Dynamic nonreversibility view of intrinsic brain organization and brain dynamic analysis of repetitive transcranial magnitude stimulation.

Intrinsic neural activities are characterized as endless spontaneous fluctuation over multiple time scales. However, how the intrinsic brain organization changes over time under local perturbation remains an open question. By means of statistical physics, we proposed an approach to capture whole-brain dynamics based on estimating time-varying nonreversibility and k-means clustering of dynamic varying nonreversibility patterns. We first used synthetic fMRI to investigate the effects of window parameters on the temporal variability of varying nonreversibility. Second, using real test-retest fMRI data, we examined the reproducibility, reliability, biological, and physiological correlation of the varying nonreversibility substates. Finally, using repetitive transcranial magnetic stimulation-fMRI data, we investigated the modulation effects of repetitive transcranial magnetic stimulation on varying nonreversibility substate dynamics. The results show that: (i) as window length increased, the varying nonreversibility variance decreased, while the sliding step almost did not alter it; (ii) the global high varying nonreversibility states and low varying nonreversibility states were reproducible across multiple datasets and different window lengths; and (iii) there were increased low varying nonreversibility states and decreased high varying nonreversibility states when the left frontal lobe was stimulated, but not the occipital lobe. Taken together, these results provide a thermodynamic equilibrium perspective of intrinsic brain organization and reorganization under local perturbation.

The alterations of repetitive transcranial magnetic stimulation on the energy landscape of resting-state networks differ across the human cortex.

Repetitive transcranial magnetic stimulation (rTMS) is a promising intervention tool for the noninvasive modulation of brain activity and behavior in neuroscience research and clinical settings. However, the resting-state dynamic evolution of large-scale functional brain networks following rTMS has rarely been investigated. Here, using resting-state fMRI images collected from 23 healthy individuals before (baseline) and after 1 Hz rTMS of the left frontal (FRO) and occipital (OCC) lobes, we examined the different effects of rTMS on brain dynamics across the human cortex. By fitting a pairwise maximum entropy model (pMEM), we constructed an energy landscape for the baseline and poststimulus conditions by fitting a pMEM. We defined dominant brain states (local minima) in the energy landscape with synergistic activation and deactivation patterns of large-scale functional networks. We calculated state dynamics including appearance probability, transitions and duration. The results showed that 1 Hz rTMS induced increased and decreased state probability, transitions and duration when delivered to the FRO and OCC targets, respectively. Most importantly, the shortest path and minimum cost between dominant brain states were altered after stimulation. The absolute sum of the costs from the source states to the destinations was lower after OCC stimulation than after FRO stimulation. In conclusion, our study characterized the dynamic trajectory of state transitions in the energy landscape and suggested that local rTMS can induce significant dynamic perturbation involving stimulated and distant functional networks, which aligns with the modern view of the dynamic and complex brain. Our results suggest low-dimensional mapping of rTMS-induced brain adaption, which will contribute to a broader and more effective application of rTMS in clinical settings.

Low-frequency repetitive transcranial magnetic stimulation alters the individual functional dynamical landscape.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive approach to modulate brain activity and behavior in humans. Still, how individual resting-state brain dynamics after rTMS evolves across different functional configurations is rarely studied. Here, using resting state fMRI data from healthy subjects, we aimed to examine the effects of rTMS to individual large-scale brain dynamics. Using Topological Data Analysis based Mapper approach, we construct the precise dynamic mapping (PDM) for each participant. To reveal the relationship between PDM and canonical functional representation of the resting brain, we annotated the graph using relative activation proportion of a set of large-scale resting-state networks (RSNs) and assigned the single brain volume to corresponding RSN-dominant or a hub state (not any RSN was dominant). Our results show that (i) low-frequency rTMS could induce changed temporal evolution of brain states; (ii) rTMS didn't alter the hub-periphery configurations underlined resting-state brain dynamics; and (iii) the rTMS effects on brain dynamics differ across the left frontal and occipital lobe. In conclusion, low-frequency rTMS significantly alters the individual temporo-spatial dynamics, and our finding further suggested a potential target-dependent alteration of brain dynamics. This work provides a new perspective to comprehend the heterogeneous effect of rTMS.

Dynamical network analysis reveals key microRNAs in progressive stages of lung cancer.

Non-coding RNAs are fundamental to the competing endogenous RNA (CeRNA) hypothesis in oncology. Previous work focused on static CeRNA networks. We construct and analyze CeRNA networks for four sequential stages of lung adenocarcinoma (LUAD) based on multi-omics data of long non-coding RNAs (lncRNAs), microRNAs and mRNAs. We find that the networks possess a two-level bipartite structure: common competing endogenous network (CCEN) composed of an invariant set of microRNAs over all the stages and stage-dependent, unique competing endogenous networks (UCENs). A systematic enrichment analysis of the pathways of the mRNAs in CCEN reveals that they are strongly associated with cancer development. We also find that the microRNA-linked mRNAs from UCENs have a higher enrichment efficiency. A key finding is six microRNAs from CCEN that impact patient survival at all stages, and four microRNAs that affect the survival from a specific stage. The ten microRNAs can then serve as potential biomarkers and prognostic tools for LUAD.

Predicting tipping points in mutualistic networks through dimension reduction.

Complex networked systems ranging from ecosystems and the climate to economic, social, and infrastructure systems can exhibit a tipping point (a "point of no return") at which a total collapse of the system occurs. To understand the dynamical mechanism of a tipping point and to predict its occurrence as a system parameter varies are of uttermost importance, tasks that are hindered by the often extremely high dimensionality of the underlying system. Using complex mutualistic networks in ecology as a prototype class of systems, we carry out a dimension reduction process to arrive at an effective 2D system with the two dynamical variables corresponding to the average pollinator and plant abundances. We show, using 59 empirical mutualistic networks extracted from real data, that our 2D model can accurately predict the occurrence of a tipping point, even in the presence of stochastic disturbances. We also find that, because of the lack of sufficient randomness in the structure of the real networks, weighted averaging is necessary in the dimension reduction process. Our reduced model can serve as a paradigm for understanding and predicting the tipping point dynamics in real world mutualistic networks for safeguarding pollinators, and the general principle can be extended to a broad range of disciplines to address the issues of resilience and sustainability.

Controlled generation of self-sustained oscillations in complex artificial neural networks.

Spatially distinct, self-sustained oscillations in artificial neural networks are fundamental to information encoding, storage, and processing in these systems. Here, we develop a method to induce a large variety of self-sustained oscillatory patterns in artificial neural networks and a controlling strategy to switch between different patterns. The basic principle is that, given a complex network, one can find a set of nodes-the minimum feedback vertex set (mFVS), whose removal or inhibition will result in a tree-like network without any loop structure. Reintroducing a few or even a single mFVS node into the tree-like artificial neural network can recover one or a few of the loops and lead to self-sustained oscillation patterns based on these loops. Reactivating various mFVS nodes or their combinations can then generate a large number of distinct neuronal firing patterns with a broad distribution of the oscillation period. When the system is near a critical state, chaos can arise, providing a natural platform for pattern switching with remarkable flexibility. With mFVS guided control, complex networks of artificial neurons can thus be exploited as potential prototypes for local, analog type of processing paradigms.

A network approach to quantifying radiotherapy effect on cancer: Radiosensitive gene group centrality.

Radiotherapy plays a vital role in cancer treatment, for which accurate prognosis is important for guiding sequential treatment and improving the curative effect for patients. An issue of great significance in radiotherapy is to assess tumor radiosensitivity for devising the optimal treatment strategy. Previous studies focused on gene expression in cells closely associated with radiosensitivity, but factors such as the response of a cancer patient to irradiation and the patient survival time are largely ignored. For clinical cancer treatment, a specific pre-treatment indicator taking into account cancer cell type and patient radiosensitivity is of great value but it has been missing. Here, we propose an effective indicator for radiosensitivity: radiosensitive gene group centrality (RSGGC), which characterizes the importance of the group of genes that are radiosensitive in the whole gene correlation network. We demonstrate, using both clinical patient data and experimental cancer cell lines, which RSGGC can provide a quantitative estimate of the effect of radiotherapy, with factors such as the patient survival time and the survived fraction of cancer cell lines under radiotherapy fully taken into account. Our main finding is that, for patients with a higher RSGGC score before radiotherapy, cancer treatment tends to be more effective. The RSGGC can have significant applications in clinical prognosis, serving as a key measure to classifying radiosensitive and radioresistant patients.

A model for meme popularity growth in social networking systems based on biological principle and human interest dynamics.

We analyze five big data sets from a variety of online social networking (OSN) systems and find that the growth dynamics of meme popularity exhibit characteristically different behaviors. For example, there is linear growth associated with online recommendation and sharing platforms, a plateaued (or an "S"-shape) type of growth behavior in a web service devoted to helping users to collect bookmarks, and an exponential increase on the largest and most popular microblogging website in China. Does a universal mechanism with a common set of dynamical rules exist, which can explain these empirically observed, distinct growth behaviors? We provide an affirmative answer in this paper. In particular, inspired by biomimicry to take advantage of cell population growth dynamics in microbial ecology, we construct a base growth model for meme popularity in OSNs. We then take into account human factors by incorporating a general model of human interest dynamics into the base model. The final hybrid model contains a small number of free parameters that can be estimated purely from data. We demonstrate that our model is universal in the sense that, with a few parameters estimated from data, it can successfully predict the distinct meme growth dynamics. Our study represents a successful effort to exploit principles in biology to understand online social behaviors by incorporating the traditional microbial growth model into meme popularity. Our model can be used to gain insights into critical issues such as classification, robustness, optimization, and control of OSN systems.

Brain Network Dynamics in Women With Primary Dysmenorrhea During the Pain-Free Periovulation Phase.

The human brain is a dynamic system that shows frequency-specific features. Neuroimaging studies have shown that both healthy individuals and those with chronic pain disorders experience pain influenced by various processes that fluctuate over time. Primary dysmenorrhea (PDM) is a chronic visceral pain that disrupts the coordinated activity of brain's functional network. However, it remains unclear whether the dynamic interactions across the whole-brain network over time and their associations with neurobehavioral symptoms are dependent on the frequency bands in patients with PDM during the pain-free periovulation phase. In this study, we used an energy landscape analysis to examine the interactions over time across the large-scale network in a sample of 59 patients with PDM and 57 healthy controls (HCs) at different frequency bands. Compared with HCs, patients with PDM exhibit aberrant brain dynamics, with more significant differences in the slow-4 frequency band. Patients with PDM show more indirect neural transition counts due to an unstable intermediate state, whereas neurotypical brain activity frequently transitions between 2 major states. This data-driven approach further revealed that the brains of individuals with PDM have more abnormal brain dynamics than HCs. Our results suggested that unstable brain dynamics were associated with the strength of brain functional segregation and the Pain Catastrophizing Scale score. Our findings provide preliminary evidence that atypical dynamics in the functional network may serve as a potential key feature and biological marker of patients with PDM during the pain-free phase. PERSPECTIVE: We applied energy landscape analysis on brain-imaging data to identify relatively stable and dominant brain activity patterns for patients with PDM. More atypical brain dynamics were found in the slow-4 band and were related to the strength of functional segregation, providing new insights into the dysfunction brain dynamics.

Persistent coexistence of cyclically competing species in spatially extended ecosystems.

A fundamental result in the evolutionary-game paradigm of cyclic competition in spatially extended ecological systems, as represented by the classic Reichenbach-Mobilia-Frey (RMF) model, is that high mobility tends to hamper or even exclude species coexistence. This result was obtained under the hypothesis that individuals move randomly without taking into account the suitability of their local environment. We incorporate local habitat suitability into the RMF model and investigate its effect on coexistence. In particular, we hypothesize the use of "basic instinct" of an individual to determine its movement at any time step. That is, an individual is more likely to move when the local habitat becomes hostile and is no longer favorable for survival and growth. We show that, when such local habitat suitability is taken into account, robust coexistence can emerge even in the high-mobility regime where extinction is certain in the RMF model. A surprising finding is that coexistence is accompanied by the occurrence of substantial empty space in the system. Reexamination of the RMF model confirms the necessity and the important role of empty space in coexistence. Our study implies that adaptation/movements according to local habitat suitability are a fundamental factor to promote species coexistence and, consequently, biodiversity.

Applying transcranial magnetic stimulation to rehabilitation of poststroke lower extremity function and an improvement: Individual-target TMS.

Stroke is the leading cause of disability globally in need of novel and effective methods of rehabilitation. Intermittent theta burst stimulation (iTBS) has been adopted as a Level B recommendation for lower limb spasticity in guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Nonetheless, the methodological differences and deficits of existing work bring about heterogenous results and therefore limit the universal clinical use of rTMS in lower extremity (LE) rehabilitation. The variation of stimulated targets across motor cortex contributes mainly to these heterogeneities. This narrative review includes studies of rTMS on LE motor function rehabilitation in patients after stroke until now. Some analyses of brain imaging and electromagnetic simulation and quantification through computational modeling were also performed. rTMS appears capable of fostering LE motor rehabilitation after stroke, but the actually stimulated targets are considerably bias making it difficult to confirm effectiveness. The main reason for this phenomenon is probably inaccurate targeting of motor cortical leg representation. An underlying updated method is proposed as Individual-Target TMS (IT-TMS) combined with brain imaging. rTMS is a promising validated method for LE function regaining. Future studies should systematically compare the effects of IT-TMS with traditional rTMS using large samples in random clinical trials. This article is categorized under: Neuroscience > Clinical Neuroscience.

Frequency dependent whole-brain coactivation patterns analysis in Alzheimer's disease.

Background: The brain in resting state has complex dynamic properties and shows frequency dependent characteristics. The frequency-dependent whole-brain dynamic changes of resting state across the scans have been ignored in Alzheimer's disease (AD). Objective: Coactivation pattern (CAP) analysis can identify different brain states. This paper aimed to investigate the dynamic characteristics of frequency dependent whole-brain CAPs in AD. Methods: We utilized a multiband CAP approach to model the state space and study brain dynamics in both AD and NC. The correlation between the dynamic characteristics and the subjects' clinical index was further analyzed. Results: The results showed similar CAP patterns at different frequency bands, but the occurrence of patterns was different. In addition, CAPs associated with the default mode network (DMN) and the ventral/dorsal visual network (dorsal/ventral VN) were altered significantly between the AD and NC groups. This study also found the correlation between the altered dynamic characteristics of frequency dependent CAPs and the patients' clinical Mini-Mental State Examination assessment scale scores. Conclusion: This study revealed that while similar CAP spatial patterns appear in different frequency bands, their dynamic characteristics in subbands vary. In addition, delineating subbands was more helpful in distinguishing AD from NC in terms of CAP.

Triple-network analysis of Alzheimer's disease based on the energy landscape.

Introduction: Research on the brain activity during resting state has found that brain activation is centered around three networks, including the default mode network (DMN), the salient network (SN), and the central executive network (CEN), and switches between multiple modes. As a common disease in the elderly, Alzheimer's disease (AD) affects the state transitions of functional networks in the resting state. Methods: Energy landscape, as a new method, can intuitively and quickly grasp the statistical distribution of system states and information related to state transition mechanisms. Therefore, this study mainly uses the energy landscape method to study the changes of the triple-network brain dynamics in AD patients in the resting state. Results: AD brain activity patterns are in an abnormal state, and the dynamics of patients with AD tend to be unstable, with an unusually high flexibility in switching between states. Also , the subjects' dynamic features are correlated with clinical index. Discussion: The atypical balance of large-scale brain systems in patients with AD is associated with abnormally active brain dynamics. Our study are helpful for further understanding the intrinsic dynamic characteristics and pathological mechanism of the resting-state brain in AD patients.

FGF binding protein 3 is required for spinal cord motor neuron development and regeneration in zebrafish.

Fibroblast growth factor binding protein 3 (Fgfbp3) have been known to be crucial for the process of neural proliferation, differentiation, migration, and adhesion. However, the specific role and the molecular mechanisms of fgfbp3 in regulating the development of motor neurons remain unclear. In this study, we have investigated the function of fgfbp3 in morphogenesis and regeneration of motor neuron in zebrafish. Firstly, we found that fgfbp3 was localized in the motor neurons and loss of fgfbp3 caused the significant decrease of the length and branching number of the motor neuron axons, which could be partially rescued by fgfbp3 mRNA injection. Moreover, the fgfbp3 knockdown (KD) embryos demonstrated similar defects of motor neurons as identified in fgfbp3 knockout (KO) embryos. Furthermore, we revealed that the locomotion and startle response of fgfbp3 KO embryos were significantly restricted, which were partially rescued by the fgfbp3 overexpression. In addition, fgfbp3 KO remarkably compromised axonal regeneration of motor neurons after injury. Lastly, the malformation of motor neurons in fgfbp3 KO embryos was rescued by overexpressing drd1b or neurod6a, respectively, which were screened by transcriptome sequencing. Taken together, our results provide strong cellular and molecular evidence that fgfbp3 is crucial for the axonal morphogenesis and regeneration of motor neurons in zebrafish.

Improved Functional Organization in Patients With Primary Insomnia After Individually-Targeted Transcranial Magnetic Stimulation.

Primary insomnia (PI) is among the most prevalent sleep-related disorders and has a far-reaching impact on daytime functioning. Repetitive transcranial magnetic stimulation (rTMS) has drawn attention because of its effectiveness and safety. The purpose of the current study was to detect changes in the topological organization of whole-brain functional networks and to determine their associations with the clinical treatment effects of rTMS. Resting-state functional magnetic resonance imaging (rsfMRI) data from 32 patients with PI were collected and compared with findings from 32 age- and gender-matched healthy controls (HCs). The patients were treated with Stanford accelerated intelligent neuromodulation therapy, which is a recently validated neuroscience-informed accelerated intermittent theta-burst stimulation protocol. Graph theoretical analysis was used to construct functional connectivity matrices and to extract the attribute features of small-world networks in insomnia. Scores on the Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and the associations between these clinical characteristics and functional metrics, were the primary outcomes. At baseline, the patients with PI showed inefficient small-world property and aberrant functional segregation and functional integration compared with the HCs. These properties showed renormalization after individualized rTMS treatment. Furthermore, low functional connectivity between the right insula and left medial frontal gyrus correlated with improvement in ISI scores. We highlight functional network dysfunctions in PI patients and provide evidence into the pathophysiological mechanisms involved and the possible mode of action of rTMS.

The longitudinal neural dynamics changes of whole brain connectome during natural recovery from poststroke aphasia.

Poststroke aphasia is one of the most dramatic functional deficits that results from direct damage of focal brain regions and dysfunction of large-scale brain networks. The reconstruction of language function depends on the hierarchical whole-brain dynamic reorganization. However, investigations into the longitudinal neural changes of large-scale brain networks for poststroke aphasia remain scarce. Here we characterize large-scale brain dynamics in left-frontal-stroke aphasia through energy landscape analysis. Using fMRI during an auditory comprehension task, we find that aphasia patients suffer serious whole-brain dynamics perturbation in the acute and subacute stages after stroke, in which the brains were restricted into two major activity patterns. Following spontaneous recovery process, the brain flexibility improved in the chronic stage. Critically, we demonstrated that the abnormal neural dynamics are correlated with the aberrant brain network coordination. Taken together, the energy landscape analysis exhibited that the acute poststroke aphasia has a constrained, low dimensional brain dynamics, which were replaced by less constrained and high dimensional dynamics at chronic aphasia. Our study provides a new perspective to profoundly understand the pathological mechanisms of poststroke aphasia.

Altered Small-World Functional Network Topology in Patients with Optic Neuritis: A Resting-State fMRI Study.

AIM: This study investigated changes in small-world topology and brain functional connectivity in patients with optic neuritis (ON) by resting-state functional magnetic resonance imaging (rs-fMRI) and based on graph theory. METHODS: A total of 21 patients with ON (8 males and 13 females) and 21 matched healthy control subjects (8 males and 13 females) were enrolled and underwent rs-fMRI. Data were preprocessed and the brain was divided into 116 regions of interest. Small-world network parameters and area under the integral curve (AUC) were calculated from pairwise brain interval correlation coefficients. Differences in brain network parameter AUCs between the 2 groups were evaluated with the independent sample t-test, and changes in brain connection strength between ON patients and control subjects were assessed by network-based statistical analysis. RESULTS: In the sparsity range from 0.08 to 0.48, both groups exhibited small-world attributes. Compared to the control group, global network efficiency, normalized clustering coefficient, and small-world value were higher whereas the clustering coefficient value was lower in ON patients. There were no differences in characteristic path length, local network efficiency, and normalized characteristic path length between groups. In addition, ON patients had lower brain functional connectivity strength among the rolandic operculum, medial superior frontal gyrus, insula, median cingulate and paracingulate gyri, amygdala, superior parietal gyrus, inferior parietal gyrus, supramarginal gyrus, angular gyrus, lenticular nucleus, pallidum, superior temporal gyrus, and cerebellum compared to the control group (P < 0.05). CONCLUSION: Patients with ON show typical "small world" topology that differed from that detected in HC brain networks. The brain network in ON has a small-world attribute but shows reduced and abnormal connectivity compared to normal subjects and likely causes symptoms of cognitive impairment.

The Requirement of Sox2 for the Spinal Cord Motor Neuron Development of Zebrafish.

Sex-determining region Y box 2 (Sox2), expressed in neural tissues, plays an important role as a transcription factor not only in the pluripotency and proliferation of neuronal cells but also in the opposite function of cell differentiation. Nevertheless, how Sox2 is linked to motor neuron development remains unknown. Here, we showed that Sox2 was localized in the motor neurons of spinal cord by in situ hybridization and cell separation, which acted as a positive regulator of motor neuron development. The deficiency of Sox2 in zebrafish larvae resulted in abnormal PMN development, including truncated but excessively branched CaP axons, loss of MiP, and increase of undifferentiated neuron cells. Importantly, transcriptome analysis showed that Sox2-depleted embryos caused many neurogenesis, axonogenesis, axon guidance, and differentiation-related gene expression changes, which further support the vital function of Sox2 in motor neuron development. Taken together, these data indicate that Sox2 plays a crucial role in the motor neuron development by regulating neuron differentiation and morphology of neuron axons.

Antifungal Mechanism of Dipicolinic Acid and Its Efficacy for the Biocontrol of Pear Valsa Canker.

Valsa pyri is a fatal canker pathogen that causes significant reduction of crop yield in pear orchards. V. pyri invades the trunk phloem, and is difficult to control by chemical treatment. In this work, it was found for the first time that Bacillus subtilis-produced dipicolinic acid (DPA) exhibits antifungal activity against different canker pathogens, including Alteraria alternata, Botryosphaeria dothidea, Rhizoctonia solani, and V. pyri. Growth inhibition of V. pyri was observed at less than 5 mM concentration (pH = 5.6). DPA showed the highest antifungal activity at acidic pH values and in the presence of bivalent metals, such as zinc(II), cobalt(II), and copper(II). Measurement of mRNA expression levels and scanning electron microscope (SEM) observations revealed that DPA causes V. pyri apoptosis via inhibition of chitin biosynthesis and subsequent cell lysis. Interestingly, DPA showed high stability in the pear bark and was able to cross the pear tree bark into the phloem, protecting the internal phases of the pear trunk. In preventive applications, DPA reduced the canker symptoms of V. pyri on Cuigan pear trees by 90%. Taken together, an efficient strategy for the management of V. pyri-caused canker disease was developed using a novel antifungal agent, DPA, with strong antifungal activity and particular diffusion properties.

Diversity of rationality affects the evolution of cooperation.

By modifying the Fermi updating rule, we present the diversity of individual rationality to the evolutionary prisoner's dilemma game, and our results shows that this diversity heavily influences the evolution of cooperation. Cluster-forming mechanism of cooperators can either be highly enhanced or severely deteriorated by different distributions of rationality. Slight change in the rationality distribution may transfer the whole system from the global absorbing state of cooperators to that of defectors. Based on mean-field argument, quantitative analysis of the stability of cooperative clusters reveals the critical role played by agents with moderate degree values in the evolution of the whole system. The inspiration from our work may provide us a deeper comprehension toward some social phenomena.