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  • Authors: Toutant, Darion;

    This thesis introduces a novel investigation into the morphological characteristics of epileptiform spikes across various sleep-wake states. A gold-standard database of spikes was created, offering insights into their variations across wakefulness, non-rapid-eye-movement (NREM) sleep stages 1-3, and particularly rapid-eye-movement (REM) sleep, and hypothesizing on the dynamics regulating its suppressive ability towards spikes. The study employed lab-developed software to categorize sleep states and validate spikes using data from 7 epilepsy monitoring unit patients. A computational pipeline was developed to assess nine morphological spike features throughout Laplacian, Referential, and Raw montages. Due to non-normal data distribution, statistical analysis was performed using the Kruskal-Wallis test, followed by Dunn's post-hoc testing and Bonferroni correction. Results revealed that the spike features of REM sleep are significantly different from those of other sleep-wake states. In particular, spikes during REM sleep had the shallowest ascending and descending slopes by nearly 50% of the other states, which were nearly symmetrical, blunter peaks with roughly twice the angle of other states and exhibited lower peak amplitudes less than 50% of the voltage of other states. Wakefulness was the most different state concerning duration while being, on average, 15% shorter. Finally, the spike area during REM was roughly twice as small as all other states. This study shows significant spike feature differences throughout sleep-wake states, with REM drastically different in most features. The driving factors for changes in spike morphology throughout the sleep-wake states are unknown. However, this thesis explores the effects of ionic, neurotransmitter, astrocytic and network dynamic processes to help shed light on these changes. Notably, this thesis provides glimpses into the roles of astrocytic involvement, orexinergic systems, and network dynamics as potential contributors to the observed morphological differences within REM. Further investigations are necessary to fully understand these complex electrobiological interactions, which may be responsible for the observed anti-epileptic properties during REM sleep. This study paves the way for future work to expose and leverage the unique anti-epileptic mechanisms of REM sleep, potentially leading to the development of REM-specific therapeutic strategies for epilepsy management.

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    Authors: Tremblay, Pascale; Gagnon, Lydia; Roy, Johanna-Pascale; Arseneault, Alison;

    Purpose: Amateur singing is a universal, accessible, and enjoyable musical activity that may have positive impacts on human communication. However, evidence of an impact of singing on speech articulation is still scarce, yet, understanding the effects of vocal training on speech production could provide a model for treating people with speech deficits. The aim of this study was to examine speech production in younger and older adults with or without amateur singing experience. Method: 38 amateur singers (aged 20–87 years, 23 females) and 40 non-musician controls (aged 23–88 years, 19 females) were recruited. A set of tasks were used to evaluate the oral motor sphere: two voice production tasks, a passage reading task and a modified diadochokinetic rates task (DDK) performed at a natural rhythm and as fast as possible. Results: Our results show that older age was associated with lower reading rate, lower articulation rate and articulation rate variability in the DDK task, as well as reduced accuracy for the phonologically complex stimuli. Most importantly, our results show an advantage for singers over cognitively active non-singers in terms of articulatory accuracy in the most challenging situations. Conclusions: This result suggests extended maximal performance capacities in amateur singers perhaps resulting from the articulatory efforts required during singing.

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    CorpusUL
    Other ORP type . 2023
    Data sources: CorpusUL
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      CorpusUL
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    Authors: McAllister, Zachary;

    Transcranial direct current stimulation (tDCS) applied to the dorsolateral prefrontal cortex (DLPFC) has been shown to have asymmetric behavioral effects, but the underlaying neurophysiological mechanisms causing these asymmetric behavioral differences are poorly understood. Functional magnetic resonance imaging (fMRI) can be used in conjunction with a behavioral measurement to better understand these mechanisms. To measure the hemispheric laterality of neurophysiological and behavioral effects of anodal tDCS applied to the left and right DLPFC using fMRI and Stroop test interference, 11 male and 28 female healthy participants were randomized into three treatment groups of 1.5mA anodal tDCS applied to sham or the left or right the DLPFC, with the cathode placed on the contralateral supraorbital region. Before and after tDCS application participants took the Stroop test and underwent resting-state fMRI. Seed-to-voxel functional connectivity and voxel-to-voxel whole brain intrinsic connectivity (IC) analyses were performed on the fMRI data. All fMRI analysis was done by using two sets of 2×2 factorial analyses between groups (real vs. sham) and time (pre- vs. post-tDCS) for each left and right tDCS, separately, while Stroop interference was measured using a repeated measures general linear model. tDCS to the left DLPFC in the voxel-to-voxel analysis resulted in three significant clusters of changed IC, with one of the clusters being an increase of IC in the left prefrontal region. tDCS to the right DLPFC in the voxel-to-voxel analysis resulted in only one significant cluster of decreased IC in the right prefrontal region. For Stroop interference, only tDCS to the right DLPFC improved Stroop interference performance with left and sham causing no significant changes. No significant changes were found for seed-to-voxel analysis. This study shows that tDCS applied to the left and right DLPFC causes asymmetric changes to IC, as well as providing further support that the DLPFC is asymmetric in interference control, with only tDCS to the right DLPFC having a significant effect on interference.

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    Authors: Parent, Camille; Rousseau, Louis-Simon; Predovan, David; Duchesne, Simon; +1 Authors

    This systematic review examined the longitudinal association between amyloid-b (Ab) accumulation and cognitive decline in cognitively healthy adults. It was conducted using the PubMed, Embase, PsycInfo, and Web of Science databases. The methodological quality of the selected articles was assessed. In fine, seventeen longitudinal clinical studies were included in this review. A minority (seven out of 17) of studies reported a statistically significant association or prediction of cognitive decline with Ab change, measured by positron emission tomography (PET; n = 6) and lumbar puncture (n = 1), with a mean follow-up duration of 3.17 years for cognition and 2.99 years for Ab. The studies reporting significant results with PET found differences in the frontal, posterior cingular, lateral parietal and global (whole brain) cortices as well as in the precuneus. Significant associations were found with episodic memory (n = 6) and global cognition (n = 1). Five of the seven studies using a composite cognitive score found significant results. A quality assessment revealed widespread methodological biases, such as failure to report or account for loss to follow up and missing data, and failure to report p-values and effect sizes of nonsignificant results. Overall, the longitudinal association between Ab accumulation and cognitive decline in preclinical Alzheimer’s disease remains unclear. The discrepancy in results between studies may be explained in part by the choice of neuroimaging technique used to measure Ab change, the duration of longitudinal studies, the heterogeneity of the healthy preclinical population, and importantly, the use of a composite score to capture cognitive changes with increased sensitivity. More longitudinal studies with larger sample sizes are needed to elucidate this relationship.

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    CorpusUL
    Other ORP type . 2023
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      CorpusUL
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Harel, Yann; Cyr, André; Boyle, Julie; Pinsard, Basile; +7 Authors

    {"references": ["Harel et al., (2023). Open design and validation of a reproducible videogame controller for MRI and MEG."]} Full documentation and files required to build the CNeuromod controller.

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  • image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
    Authors: Koch, Alexandra; Stirnberg, Rüdiger; Breteler, Monique M. B.; Estrada Leon, Edgar Santiago; +7 Authors

    This data repository contains an example of the acquired MRI sequences and the output of the post-processing pipelines in the Rhineland Study. An overview and information about the MRI sequences and post-processing pipelines can be found in our work 'Versatile MRI Acquisition and Processing Protocol for Population-Based Neuroimaging.' (under-submission)

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      2023
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  • Authors: Iyyappan Valsala, Praveen; Veldmann, Marten; Bosch, Dario; Scheffler, Klaus; +1 Authors

    This work aims to improve the speed of balanced steady-state free precession (bSSFP) acquisition with segmented 3D stack-of-spirals for functional brain studies at 9.4 T (see protocols.zip). Functional experiments were performed with full-field flickering checkerboard pattern (see radial_checkerboard.zip). The resulting data were reconstructed using an iterative algorithm with corrections for system imperfections such as trajectory deviations and B0 inhomogeneity using SpiralReco package. In the first set of experiments, we evaluated the signal change and stability with respect to echo and repetition time for a full field checkerboard stimulus. To demonstrate the high spatio-temporal resolution of the developed method, the results of three optimized protocols at submillimeter resolution (0.6 mm & 0.8 mm) and at 1.2 mm isotropic resolution for whole brain coverage were performed.

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  • Authors: Walluscheck, Sina; Canalini, Luca; Klein, Jan; Heldmann, Stefan;

    Automatic detection of abnormalities to assist radiologists in acute and screening scenarios has become a particular focus in medical imaging research. Various approaches have been proposed for the detection of anomalies in magnetic resonance (MR) data, but very little work has been done for computed tomography (CT). As far as we know, there is no satisfactory approach for anomaly detection in CT brain images. We present a novel unsupervised deep learning approach to generate a normal representation (without anomalies) of CT head scans that we use to discriminate between healthy and abnormal images. In the first step, we train a GAN with 1000 healthy CT scans to generate normal head images. Subsequently, we attach an encoder to the generator and train the auto encoder network to reconstruct healthy anatomy from new input images. The auto encoder is pre-trained with generated images using a perceptual loss function. When applied to abnormal scans, the reconstructed healthy output is then used to detect anomalies by computing the Mean Squared Error between input and output image. We evaluate our slice-wise anomaly detection on 250 test images including hemorrhages and tumors. Our approach achieves an area under receiver operating characteristic curve (AUC) of 0.90 with 85.8% sensitivity and 85.5% precision without requiring large training data sets or labeled anomaly data. Therefore, our method discriminates between normal and abnormal CT scans with good accuracy.

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    Authors: Ippolitov, Danyyl;

    Introduction: HER2+ (ErbB2+) breast cancer (BC) patients demonstrate a high incidence (30%) of brain metastases (BM). Regardless of the effectiveness of ErbB2 targeting therapies in the therapy of primary HER2+ BC, BM remains a fatal complication. Restricted drug permeability across the blood-brain barrier and specific tumor- and/or brain tumor microenvironment (TME)-derived factors determine the low effectiveness of ErbB targeted drugs in the brain. Neuregulin-1 (NRG-1) is a member of the EGF family which is commonly expressed by cells in the brain TME. NRG1 can bind to ErbB3 and/or ErbB4 receptors and potentially promote activation of alternative signaling pathways under ErbB2 inhibition. Results: The newly established patient-derived HER2+ BC model (BCBM94) that metastasizes to the brain in mice forms well-circumscribed proliferative tumors that are vascularized and surrounded by activated astrocytes. BCBM94 cells are sensitive to the pro-apoptotic actions of the reversible EGFR/ErbB2 small molecule tyrosine kinase inhibitor Lapatinib. NRG1 mitigated cytotoxicity induced by Lapatinib, as shown by higher viability in WST-1 assays and the preserved ability for long-term cell propagation in clonogenicity assays. NRG-1 blocked Lapatinib-driven PARP cleavage and activation of the pro-apoptotic caspases-3/7 and caspase-9. NRG-1 also prevented Lapatinib-induced mitochondrial damage. rhNRG1 rescued phosphorylation of kinase-impaired ErbB3 under combined Lapatinib/rhNRG1 treatment suggesting the involvement of ErbB3 in maintaining the viability of BCBM94 under Lapatinib. The essential role of ErbB3 in the apoptosis inhibiting action of rhNRG1 was confirmed by siRNA-mediated silencing (KD) of the receptor. Upon ErbB3 knockdown, rhNRG1 was no longer able to attenuate the Lapatinib-mediated apoptosis in BCBM94 and this coincided with the mitigated rescue of Survivin and XIAP expression and BAD phosphorylation in BCBM94. These rhNRG1-mediated anti-apoptotic actions were also prevented with exposure to the multi-targeted PI3K-Akt and mTORC1/C2 inhibitor (PI-103) confirming the role of the ErbB3-Akt-mTOR signaling axis in the cell viability rescue. Conclusion: The findings identify BCBM94 as a valuable brain metastasis cell model to study resistance mechanisms under ErbB2 inhibition and demonstrate an important role of NRG1 as a powerful brain TME-derived anti-apoptotic factor that can facilitate resistance of BC brain metastases to ErbB2 targeting therapies.

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  • Authors: BIDS-contributors;

    For versions >= 1.9.0, please see this record: https://zenodo.org/doi/10.5281/zenodo.10175845 ---------- This resource defines the Brain Imaging Data Structure (BIDS) specification, including the core specification as well as many modality-specific extensions. To get started, check out the introduction. For an overview of the BIDS ecosystem, visit the BIDS homepage. The entire specification can also be browsed in an HTML version. See Appendix I for a list of the BIDS contributors who jointly created this specification.

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  • Authors: Toutant, Darion;

    This thesis introduces a novel investigation into the morphological characteristics of epileptiform spikes across various sleep-wake states. A gold-standard database of spikes was created, offering insights into their variations across wakefulness, non-rapid-eye-movement (NREM) sleep stages 1-3, and particularly rapid-eye-movement (REM) sleep, and hypothesizing on the dynamics regulating its suppressive ability towards spikes. The study employed lab-developed software to categorize sleep states and validate spikes using data from 7 epilepsy monitoring unit patients. A computational pipeline was developed to assess nine morphological spike features throughout Laplacian, Referential, and Raw montages. Due to non-normal data distribution, statistical analysis was performed using the Kruskal-Wallis test, followed by Dunn's post-hoc testing and Bonferroni correction. Results revealed that the spike features of REM sleep are significantly different from those of other sleep-wake states. In particular, spikes during REM sleep had the shallowest ascending and descending slopes by nearly 50% of the other states, which were nearly symmetrical, blunter peaks with roughly twice the angle of other states and exhibited lower peak amplitudes less than 50% of the voltage of other states. Wakefulness was the most different state concerning duration while being, on average, 15% shorter. Finally, the spike area during REM was roughly twice as small as all other states. This study shows significant spike feature differences throughout sleep-wake states, with REM drastically different in most features. The driving factors for changes in spike morphology throughout the sleep-wake states are unknown. However, this thesis explores the effects of ionic, neurotransmitter, astrocytic and network dynamic processes to help shed light on these changes. Notably, this thesis provides glimpses into the roles of astrocytic involvement, orexinergic systems, and network dynamics as potential contributors to the observed morphological differences within REM. Further investigations are necessary to fully understand these complex electrobiological interactions, which may be responsible for the observed anti-epileptic properties during REM sleep. This study paves the way for future work to expose and leverage the unique anti-epileptic mechanisms of REM sleep, potentially leading to the development of REM-specific therapeutic strategies for epilepsy management.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Tremblay, Pascale; Gagnon, Lydia; Roy, Johanna-Pascale; Arseneault, Alison;

    Purpose: Amateur singing is a universal, accessible, and enjoyable musical activity that may have positive impacts on human communication. However, evidence of an impact of singing on speech articulation is still scarce, yet, understanding the effects of vocal training on speech production could provide a model for treating people with speech deficits. The aim of this study was to examine speech production in younger and older adults with or without amateur singing experience. Method: 38 amateur singers (aged 20–87 years, 23 females) and 40 non-musician controls (aged 23–88 years, 19 females) were recruited. A set of tasks were used to evaluate the oral motor sphere: two voice production tasks, a passage reading task and a modified diadochokinetic rates task (DDK) performed at a natural rhythm and as fast as possible. Results: Our results show that older age was associated with lower reading rate, lower articulation rate and articulation rate variability in the DDK task, as well as reduced accuracy for the phonologically complex stimuli. Most importantly, our results show an advantage for singers over cognitively active non-singers in terms of articulatory accuracy in the most challenging situations. Conclusions: This result suggests extended maximal performance capacities in amateur singers perhaps resulting from the articulatory efforts required during singing.

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    CorpusUL
    Other ORP type . 2023
    Data sources: CorpusUL
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      CorpusUL
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: McAllister, Zachary;

    Transcranial direct current stimulation (tDCS) applied to the dorsolateral prefrontal cortex (DLPFC) has been shown to have asymmetric behavioral effects, but the underlaying neurophysiological mechanisms causing these asymmetric behavioral differences are poorly understood. Functional magnetic resonance imaging (fMRI) can be used in conjunction with a behavioral measurement to better understand these mechanisms. To measure the hemispheric laterality of neurophysiological and behavioral effects of anodal tDCS applied to the left and right DLPFC using fMRI and Stroop test interference, 11 male and 28 female healthy participants were randomized into three treatment groups of 1.5mA anodal tDCS applied to sham or the left or right the DLPFC, with the cathode placed on the contralateral supraorbital region. Before and after tDCS application participants took the Stroop test and underwent resting-state fMRI. Seed-to-voxel functional connectivity and voxel-to-voxel whole brain intrinsic connectivity (IC) analyses were performed on the fMRI data. All fMRI analysis was done by using two sets of 2×2 factorial analyses between groups (real vs. sham) and time (pre- vs. post-tDCS) for each left and right tDCS, separately, while Stroop interference was measured using a repeated measures general linear model. tDCS to the left DLPFC in the voxel-to-voxel analysis resulted in three significant clusters of changed IC, with one of the clusters being an increase of IC in the left prefrontal region. tDCS to the right DLPFC in the voxel-to-voxel analysis resulted in only one significant cluster of decreased IC in the right prefrontal region. For Stroop interference, only tDCS to the right DLPFC improved Stroop interference performance with left and sham causing no significant changes. No significant changes were found for seed-to-voxel analysis. This study shows that tDCS applied to the left and right DLPFC causes asymmetric changes to IC, as well as providing further support that the DLPFC is asymmetric in interference control, with only tDCS to the right DLPFC having a significant effect on interference.

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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Parent, Camille; Rousseau, Louis-Simon; Predovan, David; Duchesne, Simon; +1 Authors

    This systematic review examined the longitudinal association between amyloid-b (Ab) accumulation and cognitive decline in cognitively healthy adults. It was conducted using the PubMed, Embase, PsycInfo, and Web of Science databases. The methodological quality of the selected articles was assessed. In fine, seventeen longitudinal clinical studies were included in this review. A minority (seven out of 17) of studies reported a statistically significant association or prediction of cognitive decline with Ab change, measured by positron emission tomography (PET; n = 6) and lumbar puncture (n = 1), with a mean follow-up duration of 3.17 years for cognition and 2.99 years for Ab. The studies reporting significant results with PET found differences in the frontal, posterior cingular, lateral parietal and global (whole brain) cortices as well as in the precuneus. Significant associations were found with episodic memory (n = 6) and global cognition (n = 1). Five of the seven studies using a composite cognitive score found significant results. A quality assessment revealed widespread methodological biases, such as failure to report or account for loss to follow up and missing data, and failure to report p-values and effect sizes of nonsignificant results. Overall, the longitudinal association between Ab accumulation and cognitive decline in preclinical Alzheimer’s disease remains unclear. The discrepancy in results between studies may be explained in part by the choice of neuroimaging technique used to measure Ab change, the duration of longitudinal studies, the heterogeneity of the healthy preclinical population, and importantly, the use of a composite score to capture cognitive changes with increased sensitivity. More longitudinal studies with larger sample sizes are needed to elucidate this relationship.

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    CorpusUL
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      CorpusUL
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  • image/svg+xml art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos Open Access logo, converted into svg, designed by PLoS. This version with transparent background. http://commons.wikimedia.org/wiki/File:Open_Access_logo_PLoS_white.svg art designer at PLoS, modified by Wikipedia users Nina, Beao, JakobVoss, and AnonMoos http://www.plos.org/
    Authors: Harel, Yann; Cyr, André; Boyle, Julie; Pinsard, Basile; +7 Authors

    {"references": ["Harel et al., (2023). Open design and validation of a reproducible videogame controller for MRI and MEG."]} Full documentation and files required to build the CNeuromod controller.

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    ZENODO
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  • image/svg+xml Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao Closed Access logo, derived from PLoS Open Access logo. This version with transparent background. http://commons.wikimedia.org/wiki/File:Closed_Access_logo_transparent.svg Jakob Voss, based on art designer at PLoS, modified by Wikipedia users Nina and Beao
    Authors: Koch, Alexandra; Stirnberg, Rüdiger; Breteler, Monique M. B.; Estrada Leon, Edgar Santiago; +7 Authors

    This data repository contains an example of the acquired MRI sequences and the output of the post-processing pipelines in the Rhineland Study. An overview and information about the MRI sequences and post-processing pipelines can be found in our work 'Versatile MRI Acquisition and Processing Protocol for Population-Based Neuroimaging.' (under-submission)

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  • Authors: Iyyappan Valsala, Praveen; Veldmann, Marten; Bosch, Dario; Scheffler, Klaus; +1 Authors

    This work aims to improve the speed of balanced steady-state free precession (bSSFP) acquisition with segmented 3D stack-of-spirals for functional brain studies at 9.4 T (see protocols.zip). Functional experiments were performed with full-field flickering checkerboard pattern (see radial_checkerboard.zip). The resulting data were reconstructed using an iterative algorithm with corrections for system imperfections such as trajectory deviations and B0 inhomogeneity using SpiralReco package. In the first set of experiments, we evaluated the signal change and stability with respect to echo and repetition time for a full field checkerboard stimulus. To demonstrate the high spatio-temporal resolution of the developed method, the results of three optimized protocols at submillimeter resolution (0.6 mm & 0.8 mm) and at 1.2 mm isotropic resolution for whole brain coverage were performed.

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  • Authors: Walluscheck, Sina; Canalini, Luca; Klein, Jan; Heldmann, Stefan;

    Automatic detection of abnormalities to assist radiologists in acute and screening scenarios has become a particular focus in medical imaging research. Various approaches have been proposed for the detection of anomalies in magnetic resonance (MR) data, but very little work has been done for computed tomography (CT). As far as we know, there is no satisfactory approach for anomaly detection in CT brain images. We present a novel unsupervised deep learning approach to generate a normal representation (without anomalies) of CT head scans that we use to discriminate between healthy and abnormal images. In the first step, we train a GAN with 1000 healthy CT scans to generate normal head images. Subsequently, we attach an encoder to the generator and train the auto encoder network to reconstruct healthy anatomy from new input images. The auto encoder is pre-trained with generated images using a perceptual loss function. When applied to abnormal scans, the reconstructed healthy output is then used to detect anomalies by computing the Mean Squared Error between input and output image. We evaluate our slice-wise anomaly detection on 250 test images including hemorrhages and tumors. Our approach achieves an area under receiver operating characteristic curve (AUC) of 0.90 with 85.8% sensitivity and 85.5% precision without requiring large training data sets or labeled anomaly data. Therefore, our method discriminates between normal and abnormal CT scans with good accuracy.

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    Authors: Ippolitov, Danyyl;

    Introduction: HER2+ (ErbB2+) breast cancer (BC) patients demonstrate a high incidence (30%) of brain metastases (BM). Regardless of the effectiveness of ErbB2 targeting therapies in the therapy of primary HER2+ BC, BM remains a fatal complication. Restricted drug permeability across the blood-brain barrier and specific tumor- and/or brain tumor microenvironment (TME)-derived factors determine the low effectiveness of ErbB targeted drugs in the brain. Neuregulin-1 (NRG-1) is a member of the EGF family which is commonly expressed by cells in the brain TME. NRG1 can bind to ErbB3 and/or ErbB4 receptors and potentially promote activation of alternative signaling pathways under ErbB2 inhibition. Results: The newly established patient-derived HER2+ BC model (BCBM94) that metastasizes to the brain in mice forms well-circumscribed proliferative tumors that are vascularized and surrounded by activated astrocytes. BCBM94 cells are sensitive to the pro-apoptotic actions of the reversible EGFR/ErbB2 small molecule tyrosine kinase inhibitor Lapatinib. NRG1 mitigated cytotoxicity induced by Lapatinib, as shown by higher viability in WST-1 assays and the preserved ability for long-term cell propagation in clonogenicity assays. NRG-1 blocked Lapatinib-driven PARP cleavage and activation of the pro-apoptotic caspases-3/7 and caspase-9. NRG-1 also prevented Lapatinib-induced mitochondrial damage. rhNRG1 rescued phosphorylation of kinase-impaired ErbB3 under combined Lapatinib/rhNRG1 treatment suggesting the involvement of ErbB3 in maintaining the viability of BCBM94 under Lapatinib. The essential role of ErbB3 in the apoptosis inhibiting action of rhNRG1 was confirmed by siRNA-mediated silencing (KD) of the receptor. Upon ErbB3 knockdown, rhNRG1 was no longer able to attenuate the Lapatinib-mediated apoptosis in BCBM94 and this coincided with the mitigated rescue of Survivin and XIAP expression and BAD phosphorylation in BCBM94. These rhNRG1-mediated anti-apoptotic actions were also prevented with exposure to the multi-targeted PI3K-Akt and mTORC1/C2 inhibitor (PI-103) confirming the role of the ErbB3-Akt-mTOR signaling axis in the cell viability rescue. Conclusion: The findings identify BCBM94 as a valuable brain metastasis cell model to study resistance mechanisms under ErbB2 inhibition and demonstrate an important role of NRG1 as a powerful brain TME-derived anti-apoptotic factor that can facilitate resistance of BC brain metastases to ErbB2 targeting therapies.

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  • Authors: BIDS-contributors;

    For versions >= 1.9.0, please see this record: https://zenodo.org/doi/10.5281/zenodo.10175845 ---------- This resource defines the Brain Imaging Data Structure (BIDS) specification, including the core specification as well as many modality-specific extensions. To get started, check out the introduction. For an overview of the BIDS ecosystem, visit the BIDS homepage. The entire specification can also be browsed in an HTML version. See Appendix I for a list of the BIDS contributors who jointly created this specification.

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