Attention-based fusion of multiple graphheat networks for structural to functional brain mapping.

Over the last decade, there has been growing interest in learning the mapping from structural connectivity (SC) to functional connectivity (FC) of the brain. The spontaneous fluctuations of the brain activity during the resting-state as captured by functional MRI (rsfMRI) contain rich non-stationary dynamics over a relatively fixed structural connectome. Among the modeling approaches, graph diffusion-based methods with single and multiple diffusion kernels approximating static or dynamic functional connectivity have shown promise in predicting the FC given the SC. However, these methods are computationally expensive, not scalable, and fail to capture the complex dynamics underlying the whole process. Recently, deep learning methods such as GraphHeat networks and graph diffusion have been shown to handle complex relational structures while preserving global information. In this paper, we propose a novel attention-based fusion of multiple GraphHeat networks (A-GHN) for mapping SC-FC. A-GHN enables us to model multiple heat kernel diffusion over the brain graph for approximating the complex Reaction Diffusion phenomenon. We argue that the proposed deep learning method overcomes the scalability and computational inefficiency issues but can still learn the SC-FC mapping successfully. Training and testing were done using the rsfMRI data of 1058 participants from the human connectome project (HCP), and the results establish the viability of the proposed model. On HCP data, we achieve a high Pearson correlation of 0.788 (Desikan-Killiany atlas with 87 regions) and 0.773 (AAL atlas with 86 regions). Furthermore, experiments demonstrate that A-GHN outperforms the existing methods in learning the complex nature of the structure-function relation of the human brain.

Action-outcome delays modulate the temporal expansion of intended outcomes.

The phenomenon of intentional binding pertains to the perceived connection between a voluntary action and its anticipated result. When an individual intends an outcome, it appears to subjectively extend in time due to a pre-activation of the intended result, particularly evident at shorter action-outcome delays. However, there is a concern that the operationalisation of intention might have led to a mixed interpretation of the outcome expansion attributed to the pre-activation of intention, given the sensitivity of time perception and intentional binding to external cues that could accelerate the realisation of expectations. To investigate the expansion dynamics of an intended outcome, we employed a modified version of the temporal bisection task in two experiments. Experiment 1 considered the action-outcome delay as a within-subject factor, while experiment 2 treated it as a between-subject factor. The results revealed that the temporal expansion of an intended outcome was only evident under the longer action-outcome delay condition. We attribute this observation to working memory demands and attentional allocation due to temporal relevancy and not due to pre-activation. The discrepancy in effects across studies is explained by operationalising different components of the intentional binding effect, guided by the cue integration theory. Moreover, we discussed speculative ideas regarding the involvement of specific intentions based on the proximal intent distal intent (PIDI) theory and whether causality plays a role in temporal binding. Our study contributes to the understanding of how intention influences time perception and sheds light on how various methodological factors, cues, and delays can impact the dynamics of temporal expansion associated with an intended outcome.

Number-time interaction: Search for a common magnitude system in a cross-modal setting.

A theory of magnitude (ATOM) suggests that a generalized magnitude system in the brain processes magnitudes such as space, time, and numbers. Numerous behavioral and neurocognitive studies have provided support to ATOM theory. However, the evidence for common magnitude processing primarily comes from the studies in which numerical and temporal information are presented visually. Our current understanding of such cross-dimensional magnitude interactions is limited to visual modality only. However, it is still unclear whether the ATOM-framework accounts for the integration of cross-modal magnitude information. To examine the cross-modal influence of numerical magnitude on temporal processing of the tone, we conducted three experiments using a temporal bisection task. We presented the numerical magnitude information in the visual domain and the temporal information in the auditory either simultaneously with duration judgment task (Experiment-1), before duration judgment task (Experiment-2), and before duration judgment task but with numerical magnitude also being task-relevant (Experiment-3). The results suggest that the numerical information presented in the visual domain affects temporal processing of the tone only when the numerical magnitudes were task-relevant and available while making a temporal judgment (Experiments-1 and 3). However, numerical information did not interfere with temporal information when presented temporally separated from the duration information (Experiments-2). The findings indicate that the influence of visual numbers on temporal processing in cross-modal settings may not arise from the common magnitude system but instead from general cognitive mechanisms like attention and memory.

Attention mediates the influence of numerical magnitude on temporal processing.

The processing of time and numbers has been fundamental to human cognition. One of the prominent theories of magnitude processing, a theory of magnitude (ATOM), suggests that a generalized magnitude system processes space, time, and numbers; thereby, the magnitude dimensions could potentially interact with one another. However, more recent studies have found support for domain-specific magnitude processing and argued that the magnitudes related to time and number are processed through distinct mechanisms. Such mixed findings have raised questions about whether these magnitudes are processed independently or share a common processing mechanism. In the present study, we examine the influence of numerical magnitude on temporal processing. To investigate, we conducted two experiments using a temporal comparison task, wherein we presented positive and negative numerical magnitudes (large and small) in a blocked (Experiment-1) and intermixed manner (Experiment-2). Results from experiment-1 suggest that numerical magnitude affects temporal processing only in positive numbers but not for negative numbers. Further, results from experiment-2 indicate that the polarity (positive and negative) of the numbers influences temporal processing instead of the numerical magnitude itself. Overall, the current study seems to suggest that cross-domain interaction of magnitudes arises from attentional mechanisms and may not need to posit a common magnitude processing system.

Cognitive and Motor Learning in Internally-Guided Motor Skills.

Several canonical experimental paradigms (e.g., serial reaction time task, discrete sequence production task, m × n task) have been proposed to study the typical behavioral phenomenon and the nature of learning in sequential keypress tasks. A characteristic feature of most paradigms is that they are representative of externally-specified sequencing-motor tasks where the environment or task paradigm extrinsically provides the sequence of stimuli, i.e., the responses are stimulus-driven. Previous studies utilizing such canonical paradigms have largely overlooked the learning behaviors in a more realistic class of motor tasks that involve internally-guided sequencing-where the sequence of motor actions is self-generated or internally-specified. In this work, we use the grid-navigation task as an instance of internally-guided sequencing to investigate the nature of learning in such paradigms. The participants performed Grid-Sailing Task (GST), which required navigating (by executing sequential keypresses) a 5 × 5 grid from start to goal (SG) position while using a particular key-mapping (KM) among the three cursor-movement directions and the three keyboard buttons. The participants performed two behavioral experiments-Single-SG and Mixed-SG condition. The Single-SG condition required performing GST on a single SG position repeatedly, whereas the Mixed-SG condition involved performing GST using the same KM on two novel SG positions presented in a random, inter-mixed manner. In the Single-SG condition, we show that motor learning contributes to the sequence-specific learning in GST with the repeated execution of the same trajectories. In the Mixed-SG condition, since the participants utilize the previously learned KM, we anticipate a transfer of learning from the Single-SG condition. The acquisition and transfer of a KM-specific internal model facilitates efficient trajectory planning on novel SG conditions. The acquisition of such a KM-specific internal model amounts to trajectory-independent cognitive learning in GST. We show that cognitive learning contributes to the learning in GST by showing transfer-related performance improvements in the Mixed-SG condition. In sum, we show the role of cognitive and motor learning processes in internally-guided sequencing and further make a case for using GST-like grid-navigation paradigms in investigating internally guided skill learning.

Motor Chunking in Internally Guided Sequencing.

Motor skill learning involves the acquisition of sequential motor movements with practice. Studies have shown that we learn to execute these sequences efficiently by chaining several elementary actions in sub-sequences called motor chunks. Several experimental paradigms, such as serial reaction task, discrete sequence production, and m × n task, have investigated motor chunking in externally specified sequencing where the environment or task paradigm provides the sequence of stimuli, i.e., the responses are stimulus driven. In this study, we examine motor chunking in a class of more realistic motor tasks that involve internally guided sequencing where the sequence of motor actions is self-generated or internally specified. We employ a grid-navigation task as an exemplar of internally guided sequencing to investigate practice-driven performance improvements due to motor chunking. The participants performed the grid-sailing task (GST) (Fermin et al., 2010), which required navigating (by executing sequential keypresses) a 10 × 10 grid from start to goal position while using a particular type of key mapping between the three cursor movement directions and the three keyboard buttons. We provide empirical evidence for motor chunking in grid-navigation tasks by showing the emergence of subject-specific, unique temporal patterns in response times. Our findings show spontaneous chunking without pre-specified or externally guided structures while replicating the earlier results with a less constrained, internally guided sequencing paradigm.

Numerical Magnitude Affects Accuracy but Not Precision of Temporal Judgments.

A Theory of Magnitude (ATOM) suggests that space, time, and quantities are processed through a generalized magnitude system. ATOM posits that task-irrelevant magnitudes interfere with the processing of task-relevant magnitudes as all the magnitudes are processed by a common system. Many behavioral and neuroimaging studies have found support in favor of a common magnitude processing system. However, it is largely unknown whether such cross-domain monotonic mapping arises from a change in the accuracy of the magnitude judgments or results from changes in precision of the processing of magnitude. Therefore, in the present study, we examined whether large numerical magnitude affects temporal accuracy or temporal precision, or both. In other words, whether numerical magnitudes change our temporal experience or simply bias duration judgments. The temporal discrimination (between comparison and standard duration) paradigm was used to present numerical magnitudes ("1," "5," and "9") across varied durations. We estimated temporal accuracy (PSE) and precision (Weber ratio) for each numerical magnitude. The results revealed that temporal accuracy (PSE) for large (9) numerical magnitude was significantly lower than that of small (1) and identical (5) magnitudes. This implies that the temporal duration was overestimated for large (9) numerical magnitude compared to small (1) and identical (5) numerical magnitude, in line with ATOM's prediction. However, no influence of numerical magnitude was observed on temporal precision (Weber ratio). The findings of the present study suggest that task-irrelevant numerical magnitude selectively affects the accuracy of processing of duration but not duration discrimination itself. Further, we argue that numerical magnitude may not directly affect temporal processing but could influence via attentional mechanisms.

Atypical Flexibility in Dynamic Functional Connectivity Quantifies the Severity in Autism Spectrum Disorder.

Resting-state functional connectivity (FC) analyses have shown atypical connectivity in autism spectrum disorder (ASD) as compared to typically developing (TD). However, this view emerges from investigating static FC overlooking the whole brain transient connectivity patterns. In our study, we investigated how age and disease influence the dynamic changes in functional connectivity of TD and ASD. We used resting-state functional magnetic resonance imaging (rs-fMRI) data stratified into three cohorts: children (7-11 years), adolescents (12-17 years), and adults (18+ years) for the analysis. The dynamic variability in the connection strength and the modular organization in terms of measures such as flexiblity, cohesion strength, and disjointness were explored for each subject to characterize the differences between ASD and TD. In ASD, we observed significantly higher inter-subject dynamic variability in connection strength as compared to TD. This hyper-variability relates to the symptom severity in ASD. We also found that whole-brain flexibility correlates with static modularity only in TD. Further, we observed a core-periphery organization in the resting-state, with Sensorimotor and Visual regions in the rigid core; and DMN and attention areas in the flexible periphery. TD also develops a more cohesive organization of sensorimotor areas. However, in ASD we found a strong positive correlation of symptom severity with flexibility of rigid areas and with disjointness of sensorimotor areas. The regions of the brain showing high predictive power of symptom severity were distributed across the cortex, with stronger bearings in the frontal, motor, and occipital cortices. Our study demonstrates that the dynamic framework best characterizes the variability in ASD.

Age, Disease, and Their Interaction Effects on Intrinsic Connectivity of Children and Adolescents in Autism Spectrum Disorder Using Functional Connectomics.

Brain connectivity analysis has provided crucial insights to pinpoint the differences between autistic and typically developing (TD) children during development. The aim of this study is to investigate the functional connectomics of autism spectrum disorder (ASD) versus TD and underpin the effects of development, disease, and their interactions on the observed atypical brain connectivity patterns. Resting-state functional magnetic resonance imaging (rs-fMRI) from the Autism Brain Imaging Data Exchange (ABIDE) data set, which is stratified into two cohorts: children (9-12 years) and adolescents (13-16 years), is used for the analysis. Differences in various graph theoretical network measures are calculated between ASD and TD in each group. Furthermore, two-factor analysis of variance test is used to study the effect of age, disease, and their interaction on the network measures and the network edges. Furthermore, the differences in connection strength between TD and ASD subjects are assessed using network-based statistics. The results showed that ASD exhibits increased functional integration at the expense of decreased functional segregation. In ASD adolescents, there is a significant decrease in modularity suggesting a less robust modular organization, and an increase in participation coefficient suggesting more random integration and widely distributed connection edges. Furthermore, there is significant hypoconnectivity observed in the adolescent group especially in the default mode network, while the children group shows both hyper- and hypoconnectivity. This study lends support to a model of global atypical connections and further identifies functional networks and areas that are independently affected by age, disease, and their interaction.

Machine learning models to predict the progression from early to late stages of papillary renal cell carcinoma.

Papillary Renal Cell Carcinoma (PRCC) is a heterogeneous disease with variations in disease progression and clinical outcomes. The advent of next generation sequencing techniques (NGS) has generated data from patients that can be analysed to develop a predictive model. In this study, we have adopted a machine learning approach to identify biomarkers and build classifiers to discriminate between early and late stages of PRCC from gene expression profiles. A machine learning pipeline incorporating different feature selection algorithms and classification models is developed to analyse RNA sequencing dataset (RNASeq). Further, to get a reliable feature set, we extracted features from different partitions of the training dataset and aggregated them into feature sets for classification. We evaluated the performance of different algorithms on the basis of 10-fold cross validation and independent test dataset. 10-fold cross validation was also performed on a microarray dataset of PRCC. A random forest based feature selection (varSelRF) yielded minimum number of features (104) and a best performance with area under Precision Recall curve (PR-AUC) of 0.804, MCC (Matthews Correlation Coefficient) of 0.711 and accuracy of 88% with Shrunken Centroid classifier on a test dataset. We identified 80 genes that are consistently altered between stages by different feature selection algorithms. The extracted features are related to cellular components - centromere, kinetochore and spindle, and biological process mitotic cell cycle. These observations reveal potential mechanisms for an increase in chromosome instability in the late stage of PRCC. Our study demonstrates that the gene expression profiles can be used to classify stages of PRCC.

Metastability in Senescence.

The brain during healthy aging exhibits gradual deterioration of structure but maintains a high level of cognitive ability. These structural changes are often accompanied by reorganization of functional brain networks. Existing neurocognitive theories of aging have argued that such changes are either beneficial or detrimental. Despite numerous empirical investigations, the field lacks a coherent account of the dynamic processes that occur over our lifespan. Taking advantage of the recent developments in whole-brain computational modeling approaches, we hypothesize that the continuous process of aging can be explained by the concepts of metastability - a theoretical framework that gives a systematic account of the variability of the brain. This hypothesis can bridge the gap between existing theories and the empirical findings on age-related changes.

A Unified Theoretical Framework for Cognitive Sequencing.

The capacity to sequence information is central to human performance. Sequencing ability forms the foundation stone for higher order cognition related to language and goal-directed planning. Information related to the order of items, their timing, chunking and hierarchical organization are important aspects in sequencing. Past research on sequencing has emphasized two distinct and independent dichotomies: implicit vs. explicit and goal-directed vs. habits. We propose a theoretical framework unifying these two streams. Our proposal relies on brain's ability to implicitly extract statistical regularities from the stream of stimuli and with attentional engagement organizing sequences explicitly and hierarchically. Similarly, sequences that need to be assembled purposively to accomplish a goal require engagement of attentional processes. With repetition, these goal-directed plans become habits with concomitant disengagement of attention. Thus, attention and awareness play a crucial role in the implicit-to-explicit transition as well as in how goal-directed plans become automatic habits. Cortico-subcortical loops basal ganglia-frontal cortex and hippocampus-frontal cortex loops mediate the transition process. We show how the computational principles of model-free and model-based learning paradigms, along with a pivotal role for attention and awareness, offer a unifying framework for these two dichotomies. Based on this framework, we make testable predictions related to the potential influence of response-to-stimulus interval (RSI) on developing awareness in implicit learning tasks.

Expansion and Compression of Time Correlate with Information Processing in an Enumeration Task.

Perception of temporal duration is subjective and is influenced by factors such as attention and context. For example, unexpected or emotional events are often experienced as if time subjectively expands, suggesting that the amount of information processed in a unit of time can be increased. Time dilation effects have been measured with an oddball paradigm in which an infrequent stimulus is perceived to last longer than standard stimuli in the rest of the sequence. Likewise, time compression for the oddball occurs when the duration of the standard items is relatively brief. Here, we investigated whether the amount of information processing changes when time is perceived as distorted. On each trial, an oddball stimulus of varying numerosity (1-14 items) and duration was presented along with standard items that were either short (70 ms) or long (1050 ms). Observers were instructed to count the number of dots within the oddball stimulus and to judge its relative duration with respect to the standards on that trial. Consistent with previous results, oddballs were reliably perceived as temporally distorted: expanded for longer standard stimuli blocks and compressed for shorter standards. The occurrence of these distortions of time perception correlated with perceptual processing; i.e. enumeration accuracy increased when time was perceived as expanded and decreased with temporal compression. These results suggest that subjective time distortions are not epiphenomenal, but reflect real changes in sensory processing. Such short-term plasticity in information processing rate could be evolutionarily advantageous in optimizing perception and action during critical moments.

Changing the structure of complex visuo-motor sequences selectively activates the fronto-parietal network.

Previous brain imaging studies investigating motor sequence complexity have mainly examined the effect of increasing the length of pre-learned sequences. The novel contribution of this research is that we varied the structure of complex visuo-motor sequences along two different dimensions using mxn paradigm. The complexity of sequences is increased from 12 movements (organized as a 2×6 task) to 24 movements (organized as 4×6 and 2×12 tasks). Behavioral results indicate that although the success rate attained was similar across the two complex tasks (2×12 and 4×6), a greater decrease in response times was observed for the 2×12 compared to the 4×6 condition at an intermediate learning stage. This decrease is possibly related to successful chunking across sets in the 2×12 task. In line with this, we observed a selective activation of the fronto-parietal network. Shifts of activation were observed from the ventral to dorsal prefrontal, lateral to medial premotor and inferior to superior parietal cortex from the early to intermediate learning stage concomitant with an increase in hyperset length. We suggest that these selective activations and shifts in activity during complex sequence learning are possibly related to chunking of motor sequences.

Role of CAMKII in reinforcement learning: a computational model of glutamate and dopamine signaling pathways.

Timely release of dopamine (DA) at the striatum seems to be important for reinforcement learning (RL) mediated by the basal ganglia. Houk et al. (in: Houk et al (eds) Models of information processing in the basal ganglia, (1995) proposed a cellular signaling pathway model to characterize the interaction between DA and glutamate pathways that have a role in RL. The model simulation results, using GENESIS KINETIKIT simulator, point out that there is not only prolongation of duration as proposed by Houk et al. (1995), but also an enhancement in the amplitude of autophosphorylation of CaMKII. Further, the autophosphorylated form of CaMKII may form a basis for the "eligibility trace" condition required in RL. This simulation study is the first of its kind to support the comprehensive theoretical proposal of Houk et al. (1995).

What do the basal ganglia do? A modeling perspective.

Basal ganglia (BG) constitute a network of seven deep brain nuclei involved in a variety of crucial brain functions including: action selection, action gating, reward based learning, motor preparation, timing, etc. In spite of the immense amount of data available today, researchers continue to wonder how a single deep brain circuit performs such a bewildering range of functions. Computational models of BG have focused on individual functions and fail to give an integrative picture of BG function. A major breakthrough in our understanding of BG function is perhaps the insight that activities of mesencephalic dopaminergic cells represent some form of 'reward' to the organism. This insight enabled application of tools from 'reinforcement learning,' a branch of machine learning, in the study of BG function. Nevertheless, in spite of these bright spots, we are far from the goal of arriving at a comprehensive understanding of these 'mysterious nuclei.' A comprehensive knowledge of BG function has the potential to radically alter treatment and management of a variety of BG-related neurological disorders (Parkinson's disease, Huntington's chorea, etc.) and neuropsychiatric disorders (schizophrenia, obsessive compulsive disorder, etc.) also. In this article, we review the existing modeling literature on BG and hypothesize an integrative picture of the function of these nuclei.

Analysis of n-gram based promoter recognition methods and application to whole genome promoter prediction.

Promoter prediction is an important and complex problem. Pattern recognition algorithms typically require features that could capture this complexity. A special bias towards certain combinations of base pairs in the promoter sequences may be possible. In order to determine these biases n-grams are usually extracted and analyzed. An n-gram is a selection of n contiguous characters from a given character stream, DNA sequence segments in this case. Here a systematic study is made to discover the efficacy of n-grams for n = 2, 3, 4, 5 in promoter prediction. A study of n-grams as features for a neural network classifier for E. coli and Drosophila promoters is made. In case of E. coli n=3 and in case of Drosophila n=4 seem to give optimal prediction values. Using the 3-gram features, promoter prediction in the genome sequence of E. coli is done. The results are encouraging in positive identification of promoters in the genome compared to software packages such as BPROM, NNPP, and SAK. Whole genome promoter prediction in Drosophila genome was also performed but with 4-gram features.

Protein ligand interaction database (PLID).

A comprehensive database named, protein ligand interaction database (PLID), is created with 6295 ligands bound to proteins extracted from the protein data bank (PDB). This is by far the most comprehensive database of physico-chemical properties, quantum mechanical descriptors and the residues present in the active site of proteins. It is a publicly available web-based database (via the Internet) at http://203.199.182.73/gnsmmg/databases/plid/.

Modeling the sub-cellular signaling pathways involved in reinforcement learning at the striatum.

A general discussion of various levels of models in computational neuroscience is presented. A detailed case study of modeling at the sub-cellular level is undertaken. The process of learning actions by reward or punishment is called 'Instrumental Conditioning' or 'Reinforcement Learning' (RL). Temporal difference learning (TDL) is a mathematical framework for RL. Houk et al. (1995) proposed a cellular signaling model for interaction of dopamine (DA) and glutamate activities at the striatum that forms the basis for TDL. In the model, glutamatergic input generates a membrane depolarization through N-methyl-d-aspartate (NMDA), alpha-amino-5-hydroxy-3-methyl-4-isoxazole propionic acid (AMPA), metabotropic glutamate receptors (mGluR), and opens calcium two plus ion (Ca(2+)) channels resulting in the influx of Ca(2+) into the dendritic spine. This raises the postsynaptic calcium concentration in the dendritic spine leading to the autophosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). The timely arrival of the DA input at the neck of the spine head generates a cascade of reactions which then leads to the prolongation of long-term potentiation (LTP) generated by the autophosphorylation of CaMKII. Since no simulations were done so far to support this proposal, we undertook the task of computational verification of the model. During the simulations it was found that there was enhancement and prolongation of autophosphorylation of CaMKII. This result verifies Houk's proposal for LTP in the striatum. Our simulation results are generally in line with the known biological experimental data and also suggest predictions for future experimental verification.

Analysis of E. coli promoter recognition problem in dinucleotide feature space.

MOTIVATION: Patterns in the promoter sequences within a species are known to be conserved but there exist many exceptions to this rule which makes the promoter recognition a complex problem. Although many complex feature extraction schemes coupled with several classifiers have been proposed for promoter recognition in the current literature, the problem is still open. RESULTS: A dinucleotide global feature extraction method is proposed for the recognition of sigma-70 promoters in Escherichia coli in this article. The positive data set consists of sigma-70 promoters with known transcription starting points which are part of regulonDB and promec databases. Four different kinds of negative data sets are considered, two of them biological sets (Gordon et al., 2003) and the other two synthetic data sets. Our results reveal that a single-layer perceptron using dinucleotide features is able to achieve an accuracy of 80% against a background of biological non-promoters and 96% for random data sets. A scheme for locating the promoter regions in a given genome sequence is proposed. A deeper analysis of the data set shows that there is a bifurcation of the data set into two distinct classes, a majority class and a minority class. Our results point out that majority class constituting the majority promoter and the majority non-promoter signal is linearly separable. Also the minority class is linearly separable. We further show that the feature extraction and classification methods proposed in the paper are generic enough to be applied to the more complex problem of eucaryotic promoter recognition. We present Drosophila promoter recognition as a case study. AVAILABILITY: http://202.41.85.117/htmfiles/faculty/tsr/tsr.html.