Organoids as preclinical models of human disease: progress and applications.

In the field of biomedical research, organoids represent a remarkable advancement that has the potential to revolutionize our approach to studying human diseases even before clinical trials. Organoids are essentially miniature 3D models of specific organs or tissues, enabling scientists to investigate the causes of diseases, test new drugs, and explore personalized medicine within a controlled laboratory setting. Over the past decade, organoid technology has made substantial progress, allowing researchers to create highly detailed environments that closely mimic the human body. These organoids can be generated from various sources, including pluripotent stem cells, specialized tissue cells, and tumor tissue cells. This versatility enables scientists to replicate a wide range of diseases affecting different organ systems, effectively creating disease replicas in a laboratory dish. This exciting capability has provided us with unprecedented insights into the progression of diseases and how we can develop improved treatments. In this paper, we will provide an overview of the progress made in utilizing organoids as preclinical models, aiding our understanding and providing a more effective approach to addressing various human diseases.

EEG brain network variability is correlated with other pathophysiological indicators of critical patients in neurology intensive care unit.

Continuous electroencephalogram (cEEG) plays a crucial role in monitoring and postoperative evaluation of critical patients with extensive EEG abnormalities. Recently, the temporal variability of dynamic resting-state functional connectivity has emerged as a novel approach to understanding the pathophysiological mechanisms underlying diseases. However, little is known about the underlying temporal variability of functional connections in critical patients admitted to neurology intensive care unit (NICU). Furthermore, considering the emerging field of network physiology that emphasizes the integrated nature of human organisms, we hypothesize that this temporal variability in brain activity may be potentially linked to other physiological functions. Therefore, this study aimed to investigate network variability using fuzzy entropy in 24-hour dynamic resting-state networks of critical patients in NICU, with an emphasis on exploring spatial topology changes over time. Our findings revealed both atypical flexible and robust architectures in critical patients. Specifically, the former exhibited denser functional connectivity across the left frontal and left parietal lobes, while the latter showed predominantly short-range connections within anterior regions. These patterns of network variability deviating from normality may underlie the altered network integrity leading to loss of consciousness and cognitive impairment observed in these patients. Additionally, we explored changes in 24-hour network properties and found simultaneous decreases in brain efficiency, heart rate, and blood pressure between approximately 1 pm and 5 pm. Moreover, we observed a close relationship between temporal variability of resting-state network properties and other physiological indicators including heart rate as well as liver and kidney function. These findings suggest that the application of a temporal variability-based cEEG analysis method offers valuable insights into underlying pathophysiological mechanisms of critical patients in NICU, and may present novel avenues for their condition monitoring, intervention, and treatment.

Feedback-related brain activity in individual decision: evidence from a gambling EEG study.

In this study, based on scalp electroencephalogram (EEG), we conducted cortical source localization and functional network analyses to investigate the underlying mechanism explaining the decision processes when individuals anticipate maximizing gambling benefits, particularly in situations where the decision outcomes are inconsistent with the profit goals. The findings shed light on the feedback monitoring process, wherein incongruity between outcomes and gambling goals triggers a more pronounced medial frontal negativity and activates the frontal lobe. Moreover, long-range theta connectivity is implicated in processing surprise and uncertainty caused by inconsistent feedback conditions, while middle-range delta coupling reflects a more intricate evaluation of feedback outcomes, which subsequently modifies individual decision-making for optimizing future rewards. Collectively, these findings deepen our comprehension of decision-making under circumstances where the profit goals are compromised by decision outcomes and provide electrophysiological evidence supporting adaptive adjustments in individual decision strategies to achieve maximum benefit.

The dynamic causality brain network reflects whether the working memory is solidified.

Working memory, which is foundational to higher cognitive function, is the "sketchpad of volitional control." Successful working memory is the inevitable outcome of the individual's active control and manipulation of thoughts and turning them into internal goals during which the causal brain processes information in real time. However, little is known about the dynamic causality among distributed brain regions behind thought control that underpins successful working memory. In our present study, given that correct responses and incorrect ones did not differ in either contralateral delay activity or alpha suppression, further rooting on the high-temporal-resolution EEG time-varying directed network analysis, we revealed that successful working memory depended on both much stronger top-down connections from the frontal to the temporal lobe and bottom-up linkages from the occipital to the temporal lobe, during the early maintenance period, as well as top-down flows from the frontal lobe to the central areas as the delay behavior approached. Additionally, the correlation between behavioral performance and casual interactions increased over time, especially as memory-guided delayed behavior approached. Notably, when using the network metrics as features, time-resolved multiple linear regression of overall behavioral accuracy was exactly achieved as delayed behavior approached. These results indicate that accurate memory depends on dynamic switching of causal network connections and shifting to more task-related patterns during which the appropriate intervention may help enhance memory.

Resting-state network predicts the decision-making behaviors of the proposer during the ultimatum game.

Objective. The decision-making behavior of the proposer is a key factor in achieving effective and equitable maintenance of social resources, particularly in economic interactions, and thus understanding the neurocognitive basis of the proposer's decision-making is a crucial issue. Yet the neural substrate of the proposer's decision behavior, especially from the resting-state network perspective, remains unclear.Approach. In this study, we investigated the relationship between the resting-state network and decision proposals and further established a multivariable model to predict the proposers' unfair offer rates in the ultimatum game.Main results.The results indicated the unfair offer rates of proposers are significantly related to the resting-state frontal-occipital and frontal-parietal connectivity in the delta band, as well as the network properties. And compared to the conservative decision group (low unfair offer rate), the risk decision group (high unfair offer rate) exhibited stronger resting-state long-range linkages. Finally, the established multivariable model did accurately predict the unfair offer rates of the proposers, along with a correlation coefficient of 0.466 between the actual and predicted behaviors.Significance. Together, these findings demonstrated that related resting-state frontal-occipital and frontal-parietal connectivity may serve as a dispositional indicator of the risky behaviors for the proposers and subsequently predict a highly complex decision-making behavior, which contributed to the development of artificial intelligence decision-making system with biological characteristics as well.

Altered dynamic network interactions in children with ASD during face recognition revealed by time-varying EEG networks.

Although the electrophysiological event-related potential in face processing (e.g. N170) is widely accepted as a face-sensitivity biomarker that is deficient in children with autism spectrum disorders, the time-varying brain networks during face recognition are still awaiting further investigation. To explore the social deficits in autism spectrum disorder, especially the time-varying brain networks during face recognition, the current study analyzed the N170, cortical activity, and time-varying networks under 3 tasks (face-upright, face-inverted, and house-upright) in autism spectrum disorder and typically developing children. The results revealed a smaller N170 amplitude in autism spectrum disorder compared with typically developing, along with decreased cortical activity mainly in occipitotemporal areas. Concerning the time-varying networks, the atypically stronger information flow and brain network connections across frontal, parietal, and temporal regions in autism spectrum disorder were reported, which reveals greater effort was exerted by autism spectrum disorder to obtain comparable performance to the typically developing children, although the amplitude of N170 was still smaller than that of the typically developing children. Different brain activation states and interaction patterns of brain regions during face processing were discovered between autism spectrum disorder and typically developing. These findings shed light on the face-processing mechanisms in children with autism spectrum disorder and provide new insight for understanding the social dysfunction of autism spectrum disorder.

Brain rhythmic abnormalities in convalescent patients with anti-NMDA receptor encephalitis: a resting-state EEG study.

Objective: Anti-N-methyl-D-aspartate receptor encephalitis (anti-NMDARE) is autoimmune encephalitis with a characteristic neuropsychiatric syndrome and persistent cognition deficits even after clinical remission. The objective of this study was to uncover the potential noninvasive and quantified biomarkers related to residual brain distortions in convalescent anti-NMDARE patients. Methods: Based on resting-state electroencephalograms (EEG), both power spectral density (PSD) and brain network analysis were performed to disclose the persistent distortions of brain rhythms in these patients. Potential biomarkers were then established to distinguish convalescent patients from healthy controls. Results: Oppositely configured spatial patterns in PSD and network architecture within specific rhythms were identified, as the hyperactivated PSD spanning the middle and posterior regions obstructs the inter-regional information interactions in patients and thereby leads to attenuated frontoparietal and frontotemporal connectivity. Additionally, the EEG indexes within delta and theta rhythms were further clarified to be objective biomarkers that facilitated the noninvasive recognition of convalescent anti-NMDARE patients from healthy populations. Conclusion: Current findings contributed to understanding the persistent and residual pathological states in convalescent anti-NMDARE patients, as well as informing clinical decisions of prognosis evaluation.

Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.

Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.

Auditory Dominance in Processing Chinese Semantic Abnormalities in Response to Competing Audio-visual Stimuli.

Language is a remarkable cognitive ability that can be expressed through visual (written language) or auditory (spoken language) modalities. When visual characters and auditory speech convey conflicting information, individuals may selectively attend to either one of them. However, the dominant modality in such a competing situation and the neural mechanism underlying it are still unclear. Here, we presented participants with Chinese sentences in which the visual characters and auditory speech convey conflicting information, while behavioral and electroencephalographic (EEG) responses were recorded. Results showed a prominent auditory dominance when audio-visual competition occurred. Specifically, higher accuracy (ACC), larger N400 amplitudes and more linkages in the posterior occipital-parietal areas were demonstrated in the auditory mismatch condition compared to that in the visual mismatch condition. Our research illustrates the superiority of the auditory speech over the visual characters, extending our understanding of the neural mechanisms of audio-visual competition in Chinese.

Electroencephalographic Network Topologies Predict Antidepressant Responses in Patients With Major Depressive Disorder.

Medication therapy seems to be an effective treatment for major depressive disorder (MDD). However, although the efficacies of various medicines are equal or similar on average, they vary widely among individuals. Therefore, an understanding of methods for the timely evaluation of short-term therapeutic response and prediction of symptom improvement after a specific course of medication at the individual level at the initial stage of treatment is very important. In our present study, we sought to identify a neurobiological signature of the response to short-term antidepressant treatment. Related brain network analysis was applied in resting-state electroencephalogram (EEG) datasets from patients with MDD. The corresponding EEG networks were constructed accordingly and then quantitatively measured to predict the efficacy after eight weeks of medication, as well as to distinguish the therapeutic responders from non-responders. The results of our present study revealed that the corresponding resting-state EEG networks became significantly weaker after one week of treatment, and the eventual medication efficacy was reliably predicted using the changes in those network properties within the one-week medication regimen. Moreover, the corresponding resting-state networks at baseline were also proven to precisely distinguish those responders from other individuals with an accuracy of 96.67% when using the spatial network topologies as the discriminative features. These findings consistently provide a deeper neurobiological understanding of antidepressant treatment and a reliable and quantitative approach for personalized treatment of MDD.

Predicting the Symptom Severity in Autism Spectrum Disorder Based on EEG Metrics.

Autism spectrum disorder (ASD) is associated with the impaired integrating and segregating of related information that is expanded within the large-scale brain network. The varying ASD symptom severities have been explored, relying on their behaviors and related brain activity, but how to effectively predict ASD symptom severity needs further exploration. In this study, we aim to investigate whether the ASD symptom severity could be predicted with electroencephalography (EEG) metrics. Based on a publicly available dataset, the EEG brain networks were constructed, and four types of EEG metrics were calculated. Then, we statistically compared the brain network differences among ASD children with varying severities, i.e., high/low autism diagnostic observation schedule (ADOS) scores, as well as with the typically developing (TD) children. Thereafter, the EEG metrics were utilized to validate whether they could facilitate the prediction of the ASD symptom severity. The results demonstrated that both high- and low-scoring ASD children showed the decreased long-range frontal-occipital connectivity, increased anterior frontal connectivity and altered network properties. Furthermore, we found that the four types of EEG metrics are significantly correlated with the ADOS scores, and their combination can serve as the features to effectively predict the ASD symptom severity. The current findings will expand our knowledge of network dysfunction in ASD children and provide new EEG metrics for predicting the symptom severity.

The Task-Dependent Modular Covariance Networks Unveiled by Multiple-Way Fusion-Based Analysis.

Cognitive processes induced by the specific task are underpinned by intrinsic anatomical structures with functional neural activation patterns. However, current covariance network analysis still pays much attention to brain morphologies or baseline activity due to the lack of an effective method for capturing the structural-functional covarying during tasks. Here, a multimodal covariance network (MCN) construction method was proposed to identify inter-regional covariations of the structural skeleton and functional activities by simultaneous magnetic resonance imaging and electroencephalogram (EEG). Results from two independent cohorts confirmed that MCNs could capture cognition-specific hierarchical modules in joint comprehensive multimodal features well, especially when time-resolved EEG was further integrated. The quantitative evaluation further demonstrates significantly larger modularity of MCN integrating fine-grained features from EEG. The application to the discovery cohort identified prominent modular covarying across the default mode and salience networks at rest, while the visual oddball task was accomplished by synchronous structural-functional cooperation within networks associated with attention control and working memory updating. Strikingly, the results of an external validation cohort showed a different covariant pattern corresponding to decision-specific cognitive modules. Overall, the results suggested that multimodal covariance analysis provides a reliable definition of multistate neural cognitive networks, further discloses modular-specific structural and functional co-variation.

Altered temporal variability in brain functional connectivity identified by fuzzy entropy underlines schizophrenia deficits.

Investigation of the temporal variability of resting-state brain networks informs our understanding of how neural connectivity aggregates and disassociates over time, further shedding light on the aberrant neural interactions that underlie symptomatology and psychosis development. In the current work, an electroencephalogram-based sliding window analysis was utilized for the first time to measure the nonlinear complexity of dynamic resting-state brain networks of schizophrenia (SZ) patients by applying fuzzy entropy. The results of this study demonstrated the attenuated temporal variability among multiple electrodes that were distributed in the frontal and right parietal lobes for SZ patients when compared with healthy controls (HCs). Meanwhile, a concomitant strengthening of the posterior and peripheral flexible connections that may be attributed to the excessive alertness or sensitivity of SZ patients to the external environment was also revealed. These temporal fluctuation distortions combined reflect an abnormality in the coordination of functional network switching in SZ, which is further the source of worse task performance (i.e., P300 amplitude) and the negative relationship between individual complexity metrics and P300 amplitude. Notably, when using the network metrics as features, multiple linear regressions of P300 amplitudes were also exactly achieved for both the SZ and HC groups. These findings shed light on the pathophysiological mechanisms of SZ from a temporal variability perspective and provide potential biomarkers for quantifying SZ's progressive neurophysiological deterioration.

Rehabilitation of motor function in children with cerebral palsy based on motor imagery.

To promote the rehabilitation of motor function in children with cerebral palsy (CP), we developed motor imagery (MI) based training system to assist their motor rehabilitation. Eighteen CP children, ten in short- and eight in long-term rehabilitation, participated in our study. In short-term rehabilitation, every 2 days, the MI datasets were collected; whereas the duration of two adjacency MI experiments was ten days in the long-term protocol. Meanwhile, within two adjacency experiments, CP children were requested to daily rehabilitate the motor function based on our system for 30 min. In both strategies, the promoted motor information processing was observed. In terms of the relative signal power spectra, a main effect of time was revealed, as the promoted power spectra were found for the last time of MI recording, compared to that of the first one, which first validated the effectiveness of our intervention. Moreover, as for network efficiency related to the motor information processing, compared to the first MI, the increased network properties were found for the last MI, especially in long-term rehabilitation in which CP children experienced a more obvious efficiency promotion. These findings did validate that our MI-based rehabilitation system has the potential for CP children to assist their motor rehabilitation.