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Integrating multiscale, multimodal neuroimaging data is essential for a comprehensive understanding of neural circuits. However, this is challenging due to the inherent trade-offs between spatial coverage and resolution in each modality, necessitating a computational strategy that combines modality-specific information effectively. This study introduces a dynamic causal modeling (DCM) framework designed to address the challenge of combining partially observed, multiscale signals across a larger-scale neural circuit by employing a shared neural state model with modality-specific observation models. The proposed method achieves robust circuit inference by iteratively integrating parameter estimates from local microscale and global meso- or macroscale circuits, derived from signals across various scales and modalities. Parameters estimated from high-resolution data within specific regions inform global circuit estimation by constraining neural properties in unobserved regions, while large-scale circuit data help elucidate detailed local circuitry. Using a virtual ground truth system, we validated the method across diverse experimental settings, combining calcium imaging (CaI), voltage-sensitive dye imaging (VSDI), and blood-oxygen-level-dependent (BOLD) signals-each with distinct coverage and resolution. Our reciprocal and iterative parameter estimation approach markedly improves the accuracy of neural property and connectivity estimates compared to traditional one-step estimation methods. This iterative integration of local and global parameters presents a reliable approach to inferring extensive, complex neural circuits from partially observed, multimodal, and multiscale data, showcasing how information from different scales reciprocally enhances entire circuit parameter estimation.

Attending to heartbeats for interoceptive awareness initiates distinct electrophysiological responses synchronized with the R-peaks of an electrocardiogram (ECG), such as the heartbeat-evoked potential (HEP). Beyond HEP, this study proposes heartbeat-related spectral perturbation (HRSP), a time–frequency map of the R-peak locked electroencephalogram (EEG), and explores its characteristics in identifying interoceptive attention states using a classification approach. HRSPs of EEG brain components specified by independent component analysis (ICA) were used for the offline and online classification of interoceptive states. A convolutional neural network (CNN) designed specifically for HRSP was applied to publicly available data from a binary-state experiment (attending to self-heartbeats and white noise) and data from our four-state classification experiment (attending to self-heartbeats, white noise, time passage, and toe) with diverse input feature conditions of HRSP. From the dynamic state perspective, we evaluated the primary frequency bands of HRSP and the minimal number of averaging epochs required to reflect changing interoceptive attention states without compromising accuracy. We also assessed the utility of group ICA and models for classifying HRSP in new participants. The CNN for trial-by-trial HRSP with actual R-peaks demonstrated significantly higher classification accuracy than HRSP with sham, i.e., randomly positioned, R-peaks. Gradient-weighted class activation mapping highlighted the prominent role of theta and alpha bands between 200–600 ms post-R-peak—features absent in classifications using sham HRSPs. Online classification benefits from employing a group ICA and classification model, ensuring reliable accuracy without individual EEG precollection. These results suggest HRSP’s potential to reflect interoceptive attention states, proposing transformative implications for clinical applications.

Abstract Artificial intelligence (AI) using deep learning approaches the capabilities of human experts in medical image diagnosis. However, due to liability issues in medical decisions, AI is often relegated to an assistant role. Based on this responsibility constraint, the effective use of AI to assist human intelligence in real-world clinics remains a challenge. Given the significant inter-individual variations in clinical decisions among physicians based on their expertise, AI needs to adapt to individual experts, complementing weaknesses and enhancing strengths. For this adaptation, AI should not only acquire domain knowledge but also understand the specific human experts it assists. This study introduces a meta-model for human–machine cooperation that first evaluates each expert’s class-specific diagnostic tendencies using conditional probability, based on which the meta-model adjusts the AI’s predictions. This meta-model was applied to ear disease diagnosis using otoendoscopy, highlighting improved performance when incorporating individual diagnostic characteristics, even with limited evaluation data. The highest accuracy was achieved by combining each expert’s conditional probabilities with machine classification probability, using optimal weights specific to each individual’s overall classification accuracy. This tailored model aims to mitigate potential misjudgments due to psychological effects caused by machine suggestions and to capitalize on the unique expertise of individual clinicians.

The current study investigates the neural correlates when processing prototypicality and simplicity-affecting the preference of product design. Despite its significance, not much is known about how our brain processes these visual qualities of design when forming design preferences. We posit that, although fluency is the perceptual judgment accounting for the positive effects of both prototypicality and simplicity on design preference, the neural substrates for the fluency judgment associated with prototypicality would differ from those associated with simplicity. To investigate these issues, we conducted an fMRI study of preference decisions for actual product designs with different levels of prototypicality and simplicity. The results show a significant functional gradient between the preference processing of simplicity and prototypicality-i.e., involvement of the early ventral stream of visual information processing for simplicity evaluation but recruitment of the late ventral stream and parietal-frontal brain regions for prototypicality evaluation. The interaction between the simplicity and prototypicality evaluations was found in the extrastriate cortex in the right hemisphere. The segregated brain involvements suggest that the fluency judgment for prototypicality and simplicity contribute to preference choice in different levels of cognitive hierarchy in the perceptual mechanism of the design preference.

In this research, we employed functional magnetic resonance imaging (fMRI) to examine the neurological basis for understanding wh-questions in wh-in-situ languages such as Korean, where wh-elements maintain their original positions instead of moving explicitly within the sentence. Our hypothesis centered on the role of the salience and attention network in comprehending wh-questions in wh-in-situ languages, such as the discernment of wh-elements, the demarcation between interrogative types, and the allocation of cognitive resources towards essential constituents vis-à-vis subordinate elements in order to capture the speaker's communicative intent. We explored subject and object wh-questions and scrambled wh-questions, contrasting them with yes/no questions in Korean. Increased activation was observed in the left anterior insula and bilateral frontal operculum, irrespective of the wh-position or scrambling of wh-element. These results suggest the interaction between the salience and attentional system and the syntactic linguistic system, particularly the left anterior insula and bilateral frontal operculum, in comprehending wh-questions in wh-in-situ languages.

Abstract The correlation matrix is a typical representation of node interactions in functional brain network analysis. The analysis of the correlation matrix to characterize brain networks observed in several neuroimaging modalities has been conducted predominantly in the Euclidean space by assuming that pairwise interactions are mutually independent. One way to take account of all interactions in the network as a whole is to analyze the correlation matrix under some geometric structure. Recent studies have focused on the space of correlation matrices as a strict subset of symmetric positive definite (SPD) matrices, which form a unique mathematical structure known as the Riemannian manifold. However, mathematical operations of the correlation matrix under the SPD geometry may not necessarily be coherent (i.e., the structure of the correlation matrix may not be preserved), necessitating a post-hoc normalization. The contribution of the current paper is twofold: (1) to devise a set of inferential methods on the correlation manifold and (2) to demonstrate its applicability in functional network analysis. We present several algorithms on the correlation manifold, including measures of central tendency, cluster analysis, hypothesis testing, and low-dimensional embedding. Simulation and real data analysis support the application of the proposed framework for brain network analysis.

The hierarchical characteristics of the brain are prominent in the pharmacological treatment of psychiatric diseases, primarily targeting cellular receptors that extend upward to intrinsic connectivity within a region, interregional connectivity, and, consequently, clinical observations such as an electroencephalogram (EEG). To understand the long-term effects of neuropharmacological intervention on neurobiological properties at different hierarchical levels, we explored long-term changes in neurobiological parameters of an N-methyl-D-aspartate canonical microcircuit model (CMM-NMDA) in the default mode network (DMN) and auditory hallucination network (AHN) using dynamic causal modeling of longitudinal EEG in clozapine-treated patients with schizophrenia. The neurobiological properties of the CMM-NMDA model associated with symptom improvement in schizophrenia were found across hierarchical levels, from a reduced membrane capacity of the deep pyramidal cell and intrinsic connectivity with the inhibitory population in DMN and intrinsic and extrinsic connectivity in AHN. The medication duration mainly affects the intrinsic connectivity and NMDA time constant in DMN. Virtual perturbation analysis specified the contribution of each parameter to the cross-spectral density (CSD) of the EEG, particularly intrinsic connectivity and membrane capacitances for CSD frequency shifts and progression. It further reveals that excitatory and inhibitory connectivity complements frequency-specific CSD changes, notably the alpha frequency band in DMN. Positive and negative synergistic interactions exist between neurobiological properties primarily within the same region in patients treated with clozapine. The current study shows how computational neuropharmacology helps explore the multiscale link between neurobiological properties and clinical observations and understand the long-term mechanism of neuropharmacological intervention reflected in clinical EEG.

Abstract Prior experiences of successful and failed treatments are known to influence the efficacy of a newly applied treatment. However, whether that carry-over effect applies to non-pharmacological treatments is unknown. This study investigated how a failed treatment history with placebo analgesic cream affected the therapeutic outcomes of cold-pack treatment. The neural correlates underlying those effects were also explored using functional magnetic resonance imaging. The effect of the placebo analgesic cream was induced using placebo conditioning with small (44.5 °C to 43.7 °C, negative experience) and large (44.5 °C to 40.0 °C, positive experience) thermal stimuli changes. After the placebo conditioning, brain responses and self-reported evaluations of the effect of subsequent treatment with a cold-pack were contrasted between the two groups. The negative experience group reported less pain and lower anxiety scores in the cold-pack condition than the positive experience group and exhibited significantly greater activation in the right inferior parietal lobule (IPL), which is known to be involved in pain relief. These findings suggest that an unsatisfying experience with an initial pain-relief treatment could increase the expectations for the complementary treatment outcome and improve the analgesic effect of the subsequent treatment. The IPL could be associated with this expectation-induced pain relief process.

Abstract Most psychological experiments measure human cognitive function through the response time and accuracy of the response to a set of stimuli. Since response time and accuracy complement each other, it is often difficult to interpret cognitive performance based on only one dependent measurement and raises a speed-accuracy tradeoff (SAT) problem. In overcoming this problem, SAT experimental paradigms and models that integrate response time and accuracy have been proposed to understand information processing in human cognitive function. However, due to a lengthy SAT experiment for reliable model estimation, SAT experiments' practical limitations have been pointed out. Thus, these limitations call for an efficient technique to shorten the number of trials required to estimate the SAT function reliably. Instead of using a block's stimulus-onset asynchrony (SOA) accuracy with long block-based task trials, we introduced a Bayesian SAT function estimation using trial-by-trial response time and correctness, which makes SAT tasks flexible and easily extendable to multiple trials. We then proposed a Bayesian adaptive method to select optimal SOA by maximizing information gain to estimate model parameters. Simulation results showed that the proposed Bayesian adaptive estimation was highly efficient and robust for accuracy and precision of estimating SAT function by enabling "multiple-step ahead search."

The white matter in the brain is composed of neural fibers that wire the cortical and subcortical brain systems. Considering the complexity in terms of interconnections of many neural populations within the narrow space surrounded by the folding walls of the gray matter, the brain requires a certain way of structured wiring. To explore the three-dimensional organization of wiring in an accessible manner, we focused on voxel-level wiring patterns in the white matter according to cortical distributions in which each voxel mediates the wiring. We constructed a voxel-wise connection distribution map from the whole white matter voxels to 360 cortical regions using probabilistic tractography of the 100 diffusion imaging data in the Human Connectome Project. We then explored the spatial organization of the fiber bundles at the white matter voxels in terms of the maximal and second maximal cortical connection labels and the local gradient and entropy of cortical connection density using the population connection distribution map. We presented dominant cortical connection labels, local gradient, and connection entropy for the most representative white matter regions, including the internal capsule, external capsule, corpus callosum, cingulum bundle, and uncinate fascicles, most of which were introduced in the current study. Those major tracts showed a gradient organization of connection distributions for individual voxels. This organized pattern, as reflected in the whole brain connection distribution map, could be established to optimize wiring in the entire brain within the physical space of the white matter.

We explore potential cross-informant discrepancies between child- and parent-report measures with an example of the Child Behavior Checklist (CBCL) and the Youth Self Report (YSR), parent- and self-report measures on children's behavioral and emotional problems. We propose a new way of examining the parent- and child-report differences with an interaction map estimated using a Latent Space Item Response Model (LSIRM). The interaction map enables the investigation of the dependency between items, between respondents, and between items and respondents, which is not possible with the conventional approach. The LSIRM captures the differential positions of items and respondents in the latent spaces for CBCL and YSR and identifies the relationships between each respondent and item according to their dependent structures. The results suggest that the analysis of item response in the latent space using the LSIRM is beneficial in uncovering the differential structures embedded in the response data obtained from different perspectives in children and their parents. This study also argues that the differential hidden structures of children and parents' responses should be taken together to evaluate children's behavioral problems.

The pairwise maximum entropy model (pMEM) has recently gained widespread attention to exploring the nonlinear characteristics of brain state dynamics observed in resting-state functional magnetic resonance imaging (rsfMRI). Despite its unique advantageous features, the practical application of pMEM for individuals is limited as it requires a much larger sample than conventional rsfMRI scans. Thus, this study proposes an empirical Bayes estimation of individual pMEM using the variational expectation-maximization algorithm (VEM-MEM). The performance of the VEM-MEM is evaluated for several simulation setups with various sample sizes and network sizes. Unlike conventional maximum likelihood estimation procedures, the VEM-MEM can reliably estimate the individual model parameters, even with small samples, by effectively incorporating the group information as the prior. As a test case, the individual rsfMRI of children with attention deficit hyperactivity disorder (ADHD) is analyzed compared to that of typically developed children using the default mode network, executive control network, and salient network, obtained from the Healthy Brain Network database. We found that the nonlinear dynamic properties uniquely established on the pMEM differ for each group. Furthermore, pMEM parameters are more sensitive to group differences and are better associated with the behavior scores of ADHD compared to the Pearson correlation-based functional connectivity. The simulation and experimental results suggest that the proposed method can reliably estimate the individual pMEM and characterize the dynamic properties of individuals by utilizing empirical information of the group brain state dynamics.

BackgroundDeep learning (DL)–based artificial intelligence may have different diagnostic characteristics than human experts in medical diagnosis. As a data-driven knowledge system, heterogeneous population incidence in the clinical world is considered to cause more bias to DL than clinicians. Conversely, by experiencing limited numbers of cases, human experts may exhibit large interindividual variability. Thus, understanding how the 2 groups classify given data differently is an essential step for the cooperative usage of DL in clinical application. ObjectiveThis study aimed to evaluate and compare the differential effects of clinical experience in otoendoscopic image diagnosis in both computers and physicians exemplified by the class imbalance problem and guide clinicians when utilizing decision support systems. MethodsWe used digital otoendoscopic images of patients who visited the outpatient clinic in the Department of Otorhinolaryngology at Severance Hospital, Seoul, South Korea, from January 2013 to June 2019, for a total of 22,707 otoendoscopic images. We excluded similar images, and 7500 otoendoscopic images were selected for labeling. We built a DL-based image classification model to classify the given image into 6 disease categories. Two test sets of 300 images were populated: balanced and imbalanced test sets. We included 14 clinicians (otolaryngologists and nonotolaryngology specialists including general practitioners) and 13 DL-based models. We used accuracy (overall and per-class) and kappa statistics to compare the results of individual physicians and the ML models. ResultsOur ML models had consistently high accuracies (balanced test set: mean 77.14%, SD 1.83%; imbalanced test set: mean 82.03%, SD 3.06%), equivalent to those of otolaryngologists (balanced: mean 71.17%, SD 3.37%; imbalanced: mean 72.84%, SD 6.41%) and far better than those of nonotolaryngologists (balanced: mean 45.63%, SD 7.89%; imbalanced: mean 44.08%, SD 15.83%). However, ML models suffered from class imbalance problems (balanced test set: mean 77.14%, SD 1.83%; imbalanced test set: mean 82.03%, SD 3.06%). This was mitigated by data augmentation, particularly for low incidence classes, but rare disease classes still had low per-class accuracies. Human physicians, despite being less affected by prevalence, showed high interphysician variability (ML models: kappa=0.83, SD 0.02; otolaryngologists: kappa=0.60, SD 0.07). ConclusionsEven though ML models deliver excellent performance in classifying ear disease, physicians and ML models have their own strengths. ML models have consistent and high accuracy while considering only the given image and show bias toward prevalence, whereas human physicians have varying performance but do not show bias toward prevalence and may also consider extra information that is not images. To deliver the best patient care in the shortage of otolaryngologists, our ML model can serve a cooperative role for clinicians with diverse expertise, as long as it is kept in mind that models consider only images and could be biased toward prevalent diseases even after data augmentation.

The human brain at rest exhibits intrinsic dynamics transitioning among the multiple metastable states of the inter-regional functional connectivity. Accordingly, the demand for exploring the state-specific functional connectivity increases for a deeper understanding of mental diseases. Functional connectivity, however, lacks information about the directed causal influences among the brain regions, called effective connectivity. This study presents the dynamic causal modeling (DCM) framework to explore the state-dependent effective connectivity using spectral DCM for the resting-state functional MRI (rsfMRI). We established the sequence of brain states using the hidden Markov model with the multivariate autoregressive coefficients of rsfMRI, summarizing the functional connectivity. We decomposed the state-dependent effective connectivity using a parametric empirical Bayes scheme that models the effective connectivity of consecutive windows with the time course of the discrete states as regressors. We showed the plausibility of the state-dependent effective connectivity analysis in a simulation setting. To test the clinical applicability, we applied the proposed method to characterize the state- and subtype-dependent effective connectivity of the default mode network in children with combined-type attention deficit hyperactivity disorder (ADHD-C) compared with age-matched, typically developed children (TDC). All 88 children were subtyped according to the occupation times (i.e., dwell times) of the three dominant functional connectivity states, independently of clinical diagnosis. The state-dependent effective connectivity differences between ADHD-C and TDC according to the subtypes and those between the subtypes of ADHD-C were expressed mainly in self-inhibition, magnifying the importance of excitation inhibition balance in the subtyping. These findings provide a clear motivation for decomposing the state-dependent dynamic effective connectivity and state-dependent analysis of the directed coupling in exploring mental diseases.

Background: Ear and mastoid disease can easily be treated by early detection and appropriate medical care. However, short of specialists and relatively low diagnostic accuracy calls for a new way of diagnostic strategy, in which deep learning may play a significant role. The current study presents a machine learning model to automatically diagnose ear disease using a large database of otoendoscopic images acquired in the clinical environment. Methods: Total 10,544 otoendoscopic images were used to train nine public convolution-based deep neural networks to classify eardrum and external auditory canal features into six categories of ear diseases, covering most ear diseases (Normal, Attic retraction, Tympanic perforation, Otitis externa±myringitis, Tumor). After evaluating several optimization schemes, two best-performing models were selected to compose an ensemble classifier, by combining classification scores of each classifier. Findings: According to accuracy and training time, transfer learning models based on Inception-V3 and ResNet101 were chosen and the ensemble classifier using the two models yielded a significant improvement over each model, the accuracy of which is in average 93·67% for the 5-folds cross-validation. Considering substantial data-size dependency of classifier performance in the transfer learning, evaluated in this study, the high accuracy in the current model is attributable to the large database. Interpretation: The current study is unprecedented in terms of both disease diversity and diagnostic accuracy, which is compatible or even better than an average otolaryngologist. The classifier was trained with data in a various acquisition condition, which is suitable for the practical environment. This study shows the usefulness of utilizing a deep learning model in the early detection and treatment of ear disease in the clinical situation. Fund: This research was supported by Brain Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT(NRF-2017M3C7A1049051). Keywords: Convolutional neural network, Deep learning, Otoendoscopy, Tympanic membrane, Ear disease, Ensemble learning

The control of the brain system has received increasing attention in the domain of brain science. Most brain control studies have been conducted to explore the brain network's graph-theoretic properties or to produce the desired state based on neural state dynamics, regarding the brain as a passively responding system. However, the self-adjusting nature of neural system after treatment has not been fully considered in the brain control. In the present study, we propose a computational framework for optimal control of the brain with a self-adjustment process in the effective connectivity after treatment. The neural system is modeled to adjust its outgoing effective connectivity as activity-dependent plasticity after treatment, followed by synaptic rescaling of incoming effective connectivity. To control this neural system to induce the desired function, the system's self-adjustment parameter is first estimated, based on which the treatment is optimized. Utilizing this framework, we conducted simulations of optimal control over a functional hippocampal circuitry, estimated using dynamic causal modeling of voltage-sensitive dye imaging from the wild type and mutant mice, responding to consecutive electrical stimuli. Simulation results for optimal control of the abnormal circuit toward a healthy circuit using a single node treatment, neural-type specific treatment as an analogy of medication, and combined treatments of medication and nodal treatment suggest the plausibility of the current framework in controlling the self-adjusting neural system within a restricted treatment setting. We believe the proposed computational framework of the self-adjustment system would help optimal control of the dynamic brain after treatment.

The brain is a non-linear dynamical system with a self-restoration process, which protects itself from external damage but is often a bottleneck for clinical treatment. To treat the brain to induce the desired functionality, formulation of a self-restoration process is necessary for optimal brain control. This study proposes a computational model for the brain's self-restoration process following the free-energy and degeneracy principles. Based on this model, a computational framework for brain control is established. We posited that the pre-treatment brain circuit has long been configured in response to the environmental (the other neural populations') demands on the circuit. Since the demands persist even after treatment, the treated circuit's response to the demand may gradually approximate the pre-treatment functionality. In this framework, an energy landscape of regional activities, estimated from resting-state endogenous activities by a pairwise maximum entropy model, is used to represent the pre-treatment functionality. The approximation of the pre-treatment functionality occurs via reconfiguration of interactions among neural populations within the treated circuit. To establish the current framework's construct validity, we conducted various simulations. The simulations suggested that brain control should include the self-restoration process, without which the treatment was not optimal. We also presented simulations for optimizing repetitive treatments and optimal timing of the treatment. These results suggest a plausibility of the current framework in controlling the non-linear dynamical brain with a self-restoration process.

Common representations of functional networks of resting state fMRI time series, including covariance, precision, and cross-correlation matrices, belong to the family of symmetric positive definite (SPD) matrices forming a special mathematical structure called Riemannian manifold. Due to its geometric properties, the analysis and operation of functional connectivity matrices may well be performed on the Riemannian manifold of the SPD space. Analysis of functional networks on the SPD space takes account of all the pairwise interactions (edges) as a whole, which differs from the conventional rationale of considering edges as independent from each other. Despite its geometric characteristics, only a few studies have been conducted for functional network analysis on the SPD manifold and inference methods specialized for connectivity analysis on the SPD manifold are rarely found. The current study aims to show the significance of connectivity analysis on the SPD space and introduce inference algorithms on the SPD manifold, such as regression analysis of functional networks in association with behaviors, principal geodesic analysis, clustering, state transition analysis of dynamic functional networks and statistical tests for network equality on the SPD manifold. We applied the proposed methods to both simulated data and experimental resting state fMRI data from the human connectome project and argue the importance of analyzing functional networks under the SPD geometry. All the algorithms for numerical operations and inferences on the SPD manifold are implemented as a MATLAB library, called SPDtoolbox, for public use to expediate functional network analysis on the right geometry.

Systematic evaluation of cortical differences between humans and macaques calls for inter-species registration of the cortex that matches homologous regions across species. For establishing homology across brains, structural landmarks and biological features have been used without paying sufficient attention to functional homology. The present study aimed to determine functional homology between the human and macaque cortices, defined in terms of functional network properties, by proposing an iterative functional network-based registration scheme using surface-based spherical demons. The functional connectivity matrix of resting-state functional magnetic resonance imaging (rs-fMRI) among cortical parcellations was iteratively calculated for humans and macaques. From the functional connectivity matrix, the functional network properties such as principal network components were derived to estimate a deformation field between the human and macaque cortices. The iterative registration procedure updates the parcellation map of macaques, corresponding to the human connectome project's multimodal parcellation atlas, which was used to derive the macaque's functional connectivity matrix. To test the plausibility of the functional network-based registration, we compared cortical registration using structural versus functional features in terms of cortical regional areal change. We also evaluated the interhemispheric asymmetry of regional area and its inter-subject variability in humans and macaques as an indirect validation of the proposed method. Higher inter-subject variability and interhemispheric asymmetry were found in functional homology than in structural homology, and the assessed asymmetry and variations were higher in humans than in macaques. The results emphasize the significance of functional network-based cortical registration across individuals within a species and across species.

The heterogeneous presentation of inattentive and hyperactive-impulsive core symptoms in attention deficit hyperactivity disorder (ADHD) warrants further investigation into brain network connectivity as a basis for subtype divisions in this prevalent disorder. With diffusion and resting-state functional magnetic resonance imaging data from the Healthy Brain Network database, we analyzed both structural and functional network efficiency and structure-functional network (SC-FC) coupling at the default mode (DMN), executive control (ECN), and salience (SAN) intrinsic networks in 201 children diagnosed with the inattentive subtype (ADHD-I), the combined subtype (ADHD-C), and typically developing children (TDC) to characterize ADHD symptoms relative to TDC and to test differences between ADHD subtypes. Relative to TDC, children with ADHD had lower structural connectivity and network efficiency in the DMN, without significant group differences in functional networks. Children with ADHD-C had higher SC-FC coupling, a finding consistent with diminished cognitive flexibility, for all subnetworks compared to TDC. The ADHD-C group also demonstrated increased SC-FC coupling in the DMN compared to the ADHD-I group. The correlation between SC-FC coupling and hyperactivity scores was negative in the ADHD-I, but not in the ADHD-C group. The current study suggests that ADHD-C and ADHD-I may differ with respect to their underlying neuronal connectivity and that the added dimensionality of hyperactivity may not explain this distinction.

The aim of this paper is to present a dynamic causal modeling (DCM) framework for hippocampal activity measured via voltage-sensitive dye imaging (VSDI). We propose a DCM model of the hippocampus that summarizes interactions between the hilus, CA3 and CA1 regions. The activity of each region is governed via a neuronal mass model with two inhibitory and one/two excitatory neuronal populations, which can be linked to measurement VSDI by scaling neuronal activity. To optimize the model structure for the hippocampus, we propose two Bayesian schemes: Bayesian hyperparameter optimization to estimate the unknown electrophysiological properties necessary for constructing a mesoscopic hippocampus model; and Bayesian model reduction to determine the parameterization of neural properties, and to test and include potential connections (morphologically inferred without direct evidence yet) in the model by evaluating group-level model evidence. The proposed method was applied to model spatiotemporal patterns of accumulative responses to consecutive stimuli in separate groups of wild-type mice and epileptic aristaless-related homeobox gene (Arx) conditional knock-out mutant mice (Arx−/+;Dlx5/6CRE−IRES-GFP) in order to identify group differences in the effective connectivity within the hippocampus. The causal role of each group-differing connectivity in generating mutant-like responses was further tested. The group-level analysis identified altered intra- and inter-regional effective connectivity, some of which are crucial for explaining mutant-like responses. The modelling results for the hippocampal activity suggest the plausibility of the proposed mesoscopic hippocampus model and the usefulness of utilizing the Bayesian framework for model construction in the mesoscale modeling of neural interactions using DCM.

IL-13 induces mucus metaplasia, which causes airway obstruction in asthma. Bee venom (BV) and its components have shown anti-inflammatory effects in allergic diseases such as atopic dermatitis and asthma. In this study, we investigated the effect of BV on IL-13-induced mucus metaplasia through activation of the signal transducer and activator of transcription (STAT6), and regulation of SAM-pointed domain containing Ets-like factor (SPDEF) and forkhead box A2 (FOXA2) in the airway epithelia cell line A549. In A549 cells, BV (1.0 µg/mL) inhibited IL-13 (10 ng/mL)-induced AKT phosphorylation, increase in SPDEF protein expression, and decrease in FOXA2 protein expression—but not STAT6 phosphorylation. BV also prevented the IL-13-induced increase in mucin 5AC (MUC5AC) mRNA and protein expression. Moreover, we observed that inhibition of phosphoinositide 3 kinase (PI3K)/AKT using LY294002 (50 µM) could reverse the alterations in FOXA2 and MUC5AC expression -by IL-13 and BV. However, LY294002 did not affect IL-13- and BV-induced changes in SPDEF expression. These findings indicate that BV inhibits MUC5AC production through the regulation of SPDEF and FOXA2. The inhibition of MUC5AC production through FOXA2 is mediated via the suppression of PI3K/AKT activation by BV. BV may be helpful in the prevention of mucus metaplasia in asthma.

Cognitive control is the most fundamental psychological function that underlies the execution of many other psychological functions. A mobile game application could be a useful strategy to evaluate cognitive control in the groups of children and adolescents. Although a serious game that is based on gamification would be an optimal platform for the administration of behavioral and clinical assessments of children and adolescents, most studies on gamification have been conducted among adults and older adults than among children and adolescents. This study aimed to assess cognitive control using a mobile game that used gamification and compared the results to those from traditional neuropsychological tests for children and adolescents. In order to address this objective, this study used a serious game, namely, "CoCon," which was developed to assess cognitive control in children and adolescents. This study included 100 participants from a community sample (mean age = 11.75 years, ranged from 9 to 16 years, SD = 1.40 years; Male = 59(59%), Female = 41(41%)). The analyses interrogated the relationships among various game behaviors scores of CoCon, the standardized neuropsychological tests (K-WISC-IV, CTT, and Stroop), and self-reporting executive function difficulty questionnaire. As results, a mobile game application-based assessment proved to be a reliable and valid measure of the cognitive control in children and adolescents. The index scores from the CoCon were significantly related to various cognitive control functions and differentiated between the high and low cognitive control groups. Specifically, even though the participants completed the mobile game 'CoCon' in their natural habitats, the CoCon scores were comparable to the measures from standard neuropsychological tests. In conclusion, the present findings suggest that mobile games that use advanced technology and sophisticated psychological strategies can serve as a new and expanded platform for the administration of psychological assessments.

Interrogation elicits anxiety in individuals under scrutiny regardless of their innocence, and thus, anxious responses to interrogation should be differentiated from deceptive behavior in practical lie detection settings. Despite its importance, not many empirical studies have yet been done to separate the effects of interrogation from the acts of lying or guilt state. The present fMRI study attempted to identify neural substrates of anxious responses under interrogation in either innocent or guilt contexts by developing a modified "Doubt" game. Participants in the guilt condition showed higher brain activations in the right central-executive network and bilateral basal ganglia. Regardless of the person's innocence, we observed higher activation of the salience, theory of mind and sensory-motor networks-areas associated with anxiety-related responses in the interrogative condition, compared to the waived conditions. We further explored two different types of anxious responses under interrogation-true detection anxiety in the guilty (true positive) and false detection anxiety in the innocent (false positive). Differential neural responses across these two conditions were captured at the caudate, thalamus, ventral anterior cingulate and ventromedial prefrontal cortex. We conclude that anxiety is a common neural response to interrogation, regardless of an individual's innocence, and that there are detectable differences in neural responses for true positive and false positive anxious responses under interrogation. The results of our study highlight a need to isolate complex cognitive processes involved in the deceptive acts from the emotional and regulatory responses to interrogation in lie detection schemes.

The resting-state brain is often considered a nonlinear dynamic system transitioning among multiple coexisting stable states. Despite the increasing number of studies on the multistability of the brain system, the processes of state transitions have rarely been systematically explored. Thus, we investigated the state transition processes of the human cerebral cortex system at rest by introducing a graph-theoretical analysis of the state transition network. The energy landscape analysis of brain state occurrences, estimated using the pairwise maximum entropy model for resting-state fMRI data, identified multiple local minima, some of which mediate multi-step transitions toward the global minimum. The state transition among local minima is clustered into two groups according to state transition rates and most inter-group state transitions were mediated by a hub transition state. The distance to the hub transition state determined the path length of the inter-group transition. The cortical system appeared to have redundancy in inter-group transitions when the hub transition state was removed. Such a hub-like organization of transition processes disappeared when the connectivity of the cortical system was altered from the resting-state configuration. In the state transition, the default mode network acts as a transition hub, while coactivation of the prefrontal cortex and default mode network is captured as the global minimum. In summary, the resting-state cerebral cortex has a well-organized architecture of state transitions among stable states, when evaluated by a graph-theoretical analysis of the nonlinear state transition network of the brain.

In machine learning, one of the most popular deep learning methods is the convolutional neural network (CNN), which utilizes shared local filters and hierarchical information processing analogous to the brain’s visual system. Despite its popularity in recognizing two-dimensional (2D) images, the conventional CNN is not directly applicable to semi-regular geometric mesh surfaces, on which the cerebral cortex is often represented. In order to apply the CNN to surface-based brain research, we propose a geometric CNN (gCNN) that deals with data representation on a mesh surface and renders pattern recognition in a multi-shell mesh structure. To make it compatible with the conventional CNN toolbox, the gCNN includes data sampling over the surface, and a data reshaping method for the convolution and pooling layers. We evaluated the performance of the gCNN in sex classification using cortical thickness maps of both hemispheres from the Human Connectome Project (HCP). The classification accuracy of the gCNN was significantly higher than those of a support vector machine (SVM) and a 2D CNN for thickness maps generated by a map projection. The gCNN also demonstrated position invariance of local features, which rendered reuse of its pre-trained model for applications other than that for which the model was trained without significant distortion in the final outcome. The superior performance of the gCNN is attributable to CNN properties stemming from its brain-like architecture, and its surface-based representation of cortical information. The gCNN provides much-needed access to surface-based machine learning, which can be used in both scientific investigations and clinical applications.

The idea that structural white matter connectivity constrains functional connectivity (interactions among brain regions) has widely been explored in studies of brain networks; studies have mostly focused on the “average” strength of functional connectivity. The question of how structural connectivity constrains the “variability” of functional connectivity remains unresolved. In this study, we investigated the variability of resting state functional connectivity that was acquired every 3 h within a single day from 12 participants (eight time sessions within a 24-h period, 165 scans per session). Three different types of functional connectivity (functional connectivity based on Pearson correlation, direct functional connectivity based on partial correlation, and the pseudo functional connectivity produced by their difference) were estimated from resting state functional magnetic resonance imaging data along with structural connectivity defined using fiber tractography of diffusion tensor imaging. Those types of functional connectivity were evaluated with regard to properties of structural connectivity (fiber streamline counts and lengths) and types of structural connectivity such as intra-/inter-hemispheric edges and topological edge types in the rich club organization. We observed that the structural connectivity constrained the variability of direct functional connectivity more than pseudo-functional connectivity and that the constraints depended strongly on structural connectivity types. The structural constraints were greater for intra-hemispheric and heterologous inter-hemispheric edges than homologous inter-hemispheric edges, and feeder and local edges than rich club edges in the rich club architecture. While each edge was highly variable, the multivariate patterns of edge involvement, especially the direct functional connectivity patterns among the rich club brain regions, showed low variability over time. This study suggests that structural connectivity not only constrains the strength of functional connectivity, but also the within-a-day variability of functional connectivity and connectivity patterns, particularly the direct functional connectivity among brain regions.

Thalamotomy at the ventralis intermedius nucleus for essential tremor is known to cause changes in motor circuitry, but how a focal lesion leads to progressive changes in connectivity is not clear. To understand the mechanisms by which thalamotomy exerts enduring effects on motor circuitry, a quantitative analysis of directed or effective connectivity among motor-related areas is required. We characterized changes in effective connectivity of the motor system following thalamotomy using (spectral) dynamic causal modeling (spDCM) for resting-state fMRI. To differentiate long-lasting treatment effects from transient effects, and to identify symptom-related changes in effective connectivity, we subject longitudinal resting-state fMRI data to spDCM, acquired 1 day prior to, and 1 day, 7 days, and 3 months after thalamotomy using a non-cranium-opening MRI-guided focused ultrasound ablation technique. For the group-level (between subject) analysis of longitudinal (between-session) effects, we introduce a multilevel parametric empirical Bayes (PEB) analysis for spDCM. We found remarkably selective and consistent changes in effective connectivity from the ventrolateral nuclei and the supplementary motor area to the contralateral dentate nucleus after thalamotomy, which may be mediated via a polysynaptic thalamic–cortical–cerebellar motor loop. Crucially, changes in effective connectivity predicted changes in clinical motor-symptom scores after thalamotomy. This study speaks to the efficacy of thalamotomy in regulating the dentate nucleus in the context of treating essential tremor. Furthermore, it illustrates the utility of PEB for group-level analysis of dynamic causal modeling in quantifying longitudinal changes in effective connectivity; i.e., measuring long-term plasticity in human subjects non-invasively.

This study proposes a method for classifying event-related fMRI responses in a specialized setting of many known but few unknown stimuli presented in a rapid event-related design. Compared to block design fMRI signals, classification of the response to a single or a few stimulus trial(s) is not a trivial problem due to contamination by preceding events as well as the low signal-to-noise ratio. To overcome such problems, we proposed a single trial-based classification method of rapid event-related fMRI signals utilizing sparse multivariate Bayesian decoding of spatio-temporal fMRI responses. We applied the proposed method to classification of memory retrieval processes for two different classes of episodic memories: a voluntarily conducted experience and a passive experience induced by watching a video of others' actions. A cross-validation showed higher classification performance of the proposed method compared to that of a support vector machine or of a classifier based on the general linear model. Evaluation of classification performances for one, two, and three stimuli from the same class and a correlation analysis between classification accuracy and target stimulus positions among trials suggest that presenting two target stimuli at longer inter-stimulus intervals is optimal in the design of classification experiments to identify the target stimuli. The proposed method for decoding subject-specific memory retrieval of voluntary behavior using fMRI would be useful in forensic applications in a natural environment, where many known trials can be extracted from a simulation of everyday tasks and few target stimuli from a crime scene.

Thalamotomy at the ventralis intermedius nucleus has been an effective treatment method for essential tremor, but how the brain network changes immediately responding to this deliberate lesion and then reorganizes afterwards are not clear. Taking advantage of a non-cranium-opening MRI-guided focused ultrasound ablation technique, we investigated functional network changes due to a focal lesion. To classify the diverse time courses of those network changes with respect to symptom-related long-lasting treatment effects and symptom-unrelated transient effects, we applied graph-theoretic analyses to longitudinal resting-state fMRI data before and 1 day, 7 days and 3 months after thalamotomy with essential tremor. We found reduced average connections among the motor-related areas, reduced connectivity between substantia nigra and external globus pallidum and reduced total connection in the thalamus after thalamotomy, which are all associated with clinical rating scales. The average connectivity among whole brain regions and inter-hemispheric network asymmetry show symptom-unrelated transient increases, indicating temporary reconfiguration of the whole brain network. In summary, thalamotomy regulates interactions over the motor network via symptom-related connectivity changes but accompanies transient, symptom-unrelated diaschisis in the global brain network. This study suggests the significance of longitudinal network analysis, combined with minimal-invasive treatment techniques, in understanding time-dependent diaschisis in the brain network due to a focal lesion.

Life satisfaction is an essential component of subjective well-being and provides a fundamental resource for optimal everyday functioning. The goal of the present study was to examine how life satisfaction influences self-referential processing of emotionally valenced stimuli. Nineteen individuals with high life satisfaction (HLS) and 21 individuals with low life satisfaction (LLS) were scanned using functional MRI while performing a face-word relevance rating task, which consisted of 3 types of face stimuli (self, public other, and unfamiliar other) and 3 types of word stimuli (positive, negative, and neutral). We found a significant group x word valence interaction effect, most strikingly in the dorsal medial prefrontal cortex. In the positive word condition dorsal medial prefrontal cortex activity was significantly higher in the LLS group, whereas in the negative word condition it was significantly higher in the HLS group. The two groups showed distinct functional connectivity of the dorsal medial prefrontal cortex with emotional processing-related regions. The findings suggest that, in response to emotional stimuli, individuals with HLS may successfully recruit emotion regulation-related regions in contrast to individuals with LLS. The difference in functional connectivity during self-referential processing may lead to an influence of life satisfaction on responses to emotion-eliciting stimuli.

The diagnosis and monitoring of liver fibrosis is an important clinical issue; however, this is usually achieved by invasive methods such as biopsy. We aimed to determine whether histogram analysis of hepatobiliary phase images of gadoxetic acid-enhanced magnetic resonance imaging (MRI) can provide non-invasive quantitative measurement of liver fibrosis.This retrospective study was approved by the institutional ethics committee, and a waiver of informed consent was obtained. Hepatobiliary phase images of preoperative gadoxetic acid-enhanced MRI studies of 105 patients (69 males, 36 females; age 56.1±12.2) with pathologically documented liver fibrosis grades were analyzed. Fibrosis staging was F0/F1/F2/F3/F4 (METAVIR system) for 11/20/13/15/46 patients, respectively. Four regions-of-interest (ROI, each about 2 cm2) were placed on predetermined locations of representative images. The measured signal intensity of pixels in each ROI was used to calculate corrected coefficient of variation (cCV), skewness, and kurtosis. An average value of each parameter was calculated for comparison. Statistical analysis was performed by ANOVA, receiver operating characteristic (ROC) curve analysis, and linear regression.The cCV showed statistically significant differences among pathological fibrosis grades (P

Aberrant emotional salience attribution has been reported to be an important clinical feature in patients with schizophrenia. Real life stimuli that incorporate both positive and negative emotional traits lead to affective asymmetry such as negativity bias and positivity offset. In this study, we investigated the neural correlates of emotional salience attribution in patients with schizophrenia when affective asymmetry was processed. Fifteen patients with schizophrenia and 14 healthy controls were scanned using functional magnetic resonance imaging (fMRI) while performing an emotion judgment task in which two pictures were juxtaposed. The task consisted of responding to affective asymmetry condition (ambivalent and neutral) and affective symmetry conditions (positive and negative), and group comparisons were performed for each condition. Significantly higher activity in the medial prefrontal cortex and inferior frontal gyrus was observed for the ambivalent condition than for the other conditions in controls, but not in patients. Compared with controls, patients showed decreased activities in the dorsolateral prefrontal cortex, dorsal anterior cingulate cortex, insula, and putamen for the ambivalent condition, but no changes were observed for the neutral condition. Multiple prefrontal hypoactivities during salience attribution of negativity bias in schizophrenia may underlie deficits in the integrative processing of emotional information. Regional abnormalities in the salience network may be the basis of defective emotional salience attribution in schizophrenia, which is likely involved in symptom formation and social dysfunction.

Does each cognitive task elicit a new cognitive network each time in the brain? Recent data suggest that pre-existing repertoires of a much smaller number of canonical network components are selectively and dynamically used to compute new cognitive tasks. To this end, we propose a novel method (graph-ICA) that seeks to extract these canonical network components from a limited number of resting state spontaneous networks. Graph-ICA decomposes a weighted mixture of source edge-sharing subnetworks with different weighted edges by applying an independent component analysis on cross-sectional brain networks represented as graphs. We evaluated the plausibility in our simulation study and identified 49 intrinsic subnetworks by applying it in the resting state fMRI data. Using the derived subnetwork repertories, we decomposed brain networks during specific tasks including motor activity, working memory exercises, and verb generation, and identified subnetworks associated with performance on these tasks. We also analyzed sex differences in utilization of subnetworks, which was useful in characterizing group networks. These results suggest that this method can effectively be utilized to identify task-specific as well as sex-specific functional subnetworks. Moreover, graph-ICA can provide more direct information on the edge weights among brain regions working together as a network, which cannot be directly obtained through voxel-level spatial ICA.

To investigate functional brain networks, many graph-theoretical studies have defined nodes in a graph using an anatomical atlas with about a hundred partitions. Although use of anatomical node definition is popular due to its convenience, functional inhomogeneity within each node may lead to bias or systematic errors in the graph analysis. The current study was aimed to show functional inhomogeneity of a node defined by an anatomical atlas and to show its effects on the graph topology. For this purpose, we compared functional connectivity defined using 138 resting state fMRI data among 90 cerebral nodes from the automated anatomical labeling (AAL), which is an anatomical atlas, and among 372 cerebral nodes defined using a functional connectivity-based atlas as a ground truth, which was obtained using anatomy-constrained hierarchical modularity optimization algorithm (AHMO) that we proposed to evaluate the graph properties for anatomically defined nodes. We found that functional inhomogeneity in the anatomical parcellation induced significant biases in estimating both functional connectivity and graph-theoretical network properties. We also found very high linearity in major global network properties and nodal strength at all brain regions between anatomical atlas and functional atlas with reasonable network-forming thresholds for graph construction. However, some nodal properties such as betweenness centrality did not show significant linearity in some regions. The current study suggests that the use of anatomical atlas may be biased due to its inhomogeneity, but may generally be used in most neuroimaging studies when a single atlas is used for analysis.