliably generate seizure-like synchronization activity across different network topologies, including a biologically derived mesoscale mouse brain network. The model, coupled with a novel algorithm for tracking seizure propagation, provides mechanistic insight into the dynamics of transition to the synchronized state and its dependence on resources; and identifies key brain areas that may be involved in the initiation and spatial propagation of the seizure. The model, though minimal, efficiently recapitulates several experimental and theoretical predictions from more complex models and makes novel experimentally testable predictions.

Current treatments of Parkinson's disease (PD) have limited efficacy in alleviating freezing of gait (FoG). In this context, concomitant deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) has been suggested as a potential therapeutic approach. However, the mechanisms underlying this approach are unknown. While the current rationale relies on network-based hypotheses of intensified disinhibition of brainstem locomotor areas to facilitate the release of gait motor programs, it is still unclear how simultaneous high-frequency DBS in two interconnected basal ganglia nuclei affects large-scale cortico-subcortical network activity. Here, we use a basic model of neural excitation, the susceptible-excited-refractory (SER) model, to compare effects of different stimulation modes of the network underlying FoG based on the mouse brain connectivity atlas. We develop a network-based computational framework to compare subcortical DBS targets through exhaustive analysis of the brain attractor dynamics in the healthy, PD, and DBS states. We show that combined STN+SNr DBS outperforms STN DBS in terms of the normalization of spike propagation flow in the FoG network. The framework aims to move toward a mechanistic understanding of the network effects of DBS and may be applicable to further perturbation-based therapies of brain disorders.

Mind-wandering is a frequent, daily mental activity, experienced in unique ways in each person. Yet neuroimaging evidence relating mind-wandering to brain activity, for example in the default mode network (DMN), has relied on population- rather than individual-based inferences owing to limited within-person sampling. Here, three densely sampled individuals each reported hundreds of mind-wandering episodes while undergoing multi-session functional magnetic resonance imaging. We found reliable associations between mind-wandering and DMN activation when estimating brain networks within individuals using precision functional mapping. However, the timing of spontaneous DMN activity relative to subjective reports, and the networks beyond DMN that were activated and deactivated during mind-wandering, were distinct across individuals. Connectome-based predictive modeling further revealed idiosyncratic, whole-brain functional connectivity patterns that consistently predicted mind-wandering within individuals but did not fully generalize across individuals. Predictive models of mind-wandering and attention that were derived from larger-scale neuroimaging datasets largely failed when applied to densely sampled individuals, further highlighting the need for personalized models. Our work offers novel evidence for both conserved and variable neural representations of self-reported mind-wandering in different individuals. The previously unrecognized interindividual variations reported here underscore the broader scientific value and potential clinical utility of idiographic approaches to brain-experience associations.

Discrete neural states are associated with reaching movements across the fronto-parietal network. Here, the Hidden Markov Model (HMM) applied to spiking activity of the somato-motor parietal area PE revealed a sequence of states similar to those of the contiguous visuomotor areas PEc and V6A. Using a coupled clustering and decoding approach, we proved that these neural states carried spatiotemporal information regarding behaviour in all three posterior parietal areas. However, comparing decoding accuracy, PE was less informative than V6A and PEc. In addition, V6A outperformed PEc in target inference, indicating functional differences among the parietal areas. To check the consistency of these differences, we used both a supervised and an unsupervised variant of the HMM, and compared its performance with two more common classifiers, Support Vector Machine and Long-Short Term Memory. The differences in decoding between areas were invariant to the algorithm used, still showing the dissimilarities found with HMM, thus indicating that these dissimilarities are intrinsic in the information encoded by parietal neurons. These results highlight that, when decoding from the parietal cortex, for example, in brain machine interface implementations, attention should be paid in selecting the most suitable source of neural signals, given the great heterogeneity of this cortical sector.

This study challenges the traditional focus on zero-lag statistics in resting-state functional magnetic resonance imaging (rsfMRI) research. Instead, it advocates for considering time-lag interactions to unveil the directionality and asymmetries of the brain hierarchy. Effective connectivity (EC), the state matrix in dynamical causal modeling (DCM), is a commonly used metric for studying dynamical properties and causal interactions within a linear state-space system description. Here, we focused on how time-lag statistics are incorporated within the framework of DCM resulting in an asymmetric EC matrix. Our approach involves decomposing the EC matrix, revealing a steady-state differential cross-covariance matrix that is responsible for modeling information flow and introducing time-irreversibility. Specifically, the system's dynamics, influenced by the off-diagonal part of the differential covariance, exhibit a curl steady-state flow component that breaks detailed balance and diverges the dynamics from equilibrium. Our empirical findings indicate that the EC matrix's outgoing strengths correlate with the flow described by the differential cross covariance, while incoming strengths are primarily driven by zero-lag covariance, emphasizing conditional independence over directionality.

Whole-brain functional connectivity networks (connectomes) have been characterized at different scales in humans using EEG and fMRI. Multimodal epileptic networks have also been investigated, but the relationship between EEG and fMRI defined networks on a whole-brain scale is unclear. A unified multimodal connectome description, mapping healthy and pathological networks would close this knowledge gap. Here, we characterize the spatial correlation between the EEG and fMRI connectomes in right and left temporal lobe epilepsy (rTLE/lTLE). From two centers, we acquired resting-state concurrent EEG-fMRI of 35 healthy controls and 34 TLE patients. EEG-fMRI data was projected into the Desikan brain atlas, and functional connectomes from both modalities were correlated. EEG and fMRI connectomes were moderately correlated. This correlation was increased in rTLE when compared to controls for EEG-delta/theta/alpha/beta. Conversely, multimodal correlation in lTLE was decreased in respect to controls for EEG-beta. While the alteration was global in rTLE, in lTLE it was locally linked to the default mode network. The increased multimodal correlation in rTLE and decreased correlation in lTLE suggests a modality-specific lateralized differential reorganization in TLE, which needs to be considered when comparing results from different modalities. Each modality provides distinct information, highlighting the benefit of multimodal assessment in epilepsy.

Learning new motor skills through training, also termed motor learning, is central for everyday life. Current training strategies recommend intensive task-repetitions aimed at inducing local activation of motor areas, associated with changes in oscillation amplitudes ("event-related power") during training. More recently, another neural mechanism was suggested to influence motor learning: modulation of functional connectivity (FC), that is, how much spatially separated brain regions communicate with each other before and during training. The goal of the present study was to compare the impact of these two neural processing types on motor learning. We measured EEG before, during, and after a finger-tapping task (FTT) in 20 healthy subjects. The results showed that training gain, long-term expertise (i.e., average motor performance), and consolidation were all predicted by whole-brain alpha- and beta-band FC at motor areas, striatum, and mediotemporal lobe (MTL). Local power changes during training did not predict any dependent variable. Thus, network dynamics seem more crucial than local activity for motor sequence learning, and training techniques should attempt to facilitate network interactions rather than local cortical activation.