Altered thalamus functional connectivity in patients with acute unilateral vestibulopathy: a resting-state fMRI study – Frontiers

Introduction

Acute unilateral vestibulopathy (AUVP), also called vestibular neuritis (VN), is characterised by acute or sub-acute episodes of moderate-to-severe rotational or non-rotational vertigo accompanied by instability and spontaneous horizontal nystagmus (or torsion) with out listening to impairment or brainstem dysfunction (Strupp and Magnusson, 2015; Johns and Quinn, 2020; Strupp et al., 2022). AUVP is the second main reason for peripheral vestibular vertigo (Strupp and Brandt, 2013). The incidence of AUVP ranges from 3.5∼15.5/100,000 (Strupp and Brandt, 2009). AUVP accounts for 3.2%–9% of sufferers in vertigo or neurology clinics (Strupp and Brandt, 2009). About 2%–11% of AUVP sufferers relapse, and 10%–15% of AUVP sufferers have secondary benign paroxysmal positional vertigo (Neuhauser, 2016; Le et al., 2019).

Most AUVP sufferers expertise a fast restoration that appears to be associated to a compensatory adaptation for the central vestibular info processing. Earlier research have proven that 30%∼50% of AUVP sufferers developed power dizziness, together with persistent postural-perceptual dizziness (Yan et al., 2017; Popkirov et al., 2018). Current research urged that the event of such power signs following AUVP was predominantly mediated by central mechanisms (insufficient central vestibular compensation) (Greatest et al., 2006; Panichi et al., 2017). It was reported that the vestibular nucleus would possibly play an important function in vestibular compensation in sufferers with unilateral peripheral vestibular harm or in rats mannequin of acute unilateral labyrinthotomy (Helmchen et al., 2011; Zwergal et al., 2016). A earlier positron emission tomography (PET) examine has reported modifications in regional cerebral glucose metabolism in vestibular cortex in sufferers with AUVP throughout acute stage (Bense et al., 2004). Neuroimaging research utilizing methodology of voxel-based morphometry have reported grey matter quantity modifications in areas of vestibular cortex in sufferers with AUVP (Helmchen et al., 2009; Hong et al., 2014). Purposeful and structural modifications of vestibular cortex in AUVP sufferers point out that the vestibular cortex most likely performs an vital function in vestibular compensation. Within the vestibular pathway, peripheral vestibular info is projected via vestibular nucleus to ocular motor nuclei, and in parallel to ascend through thalamus to the central vestibular cortex (Hitier et al., 2014; Kirsch et al., 2016). Up to now, few research have targeted on the purposeful compensation of thalamus in sufferers with AUVP (Becker-Bense et al., 2014; Helmchen et al., 2014; Klingner et al., 2014; Roberts et al., 2018; Cheng et al., 2023). It’s presently not clear whether or not sufferers with AUVP have irregular resting-state purposeful connectivity (FC) of the thalamus.

Subsequently, this examine aimed to discover the modifications in FC targeted on bilateral thalamus in sufferers with AUVP throughout acute section utilizing resting-state purposeful magnetic resonance imaging (fMRI), and to find out whether or not these FC abnormalities correlate with sure scientific options of the sufferers. We hypothesized that the method of central vestibular compensation in AUVP sufferers concerned purposeful modifications within the thalamus. It has been urged that adaptation is likely one of the methods for vestibular compensation (Hillier and McDonnell, 2011). The primary technique of adaptation is sensory substitution. Imaginative and prescient and proprioception are the principle sources of sensory substitution (Hillier and McDonnell, 2011; Lacour and Bernard-Demanze, 2015). It’s believed that thalamus is functionally linked with visible, somatosensory, and vestibular cortex (Wijesinghe et al., 2015; Roy et al., 2022). Thus, we speculated that sufferers with AUVP may need altered resting-state FC between thalamus and a set of mind areas concerned in vestibular, visible, and somatosensory info processing.

Supplies and strategies

Members

Based mostly on the diagnostic standards of AUVP/VN from the consensus doc of the committee for the classification of vestibular problems of the Bárány Society (Strupp et al., 2022), 40 right-handed AUVP sufferers have been recruited on the Division of Neurology of the Second Affiliated Hospital of Xuzhou Medical College. All sufferers have been evaluated inside 1 week of onset. Every affected person underwent an in depth neurological and neuro-otological analysis, together with demographic info, historical past of current sickness, previous medical historical past, neurological and vertigo bedside examination, videonystagmograph, video head impulse take a look at (vHIT), vestibular evoked myogenic potentials (VEMPs, together with ocular and cervical VEMPs), rotatory chair take a look at, pure tone take a look at, and measurement of acoustic immittance. Within the videonystagmograph analysis, a affected person with AUVP often characteristically presents as a spontaneous nystagmus (horizontal-torsional, direction-fixed, and enhanced by removing of visible fixation) with a trajectory acceptable to the semicircular canal afferents concerned. Within the vHIT and rotatory chair take a look at, a affected person with AUVP often exhibits diminished vestibulo-ocular reflex (VOR) operate on the aspect reverse the path of the quick section of the spontaneous nystagmus (VOR acquire lower than 0.7 with saccades for vHIT, or canal paresis greater than 25% for rotatory chair take a look at). As well as, examinations of VEMPs and vHIT assist us to distinguish the distribution of nerve harm in AUVP sufferers. All sufferers underwent acute or subacute onset of vertigo lasting greater than 24 h. No affected person had constructive neurological indicators past these of a unilateral peripheral vestibular lesion. Not one of the sufferers had listening to impairment or tinnitus, or different otologic signs corresponding to otalgia. No affected person had earlier historical past of neurological, neuro-otological, psychiatric, or systemic illness. To manage for laterality, all sufferers suffered harm to the left aspect. Sufferers with drug or alcohol abuse have been excluded. Sufferers with recurrent AUVP have been excluded. Sufferers who acquired vestibular operate inhibitors inside 2 days previous to assessments of vestibular operate and fMRI have been excluded. For enrolled sufferers, resting-state fMRI have been carried out inside 1 week of onset, and all fMRI scans have been obtained on the identical day because the completion of the vestibular operate analysis.

Thirty-five age, intercourse, and education-matched wholesome controls (HC) have been recruited. They acquired resting-state fMRI scanning. They’re all right-handed, with no historical past of vertigo, drug, or alcohol abuse. HC with neurological, neuro-otological, psychological, or systemic problems have been excluded. Each sufferers with AUVP and HC underwent routine MRI (T1WI + T2WI + DWI + FLAIR) scans to rule out occult central nervous system illnesses. As well as, topics with moderate-severe white matter hyperintensity on FLAIR photos have been excluded. As well as, all members underwent assessments of Hamilton Anxiousness Scale (HAMA), Hamilton Despair Scale (HAMD), and Montreal Cognitive Evaluation (MoCA). All scales and neuropsychological exams have been accomplished by a professional neuropsychological evaluator who was not conscious of the grouping of the topics.

Imaging acquisition

All MRI photos have been collected utilizing a 3.0T GE MRI scanner (GE Medical Methods) on the Second Affiliated Hospital of Xuzhou Medical College, together with excessive decision T1-weighted photos (T1WI) and resting-state fMRI. All members stored their eyes closed and lay nonetheless in the course of the MRI scanning. As well as, all topics have been requested not to consider something in the course of the MRI scanning. The T1WI photos have been obtained utilizing a 3D-BRAVO sequence with the next parameters: repetition time (TR) = 2,500 ms, echo time (TE) = 3.5 ms, flip angle (FA) = 8°, matrix = 256 × 256, thickness = 1 mm, 156 slices. A quick discipline echo-planar imaging (EPI) sequence was used to amass the entire mind fMRI photos, the scanning parameters have been as follows: TR = 2,000 ms, TE = 30 ms, FA = 90°, discipline of view (FOV) = 200 × 200 mm, matrix = 64 × 64, thickness/hole = 3.6/0 mm, 210 time factors, complete scan time = 7 min.

Imaging preprocessing

For the acquired 210 purposeful time factors, we eliminated the primary 10 time factors. The remaining 200 time factors have been preprocessed by Statistical Parametric Mapping 12 (SPM12) and CONN toolbox (Model 18b) engaged on MATLAB R2023a (MathWorks, Inc., Natick, MA, USA). The preprocessing procedures have been the default parameters throughout the CONN toolbox: (a) purposeful slice-timing correction was used to cut back the distinction within the acquisition time of every layer; (b) purposeful realignment was adopted to right head motion inside sequence; (c) we carried out purposeful outlier detection with head movement threshold set at 3 mm and world sign threshold set at z = 9; (d) with the intention to slim the distinction in structural middle brought on by guide positioning, we carried out the step of structural middle to (0, 0, 0) coordinates (translation); (e) purposeful segmentation and normalization (DARTEL); (f) spatial smoothing primarily based on a Gaussian kernel of 6-mm full-width at half most; (g) band-pass filtering (0.01–0.08 Hz); and (h) nuisance variable regression: together with the indicators of white matter, cerebrospinal fluid, and the 24 movement parameters. Six AUVP sufferers and 4 HC have been excluded as a consequence of massive head movement or poor normalization. Lastly, 34 AUVP sufferers and 31 HC have been included within the following evaluation.

Seed-based purposeful connectivity

Purposeful connectivity between the chosen seeds and the remainder of the mind areas was computed with the seed-to-voxel methodology. The bilateral thalamus have been extracted from the FSL Harvard–Oxford atlas. For every seed, we extracted the time-series from the preprocessed purposeful photos. We calculated the Pearson correlation coefficients (r) between the seed and all different voxels, which was then transformed to z scores utilizing Fisher’s r-to-z transformation.

Statistical evaluation

Evaluation of demography and scientific traits

Statistical analyses of demography and scientific traits have been carried out utilizing the Statistical Bundle for the Social Sciences (SPSS, v22.0) for Home windows (SPSS Institute Inc., Chicago, IL, USA). Two-sample t-tests have been adopted to investigate the variations in age, instructional years, scores of HAMA, HAMD, and MoCA, the Chi-square take a look at was used to look at the distinction in gender. A p < 0.05 was thought-about important for all analyses.

Evaluation of variations in FC

Two-sample t-tests have been utilized to investigate the variations of FC between AUVP sufferers and HC. Age, gender, training degree, scores of MoCA, HAMA, and HAMD have been included as covariates. Significance was decided at voxel-level threshold (p < 0.001) and cluster-level threshold [p < 0.05, false discovery rate (FDR) corrected, two-tailed].

Correlation evaluation

For FC displaying important variations between the 2 teams, z-values have been calculated. We carried out Pearson’s partial correlation evaluation to judge the correlations between z-values and sufferers’ scientific options [including duration of AUVP, values of canal paresis (CP), slow-phase velocity of spontaneous nystagmus, scores of VVAS and DHI], controlling for age, gender, training degree, scores of MoCA, HAMA, and HAMD. A p < 0.05 was thought-about important.

Outcomes

Demographic and scientific options

The overall knowledge of all topics have been summarized in Desk 1. There was no important distinction in age, gender, training degree, scores of HAMA, HAMD, and MoCA between the 2 teams (all p > 0.05, Desk 1). The scientific traits of AUVP sufferers have been proven in Desk 2. The AUVP sufferers within the current examine suffered from average to extreme vertigo signs in response to the scores of VVAS (6.4 ± 1.3), which resulted in extreme handicap as recognized by scores of DHI (61.1 ± 20.6). Of all of the 34 sufferers with AUVP we enrolled, 10 (29.4%) sufferers had a transparent historical past of higher respiratory an infection earlier than onset. All sufferers (34, 100%) had left peripherals vestibular lesions. All sufferers (34, 100%) confirmed spontaneous nystagmus (Spn), the slow-phase velocity of Spn was 12.1 ± 11.4°/s. Thirty-two (94.1%) sufferers confirmed proper aspect Spn and 1 (5.9%) affected person confirmed left aspect Spn. All sufferers (34, 100%) confirmed canal paresis (CP, 60.6% ± 20.0%) throughout rotatory chair testing. Thirty (88.2%) sufferers displayed irregular vHIT (left aspect VOR acquire discount and saccade waves). Ocular VEMP (oVEMP) was irregular in 30 circumstances (88.2%) and cervical VEMP (cVEMP) was irregular in 13 circumstances (38.2%). Outcomes of vHIT and VEMPs confirmed that 20 (58.8%) sufferers had superior vestibular nerve harm solely, 3 (8.9%) sufferers had inferior vestibular nerve harm solely, 1 (2.9%) affected person had ampullary nerve harm and 10 (29.4%) sufferers had entire vestibular nerve harm (Desk 3).

FC variations between teams

In contrast with HC, AUVP sufferers confirmed elevated FC between the left thalamus and the suitable postcentral gyrus (PCG) (Desk 4 and Determine 1). We additionally noticed decreased FC between the left thalamus and the left insula in sufferers with AUVP in contrast with HC (Desk 4 and Determine 1). As well as, in contrast with HC, AUVP sufferers confirmed elevated FC between the suitable thalamus and mind areas of the bilateral PCG, proper center frontal gyrus (MFG) and proper center occipital gyrus (MOG) (Desk 5 and Determine 2). We additionally discovered decreased FC between the suitable thalamus and mind areas of the left insula and the left supramarginal gyrus (SMG) in AUVP sufferers (Desk 5 and Determine 2).

Correlation outcomes

Correlation evaluation revealed that the FC (z-value) between the left thalamus and the left insula was negatively correlated with the worth of CP in sufferers with AUVP (p = 0.010, r = −0.434; Determine 3). There was no important correlation between the FC (z-value) and sufferers’ scientific options of illness length, slow-phase velocity of Spn, and scores of VVAS and DHI (all p > 0.05).

Dialogue

To our data, the current examine is the one one which explored resting-state FC modifications specializing in thalamus in sufferers with AUVP. We discovered that AUVP sufferers confirmed irregular thalamus resting-state FC. As well as, our outcomes urged that the altered thalamus FC was correlated with the severity of peripheral vestibular impairment (CP values) within the AUVP sufferers.

The thalamus is believed to obtain vestibular enter from vestibular nuclei and cerebellum, and transmit vestibular enter to the central vestibular cortex (Hitier et al., 2014; Kirsch et al., 2016). Earlier research have urged that the thalamus was concerned within the processing of vestibular info (Asanuma et al., 1983; Indovina et al., 2005). Purposeful and structural abnormalities of thalamus have been reported in vestibular illnesses. For instance, Meniere’s illness, vestibular migraine and visually induced dizziness (Van Ombergen et al., 2017; Borghammer and Ovesen, 2020; Chen et al., 2022; Zhe et al., 2023). In sufferers with AUVP, altered regional cerebral glucose metabolism within the thalamus was beforehand reported in the course of the acute stage (Bense et al., 2004), which was partially much like the outcomes of the current examine. Our outcomes of the altered thalamus FC supported our speculation and probably urged that modifications in thalamus purposeful exercise have been concerned within the strategy of vestibular compensation in AUVP sufferers.

The insula is a vital element of parieto-insular vestibular cortex (PIVC) (Eickhoff et al., 2006; Frank and Greenlee, 2018). The PIVC is especially positioned within the posterior insula, retroinsular area and the parietal operculum, and is now usually thought-about to be the first vestibular cortex in people (Eickhoff et al., 2006; Frank and Greenlee, 2018). The insula receives vestibular inputs from thalamus and performs a substantial function in vestibulo-thalamo-PIVC pathway (Lopez et al., 2012; zu Eulenburg et al., 2012). An 18F-fluorodeoxyglucose PET examine reported elevated regional cerebral glucose metabolism in posterior insula in AUVP sufferers (Bense et al., 2004). Research utilizing voxel-based morphometry evaluation discovered elevated grey matter quantity within the insula in AUVP sufferers in contrast with HC, and in AUVP sufferers on the restoration stage (3 months) in contrast with the identical sufferers on the acute stage (onset inside 72 h) (Helmchen et al., 2009; Hong et al., 2014). Lately, a neuroimaging examine reported that AUVP sufferers at acute stage confirmed decreased FC between left lingual gyrus and proper insula, indicating decreased FC between visible and vestibular cortex in sufferers with AUVP (Cheng et al., 2023). Partially according to earlier purposeful and structural neuroimaging research (Bense et al., 2004; Helmchen et al., 2009; Hong et al., 2014; Cheng et al., 2023), the current examine discovered that AUVP sufferers with left peripherals vestibular lesions confirmed decreased FC between the left insula and bilateral thalamus, indicating decreased thalamo-vestibular cortex neural pathway. As well as, our AUVP sufferers confirmed a major unfavorable correlation between the elevated CP (the larger the CP worth, the extra severe the harm of vestibular operate) and the decreased FC of left thalamus-insula. The lower in resting-state FC between the left thalamus and left insula was most likely associated to the impaired left aspect peripherals vestibular operate within the AUVP sufferers with left peripherals vestibular lesions.

This examine additionally noticed decreased FC between the suitable thalamus and left SMG in AUVP sufferers with left peripherals vestibular lesions. The SMG throughout the inferior parietal lobule (IPL) has been proven to be activated by vestibular stimulation (Lopez and Blanke, 2011). It was additionally reported {that a} left parietal lobe infarction involving the SMG introduced as remoted positional vertigo with rightward horizontal nystagmus (Naganuma et al., 2006). The SMG is a key area recognized in earlier research for vestibular info processing (Lopez and Blanke, 2011; zu Eulenburg et al., 2012; Dieterich and Brandt, 2018). The purposeful and structural modifications in SMG have been demonstrated in vestibular problems like benign paroxysmal positional vertigo with residual dizziness, persistent postural-perceptual dizziness, and vestibular migraine (Zhe et al., 2020; Lin et al., 2023; Maywald et al., 2023). A latest fMRI examine has revealed decreased FC between the left lingual gyrus and the bilateral SMG in sufferers with AUVP (Cheng et al., 2023). The present examine discovered decreased FC between the suitable thalamus and left SMG. This end result additionally indicated decreased thalamo-vestibular cortex neural pathway in AUVP sufferers.

The PCG is a part of the parietal lobe and is named main somatosensory cortex of human beings (Kaas et al., 1979; Geyer et al., 2000). In AUVP sufferers, elevated regional homogeneity (ReHo) values in the suitable PCG and decreased regional cerebral glucose metabolism in PCG have been beforehand reported by resting-state fMRI and 18F-fluorodeoxyglucose PET research (Bense et al., 2004; Cheng et al., 2023). The current examine noticed elevated FC between the left thalamus and proper PCG, and between the suitable thalamus and bilateral PCG. These outcomes urged elevated thalamo-somatosensory cortex neural pathway in AUVP sufferers. We additionally found elevated FC between the suitable thalamus and proper MFG in sufferers with AUVP. The MFG is a vital element of the prefrontal cortex, which is reported to be concerned within the consideration community (Vossel et al., 2014). It was reported that the MFG was activated in response to an energetic unilateral knee joint place sense take a look at, suggesting that the MFG was concerned within the processing of proprioception (Robust et al., 2023). One other examine urged that the MFG would possibly play a job within the integration of proprioceptive info within the strategy of sensory and motor info integration (Inventory et al., 2013). Subsequently, we speculated that the elevated FC between the suitable thalamus and proper MFG may also replicate elevated thalamo-somatosensory cortex neural pathway in AUVP sufferers. Much like our outcomes, it was reported that there was a shift to the somatosensory system as a consequence of an elevated processing of proprioceptive info in the suitable gracile nucleus in AUVP sufferers throughout power stage (zu Eulenburg et al., 2010). Nonetheless, much like most earlier research (zu Eulenburg et al., 2010; Hong et al., 2014; Klingner et al., 2014; Roberts et al., 2018; Cheng et al., 2023), we didn’t consider the vestibulospinal reflex (VSR) pathway for the AUVP sufferers because the VSR pathway is concerned in acute vertigo and runs via the thalamus (Helmchen et al., 2014; Carmona et al., 2023). Subsequently, the elevated thalamo-somatosensory cortex neural pathway noticed in AUVP sufferers most likely had one thing to do with the deficit in VSR pathway.

As well as, the present examine discovered elevated FC between the suitable thalamus and proper MOG in AUVP sufferers. The MOG is thought to be an vital a part of the lateral visible community and belongs to the secondary visible cortex. Thus, our examine indicated elevated thalamo-visual cortex neural pathway in AUVP sufferers. Earlier neuroimaging research have additionally demonstrated the altered operate of visible cortex in AUVP sufferers (Bense et al., 2004; Cheng et al., 2023) and in sufferers with power unilateral vestibulopathy (CUVP) (Si et al., 2022). As well as, a voxel-based morphometry examine noticed elevated grey matter quantity within the MOG in AUVP sufferers with illness length longer than 3 months in contrast with the identical sufferers at acute stage (onset inside 72 h) (Cheng et al., 2023).

It’s well-known that the upkeep of human postural steadiness will depend on the shut cooperation amongst vestibular, visible, and somatosensory techniques. We believed that the interplay and integration amongst completely different senses makes it attainable for sensory substitution in AUVP sufferers. When vestibular sense is absent, AUVP sufferers could compensate for the lacking vestibular sense with visible and somatosensory senses to keep up postural steadiness, visible stability and notion of spatial location. The current examine noticed decreased thalamo-vestibular cortex neural pathway, in addition to elevated thalamo-somatosensory and thalamo-visual cortex neural pathway in AUVP sufferers throughout acute section. This probably indicated a robust purposeful central vestibular compensation throughout the visible and somatosensory techniques when the peripheral vestibular system undergoes a considerable lack of operate. Our findings of purposeful vestibular compensation echoed an earlier voxel-based morphometry analysis that offered proof for the volumetric will increase within the visible and somatosensory cortices from the angle of structural vestibular compensation in AUVP sufferers throughout power section (zu Eulenburg et al., 2010).

Limitations

This examine had a number of potential limitations. First, the pattern dimension was comparatively small and the info have been gathered from a single middle. Second, the seeds (bilateral thalamus) we adopted contained the entire thalamus. In truth, the thalamus could be divided into a number of sub-regions, with the intention to enhance the specificity of the evaluation, future examine ought to outline anatomical parcellation of the thalamus extra particularly. The third potential limitation was that we solely adopted methodology of seed-based FC, future research ought to mix different strategies to additional discover the neuroimaging modifications of AUVP, for instance, unbiased element evaluation (ICA), purposeful community connectivity (FNC), dynamic FNC, VBM, and so forth. Fourth, we didn’t consider the VSR pathway for the AUVP sufferers. Lastly, we didn’t comply with up sufferers with AUVP to watch modifications in mind purposeful exercise after 3 months to additional confirm the outcomes of this examine.

Conclusion

In conclusion, our outcomes offered first proof for the decreased thalamo-vestibular cortex neural pathway, in addition to elevated thalamo-somatosensory and thalamo-visual cortex neural pathway in AUVP sufferers throughout acute section. These findings assist us higher perceive the underlying mechanisms of central dynamic compensatory following an acute unilateral peripheral vestibular harm.

Information availability assertion

The unique contributions introduced on this examine are included within the article/supplementary materials, additional inquiries could be directed to the corresponding authors.

Ethics assertion

The research involving people have been authorized by the Ethics Committee of the Second Affiliated Hospital of Xuzhou Medical College. The research have been carried out in accordance with the native laws and institutional necessities. The members offered their written knowledgeable consent to take part on this examine.

Writer contributions

ZC: Conceptualization, Information curation, Formal evaluation, Funding acquisition, Investigation, Methodology, Challenge administration, Software program, Visualization, Writing – unique draft, Writing – evaluate & enhancing. YC: Formal evaluation, Investigation, Visualization, Writing – unique draft, Writing – evaluate & enhancing. YL: Investigation, Methodology, Visualization, Writing – evaluate & enhancing. HL: Formal evaluation, Investigation, Methodology, Writing – evaluate & enhancing. X-EW: Formal evaluation, Investigation, Visualization, Writing – evaluate & enhancing. CL: Formal evaluation, Investigation, Writing – evaluate & enhancing. DL: Investigation, Visualization, Writing – evaluate & enhancing. LX: Information curation, Investigation, Challenge administration, Supervision, Writing – evaluate & enhancing. LR: Formal evaluation, Investigation, Challenge administration, Software program, Supervision, Writing – evaluate & enhancing.

Funding

The writer(s) declare monetary help was acquired for the analysis, authorship, and/or publication of this text. This examine was supported by the scientific analysis venture of Well being Fee of Jiangsu province (H2023014).

Acknowledgments

We thank all of the sufferers and wholesome controls for his or her participation on this examine.

Battle of curiosity

The authors declare that the analysis was carried out within the absence of any industrial or monetary relationships that may very well be construed as a possible battle of curiosity.

Writer’s be aware

All claims expressed on this article are solely these of the authors and don’t essentially characterize these of their affiliated organizations, or these of the writer, the editors and the reviewers. Any product which may be evaluated on this article, or declare which may be made by its producer, will not be assured or endorsed by the writer.

Footnotes

References

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