Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity.

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.

Cholinergic modulation supports dynamic switching of resting state networks through selective DMN suppression.

Brain activity during the resting state is widely used to examine brain organization, cognition and alterations in disease states. While it is known that neuromodulation and the state of alertness impact resting-state activity, neural mechanisms behind such modulation of resting-state activity are unknown. In this work, we used a computational model to demonstrate that change in excitability and recurrent connections, due to cholinergic modulation, impacts resting-state activity. The results of such modulation in the model match closely with experimental work on direct cholinergic modulation of Default Mode Network (DMN) in rodents. We further extended our study to the human connectome derived from diffusion-weighted MRI. In human resting-state simulations, an increase in cholinergic input resulted in a brain-wide reduction of functional connectivity. Furthermore, selective cholinergic modulation of DMN closely captured experimentally observed transitions between the baseline resting state and states with suppressed DMN fluctuations associated with attention to external tasks. Our study thus provides insight into potential neural mechanisms for the effects of cholinergic neuromodulation on resting-state activity and its dynamics.

Longitudinal assessment of ventricular volume trajectories in early-stage schizophrenia: evidence of both enlargement and shrinkage.

BACKGROUND: Lateral ventricular enlargement represents a canonical morphometric finding in chronic patients with schizophrenia; however, longitudinal studies elucidating complex dynamic trajectories of ventricular volume change during critical early disease stages are sparse. METHODS: We measured lateral ventricular volumes in 113 first-episode schizophrenia patients (FES) at baseline visit (11.7 months after illness onset, SD = 12.3) and 128 age- and sex-matched healthy controls (HC) using 3T MRI. MRI was then repeated in both FES and HC one year later. RESULTS: Compared to controls, ventricular enlargement was identified in 18.6% of patients with FES (14.1% annual ventricular volume (VV) increase; 95%CI: 5.4; 33.1). The ventricular expansion correlated with the severity of PANSS-negative symptoms at one-year follow-up (p = 0.0078). Nevertheless, 16.8% of FES showed an opposite pattern of statistically significant ventricular shrinkage during ≈ one-year follow-up (-9.5% annual VV decrease; 95%CI: -23.7; -2.4). There were no differences in sex, illness duration, age of onset, duration of untreated psychosis, body mass index, the incidence of Schneiderian symptoms, or cumulative antipsychotic dose among the patient groups exhibiting ventricular enlargement, shrinkage, or no change in VV. CONCLUSION: Both enlargement and ventricular shrinkage are equally present in the early stages of schizophrenia. The newly discovered early reduction of VV in a subgroup of patients emphasizes the need for further research to understand its mechanisms.

Sign patterns symbolization and its use in improved dependence test for complex network inference.

Inferring the dependence structure of complex networks from the observation of the non-linear dynamics of its components is among the common, yet far from resolved challenges faced when studying real-world complex systems. While a range of methods using the ordinal patterns framework has been proposed to particularly tackle the problem of dependence inference in the presence of non-linearity, they come with important restrictions in the scope of their application. Hereby, we introduce the sign patterns as an extension of the ordinal patterns, arising from a more flexible symbolization which is able to encode longer sequences with lower number of symbols. After transforming time series into sequences of sign patterns, we derive improved estimates for statistical quantities by considering necessary constraints on the probabilities of occurrence of combinations of symbols in a symbolic process with prohibited transitions. We utilize these to design an asymptotic chi-squared test to evaluate dependence between two time series and then apply it to the construction of climate networks, illustrating that the developed method can capture both linear and non-linear dependences, while avoiding bias present in the naive application of the often used Pearson correlation coefficient or mutual information.

Large-scale network dynamics underlying the first few hundred milliseconds after stimulus presentation: An investigation of visual recognition memory using iEEG.

Recognition memory is the ability to recognize previously encountered objects. Even this relatively simple, yet extremely fast, ability requires the coordinated activity of large-scale brain networks. However, little is known about the sub-second dynamics of these networks. The majority of current studies into large-scale network dynamics is primarily based on imaging techniques suffering from either poor temporal or spatial resolution. We investigated the dynamics of large-scale functional brain networks underlying recognition memory at the millisecond scale. Specifically, we analyzed dynamic effective connectivity from intracranial electroencephalography while epileptic subjects (n = 18) performed a fast visual recognition memory task. Our data-driven investigation using Granger causality and the analysis of communities with the Louvain algorithm spotlighted a dynamic interplay of two large-scale networks associated with successful recognition. The first network involved the right visual ventral stream and bilateral frontal regions. It was characterized by early, predominantly bottom-up information flow peaking at 115 ms. It was followed by the involvement of another network with predominantly top-down connectivity peaking at 220 ms, mainly in the left anterior hemisphere. The transition between these two networks was associated with changes in network topology, evolving from a more segregated to a more integrated state. These results highlight that distinct large-scale brain networks involved in visual recognition memory unfold early and quickly, within the first 300 ms after stimulus onset. Our study extends the current understanding of the rapid network changes during rapid cognitive processes.

Towards a dynamical understanding of microstate analysis of M/EEG data.

One of the interesting aspects of EEG data is the presence of temporally stable and spatially coherent patterns of activity, known as microstates, which have been linked to various cognitive and clinical phenomena. However, there is still no general agreement on the interpretation of microstate analysis. Various clustering algorithms have been used for microstate computation, and multiple studies suggest that the microstate time series may provide insight into the neural activity of the brain in the resting state. This study addresses two gaps in the literature. Firstly, by applying several state-of-the-art microstate algorithms to a large dataset of EEG recordings, we aim to characterise and describe various microstate algorithms. We demonstrate and discuss why the three "classically" used algorithms ((T)AAHC and modified K-Means) yield virtually the same results, while HMM algorithm generates the most dissimilar results. Secondly, we aim to test the hypothesis that dynamical microstate properties might be, to a large extent, determined by the linear characteristics of the underlying EEG signal, in particular, by the cross-covariance and autocorrelation structure of the EEG data. To this end, we generated a Fourier transform surrogate of the EEG signal to compare microstate properties. Here, we found that these are largely similar, thus hinting that microstate properties depend to a very high degree on the linear covariance and autocorrelation structure of the underlying EEG data. Finally, we treated the EEG data as a vector autoregression process, estimated its parameters, and generated surrogate stationary and linear data from fitted VAR. We observed that such a linear model generates microstates highly comparable to those estimated from real EEG data, supporting the conclusion that a linear EEG model can help with the methodological and clinical interpretation of both static and dynamic human brain microstate properties.

Computational modeling allows unsupervised classification of epileptic brain states across species.

Current advances in epilepsy treatment aim to personalize and responsively adjust treatment parameters to overcome patient heterogeneity in treatment efficiency. For tailoring treatment to the individual and the current brain state, tools are required that help to identify the patient- and time-point-specific parameters of epilepsy. Computational modeling has long proven its utility in gaining mechanistic insight. Recently, the technique has been introduced as a diagnostic tool to predict individual treatment outcomes. In this article, the Wendling model, an established computational model of epilepsy dynamics, is used to automatically classify epileptic brain states in intracranial EEG from patients (n = 4) and local field potential recordings from in vitro rat data (high-potassium model of epilepsy, n = 3). Five-second signal segments are classified to four types of brain state in epilepsy (interictal, preonset, onset, ictal) by comparing a vector of signal features for each data segment to four prototypical feature vectors obtained by Wendling model simulations. The classification result is validated against expert visual assessment. Model-driven brain state classification achieved a classification performance significantly above chance level (mean sensitivity 0.99 on model data, 0.77 on rat data, 0.56 on human data in a four-way classification task). Model-driven prototypes showed similarity with data-driven prototypes, which we obtained from real data for rats and humans. Our results indicate similar electrophysiological patterns of epileptic states in the human brain and the animal model that are well-reproduced by the computational model, and captured by a key set of signal features, enabling fully automated and unsupervised brain state classification in epilepsy.

Personalized dynamic network models of the human brain as a future tool for planning and optimizing epilepsy therapy.

Epilepsy is a common neurological disorder, with one third of patients not responding to currently available antiepileptic drugs. The proportion of pharmacoresistant epilepsies has remained unchanged for many decades. To cure epilepsy and control seizures requires a paradigm shift in the development of new approaches to epilepsy diagnosis and treatment. Contemporary medicine has benefited from the exponential growth of computational modeling, and the application of network dynamics theory to understanding and treating human brain disorders. In epilepsy, the introduction of these approaches has led to personalized epileptic network modeling that can explore the patient's seizure genesis and predict the functional impact of resection on its individual network's propensity to seize. The application of the dynamic systems approach to neurostimulation therapy of epilepsy allows designing stimulation strategies that consider the patient's seizure dynamics and long-term fluctuations in the stability of their epileptic networks. In this article, we review, in a nontechnical fashion suitable for a broad neuroscientific audience, recent progress in personalized dynamic brain network modeling that is shaping the future approach to the diagnosis and treatment of epilepsy.

Toward a reliable detection of arachnophobia: subjective, behavioral, and neurophysiological measures of fear response.

Introduction: The administration of questionnaires presents an easy way of obtaining important knowledge about phobic patients. However, it is not well known how these subjective measurements correspond to the patient's objective condition. Our study aimed to compare scores on questionnaires and image evaluation to the objective measurements of the behavioral approach test (BAT) and the neurophysiological effect of spiders extracted from fMRI measurements. The objective was to explore how reliably subjective statements about spiders and physiological and behavioral parameters discriminate between phobics and non-phobics, and what are the best predictors of overall brain activation. Methods: Based on a clinical interview, 165 subjects were assigned to either a "phobic" or low-fear "control" group. Finally, 30 arachnophobic and 32 healthy control subjects (with low fear of spiders) participated in this study. They completed several questionnaires (SPQ, SNAQ, DS-R) and underwent a behavioral approach test (BAT) with a live tarantula. Then, they were measured in fMRI while watching blocks of pictures including spiders and snakes. Finally, the respondents rated all the visual stimuli according to perceived fear. We proposed the Spider Fear Index (SFI) as a value characterizing the level of spider fear, computed based on the fMRI measurements. We then treated this variable as the "neurophysiological effect of spiders" and examined its contribution to the respondents' fear ratings of the stimuli seen during the fMRI using the redundancy analysis (RDA). Results: The results for fear ranks revealed that the SFI, SNAQ, DS-R, and SPQ scores had a significant effect, while BAT and SPQ scores loaded in the same direction of the first multivariate axis. The SFI was strongly correlated with both SPQ and BAT scores in the pooled sample of arachnophobic and healthy control subjects. Discussion: Both SPQ and BAT scores have a high informative value about the subject's fear of spiders and together with subjective emotional evaluation of picture stimuli can be reliable predictors of spider phobia. These parameters provide easy and non-expensive but reliable measurement wherever more expensive devices such as magnetic resonance are not available. However, SFI still reflects individual variability within the phobic group, identifying individuals with higher brain activation, which may relate to more severe phobic reactions or other sources of fMRI signal variability.

Structural connectivity-based predictors of cognitive impairment in stroke patients attributable to aging.

Despite the rising global burden of stroke and its socio-economic implications, the neuroimaging predictors of subsequent cognitive impairment are still poorly understood. We address this issue by studying the relationship of white matter integrity assessed within ten days after stroke and patients' cognitive status one year after the attack. Using diffusion-weighted imaging, we apply the Tract-Based Spatial Statistics analysis and construct individual structural connectivity matrices by employing deterministic tractography. We further quantify the graph-theoretical properties of individual networks. The Tract-Based Spatial Statistic did identify lower fractional anisotropy as a predictor of cognitive status, although this effect was mostly attributable to the age-related white matter integrity decline. We further observed the effect of age propagating into other levels of analysis. Specifically, in the structural connectivity approach we identified pairs of regions significantly correlated with clinical scales, namely memory, attention, and visuospatial functions. However, none of them persisted after the age correction. Finally, the graph-theoretical measures appeared to be more robust towards the effect of age, but still were not sensitive enough to capture a relationship with clinical scales. In conclusion, the effect of age is a dominant confounder especially in older cohorts, and unless appropriately addressed, may falsely drive the results of the predictive modelling.

Towards causal mechanisms of consciousness through focused transcranial brain stimulation.

Conscious experience represents one of the most elusive problems of empirical science, namely neuroscience. The main objective of empirical studies of consciousness has been to describe the minimal sets of neural events necessary for a specific neuronal state to become consciously experienced. The current state of the art still does not meet this objective but rather consists of highly speculative theories based on correlates of consciousness and an ever-growing list of knowledge gaps. The current state of the art is defined by the limitations of past stimulation techniques and the emphasis on the observational approach. However, looking at the current stimulation technologies that are becoming more accurate, it is time to consider an alternative approach to studying consciousness, which builds on the methodology of causal explanations via causal alterations. The aim of this methodology is to move beyond the correlates of consciousness and focus directly on the mechanisms of consciousness with the help of the currently focused brain stimulation techniques, such as geodesic transcranial electric neuromodulation. This approach not only overcomes the limitations of the correlational methodology but will also become another firm step in the following science of consciousness.

Multimodal-neuroimaging machine-learning analysis of motor disability in multiple sclerosis.

Motor disability is a dominant and restricting symptom in multiple sclerosis, yet its neuroimaging correlates are not fully understood. We apply statistical and machine learning techniques on multimodal neuroimaging data to discriminate between multiple sclerosis patients and healthy controls and to predict motor disability scores in the patients. We examine the data of sixty-four multiple sclerosis patients and sixty-five controls, who underwent the MRI examination and the evaluation of motor disability scales. The modalities used comprised regional fractional anisotropy, regional grey matter volumes, and functional connectivity. For analysis, we employ two approaches: high-dimensional support vector machines run on features selected by Fisher Score (aiming for maximal classification accuracy), and low-dimensional logistic regression on the principal components of data (aiming for increased interpretability). We apply analogous regression methods to predict symptom severity. While fractional anisotropy provides the classification accuracy of 96.1% and 89.9% with both approaches respectively, including other modalities did not bring further improvement. Concerning the prediction of motor impairment, the low-dimensional approach performed more reliably. The first grey matter volume component was significantly correlated (R = 0.28-0.46, p < 0.05) with most clinical scales. In summary, we identified the relationship between both white and grey matter changes and motor impairment in multiple sclerosis. Furthermore, we were able to achieve the highest classification accuracy based on quantitative MRI measures of tissue integrity between patients and controls yet reported, while also providing a low-dimensional classification approach with comparable results, paving the way to interpretable machine learning models of brain changes in multiple sclerosis.

Tackling the challenges of group network inference from intracranial EEG data.

Introduction: Intracranial EEG (iEEG) data is a powerful way to map brain function, characterized by high temporal and spatial resolution, allowing the study of interactions among neuronal populations that orchestrate cognitive processing. However, the statistical inference and analysis of brain networks using iEEG data faces many challenges related to its sparse brain coverage, and its inhomogeneity across patients. Methods: We review these challenges and develop a methodological pipeline for estimation of network structure not obtainable from any single patient, illustrated on the inference of the interaction among visual streams using a dataset of 27 human iEEG recordings from a visual experiment employing visual scene stimuli. 100 ms sliding window and multiple band-pass filtered signals are used to provide temporal and spectral resolution. For the connectivity analysis we showcase two connectivity measures reflecting different types of interaction between regions of interest (ROI): Phase Locking Value as a symmetric measure of synchrony, and Directed Transfer Function-asymmetric measure describing causal interaction. For each two channels, initial uncorrected significance testing at p < 0.05 for every time-frequency point is carried out by comparison of the data-derived connectivity to a baseline surrogate-based null distribution, providing a binary time-frequency connectivity map. For each ROI pair, a connectivity density map is obtained by averaging across all pairs of channels spanning them, effectively agglomerating data across relevant channels and subjects. Finally, the difference of the mean map value after and before the stimulation is compared to the same statistic in surrogate data to assess link significance. Results: The analysis confirmed the function of the parieto-medial temporal pathway, mediating visuospatial information between dorsal and ventral visual streams during visual scene analysis. Moreover, we observed the anterior hippocampal connectivity with more posterior areas in the medial temporal lobe, and found the reciprocal information flow between early processing areas and medial place area. Discussion: To summarize, we developed an approach for estimating network connectivity, dealing with the challenge of sparse individual coverage of intracranial EEG electrodes. Its application provided new insights into the interaction between the dorsal and ventral visual streams, one of the iconic dualities in human cognition.

Human brain structural connectivity matrices-ready for modelling.

The human brain represents a complex computational system, the function and structure of which may be measured using various neuroimaging techniques focusing on separate properties of the brain tissue and activity. We capture the organization of white matter fibers acquired by diffusion-weighted imaging using probabilistic diffusion tractography. By segmenting the results of tractography into larger anatomical units, it is possible to draw inferences about the structural relationships between these parts of the system. This pipeline results in a structural connectivity matrix, which contains an estimate of connection strength among all regions. However, raw data processing is complex, computationally intensive, and requires expert quality control, which may be discouraging for researchers with less experience in the field. We thus provide brain structural connectivity matrices in a form ready for modelling and analysis and thus usable by a wide community of scientists. The presented dataset contains brain structural connectivity matrices together with the underlying raw diffusion and structural data, as well as basic demographic data of 88 healthy subjects.

Assessing serial dependence in ordinal patterns processes using chi-squared tests with application to EEG data analysis.

We extend Elsinger's work on chi-squared tests for independence using ordinal patterns and investigate the general class of m-dependent ordinal patterns processes, to which belong ordinal patterns processes derived from random walk, white noise, and moving average processes. We describe chi-squared asymptotically distributed statistics for such processes that take into account necessary constraints on ordinal patterns probabilities and propose a test for m-dependence, with which we are able to quantify the range of serial dependence in a process. We apply the test to epilepsy electroencephalography time series data and observe shorter m-dependence associated with seizures, suggesting that the range of serial dependence decreases during those events.

The intra-session reliability of functional connectivity during naturalistic viewing conditions.

Functional connectivity analysis is a common approach to the characterization of brain function. While studies of functional connectivity have predominantly focused on resting-state fMRI, naturalistic paradigms, such as movie watching, are increasingly being used. This ecologically valid, yet relatively unconstrained acquisition state has been shown to improve subject compliance and, potentially, enhance individual differences. However, unlike the reliability of resting-state functional connectivity, the reliability of functional connectivity during naturalistic viewing has not yet been fully established. The current study investigates the intra-session reliability of functional connectivity during naturalistic viewing sessions to extend its understanding. Using fMRI data of 24 subjects measured at rest as well as during six naturalistic viewing conditions, we quantified the split-half reliability of each condition, as well as cross-condition reliabilities. We find that intra-session reliability is relatively high for all conditions. While cross-condition reliabilities are higher for pairings of two naturalistic viewing conditions, split-half reliability is highest for the resting state. Potential sources of variability across the conditions, as well as the strengths and limitations of using intra-session reliability as a measure in naturalistic viewing, are discussed.

Patient-Specific Network Connectivity Combined With a Next Generation Neural Mass Model to Test Clinical Hypothesis of Seizure Propagation.

Dynamics underlying epileptic seizures span multiple scales in space and time, therefore, understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. In this view, mathematical models have been developed, ranging from single neuron to neural population. In this study, we consider a neural mass model able to exactly reproduce the dynamics of heterogeneous spiking neural networks. We combine mathematical modeling with structural information from non invasive brain imaging, thus building large-scale brain network models to explore emergent dynamics and test the clinical hypothesis. We provide a comprehensive study on the effect of external drives on neuronal networks exhibiting multistability, in order to investigate the role played by the neuroanatomical connectivity matrices in shaping the emergent dynamics. In particular, we systematically investigate the conditions under which the network displays a transition from a low activity regime to a high activity state, which we identify with a seizure-like event. This approach allows us to study the biophysical parameters and variables leading to multiple recruitment events at the network level. We further exploit topological network measures in order to explain the differences and the analogies among the subjects and their brain regions, in showing recruitment events at different parameter values. We demonstrate, along with the example of diffusion-weighted magnetic resonance imaging (dMRI) connectomes of 20 healthy subjects and 15 epileptic patients, that individual variations in structural connectivity, when linked with mathematical dynamic models, have the capacity to explain changes in spatiotemporal organization of brain dynamics, as observed in network-based brain disorders. In particular, for epileptic patients, by means of the integration of the clinical hypotheses on the epileptogenic zone (EZ), i.e., the local network where highly synchronous seizures originate, we have identified the sequence of recruitment events and discussed their links with the topological properties of the specific connectomes. The predictions made on the basis of the implemented set of exact mean-field equations turn out to be in line with the clinical pre-surgical evaluation on recruited secondary networks.

Validity of the Aktibipo Self-rating Questionnaire for the Digital Self-assessment of Mood and Relapse Detection in Patients With Bipolar Disorder: Instrument Validation Study.

BACKGROUND: Self-reported mood is a valuable clinical data source regarding disease state and course in patients with mood disorders. However, validated, quick, and scalable digital self-report measures that can also detect relapse are still not available for clinical care. OBJECTIVE: In this study, we aim to validate the newly developed ASERT (Aktibipo Self-rating) questionnaire-a 10-item, mobile app-based, self-report mood questionnaire consisting of 4 depression, 4 mania, and 2 nonspecific symptom items, each with 5 possible answers. The validation data set is a subset of the ongoing observational longitudinal AKTIBIPO400 study for the long-term monitoring of mood and activity (via actigraphy) in patients with bipolar disorder (BD). Patients with confirmed BD are included and monitored with weekly ASERT questionnaires and monthly clinical scales (Montgomery-Åsberg Depression Rating Scale [MADRS] and Young Mania Rating Scale [YMRS]). METHODS: The content validity of the ASERT questionnaire was assessed using principal component analysis, and the Cronbach α was used to assess the internal consistency of each factor. The convergent validity of the depressive or manic items of the ASERT questionnaire with the MADRS and YMRS, respectively, was assessed using a linear mixed-effects model and linear correlation analyses. In addition, we investigated the capability of the ASERT questionnaire to distinguish relapse (YMRS≥15 and MADRS≥15) from a nonrelapse (interepisode) state (YMRS<15 and MADRS<15) using a logistic mixed-effects model. RESULTS: A total of 99 patients with BD were included in this study (follow-up: mean 754 days, SD 266) and completed an average of 78.1% (SD 18.3%) of the requested ASERT assessments (completion time for the 10 ASERT questions: median 24.0 seconds) across all patients in this study. The ASERT depression items were highly associated with MADRS total scores (P<.001; bootstrap). Similarly, ASERT mania items were highly associated with YMRS total scores (P<.001; bootstrap). Furthermore, the logistic mixed-effects regression model for scale-based relapse detection showed high detection accuracy in a repeated holdout validation for both depression (accuracy=85%; sensitivity=69.9%; specificity=88.4%; area under the receiver operating characteristic curve=0.880) and mania (accuracy=87.5%; sensitivity=64.9%; specificity=89.9%; area under the receiver operating characteristic curve=0.844). CONCLUSIONS: The ASERT questionnaire is a quick and acceptable mood monitoring tool that is administered via a smartphone app. The questionnaire has a good capability to detect the worsening of clinical symptoms in a long-term monitoring scenario.

Causality in Reversed Time Series: Reversed or Conserved?

The inference of causal relations between observable phenomena is paramount across scientific disciplines; however, the means for such enterprise without experimental manipulation are limited. A commonly applied principle is that of the cause preceding and predicting the effect, taking into account other circumstances. Intuitively, when the temporal order of events is reverted, one would expect the cause and effect to apparently switch roles. This was previously demonstrated in bivariate linear systems and used in design of improved causal inference scores, while such behaviour in linear systems has been put in contrast with nonlinear chaotic systems where the inferred causal direction appears unchanged under time reversal. The presented work explores the conditions under which the causal reversal happens-either perfectly, approximately, or not at all-using theoretical analysis, low-dimensional examples, and network simulations, focusing on the simplified yet illustrative linear vector autoregressive process of order one. We start with a theoretical analysis that demonstrates that a perfect coupling reversal under time reversal occurs only under very specific conditions, followed up by constructing low-dimensional examples where indeed the dominant causal direction is even conserved rather than reversed. Finally, simulations of random as well as realistically motivated network coupling patterns from brain and climate show that level of coupling reversal and conservation can be well predicted by asymmetry and anormality indices introduced based on the theoretical analysis of the problem. The consequences for causal inference are discussed.