Epilepsy surgery is the treatment of choice for drug-resistant epilepsy patients, but up to 50% of patients continue to have seizures one year after the resection. In order to aid presurgical planning and predict postsurgical outcome on a patient-by-patient basis, we developed a framework of individualized computational models that combines epidemic spreading with patient-specific connectivity and epileptogeneity maps: the Epidemic Spreading Seizure and Epilepsy Surgery framework (ESSES). ESSES parameters were fitted in a retrospective study (N = 15) to reproduce invasive electroencephalography (iEEG)-recorded seizures. ESSES reproduced the iEEG-recorded seizures, and significantly better so for patients with good (seizure-free, SF) than bad (nonseizure-free, NSF) outcome. We illustrate here the clinical applicability of ESSES with a pseudo-prospective study (N = 34) with a blind setting (to the resection strategy and surgical outcome) that emulated presurgical conditions. By setting the model parameters in the retrospective study, ESSES could be applied also to patients without iEEG data. ESSES could predict the chances of good outcome after any resection by finding patient-specific model-based optimal resection strategies, which we found to be smaller for SF than NSF patients, suggesting an intrinsic difference in the network organization or presurgical evaluation results of NSF patients. The actual surgical plan overlapped more with the model-based optimal resection, and had a larger effect in decreasing modeled seizure propagation, for SF patients than for NSF patients. Overall, ESSES could correctly predict 75% of NSF and 80.8% of SF cases pseudo-prospectively. Our results show that individualised computational models may inform surgical planning by suggesting alternative resections and providing information on the likelihood of a good outcome after a proposed resection. This is the first time that such a model is validated with a fully independent cohort and without the need for iEEG recordings.

Epilepsy surgery is the treatment of choice for drug-resistant epilepsy patients, but only leads to seizure freedom for roughly two in three patients. To address this problem, we designed a patient-specific epilepsy surgery model combining large-scale magnetoencephalography (MEG) brain networks with an epidemic spreading model. This simple model was enough to reproduce the stereo-tactical electroencephalography (SEEG) seizure propagation patterns of all patients (N = 15), when considering the resection areas (RA) as the epidemic seed. Moreover, the goodness of fit of the model predicted surgical outcome. Once adapted for each patient, the model can generate alternative hypothesis of the seizure onset zone and test different resection strategies in silico. Overall, our findings indicate that spreading models based on patient-specific MEG connectivity can be used to predict surgical outcomes, with better fit results and greater reduction on seizure propagation linked to higher likelihood of seizure freedom after surgery. Finally, we introduced a population model that can be individualized by considering only the patient-specific MEG network, and showed that it not only conserves but improves the group classification. Thus, it may pave the way to generalize this framework to patients without SEEG recordings, reduce the risk of overfitting and improve the stability of the analyses.

How temporal modulations in functional interactions are shaped by the underlying anatomical connections remains an open question. Here, we analyse the role of structural eigenmodes, in the formation and dissolution of temporally evolving functional brain networks using resting-state magnetoencephalography and diffusion magnetic resonance imaging data at the individual subject level. Our results show that even at short timescales, phase and amplitude connectivity can partly be expressed by structural eigenmodes, but hardly by direct structural connections. Albeit a stronger relationship was found between structural eigenmodes and time-resolved amplitude connectivity. Time-resolved connectivity for both phase and amplitude was mostly characterised by a stationary process, superimposed with very brief periods that showed deviations from this stationary process. For these brief periods, dynamic network states were extracted that showed different expressions of eigenmodes. Furthermore, the eigenmode expression was related to overall cognitive performance and co-occurred with fluctuations in community structure of functional networks. These results implicate that ongoing time-resolved resting-state networks, even at short timescales, can to some extent be understood in terms of activation and deactivation of structural eigenmodes and that these eigenmodes play a role in the dynamic integration and segregation of information across the cortex, subserving cognitive functions.

Epilepsy surgery is the treatment of choice for drug-resistant epilepsy patients. However, seizure-freedom is currently achieved in only 2/3 of the patients after surgery. In this study we have developed an individualized computational model based on MEG brain networks to explore seizure propagation and the efficacy of different virtual resections. Eventually, the goal is to obtain individualized models to optimize resection strategy and outcome. We have modelled seizure propagation as an epidemic process using the susceptible-infected (SI) model on individual brain networks derived from presurgical MEG. We included 10 patients who had received epilepsy surgery and for whom the surgery outcome at least one year after surgery was known. The model parameters were tuned in in order to reproduce the patient-specific seizure propagation patterns as recorded with invasive EEG. We defined a personalized search algorithm that combined structural and dynamical information to find resections that maximally decreased seizure propagation for a given resection size. The optimal resection for each patient was defined as the smallest resection leading to at least a 90% reduction in seizure propagation. The individualized model reproduced the basic aspects of seizure propagation for 9 out of 10 patients when using the resection area as the origin of epidemic spreading, and for 10 out of 10 patients with an alternative definition of the seed region. We found that, for 7 patients, the optimal resection was smaller than the resection area, and for 4 patients we also found that a resection smaller than the resection area could lead to a 100% decrease in propagation. Moreover, for two cases these alternative resections included nodes outside the resection area. Epidemic spreading models fitted with patient specific data can capture the fundamental aspects of clinically observed seizure propagation, and can be used to test virtual resections in silico. Combined with optimization algorithms, smaller or alternative resection strategies, that are individually targeted for each patient, can be determined with the ultimate goal to improve surgery outcome. MEG-based networks can provide a good approximation of structural connectivity for computational models of seizure propagation, and facilitate their clinical use.

Large-scale neurophysiological networks are often reconstructed from band-pass filtered time series derived from magnetoencephalography (MEG) data. Common practice is to reconstruct these networks separately for different frequency bands and to treat them independently. Recent evidence suggests that this separation may be inadequate, as there can be significant coupling between frequency bands (interlayer connectivity). A multilayer network approach offers a solution to analyze frequency-specific networks in one framework. We propose to use a recently developed network reconstruction method in conjunction with phase oscillator models to estimate interlayer connectivity that optimally fits the empirical data. This approach determines interlayer connectivity based on observed frequency-specific time series of the phase and a connectome derived from diffusion weighted imaging. The performance of this interlayer reconstruction method was evaluated in-silico. Our reconstruction of the underlying interlayer connectivity agreed to very high degree with the ground truth. Subsequently, we applied our method to empirical resting-state MEG data obtained from healthy subjects and reconstructed two-layered networks consisting of either alpha-to-beta or theta-to-gamma band connectivity. Our analysis revealed that interlayer connectivity is dominated by a multiplex structure, i.e. by one-to-one interactions for both alpha-to-beta band and theta-to-gamma band networks. For theta-gamma band networks, we also found a plenitude of interlayer connections between distant nodes, though weaker connectivity relative to the one-to-one connections. Our work is an stepping stone towards the identification of interdependencies across frequency-specific networks. Our results lay the ground for the use of the promising multilayer framework in this field with more-informed and justified interlayer connections.

The success of epilepsy surgery in patients with refractory epilepsy depends upon correct identification of the epileptogenic zone (EZ) and an optimal choice of the resection area. In this study we developed individualized computational models based upon structural brain networks to explore the impact of different virtual resections on the propagation of seizures. The propagation of seizures was modelled as an epidemic process [susceptible-infected-recovered (SIR) model] on individual structural networks derived from presurgical diffusion tensor imaging in 19 patients. The candidate connections for the virtual resection were all connections from the clinically hypothesized EZ, from which the seizures were modelled to start, to other brain areas. As a computationally feasible surrogate for the SIR model, we also removed the connections that maximally reduced the eigenvector centrality (EC) (large values indicate network hubs) of the hypothesized EZ, with a large reduction meaning a large effect. The optimal combination of connections to be removed for a maximal effect were found using simulated annealing. For comparison, the same number of connections were removed randomly, or based on measures that quantify the importance of a node or connection within the network. We found that 90% of the effect (defined as reduction of EC of the hypothesized EZ) could already be obtained by removing substantially less than 90% of the connections. Thus, a smaller, optimized, virtual resection achieved almost the same effect as the actual surgery yet at a considerably smaller cost, sparing on average 27.49% (standard deviation: 4.65%) of the connections. Furthermore, the maximally effective connections linked the hypothesized EZ to hubs. Finally, the optimized resection was equally or more effective than removal based on structural network characteristics both regarding reducing the EC of the hypothesized EZ and seizure spreading. The approach of using reduced EC as a surrogate for simulating seizure propagation can suggest more restrictive resection strategies, whilst obtaining an almost optimal effect on reducing seizure propagation, by taking into account the unique topology of individual structural brain networks of patients.

Functional brain networks are shaped and constrained by the underlying structural network. However, functional networks are not merely a one-to-one reflection of the structural network. Several theories have been put forward to understand the relationship between structural and functional networks. However, it remains unclear how these theories can be unified. Two existing recent theories state that 1) functional networks can be explained by all possible walks in the structural network, which we will refer to as the series expansion approach, and 2) functional networks can be explained by a weighted combination of the eigenmodes of the structural network, the so-called eigenmode approach. To elucidate the unique or common explanatory power of these approaches to estimate functional networks from the structural network, we analysed the relationship between these two existing views. Using linear algebra, we first show that the eigenmode approach can be written in terms of the series expansion approach, i.e., walks on the structural network associated with different hop counts correspond to different weightings of the eigenvectors of this network. Second, we provide explicit expressions for the coefficients for both the eigenmode and series expansion approach. These theoretical results were verified by empirical data from Diffusion Tensor Imaging (DTI) and functional Magnetic Resonance Imaging (fMRI), demonstrating a strong correlation between the mappings based on both approaches. Third, we analytically and empirically demonstrate that the fit of the eigenmode approach to measured functional data is always at least as good as the fit of the series expansion approach, and that errors in the structural data lead to large errors of the estimated coefficients for the series expansion approach. Therefore, we argue that the eigenmode approach should be preferred over the series expansion approach. Results hold for eigenmodes of the weighted adjacency matrices as well as eigenmodes of the graph Laplacian. ​Taken together, these results provide an important step towards unification of existing theories regarding the structure-function relationships in brain networks.

Clinical network neuroscience, the study of brain network topology in neurological and psychiatric diseases, has become a mainstay field within clinical neuroscience. Being a multidisciplinary group of clinical network neuroscience experts based in The Netherlands, we often discuss the current state of the art and possible avenues for future investigations. These discussions revolve around questions like “How do dynamic processes alter the underlying structural network?” and “Can we use network neuroscience for disease classification?” This opinion paper is an incomplete overview of these discussions and expands on ten questions that may potentially advance the field. By no means intended as a review of the current state of the field, it is instead meant as a conversation starter and source of inspiration to others.

There is an increasing awareness of the advantages of multi-modal neuroimaging. Networks obtained from different modalities are usually treated in isolation, which is however contradictory to accumulating evidence that these networks show non-trivial interdependencies. Even networks obtained from a single modality, such as frequency-band specific functional networks measured from magnetoencephalography (MEG) are often treated independently. Here, we discuss how a multilayer network framework allows for integration of multiple networks into a single network description and how graph metrics can be applied to quantify multilayer network organisation for group comparison. We analyse how well-known biases for single layer networks, such as effects of group differences in link density and/or average connectivity, influence multilayer networks, and we compare four schemes that aim to correct for such biases: the minimum spanning tree (MST), effective graph resistance cost minimisation, efficiency cost optimisation (ECO) and a normalisation scheme based on singular value decomposition (SVD). These schemes can be applied to the layers independently or to the multilayer network as a whole. For correction applied to whole multilayer networks, only the SVD showed sufficient bias correction. For correction applied to individual layers, three schemes (ECO, MST, SVD) could correct for biases. By using generative models as well as empirical MEG and functional magnetic resonance imaging (fMRI) data, we further demonstrated that all schemes were sensitive to identify network topology when the original networks were perturbed. In conclusion, uncorrected multilayer network analysis leads to biases. These biases may differ between centres and studies and could consequently lead to unreproducible results in a similar manner as for single layer networks. We therefore recommend using correction schemes prior to multilayer network analysis for group comparisons.

The interplay between structural connections and emerging information flow in the human brain remains an open research problem. A recent study observed global patterns of directional information flow in empirical data using the measure of transfer entropy. For higher frequency bands, the overall direction of information flow was from posterior to anterior regions whereas an anterior-to-posterior pattern was observed in lower frequency bands. In this study, we applied a simple Susceptible-Infected-Susceptible (SIS) epidemic spreading model on the human connectome with the aim to reveal the topological properties of the structural network that give rise to these global patterns. We found that direct structural connections induced higher transfer entropy between two brain regions and that transfer entropy decreased with increasing distance between nodes (in terms of hops in the structural network). Applying the SIS model, we were able to confirm the empirically observed opposite information flow patterns and posterior hubs in the structural network seem to play a dominant role in the network dynamics. For small time scales, when these hubs acted as strong receivers of information, the global pattern of information flow was in the posterior-to-anterior direction and in the opposite direction when they were strong senders. Our analysis suggests that these global patterns of directional information flow are the result of an unequal spatial distribution of the structural degree between posterior and anterior regions and their directions seem to be linked to different time scales of the spreading process.

Network science has widely studied the properties of brain networks. Recent work has observed a global back-to-front pattern of information flow for higher frequency bands in magnetoencephalography data. However, the effective connectivity at a local level remains yet to be analyzed. On a local level, the building blocks of all networks are motifs. In this study, we exploit the measure of dPTE to analyze motifs of the estimated effective connectivity networks. We find that some 3- and 4-motifs, the bidirectional two-hop path and its extended 4-node versions, are significantly overexpressed in the analyzed networks in comparison with random networks. With a recently developed motif-based clustering algorithm we separate the effective connectivity network in two main clusters which reveal its higher-order organization with a strong information flow between posterior hubs and anterior regions.

Neuronal oscillations exist across a broad frequency spectrum, and are thought to provide a mechanism of interaction between spatially separated brain regions. Since ongoing mental activity necessitates the simultaneous formation of multiple networks, it seems likely that the brain employs interactions within multiple frequency bands, as well as cross-frequency coupling, to support such networks. Here, we propose a multi-layer network framework that elucidates this pan-spectral picture of network interactions. Our network consists of multiple layers (frequency-band specific networks) that influence each other via inter-layer (cross-frequency) coupling. Applying this model to MEG resting-state data and using envelope correlations as connectivity metric, we demonstrate strong dependency between within layer structure and inter-layer coupling, indicating that networks obtained in different frequency bands do not act as independent entities. More specifically, our results suggest that frequency band specific networks are characterised by a common structure seen across all layers, superimposed by layer specific connectivity, and inter-layer coupling is most strongly associated with this common mode. Finally, using a biophysical model, we demonstrate that there are two regimes of multi-layer network behaviour; one in which different layers are independent and a second in which they operate highly dependent. Results suggest that the healthy human brain operates at the transition point between these regimes, allowing for integration and segregation between layers. Overall, our observations show that a complete picture of global brain network connectivity requires integration of connectivity patterns across the full frequency spectrum.

The relationship between structural and functional brain networks is still highly debated. Most previous studies have used a single functional imaging modality to analyze this relationship. In this work, we use multimodal data, from functional MRI, magnetoencephalography, and diffusion tensor imaging, and assume that there exists a mapping between the connectivity matrices of the resting-state functional and structural networks. We investigate this mapping employing group averaged as well as individual data. We indeed find a significantly high goodness of fit level for this structure-function mapping. Our analysis suggests that a functional connection is shaped by all walks up to the diameter in the structural network in both modality cases. When analyzing the inverse mapping, from function to structure, longer walks in the functional network also seem to possess minor influence on the structural connection strengths. Even though similar overall properties for the structure-function mapping are found for different functional modalities, our results indicate that the structure-function relationship is modality dependent.

Understanding the electrophysiological basis of resting state networks (RSNs) in the human brain is a critical step towards elucidating how inter-areal connectivity supports healthy brain function. In recent years, the relationship between RSNs (typically measured using haemodynamic signals) and electrophysiology has been explored using functional Magnetic Resonance Imaging (fMRI) and magnetoencephalography (MEG). Significant progress has been made, with similar spatial structure observable in both modalities. However, there is a pressing need to understand this relationship beyond simple visual similarity of RSN patterns. Here, we introduce a mathematical model to predict fMRI-based RSNs using MEG. Our unique model, based upon a multivariate Taylor series, incorporates both phase and amplitude based MEG connectivity metrics, as well as linear and non-linear interactions within and between neural oscillations measured in multiple frequency bands. We show that including non-linear interactions, multiple frequency bands and cross-frequency terms significantly improves fMRI network prediction. This shows that fMRI connectivity is not only the result of direct electrophysiological connections, but is also driven by the overlap of connectivity profiles between separate regions. Our results indicate that a complete understanding of the electrophysiological basis of RSNs goes beyond simple frequency-specific analysis, and further exploration of non-linear and cross-frequency interactions will shed new light on distributed network connectivity, and its perturbation in pathology.