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.

Functional brain network architecture supporting the learning of social networks in humans.

Most humans have the good fortune to live their lives embedded in richly structured social groups. Yet, it remains unclear how humans acquire knowledge about these social structures to successfully navigate social relationships. Here we address this knowledge gap with an interdisciplinary neuroimaging study drawing on recent advances in network science and statistical learning. Specifically, we collected BOLD MRI data while participants learned the community structure of both social and non-social networks, in order to examine whether the learning of these two types of networks was differentially associated with functional brain network topology. We found that participants learned the community structure of the networks, as evidenced by a slower reaction time when a trial moved between communities than when a trial moved within a community. Learning the community structure of social networks was also characterized by significantly greater functional connectivity of the hippocampus and temporoparietal junction when transitioning between communities than when transitioning within a community. Furthermore, temporoparietal regions of the default mode were more strongly connected to hippocampus, somatomotor, and visual regions for social networks than for non-social networks. Collectively, our results identify neurophysiological underpinnings of social versus non-social network learning, extending our knowledge about the impact of social context on learning processes. More broadly, this work offers an empirical approach to study the learning of social network structures, which could be fruitfully extended to other participant populations, various graph architectures, and a diversity of social contexts in future studies.

Functional disconnection of associative cortical areas predicts performance during BCI training.

Brain-computer interfaces (BCIs) have been largely developed to allow communication, control, and neurofeedback in human beings. Despite their great potential, BCIs perform inconsistently across individuals and the neural processes that enable humans to achieve good control remain poorly understood. To address this question, we performed simultaneous high-density electroencephalographic (EEG) and magnetoencephalographic (MEG) recordings in a motor imagery-based BCI training involving a group of healthy subjects. After reconstructing the signals at the cortical level, we showed that the reinforcement of motor-related activity during the BCI skill acquisition is paralleled by a progressive disconnection of associative areas which were not directly targeted during the experiments. Notably, these network connectivity changes reflected growing automaticity associated with BCI performance and predicted future learning rate. Altogether, our findings provide new insights into the large-scale cortical organizational mechanisms underlying BCI learning, which have implications for the improvement of this technology in a broad range of real-life applications.

Cliques and cavities in the human connectome.

Encoding brain regions and their connections as a network of nodes and edges captures many of the possible paths along which information can be transmitted as humans process and perform complex behaviors. Because cognitive processes involve large, distributed networks of brain areas, principled examinations of multi-node routes within larger connection patterns can offer fundamental insights into the complexities of brain function. Here, we investigate both densely connected groups of nodes that could perform local computations as well as larger patterns of interactions that would allow for parallel processing. Finding such structures necessitates that we move from considering exclusively pairwise interactions to capturing higher order relations, concepts naturally expressed in the language of algebraic topology. These tools can be used to study mesoscale network structures that arise from the arrangement of densely connected substructures called cliques in otherwise sparsely connected brain networks. We detect cliques (all-to-all connected sets of brain regions) in the average structural connectomes of 8 healthy adults scanned in triplicate and discover the presence of more large cliques than expected in null networks constructed via wiring minimization, providing architecture through which brain network can perform rapid, local processing. We then locate topological cavities of different dimensions, around which information may flow in either diverging or converging patterns. These cavities exist consistently across subjects, differ from those observed in null model networks, and - importantly - link regions of early and late evolutionary origin in long loops, underscoring their unique role in controlling brain function. These results offer a first demonstration that techniques from algebraic topology offer a novel perspective on structural connectomics, highlighting loop-like paths as crucial features in the human brain's structural architecture.

Structural Pathways Supporting Swift Acquisition of New Visuomotor Skills.

Human skill learning requires fine-scale coordination of distributed networks of brain regions linked by white matter tracts to allow for effective information transmission. Yet how individual differences in these anatomical pathways may impact individual differences in learning remains far from understood. Here, we test the hypothesis that individual differences in structural organization of networks supporting task performance predict individual differences in the rate at which humans learn a visuomotor skill. Over the course of 6 weeks, 20 healthy adult subjects practiced a discrete sequence production task, learning a sequence of finger movements based on discrete visual cues. We collected structural imaging data, and using deterministic tractography generated structural networks for each participant to identify streamlines connecting cortical and subcortical brain regions. We observed that increased white matter connectivity linking early visual regions was associated with a faster learning rate. Moreover, the strength of multiedge paths between motor and visual modules was also correlated with learning rate, supporting the potential role of extended sets of polysynaptic connections in successful skill acquisition. Our results demonstrate that estimates of anatomical connectivity from white matter microstructure can be used to predict future individual differences in the capacity to learn a new motor-visual skill, and that these predictions are supported both by direct connectivity in visual cortex and indirect connectivity between visual cortex and motor cortex.

Human learning of hierarchical graphs.

Humans are exposed to sequences of events in the environment, and the interevent transition probabilities in these sequences can be modeled as a graph or network. Many real-world networks are organized hierarchically and while much is known about how humans learn basic transition graph topology, whether and to what degree humans can learn hierarchical structures in such graphs remains unknown. We probe the mental estimates of transition probabilities via the surprisal effect phenomenon: humans react more slowly to less expected transitions. Using mean-field predictions and numerical simulations, we show that surprisal effects are stronger for finer-level than coarser-level hierarchical transitions, and that surprisal effects at coarser levels are difficult to detect for limited learning times or in small samples. Using a serial response experiment with human participants (n=100), we replicate our predictions by detecting a surprisal effect at the finer level of the hierarchy but not at the coarser level of the hierarchy. We then evaluate the presence of a trade-off in learning, whereby humans who learned the finer level of the hierarchy better also tended to learn the coarser level worse, and vice versa. This study elucidates the processes by which humans learn sequential events in hierarchical contexts. More broadly, our work charts a road map for future investigation of the neural underpinnings and behavioral manifestations of graph learning.

Measuring neuronal avalanches to inform brain-computer interfaces.

Large-scale interactions among multiple brain regions manifest as bursts of activations called neuronal avalanches, which reconfigure according to the task at hand and, hence, might constitute natural candidates to design brain-computer interfaces (BCIs). To test this hypothesis, we used source-reconstructed magneto/electroencephalography during resting state and a motor imagery task performed within a BCI protocol. To track the probability that an avalanche would spread across any two regions, we built an avalanche transition matrix (ATM) and demonstrated that the edges whose transition probabilities significantly differed between conditions hinged selectively on premotor regions in all subjects. Furthermore, we showed that the topology of the ATMs allows task-decoding above the current gold standard. Hence, our results suggest that neuronal avalanches might capture interpretable differences between tasks that can be used to inform brain-computer interfaces.

Network structure influences the strength of learned neural representations.

Human experience is built upon sequences of discrete events. From those sequences, humans build impressively accurate models of their world. This process has been referred to as graph learning, a form of structure learning in which the mental model encodes the graph of event-to-event transition probabilities [1], [2], typically in medial temporal cortex [3]-[6]. Recent evidence suggests that some network structures are easier to learn than others [7]-[9], but the neural properties of this effect remain unknown. Here we use fMRI to show that the network structure of a temporal sequence of stimuli influences the fidelity with which those stimuli are represented in the brain. Healthy adult human participants learned a set of stimulus-motor associations following one of two graph structures. The design of our experiment allowed us to separate regional sensitivity to the structural, stimulus, and motor response components of the task. As expected, whereas the motor response could be decoded from neural representations in postcentral gyrus, the shape of the stimulus could be decoded from lateral occipital cortex. The structure of the graph impacted the nature of neural representations: when the graph was modular as opposed to lattice-like, BOLD representations in visual areas better predicted trial identity in a held-out run and displayed higher intrinsic dimensionality. Our results demonstrate that even over relatively short timescales, graph structure determines the fidelity of event representations as well as the dimensionality of the space in which those representations are encoded. More broadly, our study shows that network context influences the strength of learned neural representations, motivating future work in the design, optimization, and adaptation of network contexts for distinct types of learning over different timescales.

Dual credit assignment processes underlie dopamine signals in a complex spatial environment.

Animals frequently make decisions based on expectations of future reward ("values"). Values are updated by ongoing experience: places and choices that result in reward are assigned greater value. Yet, the specific algorithms used by the brain for such credit assignment remain unclear. We monitored accumbens dopamine as rats foraged for rewards in a complex, changing environment. We observed brief dopamine pulses both at reward receipt (scaling with prediction error) and at novel path opportunities. Dopamine also ramped up as rats ran toward reward ports, in proportion to the value at each location. By examining the evolution of these dopamine place-value signals, we found evidence for two distinct update processes: progressive propagation of value along taken paths, as in temporal difference learning, and inference of value throughout the maze, using internal models. Our results demonstrate that within rich, naturalistic environments dopamine conveys place values that are updated via multiple, complementary learning algorithms.

Human Learning of Hierarchical Graphs.

Humans are constantly exposed to sequences of events in the environment. Those sequences frequently evince statistical regularities, such as the probabilities with which one event transitions to another. Collectively, inter-event transition probabilities can be modeled as a graph or network. Many real-world networks are organized hierarchically and understanding how these networks are learned by humans is an ongoing aim of current investigations. While much is known about how humans learn basic transition graph topology, whether and to what degree humans can learn hierarchical structures in such graphs remains unknown. Here, we investigate how humans learn hierarchical graphs of the Sierpinski family using computer simulations and behavioral laboratory experiments. We probe the mental estimates of transition probabilities via the surprisal effect: a phenomenon in which humans react more slowly to less expected transitions, such as those between communities or modules in the network. Using mean-field predictions and numerical simulations, we show that surprisal effects are stronger for finer-level than coarser-level hierarchical transitions. Notably, surprisal effects at coarser levels of the hierarchy are difficult to detect for limited learning times or in small samples. Using a serial response experiment with human participants (n=100), we replicate our predictions by detecting a surprisal effect at the finer-level of the hierarchy but not at the coarser-level of the hierarchy. To further explain our findings, we evaluate the presence of a trade-off in learning, whereby humans who learned the finer-level of the hierarchy better tended to learn the coarser-level worse, and vice versa. Taken together, our computational and experimental studies elucidate the processes by which humans learn sequential events in hierarchical contexts. More broadly, our work charts a road map for future investigation of the neural underpinnings and behavioral manifestations of graph learning.

Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures.

ABSTRACT: Chronic pain affects more than 50 million Americans. Treatments remain inadequate, in large part, because the pathophysiological mechanisms underlying the development of chronic pain remain poorly understood. Pain biomarkers could potentially identify and measure biological pathways and phenotypical expressions that are altered by pain, provide insight into biological treatment targets, and help identify at-risk patients who might benefit from early intervention. Biomarkers are used to diagnose, track, and treat other diseases, but no validated clinical biomarkers exist yet for chronic pain. To address this problem, the National Institutes of Health Common Fund launched the Acute to Chronic Pain Signatures (A2CPS) program to evaluate candidate biomarkers, develop them into biosignatures, and discover novel biomarkers for chronification of pain after surgery. This article discusses candidate biomarkers identified by A2CPS for evaluation, including genomic, proteomic, metabolomic, lipidomic, neuroimaging, psychophysical, psychological, and behavioral measures. Acute to Chronic Pain Signatures will provide the most comprehensive investigation of biomarkers for the transition to chronic postsurgical pain undertaken to date. Data and analytic resources generatedby A2CPS will be shared with the scientific community in hopes that other investigators will extract valuable insights beyond A2CPS's initial findings. This article will review the identified biomarkers and rationale for including them, the current state of the science on biomarkers of the transition from acute to chronic pain, gaps in the literature, and how A2CPS will address these gaps.

Neurophysiological Evidence for Cognitive Map Formation during Sequence Learning.

Humans deftly parse statistics from sequences. Some theories posit that humans learn these statistics by forming cognitive maps, or underlying representations of the latent space which links items in the sequence. Here, an item in the sequence is a node, and the probability of transitioning between two items is an edge. Sequences can then be generated from walks through the latent space, with different spaces giving rise to different sequence statistics. Individual or group differences in sequence learning can be modeled by changing the time scale over which estimates of transition probabilities are built, or in other words, by changing the amount of temporal discounting. Latent space models with temporal discounting bear a resemblance to models of navigation through Euclidean spaces. However, few explicit links have been made between predictions from Euclidean spatial navigation and neural activity during human sequence learning. Here, we use a combination of behavioral modeling and intracranial encephalography (iEEG) recordings to investigate how neural activity might support the formation of space-like cognitive maps through temporal discounting during sequence learning. Specifically, we acquire human reaction times from a sequential reaction time task, to which we fit a model that formulates the amount of temporal discounting as a single free parameter. From the parameter, we calculate each individual's estimate of the latent space. We find that neural activity reflects these estimates mostly in the temporal lobe, including areas involved in spatial navigation. Similar to spatial navigation, we find that low-dimensional representations of neural activity allow for easy separation of important features, such as modules, in the latent space. Lastly, we take advantage of the high temporal resolution of iEEG data to determine the time scale on which latent spaces are learned. We find that learning typically happens within the first 500 trials, and is modulated by the underlying latent space and the amount of temporal discounting characteristic of each participant. Ultimately, this work provides important links between behavioral models of sequence learning and neural activity during the same behavior, and contextualizes these results within a broader framework of domain general cognitive maps.

Multi-Site Observational Study to Assess Biomarkers for Susceptibility or Resilience to Chronic Pain: The Acute to Chronic Pain Signatures (A2CPS) Study Protocol.

Chronic pain has become a global health problem contributing to years lived with disability and reduced quality of life. Advances in the clinical management of chronic pain have been limited due to incomplete understanding of the multiple risk factors and molecular mechanisms that contribute to the development of chronic pain. The Acute to Chronic Pain Signatures (A2CPS) Program aims to characterize the predictive nature of biomarkers (brain imaging, high-throughput molecular screening techniques, or "omics," quantitative sensory testing, patient-reported outcome assessments and functional assessments) to identify individuals who will develop chronic pain following surgical intervention. The A2CPS is a multisite observational study investigating biomarkers and collective biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain following knee arthroplasty and thoracic surgery. This manuscript provides an overview of data collection methods and procedures designed to standardize data collection across multiple clinical sites and institutions. Pain-related biomarkers are evaluated before surgery and up to 3 months after surgery for use as predictors of patient reported outcomes 6 months after surgery. The dataset from this prospective observational study will be available for researchers internal and external to the A2CPS Consortium to advance understanding of the transition from acute to chronic postsurgical pain.

RedundancyMiner: De-replication of redundant GO categories in microarray and proteomics analysis.

BACKGROUND: The Gene Ontology (GO) Consortium organizes genes into hierarchical categories based on biological process, molecular function and subcellular localization. Tools such as GoMiner can leverage GO to perform ontological analysis of microarray and proteomics studies, typically generating a list of significant functional categories. Two or more of the categories are often redundant, in the sense that identical or nearly-identical sets of genes map to the categories. The redundancy might typically inflate the report of significant categories by a factor of three-fold, create an illusion of an overly long list of significant categories, and obscure the relevant biological interpretation. RESULTS: We now introduce a new resource, RedundancyMiner, that de-replicates the redundant and nearly-redundant GO categories that had been determined by first running GoMiner. The main algorithm of RedundancyMiner, MultiClust, performs a novel form of cluster analysis in which a GO category might belong to several category clusters. Each category cluster follows a "complete linkage" paradigm. The metric is a similarity measure that captures the overlap in gene mapping between pairs of categories. CONCLUSIONS: RedundancyMiner effectively eliminated redundancies from a set of GO categories. For illustration, we have applied it to the clarification of the results arising from two current studies: (1) assessment of the gene expression profiles obtained by laser capture microdissection (LCM) of serial cryosections of the retina at the site of final optic fissure closure in the mouse embryos at specific embryonic stages, and (2) analysis of a conceptual data set obtained by examining a list of genes deemed to be "kinetochore" genes.

Ontogenomic study of the relationship between number of gene splice variants and GO categorization.

MOTIVATION: Splice variation plays important roles in evolution and cancer. Different splice variants of a gene may be characteristic of particular cellular processes, subcellular locations or organs. Although several genomic projects have identified splice variants, there have been no large-scale computational studies of the relationship between number of splice variants and biological function. The Gene Ontology (GO) and tools for leveraging GO, such as GoMiner, now make such a study feasible. RESULTS: We partitioned genes into two groups: those with numbers of splice variants b (b=1,..., 10). Then we used GoMiner to determine whether any GO categories are enriched in genes with particular numbers of splice variants. Since there was no a priori 'appropriate' partition boundary, we studied those 'robust' categories whose enrichment did not depend on the selection of a particular partition boundary. Furthermore, because the distribution of splice variant number was a snapshot taken at a particular point in time, we confirmed that those observations were stable across successive builds of GenBank. A small number of categories were found for genes in the lower partitions. A larger number of categories were found for genes in the higher partitions. Those categories were largely associated with cell death and signal transduction. Apoptotic genes tended to have a large repertoire of splice variants, and genes with splice variants exhibited a distinctive 'apoptotic island' in clustered image maps (CIMs). AVAILABILITY: Supplementary tables and figures are available at URL http://discover.nci.nih.gov/OG/supplementaryMaterials.html. The Safari browser appears to perform better than Firefox for these particular items.

Abstract representations of events arise from mental errors in learning and memory.

Humans are adept at uncovering abstract associations in the world around them, yet the underlying mechanisms remain poorly understood. Intuitively, learning the higher-order structure of statistical relationships should involve complex mental processes. Here we propose an alternative perspective: that higher-order associations instead arise from natural errors in learning and memory. Using the free energy principle, which bridges information theory and Bayesian inference, we derive a maximum entropy model of people's internal representations of the transitions between stimuli. Importantly, our model (i) affords a concise analytic form, (ii) qualitatively explains the effects of transition network structure on human expectations, and (iii) quantitatively predicts human reaction times in probabilistic sequential motor tasks. Together, these results suggest that mental errors influence our abstract representations of the world in significant and predictable ways, with direct implications for the study and design of optimally learnable information sources.

A practical guide to methodological considerations in the controllability of structural brain networks.

OBJECTIVE: Predicting how the brain can be driven to specific states by means of internal or external control requires a fundamental understanding of the relationship between neural connectivity and activity. Network control theory is a powerful tool from the physical and engineering sciences that can provide insights regarding that relationship; it formalizes the study of how the dynamics of a complex system can arise from its underlying structure of interconnected units. APPROACH: Given the recent use of network control theory in neuroscience, it is now timely to offer a practical guide to methodological considerations in the controllability of structural brain networks. Here we provide a systematic overview of the framework, examine the impact of modeling choices on frequently studied control metrics, and suggest potentially useful theoretical extensions. We ground our discussions, numerical demonstrations, and theoretical advances in a dataset of high-resolution diffusion imaging with 730 diffusion directions acquired over approximately 1 h of scanning from ten healthy young adults. MAIN RESULTS: Following a didactic introduction of the theory, we probe how a selection of modeling choices affects four common statistics: average controllability, modal controllability, minimum control energy, and optimal control energy. Next, we extend the current state-of-the-art in two ways: first, by developing an alternative measure of structural connectivity that accounts for radial propagation of activity through abutting tissue, and second, by defining a complementary metric quantifying the complexity of the energy landscape of a system. We close with specific modeling recommendations and a discussion of methodological constraints. SIGNIFICANCE: Our hope is that this accessible account will inspire the neuroimaging community to more fully exploit the potential of network control theory in tackling pressing questions in cognitive, developmental, and clinical neuroscience.

Individual differences in learning social and nonsocial network structures.

How do people acquire knowledge about which individuals belong to different cliques or communities? And to what extent does this learning process differ from the process of learning higher-order information about complex associations between nonsocial bits of information? Here, the authors use a paradigm in which the order of stimulus presentation forms temporal associations between the stimuli, collectively constituting a complex network. They examined individual differences in the ability to learn community structure of networks composed of social versus nonsocial stimuli. Although participants were able to learn community structure of both social and nonsocial networks, their performance in social network learning was uncorrelated with their performance in nonsocial network learning. In addition, social traits, including social orientation and perspective-taking, uniquely predicted the learning of social community structure but not the learning of nonsocial community structure. Taken together, the results suggest that the process of learning higher-order community structure in social networks is partially distinct from the process of learning higher-order community structure in nonsocial networks. The study design provides a promising approach to identify neurophysiological drivers of social network versus nonsocial network learning, extending knowledge about the impact of individual differences on these learning processes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Structural, geometric and genetic factors predict interregional brain connectivity patterns probed by electrocorticography.

Electrocorticography (ECoG) data can be used to estimate brain-wide connectivity patterns. Yet, the invasiveness of ECoG, incomplete cortical coverage, and variability in electrode placement across individuals make the network analysis of ECoG data challenging. Here, we show that the architecture of whole-brain ECoG networks and the factors that shape it can be studied by analysing whole-brain, interregional and band-limited ECoG networks from a large cohort-in this case, of individuals with medication-resistant epilepsy. Using tools from network science, we characterized the basic organization of ECoG networks, including frequency-specific architecture, segregated modules and the dependence of connection weights on interregional Euclidean distance. We then used linear models to explain variabilities in the connection strengths between pairs of brain regions, and to highlight the joint role, in shaping the brain-wide organization of ECoG networks, of communication along white matter pathways, interregional Euclidean distance and correlated gene expression. Moreover, we extended these models to predict out-of-sample, single-subject data. Our predictive models may have future clinical utility; for example, by anticipating the effect of cortical resection on interregional communication.

White Matter Network Architecture Guides Direct Electrical Stimulation through Optimal State Transitions.

Optimizing direct electrical stimulation for the treatment of neurological disease remains difficult due to an incomplete understanding of its physical propagation through brain tissue. Here, we use network control theory to predict how stimulation spreads through white matter to influence spatially distributed dynamics. We test the theory's predictions using a unique dataset comprising diffusion weighted imaging and electrocorticography in epilepsy patients undergoing grid stimulation. We find statistically significant shared variance between the predicted activity state transitions and the observed activity state transitions. We then use an optimal control framework to posit testable hypotheses regarding which brain states and structural properties will efficiently improve memory encoding when stimulated. Our work quantifies the role that white matter architecture plays in guiding the dynamics of direct electrical stimulation and offers empirical support for the utility of network control theory in explaining the brain's response to stimulation.