Current research in neurobiology最新文献

{"title":"Microscale multicircuit brain stimulation: Achieving real-time brain state control for novel applications","authors":"Yuri B. Saalmann ,&nbsp;Sima Mofakham ,&nbsp;Charles B. Mikell ,&nbsp;Petar M. Djuric","doi":"10.1016/j.crneur.2022.100071","DOIUrl":"10.1016/j.crneur.2022.100071","url":null,"abstract":"<div><p>Neurological and psychiatric disorders typically result from dysfunction across multiple neural circuits. Most of these disorders lack a satisfactory neuromodulation treatment. However, deep brain stimulation (DBS) has been successful in a limited number of disorders; DBS typically targets one or two brain areas with single contacts on relatively large electrodes, allowing for only coarse modulation of circuit function. Because of the dysfunction in distributed neural circuits – each requiring fine, tailored modulation – that characterizes most neuropsychiatric disorders, this approach holds limited promise. To develop the next generation of neuromodulation therapies, we will have to achieve fine-grained, closed-loop control over multiple neural circuits. Recent work has demonstrated spatial and frequency selectivity using microstimulation with many small, closely-spaced contacts, mimicking endogenous neural dynamics. Using custom electrode design and stimulation parameters, it should be possible to achieve bidirectional control over behavioral outcomes, such as increasing or decreasing arousal during central thalamic stimulation. Here, we discuss one possible approach, which we term microscale multicircuit brain stimulation (MMBS). We discuss how machine learning leverages behavioral and neural data to find optimal stimulation parameters across multiple contacts, to drive the brain towards desired states associated with behavioral goals. We expound a mathematical framework for MMBS, where behavioral and neural responses adjust the model in real-time, allowing us to adjust stimulation in real-time. These technologies will be critical to the development of the next generation of neurostimulation therapies, which will allow us to treat problems like disorders of consciousness and cognition.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"4 ","pages":"Article 100071"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9816916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10564607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Layer-specific correlates of detected and undetected auditory targets during attention","authors":"Miriam Heynckes ,&nbsp;Agustin Lage-Castellanos ,&nbsp;Peter De Weerd ,&nbsp;Elia Formisano ,&nbsp;Federico De Martino","doi":"10.1016/j.crneur.2023.100075","DOIUrl":"10.1016/j.crneur.2023.100075","url":null,"abstract":"<div><p>In everyday life, the processing of acoustic information allows us to react to subtle changes in the auditory scene. Yet even when closely attending to sounds in the context of a task, we occasionally miss task-relevant features. The neural computations that underlie our ability to detect behavioral relevant sound changes are thought to be grounded in both feedforward and feedback processes within the auditory hierarchy. Here, we assessed the role of feedforward and feedback contributions in primary and non-primary auditory areas during behavioral detection of target sounds using submillimeter spatial resolution functional magnetic resonance imaging (fMRI) at high-fields (7 T) in humans. We demonstrate that the successful detection of subtle temporal shifts in target sounds leads to a selective increase of activation in superficial layers of primary auditory cortex (PAC). These results indicate that feedback signals reaching as far back as PAC may be relevant to the detection of targets in the auditory scene.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"4 ","pages":"Article 100075"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9a/ba/main.PMC9900365.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10742047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytes: Role in pathogenesis and effect of commonly misused drugs in the HIV infected brain","authors":"Jessalyn Pla-Tenorio ,&nbsp;Angela M. Roig ,&nbsp;Paulina A. García-Cesaní ,&nbsp;Luis A. Santiago ,&nbsp;Marian T. Sepulveda-Orengo ,&nbsp;Richard J. Noel Jr.","doi":"10.1016/j.crneur.2023.100108","DOIUrl":"https://doi.org/10.1016/j.crneur.2023.100108","url":null,"abstract":"<div><p>The roles of astrocytes as reservoirs and producers of a subset of viral proteins in the HIV infected brain have been studied extensively as a key to understanding HIV-associated neurocognitive disorders (HAND). However, their comprehensive role in the context of intersecting substance use and neurocircuitry of the reward pathway and HAND has yet to be fully explained. Use of methamphetamines, cocaine, or opioids in the context of HIV infection have been shown to lead to a faster progression of HAND. Glutamatergic, dopaminergic, and GABAergic systems are implicated in the development of HAND-induced cognitive impairments. A thorough review of scientific literature exploring the variety of mechanisms in which these drugs exert their effects on the HIV brain and astrocytes has revealed marked areas of convergence in overexcitation leading to increased drug-seeking behavior, inflammation, apoptosis, and irreversible neurotoxicity. The present review investigates astrocytes, the neural pathways, and mechanisms of drug disruption that ultimately play a larger holistic role in terms of HIV progression and drug use. There are opportunities for future research, therapeutic intervention, and preventive strategies to diminish HAND in the subset population of patients with HIV and substance use disorder.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"5 ","pages":"Article 100108"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49774771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The SARS-CoV-2 spike glycoprotein interacts with MAO-B and impairs mitochondrial energetics","authors":"Chantal A. Pileggi ,&nbsp;Gaganvir Parmar ,&nbsp;Hussein Elkhatib ,&nbsp;Corina M. Stewart ,&nbsp;Irina Alecu ,&nbsp;Marceline Côté ,&nbsp;Steffany A.L. Bennett ,&nbsp;Jagdeep K. Sandhu ,&nbsp;Miroslava Cuperlovic-Culf ,&nbsp;Mary-Ellen Harper","doi":"10.1016/j.crneur.2023.100112","DOIUrl":"https://doi.org/10.1016/j.crneur.2023.100112","url":null,"abstract":"<div><p>SARS-CoV-2 infection is associated with both acute and post-acute neurological symptoms. Emerging evidence suggests that SARS-CoV-2 can alter mitochondrial metabolism, suggesting that changes in brain metabolism may contribute to the development of acute and post-acute neurological complications. Monoamine oxidase B (MAO-B) is a flavoenzyme located on the outer mitochondrial membrane that catalyzes the oxidative deamination of monoamine neurotransmitters. Computational analyses have revealed high similarity between the SARS-CoV-2 spike glycoprotein receptor binding domain on the ACE2 receptor and MAO-B, leading to the hypothesis that SARS-CoV-2 spike glycoprotein may alter neurotransmitter metabolism by interacting with MAO-B. Our results empirically establish that the SARS-CoV-2 spike glycoprotein interacts with MAO-B, leading to increased MAO-B activity in SH-SY5Y neuron-like cells. Common to neurodegenerative disease pathophysiological mechanisms, we also demonstrate that the spike glycoprotein impairs mitochondrial bioenergetics, induces oxidative stress, and perturbs the degradation of depolarized aberrant mitochondria through mitophagy. Our findings also demonstrate that SH-SY5Y neuron-like cells expressing the SARS-CoV-2 spike protein were more susceptible to MPTP-induced necrosis, likely necroptosis. Together, these results reveal novel mechanisms that may contribute to SARS-CoV-2-induced neurodegeneration.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"5 ","pages":"Article 100112"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49780847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic structural remodeling of the human visual system prompted by bilateral retinal gene therapy","authors":"Manzar Ashtari ,&nbsp;Philip Cook ,&nbsp;Mikhail Lipin ,&nbsp;Yinxi Yu ,&nbsp;Gui-Shuang Ying ,&nbsp;Albert Maguire ,&nbsp;Jean Bennett ,&nbsp;James Gee ,&nbsp;Hui Zhang","doi":"10.1016/j.crneur.2023.100089","DOIUrl":"10.1016/j.crneur.2023.100089","url":null,"abstract":"<div><p>The impact of changes in visual input on neuronal circuitry is complex and much of our knowledge on human brain plasticity of the visual systems comes from animal studies. Reinstating vision in a group of patients with low vision through retinal gene therapy creates a unique opportunity to dynamically study the underlying process responsible for brain plasticity. Historically, increases in the axonal myelination of the visual pathway has been the biomarker for brain plasticity. Here, we demonstrate that to reach the long-term effects of myelination increase, the human brain may undergo demyelination as part of a plasticity process. The maximum change in dendritic arborization of the primary visual cortex and the neurite density along the geniculostriate tracks occurred at three months (3MO) post intervention, in line with timing for the peak changes in postnatal synaptogenesis within the visual cortex reported in animal studies. The maximum change at 3MO for both the gray and white matter significantly correlated with patients’ clinical responses to light stimulations called full field sensitivity threshold (FST). Our results shed a new light on the underlying process of brain plasticity by challenging the concept of increase myelination being the hallmark of brain plasticity and instead reinforcing the idea of signal speed optimization as a dynamic process for brain plasticity.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"4 ","pages":"Article 100089"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/27/b3/main.PMC10313860.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9745786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subcortical coding of predictable and unsupervised sound-context associations","authors":"Chi Chen ,&nbsp;Hugo Cruces-Solís ,&nbsp;Alexandra Ertman ,&nbsp;Livia de Hoz","doi":"10.1016/j.crneur.2023.100110","DOIUrl":"https://doi.org/10.1016/j.crneur.2023.100110","url":null,"abstract":"<div><p>Our environment is made of a myriad of stimuli present in combinations often patterned in predictable ways. For example, there is a strong association between where we are and the sounds we hear. Like many environmental patterns, sound-context associations are learned implicitly, in an unsupervised manner, and are highly informative and predictive of normality. Yet, we know little about where and how unsupervised sound-context associations are coded in the brain. Here we measured plasticity in the auditory midbrain of mice living over days in an enriched task-less environment in which entering a context triggered sound with different degrees of predictability. Plasticity in the auditory midbrain, a hub of auditory input and multimodal feedback, developed over days and reflected learning of contextual information in a manner that depended on the predictability of the sound-context association and not on reinforcement. Plasticity manifested as an increase in response gain and tuning shift that correlated with a general increase in neuronal frequency discrimination. Thus, the auditory midbrain is sensitive to unsupervised predictable sound-context associations, revealing a subcortical engagement in the detection of contextual sounds. By increasing frequency resolution, this detection might facilitate the processing of behaviorally relevant foreground information described to occur in cortical auditory structures.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"5 ","pages":"Article 100110"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49899182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implicit auditory memory in older listeners: From encoding to 6-month retention","authors":"Roberta Bianco ,&nbsp;Edward T.R. Hall ,&nbsp;Marcus T. Pearce ,&nbsp;Maria Chait","doi":"10.1016/j.crneur.2023.100115","DOIUrl":"https://doi.org/10.1016/j.crneur.2023.100115","url":null,"abstract":"<div><p>Any listening task, from sound recognition to sound-based communication, rests on auditory memory which is known to decline in healthy ageing. However, how this decline maps onto multiple components and stages of auditory memory remains poorly characterised. In an online unsupervised longitudinal study, we tested ageing effects on implicit auditory memory for rapid tone patterns. The test required participants (younger, aged 20–30, and older adults aged 60–70) to quickly respond to rapid regularly repeating patterns emerging from random sequences. Patterns were novel in most trials (REGn), but unbeknownst to the participants, a few distinct patterns reoccurred identically throughout the sessions (REGr). After correcting for processing speed, the response times (RT) to REGn should reflect the information held in echoic and short-term memory before detecting the pattern; long-term memory formation and retention should be reflected by the RT advantage (RTA) to REGr vs REGn which is expected to grow with exposure. Older participants were slower than younger adults in detecting REGn and exhibited a smaller RTA to REGr. Computational simulations using a model of auditory sequence memory indicated that these effects reflect age-related limitations both in early and long-term memory stages. In contrast to ageing-related accelerated forgetting of verbal material, here older adults maintained stable memory traces for REGr patterns up to 6 months after the first exposure. The results demonstrate that ageing is associated with reduced short-term memory and long-term memory formation for tone patterns, but not with forgetting, even over surprisingly long timescales.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"5 ","pages":"Article 100115"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2665945X23000438/pdfft?md5=53fdf11172fa5e518c3696cf7a910c0b&pid=1-s2.0-S2665945X23000438-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134654036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Order of statistical learning depends on perceptive uncertainty","authors":"Tatsuya Daikoku ,&nbsp;Masato Yumoto","doi":"10.1016/j.crneur.2023.100080","DOIUrl":"10.1016/j.crneur.2023.100080","url":null,"abstract":"<div><p>Statistical learning (SL) is an innate mechanism by which the brain automatically encodes the <em>n</em>-th order transition probability (TP) of a sequence and grasps the uncertainty of the TP distribution. Through SL, the brain predicts a subsequent event (<em>e</em>_<em>n+1</em>) based on the preceding events (<em>e</em>_<em>n</em>) that have a length of “<em>n”</em>. It is now known that uncertainty modulates prediction in top-down processing by the human predictive brain. However, the manner in which the human brain modulates the order of SL strategies based on the degree of uncertainty remains an open question. The present study examined how uncertainty modulates the neural effects of SL and whether differences in uncertainty alter the order of SL strategies. It used auditory sequences in which the uncertainty of sequential information is manipulated based on the conditional entropy. Three sequences with different TP ratios of 90:10, 80:20, and 67:33 were prepared as low-, intermediate, and high-uncertainty sequences, respectively (conditional entropy: 0.47, 0.72, and 0.92 bit, respectively). Neural responses were recorded when the participants listened to the three sequences. The results showed that stimuli with lower TPs elicited a stronger neural response than those with higher TPs, as demonstrated by a number of previous studies. Furthermore, we found that participants adopted higher-order SL strategies in the high uncertainty sequence. These results may indicate that the human brain has an ability to flexibly alter the order based on the uncertainty. This uncertainty may be an important factor that determines the order of SL strategies. Particularly, considering that a higher-order SL strategy mathematically allows the reduction of uncertainty in information, we assumed that the brain may take higher-order SL strategies when encountering high uncertain information in order to reduce the uncertainty. The present study may shed new light on understanding individual differences in SL performance across different uncertain situations.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"4 ","pages":"Article 100080"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9188422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural substrates of perception in the vestibular thalamus during natural self-motion: A review","authors":"Kathleen E. Cullen ,&nbsp;Maurice J. Chacron","doi":"10.1016/j.crneur.2023.100073","DOIUrl":"10.1016/j.crneur.2023.100073","url":null,"abstract":"<div><p>Accumulating evidence across multiple sensory modalities suggests that the thalamus does not simply relay information from the periphery to the cortex. Here we review recent findings showing that vestibular neurons within the ventral posteriolateral area of the thalamus perform nonlinear transformations on their afferent input that determine our subjective awareness of motion. Specifically, these neurons provide a substrate for previous psychophysical observations that perceptual discrimination thresholds are much better than predictions from Weber's law. This is because neural discrimination thresholds, which are determined from both variability and sensitivity, initially increase but then saturate with increasing stimulus amplitude, thereby matching the previously observed dependency of perceptual self-motion discrimination thresholds. Moreover, neural response dynamics give rise to unambiguous and optimized encoding of natural but not artificial stimuli. Finally, vestibular thalamic neurons selectively encode passively applied motion when occurring concurrently with voluntary (i.e., active) movements. Taken together, these results show that the vestibular thalamus plays an essential role towards generating motion perception as well as shaping our vestibular sense of agency that is not simply inherited from afferent input.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"4 ","pages":"Article 100073"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9451849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thalamic nuclei changes in early and late onset Alzheimer's disease","authors":"Gonzalo Forno ,&nbsp;Manojkumar Saranathan ,&nbsp;Jose Contador ,&nbsp;Nuria Guillen ,&nbsp;Neus Falgàs ,&nbsp;Adrià Tort-Merino ,&nbsp;Mircea Balasa ,&nbsp;Raquel Sanchez-Valle ,&nbsp;Michael Hornberger ,&nbsp;Albert Lladó","doi":"10.1016/j.crneur.2023.100084","DOIUrl":"10.1016/j.crneur.2023.100084","url":null,"abstract":"<div><p>Alzheimer's disease (AD) is the most common cause of dementia worldwide. Increasing evidence points to the thalamus as an important hub in the clinical symptomatology of the disease, with the ‘limbic thalamus’ been described as especially vulnerable. In this work, we examined thalamic atrophy in early-onset AD (EOAD) and late-onset AD (LOAD) compared to young and old healthy controls (YHC and OHC, respectively) using a recently developed cutting-edge thalamic nuclei segmentation method. A deep learning variant of Thalamus Optimized Multi Atlas Segmentation (THOMAS) was used to parcellate 11 thalamic nuclei per hemisphere from T1-weighted MRI in 88 biomarker-confirmed AD patients (49 EOAD and 39 LOAD) and 58 healthy controls (41 YHC and 17 OHC) with normal AD biomarkers. Nuclei volumes were compared among groups using MANCOVA. Further, Pearson's correlation coefficient was computed between thalamic nuclear volume and cortical—subcortical regions, CSF tau levels, and neuropsychological scores. The results showed widespread thalamic nuclei atrophy in EOAD and LOAD compared to their respective healthy control groups, with EOAD showing additional atrophy in the centromedian and ventral lateral posterior nuclei compared to YHC. In EOAD, increased thalamic nuclei atrophy was associated with posterior parietal atrophy and worse visuospatial abilities, while LOAD thalamic nuclei atrophy was preferentially associated with medial temporal atrophy and worse episodic memory and executive function. Our findings suggest that thalamic nuclei may be differentially affected in AD according to the age at symptoms onset, associated with specific cortical—subcortical regions, CSF total tau and cognition.</p></div>","PeriodicalId":72752,"journal":{"name":"Current research in neurobiology","volume":"4 ","pages":"Article 100084"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/71/12/main.PMC10313877.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9737076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}