Neuroscience Insights最新文献

{"title":"Widespread neuronal activity related to bimanual coordination in non-human primates: evidence from Fos-like activation during bimanual versus unimanual motor task.","authors":"Yu Liu, Eric M Rouiller","doi":"10.1177/26331055251352807","DOIUrl":"10.1177/26331055251352807","url":null,"abstract":"<p><p>Electrophysiological data support the notion that spatial and temporal coordination between the forelimbs in primates takes place in a wide network of cortical and subcortical brain structures. However, single neuron electrophysiology is biased towards large, long distance projecting neurons. The aim of the present study was to assess whether the same neural network is involved when small and medium size neurons are considered. To address this issue, neuronal activity with cellular resolution was investigated and quantified using the c-fos mapping technique, targeting small and medium size diameter neurons, in adult non-human primates. Two male macaque monkeysⁱ were trained to perform a reach and grasp drawer task, executed either bimanually (BIM) or unimanually (UNI). Extensive single unit electrophysiological recordings were conducted in these two monkeys over a two-year period, preceding a final terminal c-fos session during which one monkey (Mk-1) performed exclusively the BIM task, while the second monkey (Mk-2) performed the UNI task only (250 trials each). One additional monkey (control Mk-3) did not perform any task. Fos-like immunoreactivity (FLI) was significantly higher in both Mk-1 and Mk-2 in motor brain areas than in the control monkey, demonstrating that motor activity triggered c-fos. Although the overall muscle activity was roughly comparable in both tasks, Mk-1 (BIM) exhibited a clearly stronger FLI than Mk-2 all along the rostrocaudal axis of the primary, supplementary and cingulate motor cortices, as well as the striatum. In contrast, Mk-1 and Mk-2 displayed a comparable FLI in non-motor regions, such as the visual and auditory thalamus. The present study, a very rare c-fos mapping investigation conducted in macaques performing a complex behavioral task, suggests that small and medium size (local) neurons may also contribute to the specific neural activity responsible for precise interlimb coordination, within a network associating motor cortical areas and the basal ganglia.</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251352807"},"PeriodicalIF":2.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144545180","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":"The Flipons, Infections, and Amyloids that Foreshadow the Fading Memories of Alzheimer's Disease.","authors":"Alan Herbert","doi":"10.1177/26331055251338815","DOIUrl":"10.1177/26331055251338815","url":null,"abstract":"<p><p>Our memories are almost magical. We can experience an event for a short moment in time and quickly recall it decades later. This review explores the impact of some relatively new discoveries in the field of flipon biology that provide insight into diseases associated with impaired memory function. I examine how an ancient immune system based on Z-DNA and Z-RNA (collectively called ZNAs) regulates pathways that impact the memories modeled by synapses. The outcomes depend on intracellular defenses activated by endogenous retroelements (ERE) and virus, and on extracellular responses to ZNAs in bacterial biofilms. The bacterial amyloids and complement activation pathways further exacerbate the decline of cognitive and affective functions by inducing remodeling of synapses. In addition to immune EREs, a class of memory EREs potentially acts as ribotransmitters. These RNAs are transported across the synapse to program the connections between neurons that underlie the formation and remodeling of memories. Examples exist of ribotransmitters derived from ERE transcripts and assembled into capsids capable of transsynaptic transmission. In contrast, the immune EREs protect the nervous system by dismantling synapses to prevent viruses and retrotransposons from crossing them. The complexity of the interactions between memory and immune EREs likely give rise to the inverted U-shaped dose-response curves for the therapeutics currently available to treat cognitive decline. Other approaches for disease prevention are suggested, along with those that promote the regeneration and reprogramming of neuronal circuits.</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251338815"},"PeriodicalIF":2.9,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12144360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250075","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":"Rare Copy Number Variants Intersecting Parkinson's-associated Genes in a Cohort of children With Autism Spectrum Disorders.","authors":"Alina Erbescu, Sorina Mihaela Papuc, Magdalena Budișteanu, Maria Dobre, Catrinel Iliescu, Mihail Eugen Hinescu, Aurora Arghir, Monica Neagu","doi":"10.1177/26331055251334595","DOIUrl":"10.1177/26331055251334595","url":null,"abstract":"<p><p>Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by important clinical and genetic heterogeneity. Recent studies suggested an overlap between ASD and Parkinson's disease (PD) in terms of clinical manifestation and underlying genetic defects. Our aim was to assess using a chromosomal microarray assay the frequency of rare exonic deletions that overlap with PD associated genes in a pediatric ASD group. Three hundred and five children diagnosed with ASD were enrolled in a study focused on deep phenotyping and genomic profiling by chromosomal microarrays. In the investigated group, four children with ASD harbored deletions encompassing genes involved in Mendelian forms of PD or contributing to PD risk. Deletions of Parkin RBR E3 ubiquitin protein ligase (<i>PRKN)</i> and synuclein alpha interacting protein (<i>SNCAIP</i>) were found in one patient, each; two other patients showed intragenic deletions of Rab9 effector protein with kelch motifs (<i>RABEPK</i>). Our study found that deletions involving genes associated with PD are rare events, as we identified approximately 1% in the ASD cohort of children. Our data adds to the previous reports of rare genomic imbalances of PD associated genes in ASD, further supporting the hypothesis that these conditions might share molecular mechanisms of pathogenesis.</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251334595"},"PeriodicalIF":2.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12138218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235454","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":"Long-term Neurological Consequences of COVID-19 in Patients With Pre-existing Alzheimer's and Parkinson's Disease: A Comprehensive Review.","authors":"Kelechi Wisdom Elechi, Ogundipe Oyepeju Nkem, Ndubuisi Timothy Chibueze, Ubalaeze Solomon Elechi, Kenechukwu Franklin Chimaobi","doi":"10.1177/26331055251342755","DOIUrl":"10.1177/26331055251342755","url":null,"abstract":"<p><p>SARS-CoV-2, the causative agent of COVID-19, has profound systemic effects, including significant impacts on the central nervous system (CNS). Emerging evidence suggests a potential link between SARS-CoV-2-induced neuroinflammation and the exacerbation or initiation of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). This review explores the mechanisms by which SARS-CoV-2 may contribute to neurodegenerative processes. We first discuss the pathways of viral entry into the CNS, including transneuronal and hematogenous routes, leading to blood-brain barrier (BBB) dysfunction. Neuroinflammation, mediated by the activation of microglia and astrocytes and the release of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β, is highlighted as a critical factor exacerbating neuronal damage. Oxidative stress and vascular damage are further examined as complementary mechanisms promoting neurodegeneration. In addition, we review how SARS-CoV-2 infection influences proteinopathies by accelerating the aggregation of pathological proteins like alpha-synuclein, tau, and TDP-43, contributing to disease progression in PD, AD, and related disorders. Clinical studies reporting cognitive and motor dysfunctions in post-COVID-19 patients with pre-existing neurodegenerative diseases are also summarized. Finally, this review identifies knowledge gaps and emphasizes the need for further research to clarify the long-term neurological consequences of SARS-CoV-2 infection. Understanding these mechanisms is critical for developing targeted therapeutic strategies to mitigate the risk of neurodegeneration in vulnerable populations.</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251342755"},"PeriodicalIF":2.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12126688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144200331","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":"Pulsed Radiofrequency Relieves Neuropathic Pain by Repairing the Ultrastructural Damage of Chronically Compressed Dorsal Root Ganglion.","authors":"Xuelian Li, Ying Yang, Dong Huang, Jiahui Ma, Yuzhao Huang","doi":"10.1177/26331055251339081","DOIUrl":"10.1177/26331055251339081","url":null,"abstract":"<p><p>Pulsed radiofrequency (PRF) has demonstrated therapeutic potential for neuropathic pain, yet its efficacy in alleviating pain induced by chronic dorsal root ganglion (DRG) compression remains unclear. This study evaluated the analgesic effects of DRG-targeted PRF in a chronic compression of DRG (CCD) rat model. Adult male Sprague Dawley rats were divided into four groups: sham, CCD, CCD+PRF, and CCD+freePRF. CCD was induced by inserting stainless-steel rods into the intervertebral foramen to compress L4/L5 DRGs. Pain behaviors, including spontaneous pain, mechanical/cold allodynia, and heat hypersensitivity, were assessed pre- and post-PRF treatment. On day 14 post-CCD, DRG ultrastructural changes and myelin basic protein (MBP) expression were analyzed via transmission electron microscopy and immunofluorescence. Compared to sham rats, CCD animals exhibited significant pain behaviors (<i>P</i> < .0001). PRF treatment in CCD+PRF rats significantly attenuated these behaviors (<i>P</i> < .01). Ultrastructural analysis revealed intact myelin sheaths in sham DRGs, whereas CCD DRGs showed myelin damage and reduced MBP expression (<i>P</i> < .01). Notably, PRF repaired myelin structural integrity and restored MBP levels. These findings demonstrate that DRG PRF alleviates neuropathic pain by reversing ultrastructural damage caused by chronic compression, providing mechanistic insights into PRF's analgesic effects and supporting its therapeutic value for neuropathic pain management.</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251339081"},"PeriodicalIF":2.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174046","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":"Surface Versus Penetrative rTMS Stimulation May Be More Effective for AD Patients with Cerebrovascular Disease.","authors":"Brian J Lithgow, Chandan Saha, Zeinab Dastgheib, Zahra Moussavi","doi":"10.1177/26331055251328355","DOIUrl":"10.1177/26331055251328355","url":null,"abstract":"<p><p>Repetitive Transcranial Magnetic Stimulation (rTMS) has been applied as an investigational therapy for Alzheimer's Disease (AD). The recent largest (N = 135) double-blind study with 6 months post-treatment follow-up investigating rTMS efficacy as a treatment for AD found about 72% of participants in each group of active and sham were positively responsive to rTMS (using Magstim AirFilm active and sham coils). Since the used sham coil produced about 25.3% of the peak active stimulus, it was hypothesized it could evoke a measurable response in AD patients. This study looks at the details of the above study's sham responses to determine why and how such a response might occur and how cerebrovascular symptomatology may have impacted that response. In the above-mentioned study, 90 and 45 patients were randomly assigned to active and sham groups, respectively. Those with modified Hachinski Ischemic Scores (HIS) below and above 2 were labeled AD₂ and ADcvd₂, respectively. Analysis of the primary outcome measure ADAS-Cog score change from baseline to post-treatment and follow-ups showed the ADcvd₂ in the sham group had a significantly (<i>p</i> = .034) greater improvement or less decline at post-treatment and follow-up sessions compared to the ADcvd₂ in the active group. Additionally, the improvement of the ADcvd₂ sham compared to those in the active group persisted longer. Also, there was a significant (<i>p</i> = .036) improvement for AD₂ individuals in the active compared to AD₂ sham stimulation group at 2-months post-treatment. Overall, the sham rTMS stimulus did evoke a measurable response which was more effective for ADcvd₂ in sham than ADcvd₂ in active support of a vascular mechanism likely linked to the shallower sham stimulus penetration.</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251328355"},"PeriodicalIF":2.9,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721616","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":"A Cross-over Pilot Study on the Effects of Classical Guitar Instruction on Motor and Non-Motor Symptoms in People with Parkinson's Disease.","authors":"Christopher Adams, Greg Fulton","doi":"10.1177/26331055251329878","DOIUrl":"10.1177/26331055251329878","url":null,"abstract":"<p><strong>Background: </strong>A previous randomized pre-post cross-over study with 26 participants found positive changes in motor and non-motor symptoms in people with Parkinson's disease (PwPD) after six weeks of group classical guitar sessions but not customary and usual treatment.</p><p><strong>Objective: </strong>To determine if a six-week group classical guitar instruction program improved motor function, mood, and quality of life for PwPD in comparison to a six-week group exercise program in a non-randomized cross-over pilot study.</p><p><strong>Methods: </strong>Eighteen PwPD were enrolled and 15 completed the study. Group 1 (N = 10) received a six-week group guitar instruction program, and then a six-week group exercise program. Group 2 (N = 8) received a six-week group exercise program, and then a six-week guitar instruction program. Assessments were at baseline, six weeks, and 12 weeks. The groups were combined for analysis by two-tailed paired <i>t</i>-tests due to the low sample size. Assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor sub-section, Hoehn and Yahr scale, Parkinson's Disease Questionnaire-39 (PDQ-39), Apathy Evaluation Scale-Self (AES-S), and Beck Depression Inventory II (BDI-II).</p><p><strong>Results: </strong>MDS-UPDRS mean motor scores decreased compared to pre-test scores with group guitar instruction (-5.3 points, <i>P</i> < .001), but not group exercise (-0.47 points, <i>P</i> = .85). BDI-II mean scores decreased by 2.13 (<i>P</i> = .08) and 1.87 points (<i>P</i> = .02) with group guitar instruction and group exercise, respectively. PDQ-39 mean scores decreased by 1.93 (<i>P</i> = .02) and 2.52 (<i>P</i> = .02) points with group guitar instruction and group exercise, respectively. AES-S mean scores decreased with group exercise (-2.40 points, <i>P</i> = .03) but not group guitar instruction (-2.4 points, <i>P</i> = .26).</p><p><strong>Conclusions: </strong>Group guitar instruction could potentially help with both motor and non-motor symptoms in PwPD. There appears to be a specific effect of group guitar instruction on MDS-UPDRS motor scores that is not due to regular meetings and general exercises. This unfunded study was registered at ClinicalTrials.gov (NCT05917704).</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251329878"},"PeriodicalIF":2.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721629","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":"Traumatic Brain Injury and Alzheimer's Disease: A Shared Neurovascular Hypothesis.","authors":"Gabrielle Cognacq, Jonathan E Attwood, Gabriele C DeLuca","doi":"10.1177/26331055251323292","DOIUrl":"10.1177/26331055251323292","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a modifiable risk factor for Alzheimer's disease (AD). TBI and AD share several histopathological hallmarks: namely, beta-amyloid aggregation, tau hyperphosphorylation, and plasma protein infiltration. The relative contributions of these proteinopathies and their interplay in the pathogenesis of both conditions remains unclear although important differences are emerging. This review synthesises emerging evidence for the critical role of the neurovascular unit in mediating protein accumulation and neurotoxicity in both TBI and AD. We propose a shared pathogenic cascade centred on a neurovascular unit, in which increased blood-brain barrier permeability induces a series of noxious mechanisms leading to neuronal loss, synaptic dysfunction and ultimately cognitive dysfunction in both conditions. We explore the application of this hypothesis to outstanding research questions and potential treatments for TBI and AD, as well as other neurodegenerative and neuroinflammatory conditions. Limitations of this hypothesis, including the challenges of establishing a causal relationship between neurovascular damage and proteinopathies, are also discussed.</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251323292"},"PeriodicalIF":2.9,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11926848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693341","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":"Beyond the Hit: The Hidden Costs of Repetitive Head Trauma.","authors":"Sikandar Khan, Lora Talley","doi":"10.1177/26331055251316315","DOIUrl":"10.1177/26331055251316315","url":null,"abstract":"<p><p>Repetitive head trauma in sports, particularly concussions, has been strongly associated with neurocognitive impairments, including depression, chronic traumatic encephalopathy (CTE), and altered brain function. These injuries can have significant consequences on major cognitive processes, such as learning and memory. This review synthesizes research that examines the effects of sports-related head trauma, particularly in football, on cognitive functioning. Post-mortem analyses of players across all positions have revealed neuropathological evidence of CTE, including a distinct reduction in hippocampal volume. Notably, episodic memory, a component of declarative memory, is frequently compromised in individuals with CTE. Furthermore, deficits in working memory may contribute to decreased performance during play. Early detection of head trauma and implementation of preventive strategies are crucial for mitigating long-term consequences. While impact-reducing techniques have shown some efficacy in decreasing brain injury incidence, proper tackling techniques, such as \"heads-up play,\" also play a vital role in minimizing risk. Further research and increased awareness are needed to ensure athletes are fully informed of the potential cognitive risks associated with participation in high-impact sports.</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251316315"},"PeriodicalIF":2.9,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190795","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":"From Pregnancy to Postpartum: The Dynamic Reorganization of the Maternal Brain.","authors":"Natalia Chechko, Susanne Nehls","doi":"10.1177/26331055251315488","DOIUrl":"10.1177/26331055251315488","url":null,"abstract":"<p><p>The postpartum period is marked by radical changes in the maternal brain. Seeking to explore the mechanisms that underlie these changes, this article focuses on the relevant hormonal, inflammatory, and behavioral factors. Longitudinal imaging studies have shed valuable light on both short- and long-term alterations in postpartum brain structure and connectivity, particularly in the regions that play key roles in emotion regulation and stress response. It is plausible that these peripartum changes contribute to the mental health challenges new mothers face, including postpartum depression. Adding to our understanding of postpartum neurobiology, this insight highlights the importance of personalized intervention in the promotion of maternal well-being.</p>","PeriodicalId":36527,"journal":{"name":"Neuroscience Insights","volume":"20 ","pages":"26331055251315488"},"PeriodicalIF":2.9,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11744624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013366","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}