Frontiers in neuroimaging最新文献

{"title":"Multimodal functional imaging and clinical correlates of pain regions in chronic low-back pain patients treated with spinal cord stimulation: a pilot study.","authors":"Yazan Shamli Oghli, Arjun Ashok, Steven Glener, Isaiah Ailes, Mashaal Syed, Ki Chang Kang, Sara Naghizadehkashani, Islam Fayed, Feroze B Mohamed, Kiran Talekar, Laura Krisa, Chengyuan Wu, Caio Matias, Mahdi Alizadeh","doi":"10.3389/fnimg.2024.1474060","DOIUrl":"https://doi.org/10.3389/fnimg.2024.1474060","url":null,"abstract":"<p><strong>Objective: </strong>Spinal cord stimulation (SCS) is an invasive treatment option for patients suffering from chronic low-back pain (cLBP). It is an effective treatment that has been shown to reduce pain and increase the quality of life in patients. However, the activation of pain processing regions of cLBP patients receiving SCS has not been assessed using objective, quantitative functional imaging techniques. The purpose of the present study was to compare quantitative resting-state (rs)-fMRI and arterial spin labeling (ASL) measures between SCS patients and healthy controls and to correlate clinical measures with quantitative multimodal imaging indices in pain regions.</p><p><strong>Methods: </strong>Multi-delay 3D GRASE pseudo-continuous ASL and rs-fMRI data were acquired from five patients post-SCS with cLBP and five healthy controls. Three ASL measures and four rs-fMRI measures were derived and normalized into MNI space and smoothed. Averaged values for each measure from a pain atlas were extracted and compared between patients and controls. Clinical pain scores assessing intensity, sensitization, and catastrophizing, as well as others assessing global pain effects (sleep quality, disability, anxiety, and depression), were obtained in patients and correlated with pain regions using linear regression analysis.</p><p><strong>Results: </strong>Arterial transit time derived from ASL and several rs-fMRI measures were significantly different in patients in regions involved with sensation (primary somatosensory cortex and ventral posterolateral thalamus [VPL]), pain input (posterior short gyrus of the insula [PS]), cognition (dorsolateral prefrontal cortex [DLPC] and posterior cingulate cortex [PCC]), and fear/stress response (hippocampus and hypothalamus). Unidimensional pain rating and sensitization scores were linearly associated with PS, VPL, DLPC, PCC, and/or amygdala activity in cLBP patients.</p><p><strong>Conclusion: </strong>The present results provide evidence that ASL and rs-fMRI can contrast functional activation in pain regions of cLBP patients receiving SCS and healthy subjects, and they can be associated with clinical pain evaluations as quantitative assessment tools.</p>","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":"3 ","pages":"1474060"},"PeriodicalIF":0.0,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11470492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482340","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":"Quantitative reliability assessment of brain MRI volumetric measurements in type II GM1 gangliosidosis patients.","authors":"Christopher Zoppo, Josephine Kolstad, Jean Johnston, Precilla D'Souza, Anna Luisa Kühn, Zeynep Vardar, Ahmet Peker, Clifford Lindsay, Zubir S Rentiya, Robert King, Heather Gray-Edwards, Behroze Vachha, Maria T Acosta, Cynthia J Tifft, Mohammed Salman Shazeeb","doi":"10.3389/fnimg.2024.1410848","DOIUrl":"10.3389/fnimg.2024.1410848","url":null,"abstract":"<p><strong>Purpose: </strong>GM1-gangliosidosis (GM1) leads to extensive neurodegenerative changes and atrophy that precludes the use of automated MRI segmentation techniques for generating brain volumetrics. We developed a standardized segmentation protocol for brain MRIs of patients with type II GM1 and then assessed the inter- and intra-rater reliability of this methodology. The volumetric data may be used as a biomarker of disease burden and progression, and standardized methodology may support research into the natural history of the disease which is currently lacking in the literature.</p><p><strong>Approach: </strong>Twenty-five brain MRIs were included in this study from 22 type II GM1 patients of which 8 were late-infantile subtype and 14 were juvenile subtype. The following structures were segmented by two rating teams on a slice-by-slice basis: whole brain, ventricles, cerebellum, lentiform nucleus, thalamus, corpus callosum, and caudate nucleus. The inter- and intra-rater reliability of the segmentation method was assessed with an intraclass correlation coefficient as well as Sorensen-Dice and Jaccard coefficients.</p><p><strong>Results: </strong>Based on the Sorensen-Dice and Jaccard coefficients, the inter- and intra-rater reliability of the segmentation method was significantly better for the juvenile patients compared to late-infantile (<i>p</i> < 0.01). In addition, the agreement between the two rater teams and within themselves can be considered good with all <i>p</i>-values < 0.05.</p><p><strong>Conclusions: </strong>The standardized segmentation approach described here has good inter- and intra-rater reliability and may provide greater accuracy and reproducibility for neuromorphological studies in this group of patients and help to further expand our understanding of the natural history of this disease.</p>","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":"3 ","pages":"1410848"},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11440193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142333851","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":"Probing hippocampal stimulation in experimental temporal lobe epilepsy with functional MRI.","authors":"Niels Schwaderlapp, Enya Paschen, Pierre LeVan, Dominik von Elverfeldt, Carola A Haas","doi":"10.3389/fnimg.2024.1423770","DOIUrl":"https://doi.org/10.3389/fnimg.2024.1423770","url":null,"abstract":"<p><p>Electrical neurostimulation is currently used to manage epilepsy, but the most effective approach for minimizing seizure occurrence is uncertain. While functional MRI (fMRI) can reveal which brain areas are affected by stimulation, simultaneous deep brain stimulation (DBS)-fMRI examinations in patients are rare and the possibility to investigate multiple stimulation protocols is limited. In this study, we utilized the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy (mTLE) to systematically examine the brain-wide responses to electrical stimulation using fMRI. We compared fMRI responses of saline-injected controls and epileptic mice during stimulation in the septal hippocampus (HC) at 10 Hz and demonstrated the effects of different stimulation amplitudes (80-230 μA) and frequencies (1-100 Hz) in epileptic mice. Motivated by recent studies exploring 1 Hz stimulation to prevent epileptic seizures, we furthermore investigated the effect of prolonged 1 Hz stimulation with fMRI. Compared to sham controls, epileptic mice showed less propagation to the contralateral HC, but significantly stronger responses in the ipsilateral HC and a wider spread to the entorhinal cortex and septal region. Varying the stimulation amplitude had little effect on the resulting activation patterns, whereas the stimulation frequency represented the key parameter and determined whether the induced activation remained local or spread from the hippocampal formation into cortical areas. Prolonged stimulation of epileptic mice at 1 Hz caused a slight reduction in local excitability. In this way, our study contributes to a better understanding of these stimulation paradigms.</p>","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":"3 ","pages":"1423770"},"PeriodicalIF":0.0,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115659","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 importance of brain mapping for rehabilitation in birth nonprogressive neuromuscular diseases","authors":"Aleksandra Tolmacheva, Olga Agranovich, E. Blagovechtchenski","doi":"10.3389/fnimg.2024.1359491","DOIUrl":"https://doi.org/10.3389/fnimg.2024.1359491","url":null,"abstract":"While motor mapping has been extensively studied in acquired motor conditions, a lack has been observed in terms of research on neurological disorders present since birth, with damage to the spinal cord and peripheral nerves (hence, defined in this study as nonprogressive neuromuscular diseases). Despite an injury at the level below the brain, the subsequent changes in the motor system involve cortical reorganization. In the scientific community, the need for a comprehensive approach targeting the brain is increasingly recognized for greater motor recovery in these patients. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) are the most utilized techniques for motor mapping. The knowledge obtained through motor mapping may be used to develop effective individual neuromodulation therapy that helps in functional motor recovery. This brief review compares the results of the brain mapping of a few existing studies in individuals with nonprogressive motor disorders of nonbrain origin present at birth to the brain mapping of individuals with similar acquired motor conditions. The review reveals some particular features in terms of central adaptation in individuals with birth conditions compared to their acquired counterparts, such as the nonsomatotopic presentation of involved muscles in the sensorimotor cortex and nonadjacent cortical areas. This topic is undoubtedly intriguing, justifying further research in the field. This review also discusses the benefits these patients can obtain from neuromodulation therapy addressed to the central nervous system and the importance of individual neurophysiological assessment in designing rehabilitation therapy for children with birth motor disorders.","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":"26 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141645502","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 off-resonance correction improves functional image analysis in fMRI of awake behaving non-human primates.","authors":"Mo Shahdloo, Nima Khalighinejad, Luke Priestley, Matthew Rushworth, Mark Chiew","doi":"10.3389/fnimg.2024.1336887","DOIUrl":"10.3389/fnimg.2024.1336887","url":null,"abstract":"<p><strong>Introduction: </strong>Use of functional MRI in awake non-human primate (NHPs) has recently increased. Scanning animals while awake makes data collection possible in the absence of anesthetic modulation and with an extended range of possible experimental designs. Robust awake NHP imaging however is challenging due to the strong artifacts caused by time-varying off-resonance changes introduced by the animal's body motion. In this study, we sought to thoroughly investigate the effect of a newly proposed dynamic off-resonance correction method on brain activation estimates using extended awake NHP data.</p><p><strong>Methods: </strong>We correct for dynamic B0 changes in reconstruction of highly accelerated simultaneous multi-slice EPI acquisitions by estimating and correcting for dynamic field perturbations. Functional MRI data were collected in four male rhesus monkeys performing a decision-making task in the scanner, and analyses of improvements in sensitivity and reliability were performed compared to conventional image reconstruction.</p><p><strong>Results: </strong>Applying the correction resulted in reduced bias and improved temporal stability in the reconstructed time-series data. We found increased sensitivity to functional activation at the individual and group levels, as well as improved reliability of statistical parameter estimates.</p><p><strong>Conclusions: </strong>Our results show significant improvements in image fidelity using our proposed correction strategy, as well as greatly enhanced and more reliable activation estimates in GLM analyses.</p>","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":"3 ","pages":"1336887"},"PeriodicalIF":0.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11231096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141565315","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":"Neuroimaging evaluation of the long term impact of a novel paired meditation practice on brain function","authors":"Andrew B. Newberg, N. Wintering, Chloe Hriso, Faezeh Vedaei, Sara Gottfried, Reneita Ross","doi":"10.3389/fnimg.2024.1368537","DOIUrl":"https://doi.org/10.3389/fnimg.2024.1368537","url":null,"abstract":"A growing number of advanced neuroimaging studies have compared brain structure and function in long term meditators to non-meditators. The goal is to determine if there may be long term effects on the brain from practicing meditation. In this paper, we present new data on the long term effects of a novel meditation practice in which the focus is on clitoral stimulation. The findings from such a study have implications for potential therapeutic uses with regard to various neurological or psychiatric conditions.We evaluated the cerebral glucose metabolism in 40 subjects with an extended history (>1 year of practice, 2–3 times per week) performing the meditation practice called Orgasmic Meditation (OM) and compared their brains to a group of non-meditating healthy controls (N = 19). Both meditation and non-meditation subjects underwent brain PET after injection with 148 to 296 MBq of FDG using a standard imaging protocol. Resting FDG PET scans of the OM group were compared to the resting scans of healthy, non-meditating, controls using statistical parametric mapping.The OM group showed significant differences in metabolic activity at rest compared to the controls. Specifically, there was significantly lower metabolism in select areas of the frontal, temporal, and parietal lobes, as well as the anterior cingulate, insula, and thalamus, in the OM group compared to the controls. In addition, there were notable distinctions between the males and females with the females demonstrating significantly lower metabolism in the thalamus and insula.Overall, these findings suggest that the long term meditation practitioners of OM have different patterns of resting brain metabolism. Since these areas of the brain in which OM practitioners differ from controls are involved in cognition, attention, and emotional regulation, such findings have implications for understanding how this meditation practice might affect practitioners over long periods of time.","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":" October","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141364647","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":"3D inversion recovery ultrashort echo time MRI can detect demyelination in cuprizone-treated mice.","authors":"Adam C Searleman, Yajun Ma, Srihari Sampath, Srinath Sampath, Robert Bussell, Eric Y Chang, Lisa Deaton, Andrew M Schumacher, Jiang Du","doi":"10.3389/fnimg.2024.1356713","DOIUrl":"10.3389/fnimg.2024.1356713","url":null,"abstract":"<p><strong>Purpose: </strong>To test the ability of inversion-recovery ultrashort echo time (IR-UTE) MRI to directly detect demyelination in mice using a standard cuprizone mouse model.</p><p><strong>Methods: </strong>Non-aqueous myelin protons have ultrashort T₂s and are \"invisible\" with conventional MRI sequences but can be detected with UTE sequences. The IR-UTE sequence uses an adiabatic inversion-recovery preparation to suppress the long T₂ water signal so that the remaining signal is from the ultrashort T₂ myelin component. In this study, eight 8-week-old C57BL/6 mice were fed cuprizone (<i>n</i> = 4) or control chow (<i>n</i> = 4) for 5 weeks and then imaged by 3D IR-UTE MRI. The differences in IR-UTE signal were compared in the major white matter tracts in the brain and correlated with the Luxol Fast Blue histochemical marker of myelin.</p><p><strong>Results: </strong>IR-UTE signal decreased in cuprizone-treated mice in white matter known to be sensitive to demyelination in this model, such as the corpus callosum, but not in white matter known to be resistant to demyelination, such as the internal capsule. These findings correlated with histochemical staining of myelin content.</p><p><strong>Conclusions: </strong>3D IR-UTE MRI was sensitive to cuprizone-induced demyelination in the mouse brain, and is a promising noninvasive method for measuring brain myelin content.</p>","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":"3 ","pages":"1356713"},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11111995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141089409","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":"Corrigendum: A structural connectivity atlas of limbic brainstem nuclei.","authors":"Simon Levinson, Michelle Miller, Ahmed Iftekhar, Monica Justo, Daniel Arriola, Wenxin Wei, Saman Hazany, Josue M Avecillas-Chasin, Taylor P Kuhn, Andreas Horn, Ausaf A Bari","doi":"10.3389/fnimg.2024.1405806","DOIUrl":"https://doi.org/10.3389/fnimg.2024.1405806","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fnimg.2022.1009399.].</p>","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":"3 ","pages":"1405806"},"PeriodicalIF":0.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946562","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":"Construction and evaluation of a neurofeedback system using finger tapping and near-infrared spectroscopy","authors":"Shingo Takahashi, Daishi Takahashi, Yuki Kuroiwa, Noriko Sakurai, Naoki Kodama","doi":"10.3389/fnimg.2024.1361513","DOIUrl":"https://doi.org/10.3389/fnimg.2024.1361513","url":null,"abstract":"Neurofeedback using near-infrared spectroscopy (NIRS) has been used in patients with stroke and other patients, but few studies have included older people or patients with cognitive impairment.We constructed a NIRS-based neurofeedback system and used finger tapping to investigate whether neurofeedback can be implemented in older adults while finger tapping and whether brain activity improves in older adults and healthy participants. Our simple neurofeedback system was constructed using a portable wearable optical topography (WOT-HS) device. Brain activity was evaluated in 10 older and 31 healthy young individuals by measuring oxygenated hemoglobin concentration during finger tapping and neurofeedback implementation.During neurofeedback, the concentration of oxygenated hemoglobin increased in the prefrontal regions in both the young and older participants.The results of this study demonstrate the usefulness of neurofeedback using simple NIRS devices for older adults and its potential to mitigate cognitive decline.","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":"52 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140656641","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":"Evaluation of partial volume correction and analysis of longitudinal [18F]GTP1 tau PET imaging in Alzheimer's disease using linear mixed-effects models","authors":"S. S. Sanabria Bohórquez, Suzanne Baker, P. Manser, Matteo Tonietto, Christopher Galli, Kristin R. Wildsmith, Yixuan Zou, G. Kerchner, R. Weimer, E. Teng","doi":"10.3389/fnimg.2024.1355402","DOIUrl":"https://doi.org/10.3389/fnimg.2024.1355402","url":null,"abstract":"We evaluated the impact of partial volume correction (PVC) methods on the quantification of longitudinal [18F]GTP1 tau positron-emission tomography (PET) in Alzheimer's disease and the suitability of describing the tau pathology burden temporal trajectories using linear mixed-effects models (LMEM).We applied van Cittert iterative deconvolution (VC), 2-compartment, and 3-compartment, and the geometric transfer matrix plus region-based voxelwise methods to data acquired in an Alzheimer's disease natural history study over 18 months at a single imaging site. We determined the optimal PVC method by comparing the standardized uptake value ratio change (%ΔSUVR) between diagnostic and tau burden–level groups and the longitudinal repeatability derived from the LMEM. The performance of LMEM analysis for calculating %ΔSUVR was evaluated in a natural history study and in a multisite clinical trial of semorinemab in prodromal to mild Alzheimer's disease by comparing results to traditional per-visit estimates.The VC, 2-compartment, and 3-compartment PVC methods had similar performance, whereas region-based voxelwise overcorrected regions with a higher tau burden. The lowest within-subject variability and acceptable group separation scores were observed without PVC. The LMEM-derived %ΔSUVR values were similar to the per-visit estimates with lower variability.The results indicate that the tested PVC methods do not offer a clear advantage or improvement over non-PVC images for the quantification of longitudinal [18F]GTP1 PET data. LMEM offers a robust framework for the longitudinal tau PET quantification with low longitudinal test–retest variability.NCT02640092 and NCT03289143.","PeriodicalId":73094,"journal":{"name":"Frontiers in neuroimaging","volume":"29 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140371939","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}