Causation in neuroscience: keeping mechanism meaningful.

A fundamental goal of research in neuroscience is to uncover the causal structure of the brain. This focus on causation makes sense, because causal information can provide explanations of brain function and identify reliable targets with which to understand cognitive function and prevent or change neurological conditions and psychiatric disorders. In this research, one of the most frequently used causal concepts is 'mechanism' - this is seen in the literature and language of the field, in grant and funding inquiries that specify what research is supported, and in journal guidelines on which contributions are considered for publication. In these contexts, mechanisms are commonly tied to expressions of the main aims of the field and cited as the 'fundamental', 'foundational' and/or 'basic' unit for understanding the brain. Despite its common usage and perceived importance, mechanism is used in different ways that are rarely distinguished. Given that this concept is defined in different ways throughout the field - and that there is often no clarification of which definition is intended - there remains a marked ambiguity about the fundamental goals, orientation and principles of the field. Here we provide an overview of causation and mechanism from the perspectives of neuroscience and philosophy of science, in order to address these challenges.

Network models to enhance the translational impact of cross-species studies.

Neuroscience studies are often carried out in animal models for the purpose of understanding specific aspects of the human condition. However, the translation of findings across species remains a substantial challenge. Network science approaches can enhance the translational impact of cross-species studies by providing a means of mapping small-scale cellular processes identified in animal model studies to larger-scale inter-regional circuits observed in humans. In this Review, we highlight the contributions of network science approaches to the development of cross-species translational research in neuroscience. We lay the foundation for our discussion by exploring the objectives of cross-species translational models. We then discuss how the development of new tools that enable the acquisition of whole-brain data in animal models with cellular resolution provides unprecedented opportunity for cross-species applications of network science approaches for understanding large-scale brain networks. We describe how these tools may support the translation of findings across species and imaging modalities and highlight future opportunities. Our overarching goal is to illustrate how the application of network science tools across human and animal model studies could deepen insight into the neurobiology that underlies phenomena observed with non-invasive neuroimaging methods and could simultaneously further our ability to translate findings across species.

Connectome-based modelling of neurodegenerative diseases: towards precision medicine and mechanistic insight.

Neurodegenerative diseases are the most common cause of dementia. Although their underlying molecular pathologies have been identified, there is substantial heterogeneity in the patterns of progressive brain alterations across and within these diseases. Recent advances in neuroimaging methods have revealed that pathological proteins accumulate along specific macroscale brain networks, implicating the network architecture of the brain in the system-level pathophysiology of neurodegenerative diseases. However, the extent to which 'network-based neurodegeneration' applies across the wide range of neurodegenerative disorders remains unclear. Here, we discuss the state-of-the-art of neuroimaging-based connectomics for the mapping and prediction of neurodegenerative processes. We review findings supporting brain networks as passive conduits through which pathological proteins spread. As an alternative view, we also discuss complementary work suggesting that network alterations actively modulate the spreading of pathological proteins between connected brain regions. We conclude this Perspective by proposing an integrative framework in which connectome-based models can be advanced along three dimensions of innovation: incorporating parameters that modulate propagation behaviour on the basis of measurable biological features; building patient-tailored models that use individual-level information and allowing model parameters to interact dynamically over time. We discuss promises and pitfalls of these strategies for improving disease insights and moving towards precision medicine.

Information decomposition in complex systems via machine learning.

One of the fundamental steps toward understanding a complex system is identifying variation at the scale of the system's components that is most relevant to behavior on a macroscopic scale. Mutual information provides a natural means of linking variation across scales of a system due to its independence of functional relationship between observables. However, characterizing the manner in which information is distributed across a set of observables is computationally challenging and generally infeasible beyond a handful of measurements. Here, we propose a practical and general methodology that uses machine learning to decompose the information contained in a set of measurements by jointly optimizing a lossy compression of each measurement. Guided by the distributed information bottleneck as a learning objective, the information decomposition identifies the variation in the measurements of the system state most relevant to specified macroscale behavior. We focus our analysis on two paradigmatic complex systems: a Boolean circuit and an amorphous material undergoing plastic deformation. In both examples, the large amount of entropy of the system state is decomposed, bit by bit, in terms of what is most related to macroscale behavior. The identification of meaningful variation in data, with the full generality brought by information theory, is made practical for studying the connection between micro- and macroscale structure in complex systems.

Mindful attention promotes control of brain network dynamics for self-regulation and discontinues the past from the present.

Mindful attention is characterized by acknowledging the present experience as a transient mental event. Early stages of mindfulness practice may require greater neural effort for later efficiency. Early effort may self-regulate behavior and focalize the present, but this understanding lacks a computational explanation. Here we used network control theory as a model of how external control inputs-operationalizing effort-distribute changes in neural activity evoked during mindful attention across the white matter network. We hypothesized that individuals with greater network controllability, thereby efficiently distributing control inputs, effectively self-regulate behavior. We further hypothesized that brain regions that utilize greater control input exhibit shorter intrinsic timescales of neural activity. Shorter timescales characterize quickly discontinuing past processing to focalize the present. We tested these hypotheses in a randomized controlled study that primed participants to either mindfully respond or naturally react to alcohol cues during fMRI and administered text reminders and measurements of alcohol consumption during 4 wk postscan. We found that participants with greater network controllability moderated alcohol consumption. Mindful regulation of alcohol cues, compared to one's own natural reactions, reduced craving, but craving did not differ from the baseline group. Mindful regulation of alcohol cues, compared to the natural reactions of the baseline group, involved more-effortful control of neural dynamics across cognitive control and attention subnetworks. This effort persisted in the natural reactions of the mindful group compared to the baseline group. More-effortful neural states had shorter timescales than less effortful states, offering an explanation for how mindful attention promotes being present.

Optimizing the human learnability of abstract network representations.

Precisely how humans process relational patterns of information in knowledge, language, music, and society is not well understood. Prior work in the field of statistical learning has demonstrated that humans process such information by building internal models of the underlying network structure. However, these mental maps are often inaccurate due to limitations in human information processing. The existence of such limitations raises clear questions: Given a target network that one wishes for a human to learn, what network should one present to the human? Should one simply present the target network as-is, or should one emphasize certain parts of the network to proactively mitigate expected errors in learning? To investigate these questions, we study the optimization of network learnability in a computational model of human learning. Evaluating an array of synthetic and real-world networks, we find that learnability is enhanced by reinforcing connections within modules or clusters. In contrast, when networks contain significant core-periphery structure, we find that learnability is best optimized by reinforcing peripheral edges between low-degree nodes. Overall, our findings suggest that the accuracy of human network learning can be systematically enhanced by targeted emphasis and de-emphasis of prescribed sectors of information.

Microscale Neuronal Activity Collectively Drives Chaotic and Inflexible Dynamics at the Macroscale in Seizures.

Neuronal activity propagates through the network during seizures, engaging brain dynamics at multiple scales. Such propagating events can be described through the avalanches framework, which can relate spatiotemporal activity at the microscale with global network properties. Interestingly, propagating avalanches in healthy networks are indicative of critical dynamics, where the network is organized to a phase transition, which optimizes certain computational properties. Some have hypothesized that the pathologic brain dynamics of epileptic seizures are an emergent property of microscale neuronal networks collectively driving the brain away from criticality. Demonstrating this would provide a unifying mechanism linking microscale spatiotemporal activity with emergent brain dysfunction during seizures. Here, we investigated the effect of drug-induced seizures on critical avalanche dynamics, using in vivo whole-brain two-photon imaging of GCaMP6s larval zebrafish (males and females) at single neuron resolution. We demonstrate that single neuron activity across the whole brain exhibits a loss of critical statistics during seizures, suggesting that microscale activity collectively drives macroscale dynamics away from criticality. We also construct spiking network models at the scale of the larval zebrafish brain, to demonstrate that only densely connected networks can drive brain-wide seizure dynamics away from criticality. Importantly, such dense networks also disrupt the optimal computational capacities of critical networks, leading to chaotic dynamics, impaired network response properties and sticky states, thus helping to explain functional impairments during seizures. This study bridges the gap between microscale neuronal activity and emergent macroscale dynamics and cognitive dysfunction during seizures.SIGNIFICANCE STATEMENT Epileptic seizures are debilitating and impair normal brain function. It is unclear how the coordinated behavior of neurons collectively impairs brain function during seizures. To investigate this we perform fluorescence microscopy in larval zebrafish, which allows for the recording of whole-brain activity at single-neuron resolution. Using techniques from physics, we show that neuronal activity during seizures drives the brain away from criticality, a regime that enables both high and low activity states, into an inflexible regime that drives high activity states. Importantly, this change is caused by more connections in the network, which we show disrupts the ability of the brain to respond appropriately to its environment. Therefore, we identify key neuronal network mechanisms driving seizures and concurrent cognitive dysfunction.

Diffusion MRI head motion correction methods are highly accurate but impacted by denoising and sampling scheme.

Head motion correction is particularly challenging in diffusion-weighted MRI (dMRI) scans due to the dramatic changes in image contrast at different gradient strengths and directions. Head motion correction is typically performed using a Gaussian Process model implemented in FSL's Eddy. Recently, the 3dSHORE-based SHORELine method was introduced that does not require shell-based acquisitions, but it has not been previously benchmarked. Here we perform a comprehensive evaluation of both methods on realistic simulations of a software fiber phantom that provides known ground-truth head motion. We demonstrate that both methods perform remarkably well, but that performance can be impacted by sampling scheme and the extent of head motion and the denoising strategy applied before head motion correction. Furthermore, we find Eddy benefits from denoising the data first with MP-PCA. In sum, we provide the most extensive known benchmarking of dMRI head motion correction, together with extensive simulation data and a reproducible workflow. PRACTITIONER POINTS: Both Eddy and SHORELine head motion correction methods performed quite well on a large variety of simulated data. Denoising with MP-PCA can improve head motion correction performance when Eddy is used. SHORELine effectively corrects motion in non-shelled diffusion spectrum imaging data.

Machine-Learning Optimized Measurements of Chaotic Dynamical Systems via the Information Bottleneck.

Deterministic chaos permits a precise notion of a "perfect measurement" as one that, when obtained repeatedly, captures all of the information created by the system's evolution with minimal redundancy. Finding an optimal measurement is challenging and has generally required intimate knowledge of the dynamics in the few cases where it has been done. We establish an equivalence between a perfect measurement and a variant of the information bottleneck. As a consequence, we can employ machine learning to optimize measurement processes that efficiently extract information from trajectory data. We obtain approximately optimal measurements for multiple chaotic maps and lay the necessary groundwork for efficient information extraction from general time series.

Alprazolam modulates persistence energy during emotion processing in first-degree relatives of individuals with schizophrenia: a network control study.

Schizophrenia is marked by deficits in facial affect processing associated with abnormalities in GABAergic circuitry, deficits also found in first-degree relatives. Facial affect processing involves a distributed network of brain regions including limbic regions like amygdala and visual processing areas like fusiform cortex. Pharmacological modulation of GABAergic circuitry using benzodiazepines like alprazolam can be useful for studying this facial affect processing network and associated GABAergic abnormalities in schizophrenia. Here, we use pharmacological modulation and computational modeling to study the contribution of GABAergic abnormalities toward emotion processing deficits in schizophrenia. Specifically, we apply principles from network control theory to model persistence energy - the control energy required to maintain brain activation states - during emotion identification and recall tasks, with and without administration of alprazolam, in a sample of first-degree relatives and healthy controls. Here, persistence energy quantifies the magnitude of theoretical external inputs during the task. We find that alprazolam increases persistence energy in relatives but not in controls during threatening face processing, suggesting a compensatory mechanism given the relative absence of behavioral abnormalities in this sample of unaffected relatives. Further, we demonstrate that regions in the fusiform and occipital cortices are important for facilitating state transitions during facial affect processing. Finally, we uncover spatial relationships (i) between regional variation in differential control energy (alprazolam versus placebo) and (ii) both serotonin and dopamine neurotransmitter systems, indicating that alprazolam may exert its effects by altering neuromodulatory systems. Together, these findings provide a new perspective on the distributed emotion processing network and the effect of GABAergic modulation on this network, in addition to identifying an association between schizophrenia risk and abnormal GABAergic effects on persistence energy during threat processing.

Disorganization of language and working memory systems in frontal versus temporal lobe epilepsy.

Cognitive impairment is a common comorbidity of epilepsy and adversely impacts people with both frontal lobe (FLE) and temporal lobe (TLE) epilepsy. While its neural substrates have been investigated extensively in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devised a multiscale approach to map brain activation and deactivation during cognition and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems; and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, as well as reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE are broadly similar to those in TLE, but some patterns are syndrome-specific: altered default-mode deactivation is more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands is more marked in TLE. Functional abnormalities in FLE and TLE appear overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies and sheds light on system behaviour that may be amenable to future remediation strategies.

Breaking reflection symmetry: evolving long dynamical cycles in Boolean systems.

In interacting dynamical systems, specific local interaction rules for system components give rise to diverse and complex global dynamics. Long dynamical cycles are a key feature of many natural interacting systems, especially in biology. Examples of dynamical cycles range from circadian rhythms regulating sleep to cell cycles regulating reproductive behavior. Despite the crucial role of cycles in nature, the properties of network structure that give rise to cycles still need to be better understood. Here, we use a Boolean interaction network model to study the relationships between network structure and cyclic dynamics. We identify particular structural motifs that support cycles, and other motifs that suppress them. More generally, we show that the presence of dynamical reflection symmetry in the interaction network enhances cyclic behavior. In simulating an artificial evolutionary process, we find that motifs that break reflection symmetry are discarded. We further show that dynamical reflection symmetries are over-represented in Boolean models of natural biological systems. Altogether, our results demonstrate a link between symmetry and functionality for interacting dynamical systems, and they provide evidence for symmetry's causal role in evolving dynamical functionality.

A socioemotional network perspective on momentary experiences of family conflict in young adults.

Family conflict is an established predictor of psychopathology in youth. Traditional approaches focus on between-family differences in conflict. Daily fluctuations in conflict within families might also impact psychopathology, but more research is needed to understand how and why. Using 21 days of daily diary data and 6-times a day experience-sampling data (N = 77 participants; mean age = 21.18, SD = 1.75; 63 women, 14 men), we captured day-to-day and within-day fluctuations in family conflict, anger, anxiety, and sadness. Using multilevel models, we find that days of higher-than-usual anger are also days of higher-than-usual family conflict. Examining associations between family conflict and emotions within days, we find that moments of higher-than-usual anger predict higher-than-usual family conflict later in the day. We observe substantial between-family differences in these patterns with implications for psychopathology; youth showing the substantial interplay between family conflict and emotions across time had a more perseverative family conflict and greater trait anxiety. Overall, findings indicate the importance of increases in youth anger for experiences of family conflict during young adulthood and demonstrate how intensive repeated measures coupled with network analytic approaches can capture long-theorized notions of reciprocal processes in daily family life.

The Age of Reason: Functional Brain Network Development during Childhood.

Human childhood is characterized by dramatic changes in the mind and brain. However, little is known about the large-scale intrinsic cortical network changes that occur during childhood because of methodological challenges in scanning young children. Here, we overcome this barrier by using sophisticated acquisition and analysis tools to investigate functional network development in children between the ages of 4 and 10 years ([Formula: see text]; 50 female, 42 male). At multiple spatial scales, age is positively associated with brain network segregation. At the system level, age was associated with segregation of systems involved in attention from those involved in abstract cognition, and with integration among attentional and perceptual systems. Associations between age and functional connectivity are most pronounced in visual and medial prefrontal cortex, the two ends of a gradient from perceptual, externally oriented cortex to abstract, internally oriented cortex. These findings suggest that both ends of the sensory-association gradient may develop early, in contrast to the classical theories that cortical maturation proceeds from back to front, with sensory areas developing first and association areas developing last. More mature patterns of brain network architecture, controlling for age, were associated with better visuospatial reasoning abilities. Our results suggest that as cortical architecture becomes more specialized, children become more able to reason about the world and their place in it.SIGNIFICANCE STATEMENT Anthropologists have called the transition from early to middle childhood the "age of reason", when children across cultures become more independent. We employ cutting-edge neuroimaging acquisition and analysis approaches to investigate associations between age and functional brain architecture in childhood. Age was positively associated with segregation between cortical systems that process the external world and those that process abstract phenomena like the past, future, and minds of others. Surprisingly, we observed pronounced development at both ends of the sensory-association gradient, challenging the theory that sensory areas develop first and association areas develop last. Our results open new directions for research into how brains reorganize to support rapid gains in cognitive and socioemotional skills as children reach the age of reason.

CoCoA: conditional correlation models with association size.

Many scientific questions can be formulated as hypotheses about conditional correlations. For instance, in tests of cognitive and physical performance, the trade-off between speed and accuracy motivates study of the two variables together. A natural question is whether speed-accuracy coupling depends on other variables, such as sustained attention. Classical regression techniques, which posit models in terms of covariates and outcomes, are insufficient to investigate the effect of a third variable on the symmetric relationship between speed and accuracy. In response, we propose a conditional correlation model with association size, a likelihood-based statistical framework to estimate the conditional correlation between speed and accuracy as a function of additional variables. We propose novel measures of the association size, which are analogous to effect sizes on the correlation scale while adjusting for confound variables. In simulation studies, we compare likelihood-based estimators of conditional correlation to semiparametric estimators adapted from genomic studies and find that the former achieves lower bias and variance under both ideal settings and model assumption misspecification. Using neurocognitive data from the Philadelphia Neurodevelopmental Cohort, we demonstrate that greater sustained attention is associated with stronger speed-accuracy coupling in a complex reasoning task while controlling for age. By highlighting conditional correlations as the outcome of interest, our model provides complementary insights to traditional regression modeling and partitioned correlation analyses.

Within-Person Temporal Associations Among Self-Reported Physical Activity, Sleep, and Well-Being in College Students.

OBJECTIVE: A holistic understanding of the naturalistic dynamics among physical activity, sleep, emotions, and purpose in life as part of a system reflecting wellness is key to promoting well-being. The main aim of this study was to examine the day-to-day dynamics within this wellness system. METHODS: Using self-reported emotions (happiness, sadness, anger, anxiousness) and physical activity periods collected twice per day, and daily reports of sleep and purpose in life via smartphone experience sampling, more than 28 days as college students ( n = 226 young adults; mean [standard deviation] = 20.2 [1.7] years) went about their daily lives, we examined day-to-day temporal and contemporaneous dynamics using multilevel vector autoregressive models that consider the network of wellness together. RESULTS: Network analyses revealed that higher physical activity on a given day predicted an increase of happiness the next day. Higher sleep quality on a given night predicted a decrease in negative emotions the next day, and higher purpose in life predicted decreased negative emotions up to 2 days later. Nodes with the highest centrality were sadness, anxiety, and happiness in the temporal network and purpose in life, anxiety, and anger in the contemporaneous network. CONCLUSIONS: Although the effects of sleep and physical activity on emotions and purpose in life may be shorter term, a sense of purpose in life is a critical component of wellness that can have slightly longer effects, bleeding into the next few days. High-arousal emotions and purpose in life are central to motivating people into action, which can lead to behavior change.

Altered functional brain dynamics in chromosome 22q11.2 deletion syndrome during facial affect processing.

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disorder associated with multiple congenital anomalies, variable medical features, and neurodevelopmental differences resulting in diverse psychiatric phenotypes, including marked deficits in facial memory and social cognition. Neuroimaging in individuals with 22q11.2DS has revealed differences relative to matched controls in BOLD fMRI activation during facial affect processing tasks. However, time-varying interactions between brain areas during facial affect processing have not yet been studied with BOLD fMRI in 22q11.2DS. We applied constrained principal component analysis to identify temporally overlapping brain activation patterns from BOLD fMRI data acquired during an emotion identification task from 58 individuals with 22q11.2DS and 58 age-, race-, and sex-matched healthy controls. Delayed frontal-motor feedback signals were diminished in individuals with 22q11.2DS, as were delayed emotional memory signals engaging amygdala, hippocampus, and entorhinal cortex. Early task-related engagement of motor and visual cortices and salience-related insular activation were relatively preserved in 22q11.2DS. Insular activation was associated with task performance within the 22q11.2DS sample. Differences in cortical surface area, but not cortical thickness, showed spatial alignment with an activation pattern associated with face processing. These findings suggest that relative to matched controls, primary visual processing and insular function are relatively intact in individuals with 22q11.22DS, while motor feedback, face processing, and emotional memory processes are more affected. Such insights may help inform potential interventional targets and enhance the specificity of neuroimaging indices of cognitive dysfunction in 22q11.2DS.

Atypical intrinsic neural timescales in temporal lobe epilepsy.

OBJECTIVE: Temporal lobe epilepsy (TLE) is the most common pharmacoresistant epilepsy in adults. Here we profiled local neural function in TLE in vivo, building on prior evidence that has identified widespread structural alterations. Using resting-state functional magnetic resonance imaging (rs-fMRI), we mapped the whole-brain intrinsic neural timescales (INT), which reflect temporal hierarchies of neural processing. Parallel analysis of structural and diffusion MRI data examined associations with TLE-related structural compromise. Finally, we evaluated the clinical utility of INT. METHODS: We studied 46 patients with TLE and 44 healthy controls from two independent sites, and mapped INT changes in patients relative to controls across hippocampal, subcortical, and neocortical regions. We examined region-specific associations to structural alterations and explored the effects of age and epilepsy duration. Supervised machine learning assessed the utility of INT for identifying patients with TLE vs controls and left- vs right-sided seizure onset. RESULTS: Relative to controls, TLE showed marked INT reductions across multiple regions bilaterally, indexing faster changing resting activity, with strongest effects in the ipsilateral medial and lateral temporal regions, and bilateral sensorimotor cortices as well as thalamus and hippocampus. Findings were similar, albeit with reduced effect sizes, when correcting for structural alterations. INT reductions in TLE increased with advancing disease duration, yet findings differed from the aging effects seen in controls. INT-derived classifiers discriminated patients vs controls (balanced accuracy, 5-fold: 76% ± 2.65%; cross-site, 72%-83%) and lateralized the focus in TLE (balanced accuracy, 5-fold: 96% ± 2.10%; cross-site, 95%-97%), with high accuracy and cross-site generalizability. Findings were consistent across both acquisition sites and robust when controlling for motion and several methodological confounds. SIGNIFICANCE: Our findings demonstrate atypical macroscale function in TLE in a topography that extends beyond mesiotemporal epicenters. INT measurements can assist in TLE diagnosis, seizure focus lateralization, and monitoring of disease progression, which emphasizes promising clinical utility.

Normative intracranial EEG maps epileptogenic tissues in focal epilepsy.

Planning surgery for patients with medically refractory epilepsy often requires recording seizures using intracranial EEG. Quantitative measures derived from interictal intracranial EEG yield potentially appealing biomarkers to guide these surgical procedures; however, their utility is limited by the sparsity of electrode implantation as well as the normal confounds of spatiotemporally varying neural activity and connectivity. We propose that comparing intracranial EEG recordings to a normative atlas of intracranial EEG activity and connectivity can reliably map abnormal regions, identify targets for invasive treatment and increase our understanding of human epilepsy. Merging data from the Penn Epilepsy Center and a public database from the Montreal Neurological Institute, we aggregated interictal intracranial EEG retrospectively across 166 subjects comprising >5000 channels. For each channel, we calculated the normalized spectral power and coherence in each canonical frequency band. We constructed an intracranial EEG atlas by mapping the distribution of each feature across the brain and tested the atlas against data from novel patients by generating a z-score for each channel. We demonstrate that for seizure onset zones within the mesial temporal lobe, measures of connectivity abnormality provide greater distinguishing value than univariate measures of abnormal neural activity. We also find that patients with a longer diagnosis of epilepsy have greater abnormalities in connectivity. By integrating measures of both single-channel activity and inter-regional functional connectivity, we find a better accuracy in predicting the seizure onset zones versus normal brain (area under the curve = 0.77) compared with either group of features alone. We propose that aggregating normative intracranial EEG data across epilepsy centres into a normative atlas provides a rigorous, quantitative method to map epileptic networks and guide invasive therapy. We publicly share our data, infrastructure and methods, and propose an international framework for leveraging big data in surgical planning for refractory epilepsy.