Shenzhen Institute of Neuroscience

Neuroimaging has evolved into a widely used method to investigate the functional neuroanatomy, brain-behaviour relationships, and pathophysiology of brain disorders, yielding a literature of more than 30,000 papers. With such an explosion of data, it is increasingly difficult to sift through the literature and distinguish spurious from replicable findings. Furthermore, due to the large number of studies, it is challenging to keep track of the wealth of findings. A variety of meta-analytical methods (coordinate-based and image-based) have been developed to help summarise and integrate the vast amount of data arising from neuroimaging studies. However, the field lacks specific guidelines for the conduct of such meta-analyses. Based on our combined experience, we propose best-practice recommendations that researchers from multiple disciplines may find helpful. In addition, we provide specific guidelines and a checklist that will hopefully improve the transparency, traceability, replicability and reporting of meta-analytical results of neuroimaging data.

Cryogenic electron tomography (cryoET) allows visualization of cellular structures in situ. However, anisotropic resolution arising from the intrinsic "missing-wedge" problem has presented major challenges in visualization and interpretation of tomograms. Here, we have developed IsoNet, a deep learning-based software package that iteratively reconstructs the missing-wedge information and increases signal-to-noise ratio, using the knowledge learned from raw tomograms. Without the need for sub-tomogram averaging, IsoNet generates tomograms with significantly reduced resolution anisotropy. Applications of IsoNet to three representative types of cryoET data demonstrate greatly improved structural interpretability: resolving lattice defects in immature HIV particles, establishing architecture of the paraflagellar rod in Eukaryotic flagella, and identifying heptagon-containing clathrin cages inside a neuronal synapse of cultured cells. Therefore, by overcoming two fundamental limitations of cryoET, IsoNet enables functional interpretation of cellular tomograms without sub-tomogram averaging. Its application to high-resolution cellular tomograms should also help identify differently oriented complexes of the same kind for sub-tomogram averaging.

Gendicine (recombinant human p53 adenovirus), developed by Shenzhen SiBiono GeneTech Co. Ltd., was approved in 2003 by the China Food and Drug Administration (CFDA) as a first-in-class gene therapy product to treat head and neck cancer, and entered the commercial market in 2004. Gendicine is a biological therapy that is delivered via minimally invasive intratumoral injection, as well as by intracavity or intravascular infusion. The wild-type (wt) p53 protein expressed by Gendicine-transduced cells is a tumor suppressor that is activated by cellular stress, and mediates cell-cycle arrest and DNA repair, or induces apoptosis, senescence, and/or autophagy, depending upon cellular stress conditions. Based on 12 years of commercial use in >30,000 patients, and >30 published clinical studies, Gendicine has exhibited an exemplary safety record, and when combined with chemotherapy and radiotherapy has demonstrated significantly higher response rates than for standard therapies alone. In addition to head and neck cancer, Gendicine has been successfully applied to treat various other cancer types and different stages of disease. Thirteen published studies that include long-term survival data showed that Gendicine combination regimens yield progression-free survival times that are significantly longer than standard therapies alone. Although the p53 gene is mutated in >50% of all human cancers, p53 mutation status did not significantly influence efficacy outcomes and long-term survival rate for Ad- p53 -treated patients. To date, Shenzhen SiBiono GeneTech has manufactured 41 batches of Gendicine in compliance with CFDA QC/QA requirements, and 169,571 vials (1.0 × 10 12 vector particles per vial) have been used to treat patients. No serious adverse events have been reported, except for vector-associated transient fever, which occurred in 50–60% of patients and persisted for only a few hours. The manufacturing accomplishments and clinical experience with Gendicine, as well as the understanding of its cellular mechanisms of action and implications, could provide valuable insights for the international gene therapy community and add valuable data to promote further developments and advancements in the gene therapy field.

Background: Accumulating research demonstrates that the timing of exercise plays an important role in influencing episodic memory. However, we have a limited understanding as to the factors that moderate this temporal effect. Thus, the purpose of this systematic review with meta-analysis was to evaluate the effects of study characteristics (e.g., exercise modality, intensity and duration of acute exercise) and participant attributes (e.g., age, sex) across each of the temporal periods of acute exercise on episodic memory (i.e., acute exercise occurring before memory encoding, and during memory encoding, early consolidation, and late consolidation). Methods: The following databases were used for our computerized searches: Embase/PubMed, Web of Science, Google Scholar, Sports Discus and PsychInfo. Studies were included if they: (1) Employed an experimental design with a comparison to a control group/visit, (2) included human participants, (3) evaluated exercise as the independent variable, (4) employed an acute bout of exercise (defined as a single bout of exercise), (5) evaluated episodic memory as the outcome variable (defined as the retrospective recall of information either in a spatial or temporal manner), and (6) provided sufficient data (e.g., mean, SD, and sample size) for a pooled effect size estimate. Results: In total, 25 articles met our inclusionary criteria and were meta-analyzed. Acute exercise occurring before memory encoding (d = 0.11, 95% CI: −0.01, 0.23, p = 0.08), during early memory consolidation (d = 0.47, 95% CI: 0.28, 0.67; p < 0.001) and during late memory consolidation (d = 1.05, 95% CI: 0.32, 1.78; p = 0.005) enhanced episodic memory function. Conversely, acute exercise occurring during memory encoding had a negative effect on episodic memory (d = −0.12, 95% CI: −0.22, −0.02; p = 0.02). Various study designs and participant characteristics moderated the temporal effects of acute exercise on episodic memory function. For example, vigorous-intensity acute exercise, and acute exercise among young adults, had greater effects when the acute bout of exercise occurred before memory encoding or during the early memory consolidation period. Conclusions: The timing of acute exercise plays an important role in the exercise-memory interaction. Various exercise- and participant-related characteristics moderate this temporal relationship.

The dorsolateral prefrontal cortex (DLPFC) and ventrolateral PFC (VLPFC) are both crucial structures involved in voluntary emotional regulation. However, it remains unclear whether the functions of these two cortical regions that are involved in emotional regulation, which are usually active in non-social situations, could be generalized to the regulation of social pain as well. This study employed transcranial magnetic stimulation (TMS) to examine the causal relationship between the DLPFC/VLPFC and the emotional regulation of social pain via distraction and reappraisal. Ninety human participants (45 males and 45 females) initially underwent either active (DLPFC/VLPFC, n = 30/30) or sham (vertex, n = 30) TMS sessions. Participants were then instructed to use both distraction and reappraisal strategies to downregulate any negative emotions evoked by social exclusion pictures. Convergent results of the subjective emotional rating and electrophysiological indices demonstrated that: (1) both the DLPFC and VLPFC highly facilitate the downregulation of affective responses caused by social exclusion, revealing a causal role of these lateral PFCs in voluntary emotional regulation of both non-social and social pain; and (2) these two cortical regions showed relative functional specificity for distraction (DLPFC) and reappraisal (VLPFC) strategies, which helps to refine the cortical targeting of therapeutic protocols. In addition, the TMS effect was sustainable for at least 1 h, showcasing the potential feasibility of using this method in clinical practice. Together, these findings provide cognitive and neural evidence for the targeting of the VLPFC and/or the DLPFC to improve emotional regulation abilities, especially in social contexts. SIGNIFICANCE STATEMENT This study aimed to examine the role of the dorsolateral prefrontal cortex (DLPFC) and ventrolateral PFC (VLPFC) in emotional regulation, particularly in response to social pain through the use of distraction and reappraisal strategies, as this is a relatively underexplored area of inquiry. This study makes a significant contribution to the literature because our results provide novel empirical information on the role of these cortical structures in the processing of negative emotions elicited within certain social contexts. As such, our findings have potential clinical implications, paving the way for future clinicians to be able to accurately target specific brain regions among patients struggling with impaired social cognition abilities, including those diagnosed with posttraumatic stress disorder, autism spectrum disorder, social anxiety disorder, and depression.

Animal behavior usually has a hierarchical structure and dynamics. Therefore, to understand how the neural system coordinates with behaviors, neuroscientists need a quantitative description of the hierarchical dynamics of different behaviors. However, the recent end-to-end machine-learning-based methods for behavior analysis mostly focus on recognizing behavioral identities on a static timescale or based on limited observations. These approaches usually lose rich dynamic information on cross-scale behaviors. Here, inspired by the natural structure of animal behaviors, we address this challenge by proposing a parallel and multi-layered framework to learn the hierarchical dynamics and generate an objective metric to map the behavior into the feature space. In addition, we characterize the animal 3D kinematics with our low-cost and efficient multi-view 3D animal motion-capture system. Finally, we demonstrate that this framework can monitor spontaneous behavior and automatically identify the behavioral phenotypes of the transgenic animal disease model. The extensive experiment results suggest that our framework has a wide range of applications, including animal disease model phenotyping and the relationships modeling between the neural circuits and behavior.

Abstract cAMP is a key second messenger that regulates diverse cellular functions including neural plasticity. However, the spatiotemporal dynamics of intracellular cAMP in intact organisms are largely unknown due to low sensitivity and/or brightness of current genetically encoded fluorescent cAMP indicators. Here, we report the development of the new circularly permuted GFP (cpGFP)-based cAMP indicator G-Flamp1, which exhibits a large fluorescence increase (a maximum Δ F / F 0 of 1100% in HEK293T cells), decent brightness, appropriate affinity (a K d of 2.17 μM) and fast response kinetics (an association and dissociation half-time of 0.20 and 0.087 s, respectively). Furthermore, the crystal structure of the cAMP-bound G-Flamp1 reveals one linker connecting the cAMP-binding domain to cpGFP adopts a distorted β-strand conformation that may serve as a fluorescence modulation switch. We demonstrate that G-Flamp1 enables sensitive monitoring of endogenous cAMP signals in brain regions that are implicated in learning and motor control in living organisms such as fruit flies and mice.

A large body of previous neuroimaging studies suggests that multiple languages are processed and organized in a single neuroanatomical system in the bilingual brain, although differential activation may be seen in some studies because of different proficiency levels and/or age of acquisition of the two languages. However, one important possibility is that the two languages may involve interleaved but functionally independent neural populations within a given cortical region, and thus, distinct patterns of neural computations may be pivotal for the processing of the two languages. Using functional magnetic resonance imaging (fMRI) and multivariate pattern analyses, we tested this possibility in Chinese-English bilinguals when they performed an implicit reading task. We found a broad network of regions wherein the two languages evoked different patterns of activity, with only partially overlapping patterns of voxels in a given region. These regions, including the middle occipital cortices, fusiform gyri, and lateral temporal, temporoparietal, and prefrontal cortices, are associated with multiple aspects of language processing. The results suggest the functional independence of neural computations underlying the representations of different languages in bilinguals.

Teamwork is indispensable in human societies. However, due to the complexity of studying ecologically valid synchronous team actions, requiring multiple members and a range of subjective and objective measures, the mechanism underlying the impact of synchrony on team performance is still unclear. In this paper, we simultaneously measured groups of nine-participants' (total N = 180) fronto-temporal activations during a drum beating task using functional near infrared spectroscopy (fNIRS)-based hyperscanning and multi-brain network modeling, which can assess patterns of shared neural synchrony and attention/information sharing across entire teams. Participants (1) beat randomly without considering others' drumming (random condition), (2) actively coordinated their beats with the entire group without other external cue (team-focus condition), and (3) beat together based on a metronome (shared-focus condition). Behavioral data revealed higher subjective and objective measures of drum-beat synchronization in the team-focus condition, as well as higher felt interdependence. The fNIRS data revealed that participants in the team-focus condition also showed higher interpersonal neural synchronization (INS) and higher Global Network Efficiency in their left TPJ and mPFC. Higher left TPJ Global Network Efficiency also predicted higher actual synchrony in the team-focus condition, with an effect size roughly 1.5 times that of subjective measures, but not in the metronome-enabled shared-focus condition. This result suggests that shared mental representations with high efficiency of information exchange across the entire team may be a key component of synchrony, adding to the understanding of the actual relation to team work.

Impulsivity, which is linked to a wide range of psychiatric disorders, is often characterized by a preference for immediate but smaller rewards over delayed but larger rewards. However, debate exists on the relationship between anxiety and impulsivity. Here we use event-related potential (ERP) components as biomarkers in the temporal discounting task to examine the effect of anxiety on inter-temporal decision-making. Our behavioral results indicated that the high trait anxiety (HTA) group made significantly more immediate choices than the low trait anxiety (LTA) group. Compared with the LTA group, shorter response time was associated with immediate rewards in the HTA group. Furthermore, previous studies have demonstrated three ERP components that are associated with impulsivity and/or delay discounting. First, the N1 is an early sensory component involved in selective attention and attention processing for goal-directed actions. Second, the reward positivity (RewP) reflects reward-related dopaminergic activity and encodes reward values. Third, the P3 is regarded as a measure of motivational significance in the decision-making literature. Accordingly, this study found in the immediate-option-evoked ERPs that the HTA group had a larger N1 than the LTA group did. For the delayed-option-evoked ERPs, the HTA group had larger N1 and RewP for the immediate choice than the LTA group did, while the LTA group had a larger P3 for the delayed choice than the HTA group did. These results support the notion that anxiety individuals are impulsive decision-makers in the Delay Discounting Task.

Abstract The nucleus accumbens (NAc) is critical in mediating reward seeking and is also involved in negative emotion processing, but the cellular and circuitry mechanisms underlying such opposing behaviors remain elusive. Here, using the recently developed AAV1-mediated anterograde transsynaptic tagging technique in mice, we show that NAc neurons receiving basolateral amygdala inputs (NAc BLA ) promote positive reinforcement via disinhibiting dopamine neurons in the ventral tegmental area (VTA). In contrast, NAc neurons receiving paraventricular thalamic inputs (NAc PVT ) innervate GABAergic neurons in the lateral hypothalamus (LH) and mediate aversion. Silencing the synaptic output of NAc BLA neurons impairs reward seeking behavior, while silencing of NAc PVT or NAc PVT →LH pathway abolishes aversive symptoms of opiate withdrawal. Our results elucidate the afferent-specific circuit architecture of the NAc in controlling reward and aversion.

Anxiety-related illnesses are highly prevalent in human society. Being able to identify neurobiological markers signaling high trait anxiety could aid the assessment of individuals with high risk for mental illness. Here, we applied connectome-based predictive modeling (CPM) to whole-brain resting-state functional connectivity (rsFC) data to predict the degree of trait anxiety in 76 healthy participants. Using a computational "lesion" approach in CPM, we then examined the weights of the identified main brain areas as well as their connectivity. Results showed that the CPM successfully predicted individual anxiety based on whole-brain rsFC, especially the rsFC between limbic areas and prefrontal cortex. The prediction power of the model significantly decreased from simulated lesions of limbic areas, lesions of the connectivity within limbic areas, and lesions of the connectivity between limbic areas and prefrontal cortex. Importantly, this neural model generalized to an independent large sample (n = 501). These findings highlight important roles of the limbic system and prefrontal cortex in anxiety prediction. Our work provides evidence for the usefulness of connectome-based modeling in predicting individual personality differences and indicates its potential for identifying personality factors at risk for psychopathology.

Abstract Imbalances in NAD + homeostasis have been linked to aging and various diseases. Nicotine, a metabolite of the NAD + metabolic pathway, has been found to possess anti-inflammatory and neuroprotective properties, yet the underlying molecular mechanisms remained unknown. Here we find that, independent of nicotinic acetylcholine receptors, low-dose nicotine can restore the age-related decline of NAMPT activity through SIRT1 binding and subsequent deacetylation of NAMPT, thus increasing NAD + synthesis. 18 F-FDG PET imaging revealed that nicotine is also capable of efficiently inhibiting glucose hypermetabolism in aging male mice. Additionally, nicotine ameliorated cellular energy metabolism disorders and deferred age-related deterioration and cognitive decline by stimulating neurogenesis, inhibiting neuroinflammation, and protecting organs from oxidative stress and telomere shortening. Collectively, these findings provide evidence for a mechanism by which low-dose nicotine can activate NAD + salvage pathways and improve age-related symptoms.

The BrainMap database is a community resource that curates peer-reviewed, coordinate-based human neuroimaging literature. By pairing the results of neuroimaging studies with their relevant meta-data, BrainMap facilitates coordinate-based meta-analysis (CBMA) of the neuroimaging literature en masse or at the level of experimental paradigm, clinical disease, or anatomic location. Initially dedicated to the functional, task-activation literature, BrainMap is now expanding to include voxel-based morphometry (VBM) studies in a separate sector, titled: BrainMap VBM. VBM is a whole-brain, voxel-wise method that measures significant structural differences between or within groups which are reported as standardized, peak x-y-z coordinates. Here we describe BrainMap VBM, including the meta-data structure, current data volume, and automated reverse inference functions (region-to-disease profile) of this new community resource. CBMA offers a robust methodology for retaining true-positive and excluding false-positive findings across studies in the VBM literature. As with BrainMap's functional database, BrainMap VBM may be synthesized en masse or at the level of clinical disease or anatomic location. As a use-case scenario for BrainMap VBM, we illustrate a trans-diagnostic data-mining procedure wherein we explore the underlying network structure of 2,002 experiments representing over 53,000 subjects through independent components analysis (ICA). To reduce data-redundancy effects inherent to any database, we demonstrate two data-filtering approaches that proved helpful to ICA. Finally, we apply hierarchical clustering analysis (HCA) to measure network- and disease-specificity. This procedure distinguished psychiatric from neurological diseases. We invite the neuroscientific community to further exploit BrainMap VBM with other modeling approaches.

Loneliness is an increasingly prevalent condition linking with enhanced morbidity and premature mortality. Despite recent proposal on medicalization of loneliness, so far no effort has been made to establish a model capable of predicting loneliness at the individual level. Here, we applied a machine-learning approach to decode loneliness from whole-brain resting-state functional connectivity (RSFC). The relationship between whole-brain RSFC and loneliness was examined in a linear predictive model. The results revealed that individual loneliness could be predicted by within- and between-network connectivity of prefrontal, limbic and temporal systems, which are involved in cognitive control, emotional processing and social perceptions and communications, respectively. Key nodes that contributed to the prediction model comprised regions previously implicated in loneliness, including the dorsolateral prefrontal cortex, lateral orbital frontal cortex, ventromedial prefrontal cortex, caudate, amygdala and temporal regions. Our findings also demonstrated that both loneliness and associated neural substrates are modulated by levels of neuroticism and extraversion. The current data-driven approach provides the first evidence on the predictive brain features of loneliness based on organizations of intrinsic brain networks. Our work represents initial efforts in the direction of making individualized prediction of loneliness that could be useful for diagnosis, prognosis and treatment.

Background: Chronic low back pain (CLBP) is a common health issue worldwide. Tai Chi, Qigong, and Yoga, as the most widely practiced mindful exercises, have promising effects for CLBP-specific symptoms. Objective: We therefore conducted a comprehensive review investigating the effects of mindful exercises versus active and/or non-active controls while evaluating the safety and pain-related effects of mindful exercises in adults with CLBP. Methods: We searched five databases (MEDLINE, EMBASE, SCOPUS, Web of Science, and Cochrane Library) from inception to February 2019. Two investigators independently selected 17 eligible randomized controlled trials (RCT) against inclusion and exclusion criteria, followed by data extraction and study quality assessment. Standardized mean difference (SMD) was used to determine the magnitude of mindful exercises versus controls on pain- and disease-specific outcome measures. Results: As compared to control groups, we observed significantly favorable effects of mindful exercises on reducing pain intensity (SMD = −0.37, 95% CI −0.5 to −0.23, p < 0.001, I2 = 45.9 %) and disability (SMD = −0.39, 95% CI −0.49 to −0.28, p < 0.001, I2 = 0 %). When compared with active control alone, mindful exercises showed significantly reduced pain intensity (SMD = −0.40, p < 0.001). Furthermore, of the three mindful exercises, Tai Chi has a significantly superior effect on pain management (SMD= −0.75, 95% CI −1.05 to −0.46, p < 0.001), whereas Yoga-related adverse events were reported in five studies. Conclusion: Findings of our systematic review suggest that mindful exercises (Tai Chi and Qigong) may be beneficial for CLBP symptomatic management. In particular, Tai Chi appears to have a superior effect in reducing pain intensity irrespective of non-control comparison or active control comparison (conventional exercises, core training, and physical therapy programs). Importantly, training in these mindful exercises should be implemented with certified instructors to ensure quality of movement and injury prevention.

A highly sensitive and selective near-infrared excited potassium nanosensor has been developed for brain activity monitoring.

Narcissism is one of the most fundamental personality traits in which individuals in general population exhibit a large heterogeneity. Despite a surge of interest in examining behavioral characteristics of narcissism in the past decades, the neurobiological substrates underlying narcissism remain poorly understood. Here, we addressed this issue by applying a machine learning approach to decode trait narcissism from whole-brain resting-state functional connectivity (RSFC). Resting-state functional MRI (fMRI) data were acquired for a large sample comprising 155 healthy adults, each of whom was assessed for trait narcissism. Using a linear prediction model, we examined the relationship between whole-brain RSFC and trait narcissism. We demonstrated that the machine-learning model was able to decode individual trait narcissism from RSFC across multiple neural systems, including functional connectivity between and within limbic and prefrontal systems as well as their connectivity with other networks. Key nodes that contributed to the prediction model included the amygdala, prefrontal and anterior cingulate regions that have been linked to trait narcissism. These findings remained robust using different validation procedures. Our findings thus demonstrate that RSFC among multiple neural systems predicts trait narcissism at the individual level.

Functional near-infrared spectroscopy (fNIRS) is a fast-developing non-invasive functional brain imaging technology widely used in cognitive neuroscience, clinical research and neural engineering. However, it is a challenge to effectively remove the global physiological noise in the fNIRS signal. The global physiological noise in fNIRS arises from multiple physiological origins in both superficial tissues and the brain. It has complex temporal, spatial and frequency characteristics, casting significant influence on the results. In the present study, we developed a novel wavelet-based method for fNIRS global physiological noise removal. The method is data-driven and does not rely on any additional hardware or subjective noise component selection procedure. It consists of two steps. Firstly, we use wavelet transform coherence to automatically detect the time-frequency points contaminated by the global physiological noise. Secondly, we decompose the fNIRS signal by using the wavelet transform, and then suppress the wavelet energy of the contaminated time-frequency points. Finally, we transform the signal back to a time series. We validated the method by using simulation and real data at both task- and resting-state. The results showed that our method can effectively remove the global physiological noise from the fNIRS signal and improve the spatial specificity of the task activation and the resting-state functional connectivity pattern.

Alexithymia refers to deficiencies in identifying and expressing emotions. This might be related to changes in structural brain volumes, but its neuroanatomical basis remains uncertain as studies have shown heterogeneous findings. Therefore, we conducted a parametric coordinate-based meta-analysis. We identified seventeen structural neuroimaging studies (including a total of 2586 individuals with different levels of alexithymia) investigating the association between gray matter volume and alexithymia. Volumes of the left insula, left amygdala, orbital frontal cortex and striatum were consistently smaller in people with high levels of alexithymia. These areas are important for emotion perception and emotional experience. Smaller volumes in these areas might lead to deficiencies in appropriately identifying and expressing emotions. These findings provide the first quantitative integration of results pertaining to the structural neuroanatomical basis of alexithymia.