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  • 1.
    Akerlund, Cecilia A., I
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Anaesthesiol & Intens Care, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Funct Perioperat Med & Intens Care, Stockholm, Sweden..
    Holst, Anders
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Bhattacharyay, Shubhayu
    Univ Cambridge, Dept Med, Div Anaesthesia, Cambridge, England..
    Stocchetti, Nino
    Univ Cambridge, Cambridge, England.;Milan Univ, Dept Physiopathol & Transplant, Milan, Italy.;Osped Maggiore Policlin, Fdn IRCCS Ca Granda, Milan, Italy..
    Steyerberg, Ewout
    Leiden Univ Med Ctr, Dept Biomed Data Sci, Leiden, Netherlands..
    Smielewski, Peter
    Univ Cambridge, Clin Neurosci, Cambridge, England..
    Menon, David K.
    Univ Cambridge, Dept Med, Div Anaesthesia, Cambridge, England..
    Ercole, Ari
    Univ Cambridge, Dept Med, Div Anaesthesia, Cambridge, England.;Univ Cambridge, Ctr Artificial Intelligence Med, Cambridge, England..
    Nelson, David W.
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Anaesthesiol & Intens Care, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Funct Perioperat Med & Intens Care, Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Sect Anaesthes & Intens Care, S-171 77 Stockholm, Sweden..
    Clinical descriptors of disease trajectories in patients with traumatic brain injury in the intensive care unit (CENTER-TBI): a multicentre observational cohort study2024In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 23, no 1, p. 71-80Article in journal (Refereed)
    Abstract [en]

    Background Patients with traumatic brain injury are a heterogeneous population, and the most severely injured individuals are often treated in an intensive care unit (ICU). The primary injury at impact, and the harmful secondary events that can occur during the first week of the ICU stay, will affect outcome in this vulnerable group of patients. We aimed to identify clinical variables that might distinguish disease trajectories among patients with traumatic brain injury admitted to the ICU. Methods We used data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. We included patients aged 18 years or older with traumatic brain injury who were admitted to the ICU at one of the 65 CENTER-TBI participating centres, which range from large academic hospitals to small rural hospitals. For every patient, we obtained pre-injury data and injury features, clinical characteristics on admission, demographics, physiological parameters, laboratory features, brain biomarkers (ubiquitin carboxy-terminal hydrolase L1 [UCH-L1], S100 calcium-binding protein B [S100B], tau, neurofilament light [NFL], glial fibrillary acidic protein [GFAP], and neuron-specific enolase [NSE]), and information about intracranial pressure lowering treatments during the first 7 days of ICU stay. To identify clinical variables that might distinguish disease trajectories, we applied a novel clustering method to these data, which was based on a mixture of probabilistic graph models with a Markov chain extension. The relation of clusters to the extended Glasgow Outcome Scale (GOS-E) was investigated. Findings Between Dec 19, 2014, and Dec 17, 2017, 4509 patients with traumatic brain injury were recruited into the CENTER-TBI core dataset, of whom 1728 were eligible for this analysis. Glucose variation (defined as the difference between daily maximum and minimum glucose concentrations) and brain biomarkers (S100B, NSE, NFL, tau, UCH-L1, and GFAP) were consistently found to be the main clinical descriptors of disease trajectories (ie, the leading variables contributing to the distinguishing clusters) in patients with traumatic brain injury in the ICU. The disease trajectory cluster to which a patient was assigned in a model was analysed as a predictor together with variables from the IMPACT model, and prediction of both mortality and unfavourable outcome (dichotomised GOS-E <= 4) was improved. Interpretation First-day ICU admission data are not the only clinical descriptors of disease trajectories in patients with traumatic brain injury. By analysing temporal variables in our study, variation of glucose was identified as the most important clinical descriptor that might distinguish disease trajectories in the ICU, which should direct further research. Biomarkers of brain injury (S100B, NSE, NFL, tau, UCH-L1, and GFAP) were also top clinical descriptors over time, suggesting they might be important in future clinical practice.

  • 2. Asplund Högelin, K.
    et al.
    Ruffin, N.
    Pin, Elisa
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Hober, Sophia
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Starvaggi Cucuzza, C.
    Khademi, M.
    Olsson, T.
    Piehl, F.
    Al Nimer, F.
    B-cell repopulation dynamics and drug pharmacokinetics impact SARS-CoV-2 vaccine efficacy in anti-CD20-treated multiple sclerosis patients2022In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 29, no 11, p. 3317-3328Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Recent findings document a blunted humoral response to SARS-CoV-2 vaccination in patients on anti-CD20 treatment. Although most patients develop a cellular response, it is still important to identify predictors of seroconversion to optimize vaccine responses. Methods: We determined antibody responses after SARS-CoV-2 vaccination in a real-world cohort of multiple sclerosis patients (n = 94) treated with anti-CD20, mainly rituximab, with variable treatment duration (median = 2.9, range = 0.4–9.6 years) and time from last anti-CD20 infusion to vaccination (median = 190, range = 60–1032 days). Results: We find that presence of B cells and/or rituximab in blood predict seroconversion better than time since last infusion. Using multiple logistic regression, presence of &gt;0.5% B cells increased probability of seroconversion with an odds ratio (OR) of 5.0 (95% confidence interval [CI] = 1.0–28.1, p = 0.055), whereas the corresponding OR for ≥6 months since last infusion was 1.45 (95% CI = 0.20–10.15, p = 0.705). In contrast, detectable rituximab levels were negatively associated with seroconversion (OR = 0.05, 95% CI = 0.002–0.392, p = 0.012). Furthermore, naïve and memory IgG+ B cells correlated with antibody levels. Although retreatment with rituximab at 4 weeks or more after booster depleted spike-specific B cells, it did not noticeably affect the rate of decline in antibody titers. Interferon-γ and/or interleukin-13 T-cell responses to the spike S1 domain were observed in most patients, but with no correlation to spike antibody levels. Conclusions: These findings are relevant for providing individualized guidance to patients and planning of vaccination schemes, in turn optimizing benefit–risk with anti-CD20. 

  • 3.
    Aydin, Nursah
    et al.
    Erzurum Tech Univ, Dept Mol Biol & Genet, TR-25050 Erzurum, Turkey..
    Turkez, Hasan
    Ataturk Univ, Fac Med, Dept Med Biol, TR-25240 Erzurum, Turkey.;Ataturk Univ, East Anatolia High Technol Applicat & Res Ctr DAY, TR-25240 Erzurum, Turkey..
    Tozlu, Ozlem Ozdemir
    Erzurum Tech Univ, Dept Mol Biol & Genet, TR-25050 Erzurum, Turkey..
    Arslan, Mehmet Enes
    Erzurum Tech Univ, Dept Mol Biol & Genet, TR-25050 Erzurum, Turkey..
    Yavuz, Mehmet
    REEM Neuropsychiat Clin, TR-34245 Istanbul, Turkey..
    Sonmez, Erdal
    Ataturk Univ, Grad Sch Nat & Appl Sci, Dept Nanosci & Nanoengn, TR-25240 Erzurum, Turkey.;Ataturk Univ, Kazim Karabekir Educ Fac, Dept Phys, TR-25240 Erzurum, Turkey..
    Ozpolat, Ozgur Firat
    Ataturk Univ, Comp Sci Res & Applicat Ctr, TR-25240 Erzurum, Turkey..
    Cacciatore, Ivana
    Univ G Annunzio Chieti Pescara, Dept Pharm, Via Vestini 31, I-66100 Chieti, CH, Italy..
    Di Stefano, Antonio
    Univ G Annunzio Chieti Pescara, Dept Pharm, Via Vestini 31, I-66100 Chieti, CH, Italy..
    Mardinoglu, Adil
    KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology. Kings Coll London, Fac Dent Oral & Craniofacial Sci, Ctr Host Microbiome Interact, London SE1 9RT, England..
    Ameliorative Effects by Hexagonal Boron Nitride Nanoparticles against Beta Amyloid Induced Neurotoxicity2022In: Nanomaterials, E-ISSN 2079-4991, Vol. 12, no 15, p. 2690-, article id 2690Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is considered as the most common neurodegenerative disease. Extracellular amyloid beta (A beta) deposition is a hallmark of AD. The options based on degradation and clearance of A beta are preferred as promising therapeutic strategies for AD. Interestingly, recent findings indicate that boron nanoparticles not only act as a carrier but also play key roles in mediating biological effects. In the present study, the aim was to investigate the effects of different concentrations (0-500 mg/L) of hexagonal boron nitride nanoparticles (hBN-NPs) against neurotoxicity by beta amyloid (A beta(1-42)) in differentiated human SH-SY5Y neuroblastoma cell cultures for the first time. The synthesized hBN-NPs were characterized by X-ray diffraction (XRD) measurements, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). A beta(1-42)-induced neurotoxicity and therapeutic potential by hBN-NPs were assessed on differentiated SH-SY5Y cells using MTT and LDH release assays. Levels of total antioxidant capacity (TAC) and total oxidant status (TOS), expression levels of genes associated with AD and cellular morphologies were examined. The exposure to A beta(1-42) significantly decreased the rates of viable cells which was accompanied by elevated TOS level. A beta(1-42) induced both apoptotic and necrotic cell death. A beta exposure led to significant increases in expression levels of APOE, BACE 1, EGFR, NCTSN and TNF-alpha genes and significant decreases in expression levels of ADAM 10, APH1A, BDNF, PSEN1 and PSENEN genes (p < 0.05). All the A beta(1-42)-induced neurotoxic insults were inhibited by the applications with hBN-NPs. hBN-NPs also suppressed the remarkable elevation in the signal for A beta following exposure to A beta(1-42) for 48 h. Our results indicated that hBN-NPs could significantly prevent the neurotoxic damages by A beta. Thus, hBN-NPs could be a novel and promising anti-AD agent for effective drug development, bio-nano imaging or drug delivery strategies.

  • 4.
    Ayoglu, Burcu
    et al.
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Kockum, Ingrid
    Olsson, Tomas
    Nilsson, Peter
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Anoctamin 2 identified as an autoimmune target in multiple sclerosis2016In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, p. 10-10Article in journal (Other academic)
  • 5.
    Ayoglu, Burcu
    et al.
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Mitsios, N.
    Karolinska Inst, Neurosci, Stockholm, Sweden..
    Kockum, I.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Olsson, T.
    Karolinska Inst, Clin Neurosci, Stockholm, Sweden..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Anoctamin 2 identified as an autoimmune target in multiple sclerosis2016In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 23, p. 57-57Article in journal (Other academic)
  • 6.
    Blom, Hans
    et al.
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bernhem, Kristoffer
    KTH, School of Engineering Sciences (SCI), Applied Physics.
    Brismar, Hjalmar
    KTH, School of Engineering Sciences (SCI), Applied Physics. KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institutet, Sweden.
    Sodium pump organization in dendritic spines2016In: NEUROPHOTONICS, ISSN 2329-423X, Vol. 3, no 4, article id 041803Article in journal (Refereed)
    Abstract [en]

    Advancement in fluorescence imaging with the invention of several super-resolution microscopy modalities (e.g., PALM/STORM and STED) has opened up the possibility of deciphering molecular distributions on the nanoscale. In our quest to better elucidate postsynaptic protein distribution in dendritic spines, we have applied these nanoscopy methods, where generated results could help improve our understanding of neuronal functions. In particular, we have investigated the principal energy transformer in the brain, i.e., the Na+; K+-ATPase (or sodium pump), an essential protein responsible for maintaining resting membrane potential and a major controller of intracellular ion homeostasis. In these investigations, we have focused on estimates of protein amount, giving assessments of how variations may depend on labeling strategies, sample analysis, and choice of nanoscopic imaging method, concluding that all can be critical factors for quantification. We present a comparison of these results and discuss the influences this may have for homeostatic sodium regulation in neurons and energy consumption.

  • 7.
    Brusini, Irene
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging. Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    MacNicol, Eilidh
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England..
    Kim, Eugene
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England..
    Smedby, Örjan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Wang, Chunliang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Medical Imaging.
    Westman, Eric
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden..
    Veronese, Mattia
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England.;Univ Padua, Dept Informat Engn, Padua, Italy..
    Turkheimer, Federico
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England..
    Cash, Diana
    Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Neuroimaging, London, England..
    MRI-derived brain age as a biomarker of ageing in rats: validation using a healthy lifestyle intervention2022In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 109, p. 204-215Article in journal (Refereed)
    Abstract [en]

    The difference between brain age predicted from MRI and chronological age (the so-called BrainAGE) has been proposed as an ageing biomarker. We analyse its cross-species potential by testing it on rats undergoing an ageing modulation intervention. Our rat brain age prediction model combined Gaussian process regression with a classifier and achieved a mean absolute error (MAE) of 4.87 weeks using cross-validation on a longitudinal dataset of 31 normal ageing rats. It was then tested on two groups of 24 rats (MAE = 9.89 weeks, correlation coefficient = 0.86): controls vs. a group under long-term environmental enrichment and dietary restriction (EEDR). Using a linear mixed-effects model, BrainAGE was found to increase more slowly with chronological age in EEDR rats ( p = 0 . 015 for the interaction term). Cox re-gression showed that older BrainAGE at 5 months was associated with higher mortality risk ( p = 0 . 03 ). Our findings suggest that lifestyle-related prevention approaches may help to slow down brain ageing in rodents and the potential of BrainAGE as a predictor of age-related health outcomes.

  • 8.
    Chen, Yue
    et al.
    Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Zhang, Bosong
    Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Yu, Lina
    Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Zhang, Jinyu
    Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Zhao, Yufang
    Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    Yao, Lifen
    Harbin Med Univ, Dept Neurol, Affiliated Hosp 1, Harbin 150080, Peoples R China..
    Yan, Hongji
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Glycoscience. AIMES Ctr Adv Integrated Med & Engn Sci, Karolinska Inst, Stockholm, Sweden.;Karolinska Inst, Dept Neurosci, SE-17177 Stockholm, Sweden..
    Tian, Weiming
    Harbin Inst Technol, Sch Life Sci & Technol, Harbin 150080, Peoples R China..
    A novel nanoparticle system targeting damaged mitochondria for the treatment of Parkinson's disease2022In: BIOMATERIALS ADVANCES, ISSN 2772-9508, Vol. 138, article id 212876Article in journal (Refereed)
    Abstract [en]

    Mitochondrial damage is one of the primary causes of neuronal cell death in Parkinson's disease (PD). In PD patients, the mitochondrial damage can be repaired or irreversible. Therefore, mitochondrial damage repair becomes a promising strategy for PD treatment. In this research, hyaluronic acid nanoparticles (HA-NPs) of different molecular weights are used to protect the mitochondria and salvage the mild and limited damage in mitochondria. The HA-NPs with 2190 k Dalton (kDa) HA can improve the mitochondrial function of SH-SY5Y cells and PTEN induced putative kinase 1 (PINK1) knockout mouse embryo fibroblast (MEF) cells. In cases of irreversible damage, NPs with ubiquitin specific peptidase 30 (USP30) siRNA are used to promote mitophagy. Meanwhile, by adding PINK1 antibodies, the NPs can selectively target the irreversibly damaged mitochondria, preventing the excessive clearance of healthy mitochondria.

  • 9.
    Chireh, Arvin
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Grankvist, Rikard
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Sandell, Mikael
    KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Royal Inst Technol, Div Micro & Nanosyst, Stockholm, Sweden.;MedTechLabs, Solna, Sweden..
    Mukarram, Abdul Kadir
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Arnberg, Fabian
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden..
    Lundberg, Johan
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden..
    Daub, Carsten O.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden..
    Holmin, Staffan
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Neuroradiol, Stockholm, Sweden..
    Micro-biopsy for detection of gene expression changes in ischemic swine myocardium: A pilot study2021In: PLOS ONE, E-ISSN 1932-6203, Vol. 16, no 4, p. e0250582-, article id e0250582Article in journal (Refereed)
    Abstract [en]

    Micro-endomyocardial biopsy (micro-EMB) is a novel catheter-based biopsy technique, aiming to increase flexibility and safety compared to conventional EMB. The technique was developed and evaluated in healthy swine. Therefore, the ability to detect disease related tissue changes could not be evaluated. The aim of the present pilot study was to investigate the ability to detect disease related gene expression changes using micro-EMB. Myocardial infarction was induced in three swine by coronary artery balloon occlusion. Micro-EMB samples (n = 164) were collected before, during, and after occlusion. RNA-sequencing was performed on 85 samples, and 53 of these were selected for bioinformatic analysis. A large number of responding genes was detected from the infarcted area (n = 1911). The early responding genes (n = 1268) were mostly related to apoptosis and inflammation. There were fewer responding genes two days after infarction (n = 6), which were related to extra-cellular matrix changes, and none after 14 days. In contrast to the infarcted area, samples harvested from a non-infarcted myocardial region showed considerably fewer regulated genes (n = 33). Deconvolution analysis, to estimate the proportion of different cell types, revealed a higher proportion of fibroblasts and a reduced proportion of cardiomyocytes two days after occlusion compared to baseline (p < 0.02 and p < 0.01, respectively. S5 File). In conclusion, this pilot study demonstrates the capabilities of micro-EMB to detect local gene expression responses at an early stage after ischemia, but not at later timepoints.

  • 10. Crook, S. M.
    et al.
    Bednar, J. A.
    Berger, S.
    Cannon, R.
    Davison, A. P.
    Djurfeldt, Mikael
    KTH, School of Computer Science and Communication (CSC), Centres, Centre for High Performance Computing, PDC.
    Eppler, J.
    Kriener, B.
    Furber, S.
    Graham, B.
    Plesser, H. E.
    Schwabe, L.
    Smith, L.
    Steuber, V.
    Van Albada, S.
    Creating, documenting and sharing network models2012In: Network, ISSN 0954-898X, E-ISSN 1361-6536, Vol. 23, no 4, p. 131-149Article, review/survey (Refereed)
    Abstract [en]

    As computational neuroscience matures, many simulation environments are available that are useful for neuronal network modeling. However, methods for successfully documenting models for publication and for exchanging models and model components among these projects are still under development. Here we briefly review existing software and applications for network model creation, documentation and exchange. Then we discuss a few of the larger issues facing the field of computational neuroscience regarding network modeling and suggest solutions to some of these problems, concentrating in particular on standardized network model terminology, notation, and descriptions and explicit documentation of model scaling. We hope this will enable and encourage computational neuroscientists to share their models more systematically in the future.

  • 11. Damangir, Soheil
    et al.
    Manzouri, Amirhossein
    Oppedal, Ketil
    Carlsson, Stefan
    KTH, School of Computer Science and Communication (CSC), Computer Vision and Active Perception, CVAP.
    Firbank, Michael J.
    Sonnesyn, Hogne
    Tysnes, Ole-Bjorn
    O'Brien, John T.
    Beyer, Mona K.
    Westman, Eric
    Aarsland, Dag
    Wahlund, Lars-Olof
    Spulber, Gabriela
    Multispectral MRI segmentation of age related white matter changes using a cascade of support vector machines2012In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 322, no 1-2, p. 211-216Article in journal (Refereed)
    Abstract [en]

    White matter changes (WMC) are the focus of intensive research and have been linked to cognitive impairment and depression in the elderly. Cumbersome manual outlining procedures make research on WMC labor intensive and prone to subjective bias. We present a fast, fully automated method for WMC segmentation using a cascade of reduced support vector machines (SVMs) with active learning. Data of 102 subjects was used in this study. Two MRI sequences (T1-weighted and FLAIR) and masks of manually outlined WMC from each subject were used for the image analysis. The segmentation framework comprises pre-processing, classification (training and core segmentation) and post-processing. After pre-processing, the model was trained on two subjects and tested on the remaining 100 subjects. The effectiveness and robustness of the classification was assessed using the receiver operating curve technique. The cascade of SVMs segmentation framework outputted accurate results with high sensitivity (90%) and specificity (99.5%) values, with the manually outlined WMC as reference. An algorithm for the segmentation of WMC is proposed. This is a completely competitive and fast automatic segmentation framework, capable of using different input sequences, without changes or restrictions of the image analysis algorithm.

  • 12.
    de Giorgio, Andrea
    et al.
    KTH, School of Industrial Engineering and Management (ITM), Production Engineering.
    Cacace, Stefania
    Politecn Milan, Dept Mech Engn, Via La Masa 1, I-20156 Milan, Italy..
    Maffei, Antonio
    KTH, School of Industrial Engineering and Management (ITM), Production Engineering.
    Monetti, Fabio Marco
    KTH, School of Industrial Engineering and Management (ITM), Production Engineering, Digital Smart Production.
    Roci, Malvina
    KTH, School of Industrial Engineering and Management (ITM), Production Engineering, Manufacturing and Metrology Systems.
    Onori, Mauro
    KTH, School of Industrial Engineering and Management (ITM), Production Engineering.
    Wang, Lihui
    KTH, School of Industrial Engineering and Management (ITM), Production Engineering, Sustainable Production Systems.
    Assessing the influence of expert video aid on assembly learning curves2022In: Journal of manufacturing systems, ISSN 0278-6125, E-ISSN 1878-6642, Vol. 62, p. 263-269Article in journal (Refereed)
    Abstract [en]

    Since the introduction of the concept of learning curves in manufacturing, many articles have been applying the model to study learning phenomena. In assembly, several studies present a learning curve when an operator is trained over a new assembly task; however, when comparisons are made between learning curves corresponding to different training methods, unaware researchers can show misleading results. Often, these studies neglect either or both the stochastic nature of the learning curves produced by several operators under experimental conditions, and the high correlation of the experimental samples collected from each operator that constitute one learning curve. Furthermore, recent studies are testing newer technologies, such as assembly animations or augmented reality, to provide assembly aid, but they fail to observe deeper implications on how these digital training methods truly influence the learning curves of the operators. This article proposes a novel statistical study of the influence of expert video aid on the learning curves in terms of assembly time by means of functional analysis of variance (FANOVA). This method is better suited to compare learning curves than common analysis of variance (ANOVA), due to correlated data, or graphical comparisons, due to the stochastic nature of the aggregated learning curves. The results show that two main effects of the expert video aid influence the learning curves: one in the transient and another in the steady state of the learning curve. The transient effect of the expert video aid, where the statistical tests suffer from a high variance in the data, appears to be a reduction in terms of assembly time for the first assemblies: the operators seem to benefit from the expert video aid. As soon as the steady state is reached, a slower and statistically significant effect appears to favor the learning processes of the operators who do not receive any training aid. Since the steady state of the learning curves represents the long term production efficiency of the operators, the latter effect might require more attention from industry and researchers.

  • 13.
    de Thonel, Aurelie
    et al.
    Univ Paris, CNRS, Epigenet & Cell Fate, F-75013 Paris, France..
    Vihervaara, Anniina
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Gene Technology. Abo Akad Univ, Fac Sci & Engn, Cell Biol, Turku, Finland.;Univ Turku, Turku Biosci Ctr, Turku, Finland..
    Mezger, Valerie
    Univ Paris, CNRS, Epigenet & Cell Fate, F-75013 Paris, France..
    et al.,
    CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 7002Article in journal (Refereed)
    Abstract [en]

    Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder with unclear underlying mechanisms. Here, the authors unravel the contribution of a stress-responsive pathway to RSTS where impaired HSF2 acetylation, due to RSTS-associated CBP/EP300 mutations, alters the expression of neurodevelopmental players, in keeping with hallmarks of cell-cell adhesion defects. Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

  • 14. Ercole, A.
    et al.
    Thelin, E. P.
    Holst, Anders
    KTH, School of Computer Science and Communication (CSC), Computational Science and Technology (CST).
    Bellander, B. M.
    Nelson, D. W.
    Kinetic modelling of serum S100b after traumatic brain injury2016In: BMC Neurology, E-ISSN 1471-2377, Vol. 16, article id 93Article in journal (Refereed)
    Abstract [en]

    Background: An understanding of the kinetics of a biomarker is essential to its interpretation. Despite this, little kinetic modelling of blood biomarkers can be found in the literature. S100b is an astrocyte related marker of brain injury used primarily in traumatic brain injury (TBI). Serum levels are expected to be the net result of a multi-compartmental process. The optimal sample times for TBI prognostication, and to follow injury development, are unclear. The purpose of this study was to develop a kinetic model to characterise the temporal course of serum S100b concentration after primary traumatic brain injury. Methods: Data of serial serum S100b samples from 154 traumatic brain injury patients in a neurointensive care unit were retrospectively analysed, including only patients without secondary peaks of this biomarker. Additionally, extra-cranial S100b can confound samples earlier than 12 h after trauma and were therefore excluded. A hierarchical, Bayesian gamma variate kinetic model was constructed and the parameters estimated by Markov chain Monte Carlo sampling. Results: We demonstrated that S100b concentration changes dramatically over timescales that are clinically important for early prognostication with a peak at 27.2 h (95 % credible interval [25.6, 28.8]). Baseline S100b levels was found to be 0.11 mu g/L (95 % credible interval [0.10, 0.12]). Conclusions: Even small differences in injury to sample time may lead to marked changes in S100b during the first days after injury. This must be taken into account in interpretation. The model offers a way to predict the peak and trajectory of S100b from 12 h post trauma in TBI patients, and to identify deviations from this, possibly indicating a secondary event. Kinetic modelling, providing an equation for the peak and projection, may offer a way to reduce the ambiguity in interpretation of, in time, randomly sampled acute biomarkers and may be generally applicable to biomarkers with, in time, well defined hits.

  • 15.
    Eriksson, Olivia
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Bhalla, Upinder Singh
    Tata Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore, Karnataka, India..
    Blackwell, Kim T.
    George Mason Univ, Volgenau Sch Engn, Dept Bioengn, Fairfax, VA 22030 USA..
    Crook, Sharon M.
    Arizona State Univ, Sch Math & Stat Sci, Tempe, AZ USA..
    Keller, Daniel
    Ecole Polytech Fed Lausanne, Blue Brain Project, Lausanne, Switzerland..
    Kramer, Andrei
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Linne, Marja-Leena
    Tampere Univ, Fac Med & Hlth Technol, Tampere, Finland..
    Saudargiene, Ausra
    Lithuanian Univ Hlth Sci, Neurosci Inst, Kaunas, Lithuania.;Vytautas Magnus Univ, Dept Informat, Kaunas, Lithuania..
    Wade, Rebecca C.
    Heidelberg Inst Theoret Studies HITS, Mol & Cellular Modeling Grp, Heidelberg, Germany.;Heidelberg Univ, Ctr Mol Biol ZMBH, ZMBH DKFZ Alliance, Heidelberg, Germany.;Heidelberg Univ, Interdisciplinary Ctr Sci Comp IWR, Heidelberg, Germany..
    Hellgren Kotaleski, Jeanette
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST). KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Combining hypothesis- and data-driven neuroscience modeling in FAIR workflows2022In: eLIFE, E-ISSN 2050-084X, Vol. 11, article id e69013Article, review/survey (Refereed)
    Abstract [en]

    Modeling in neuroscience occurs at the intersection of different points of view and approaches. Typically, hypothesis-driven modeling brings a question into focus so that a model is constructed to investigate a specific hypothesis about how the system works or why certain phenomena are observed. Data-driven modeling, on the other hand, follows a more unbiased approach, with model construction informed by the computationally intensive use of data. At the same time, researchers employ models at different biological scales and at different levels of abstraction. Combining these models while validating them against experimental data increases understanding of the multiscale brain. However, a lack of interoperability, transparency, and reusability of both models and the workflows used to construct them creates barriers for the integration of models representing different biological scales and built using different modeling philosophies. We argue that the same imperatives that drive resources and policy for data - such as the FAIR (Findable, Accessible, Interoperable, Reusable) principles - also support the integration of different modeling approaches. The FAIR principles require that data be shared in formats that are Findable, Accessible, Interoperable, and Reusable. Applying these principles to models and modeling workflows, as well as the data used to constrain and validate them, would allow researchers to find, reuse, question, validate, and extend published models, regardless of whether they are implemented phenomenologically or mechanistically, as a few equations or as a multiscale, hierarchical system. To illustrate these ideas, we use a classical synaptic plasticity model, the Bienenstock-Cooper-Munro rule, as an example due to its long history, different levels of abstraction, and implementation at many scales.

  • 16. Faresjö, R.
    et al.
    Lindberg, Hanna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Ståhl, Stefan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
    Löfblom, John
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
    Syvänen, S.
    Sehlin, D.
    Transferrin Receptor Binding BBB-Shuttle Facilitates Brain Delivery of Anti-Aβ-Affibodies2022In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 39, no 7, p. 1509-1521Article in journal (Refereed)
    Abstract [en]

    Affibodies targeting amyloid-beta (Aβ) could potentially be used as therapeutic and diagnostic agents in Alzheimer’s disease (AD). Affibodies display suitable characteristics for imaging applications such as high stability and a short biological half-life. The aim of this study was to explore brain delivery and retention of Aβ protofibril-targeted affibodies in wild-type (WT) and AD transgenic mice and to evaluate their potential as imaging agents. Two affibodies, Z5 and Z1, were fused with the blood–brain barrier (BBB) shuttle single-chain variable fragment scFv8D3. In vitro binding of 125I-labeled affibodies with and without scFv8D3 was evaluated by ELISA and autoradiography. Brain uptake and retention of the affibodies at 2 h and 24 h post injection was studied ex vivo in WT and transgenic (tg-Swe and tg-ArcSwe) mice. At 2 h post injection, [125I]I-Z5 and [125I]I-Z1 displayed brain concentrations of 0.37 ± 0.09% and 0.46 ± 0.08% ID/g brain, respectively. [125I]I-scFv8D3-Z5 and [125I]I-scFv8D3-Z1 showed increased brain concentrations of 0.53 ± 0.16% and 1.20 ± 0.35%ID/g brain. At 24 h post injection, brain retention of [125I]I-Z1 and [125I]I-Z5 was low, while [125I]I-scFv8D3-Z1 and [125I]I-scFv8D3-Z5 showed moderate brain retention, with a tendency towards higher retention of [125I]I-scFv8D3-Z5 in AD transgenic mice. Nuclear track emulsion autoradiography showed greater parenchymal distribution of [125I]I-scFv8D3-Z5 and [125I]I-scFv8D3-Z1 compared with the affibodies without scFv8D3, but could not confirm specific affibody accumulation around Aβ deposits. Affibody-scFv8D3 fusions displayed increased brain and parenchymal delivery compared with the non-fused affibodies. However, fast brain washout and a suboptimal balance between Aβ and mTfR1 affinity resulted in low intrabrain retention around Aβ deposits. 

  • 17.
    Farewik, Lanie
    KTH, School of Engineering Sciences (SCI), Mechanics, Biomechanics. University of Michigan, Department of Mechanical Engineering, Division of Biomechanics.
    Mild diabetic neuropathy affects ankle motor function2001In: Clinical Biomechanics, ISSN 0268-0033, E-ISSN 1879-1271, Vol. 16, no 6, p. 522-528Article in journal (Refereed)
    Abstract [en]

    Objective. To evaluate the effect of age and diabetic neuropathy on ankle motor function in the frontal plane in terms of rate of torque development and capability for balance recovery.

    Design. Case control study. Six older women with diabetic neuropathy compared to six women without neuropathy, matched for age and presence of diabetes mellitus; and nine healthy young women.

    Background. Neuropathy causes a distal impairment in lower extremity sensory function which increases fall risk. Impairments in ankle inversion/eversion proprioceptive thresholds have been identified, but the effect of neuropathy on ankle motor strength in the frontal plane is unknown.

    Methods. Subjects' abilities to recover from a lateral lean (with center of gravity offset as percentage of foot width) while standing on one foot, and to rapidly generate inversion torque about the ankle, were quantified.

    Results. All nine of the young, but only one of six older, control subjects recovered from a 10% lean (P=0.0052). Three of six older controls, but no neuropathy subject, recovered from a 5% lean (P=0.083). Neuropathy subjects demonstrated half the ankle rate of torque development [78.2 (50.8) N m/s; P=0.016] of the young and older controls [162.0 (54.6) and 152.7 (22.2) N m/s, respectively].

    Conclusions. Diabetic neuropathy leads to a decrease in rapidly available ankle strength which impairs balance recovery among older women. Younger women demonstrate similar ankle strength but superior balance recovery compared to older women without neuropathy.Relevance

    Older women with diabetic neuropathy and normal ankle strength, as judged by clinical muscle testing, demonstrate a sub-clinical impairment in ankle motor function suggesting a target for intervention.

  • 18.
    Fiebig, Florian
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Lansner, Anders
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Memory consolidation from seconds to weeks: a three-stage neural network model with autonomous reinstatement dynamics2014In: Frontiers in Computational Neuroscience, E-ISSN 1662-5188, Vol. 8, p. 64-Article in journal (Refereed)
    Abstract [en]

    Declarative long-term memories are not created in an instant. Gradual stabilization and temporally shifting dependence of acquired declarative memories in different brain regions called systems consolidation- can be tracked in time by lesion experiments. The observation of temporally graded retrograde amnesia(RA) following hippocampal lesions points to a gradual transfer of memory from hippocampus to neocortical long-term memory. Spontaneous reactivations of hippocampal memories, asobserved in place cell reactivations during slow wave- sleep, are supposed to driven eocortical reinstatements and facilitate this process. We proposea functional neural network implementation of these ideas and further more suggest anextended three-state framework that includes the prefrontal cortex( PFC). It bridges the temporal chasm between working memory percepts on the scale of seconds and consolidated long-term memory on the scale of weeks or months. Wes how that our three-stage model can autonomously produce the necessary stochastic reactivation dynamics for successful episodic memory consolidation. There sulting learning system is shown to exhibit classical memory effects seen in experimental studies, such as retrograde and anterograde amnesia(AA) after simulated hippocampal lesioning; further more the model reproduces peculiar biological findings on memory modulation, such as retrograde facilitation of memory after suppressed acquisition of new longterm memories- similar to the effects of benzodiazepines on memory.

    Download full text (pdf)
    MemoryConsolidation
  • 19.
    Forsberg, L.
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Glaser, A.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Manouchehrinia, A.
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med CMM, Stockholm, Sweden..
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.). Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Spelman, T.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Klyve, P.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Drahota, J.
    IMPULS Endowment Fund, Czech Natl Multple Sclerosis ReMuS, Prague, Czech Republic..
    Horakova, D.
    Charles Univ Prague, Fac Med 1, Prague, Czech Republic.;Gen Univ Hosp, Dept Neurol, Prague, Czech Republic.;Ctr Clin Neurosci, Prague, Czech Republic..
    Joensen, H.
    Rigshosp, Danish Multiple Sclerosis Registry, Dept Neurol, Copenhagen, Denmark..
    Pontieri, L.
    Rigshosp, Danish Multiple Sclerosis Registry, Dept Neurol, Copenhagen, Denmark..
    Magyari, M.
    Rigshosp, Danish Multiple Sclerosis Registry, Dept Neurol, Copenhagen, Denmark.;Rigshosp, Danish Multiple Sclerosis Ctr, Dept Neurol, Copenhagen, Denmark..
    Ellenberger, D.
    MS Forsch & Projektentwicklungs gGmbH, Hannover, Germany..
    Stahmann, A.
    MS Forsch & Projektentwicklungs gGmbH, Hannover, Germany..
    Van der Walt, A.
    Monash Univ, Dept Neurosci, Cent Clin Sch, Melbourne, Vic, Australia..
    Rodgers, J.
    Swansea Univ, Sch Med, Swansea, W Glam, Wales..
    Witts, J.
    Swansea Univ, Sch Med, Swansea, W Glam, Wales..
    Middleton, R.
    Swansea Univ, Sch Med, Swansea, W Glam, Wales..
    Nicholas, R.
    Imperial Coll London, Dept Cellular & Mol Neurosci, London, England.;UCL Inst Ophthalmol, Dept Visual Neurosci, London, England..
    Bezlyak, V.
    Novartis Pharma AG, Basel, Switzerland..
    Lines, C.
    Novartis Pharma AG, Basel, Switzerland..
    Hillert, J.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Contributors to secondary progressive multiple sclerosis conversion age - a federated learning analysis across five European MS registries2021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no 2_SUPPL, p. 201-202Article in journal (Other academic)
  • 20. Fournier, M
    et al.
    Scolamiero, Martina
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Gholam-Rezaee, M M
    Cleusix, M
    Jenni, R
    Ferrari, C
    Golay, P
    Baumann, P S
    Cuenod, M
    Conus, P
    Do, K Q
    Hess, K
    Topology predicts long-term functional outcome in early psychosis2020In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578Article in journal (Refereed)
    Abstract [en]

    Early intervention in psychosis is crucial to improving patient response to treatment and the functional deficits that critically affect their long-term quality of life. Stratification tools are needed to personalize functional deficit prevention strategies at an early stage. In the present study, we applied topological tools to analyze symptoms of early psychosis patients, and detected a clear stratification of the cohort into three groups. One of the groups had a significantly better psychosocial outcome than the others after a 3-year clinical follow-up. This group was characterized by a metabolic profile indicative of an activated antioxidant response, while that of the groups with poorer outcome was indicative of oxidative stress. We replicated in a second cohort the finding that the three distinct clinical profiles at baseline were associated with distinct outcomes at follow-up, thus validating the predictive value of this new stratification. This approach could assist in personalizing treatment strategies. 

  • 21.
    Fransén, Erik
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Ionic Mechanisms in Peripheral Pain2014In: Computational Neuroscience / [ed] Blackwell, K.T., Elsevier, 2014, p. 23-51Chapter in book (Refereed)
    Abstract [en]

    Chronic pain constitutes an important and growing problem in society with large unmet needs with respect to treatment and clear implications for quality of life. Computational modeling is used to complement experimental studies to elucidate mechanisms involved in pain states. Models representing the peripheral nerve ending often address questions related to sensitization or reduction in pain detection threshold. In models of the axon or the cell body of the unmyelinated C-fiber, a large body of work concerns the role of particular sodium channels and mutations of these. Furthermore, in central structures: spinal cord or higher structures, sensitization often refers not only to enhanced synaptic efficacy but also to elevated intrinsic neuronal excitability. One of the recent developments in computational neuroscience is the emergence of computational neuropharmacology. In this area, computational modeling is used to study mechanisms of pathology with the objective of finding the means of restoring healthy function. This research has received increased attention from the pharmaceutical industry as ion channels have gained increased interest as drug targets. Computational modeling has several advantages, notably the ability to provide mechanistic links between molecular and cellular levels on the one hand and functions at the systems level on the other hand. These characteristics make computational modeling an additional tool to be used in the process of selecting pharmaceutical targets. Furthermore, large-scale simulations can provide a framework to systematically study the effects of several interacting disease parameters or effects from combinations of drugs.

  • 22.
    Fransén, Erik A.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Mechanisms of Graded Persistent Activity: Implications for Epilepsy2008In: Computational Neuroscience in Epilepsy, Elsevier, 2008, p. 215-231Chapter in book (Other academic)
    Abstract [en]

    One major topic in epilepsy is factors contributing to neuronal excitability. This chapter considers depolarizing sources from cationic currents. These ion channels of the TRP-type are permeable to Na, K and sometimes Ca, and show a slow time dynamics. They can therefore provide the dendrites with integrative properties over seconds and perhaps even minutes. This makes them powerful as integrators of synaptic input. Further, their activation depends to a large degree on intracellular calcium. They may therefore during seizures become strongly activated and thereby further contribute to epileptogenic activity directly by depolarization and indirectly by their calcium permeability. Cationic currents are widely distributed throughout the nervous system, including cortical, cerebellar and subcortical neurons. This chapter describes the work in entorhinal cortex and, specifically, the plateau firing characteristics found in pyramidal cells of layer V. These cells show persistent action potential firing at plateaus, which may last over ten minutes. Intriguingly, these plateaus are graded in that input, synaptic or by current injection, can shift them up and down in frequency. After the original finding, graded plateaus have been found also in perirhinal cortex and amygdala. Functionally, cationic neuronal integrator capacity has been shown to be involved in sensory-motor integration. Finally, anticonvulsants like lamotrigine and phenytoin have been found to reduce depolarizations involving cationic currents. Cation currents may therefore be targets in treatments of epilepsy.

  • 23.
    Frykberg, Gunilla
    et al.
    Uppsala University.
    Åberg, Anna Cristina
    The Swedish School of Sport and Health Sciences.
    Halvorsen, Kjartan
    The Swedish School of Sports and Health Sciences.
    Hirschfeld, Helga
    Karolinska Institute.
    Temporal characteristics of the sit-to-walk task in subjects with stroke and in controls: Preliminary results2007In: Proceedings of the 16th annual meeting of ESMAC, 2007Conference paper (Refereed)
  • 24. Gilvesy, A.
    et al.
    Husen, E.
    Magloczky, Z.
    Mihaly, O.
    Hortobágyi, T.
    Kanatani, S.
    Heinsen, H.
    Renier, N.
    Hökfelt, T.
    Mulder, J.
    Uhlén, Mathias
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Kovacs, G. G.
    Adori, C.
    Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus–pericoerulear complex by three-dimensional imaging2022In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 144, no 4, p. 651-676Article in journal (Refereed)
    Abstract [en]

    Tau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age-related neurodegenerative disorders, including Alzheimer’s disease. However, a comprehensive neuropathological examination of the LC is difficult due to its small size and rod-like shape. To investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease-associated tau in an unprecedented large-scale three-dimensional view, we utilized volume immunostaining and optical clearing technology combined with light sheet fluorescence microscopy. We examined AT8+ pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0–6. We demonstrate an intriguing morphological complexity and heterogeneity of AT8+ cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8+ cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle-bearing neurons, even preceding axonal lesions. Interestingly, irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer’s disease, like the hippocampus or neocortical areas, compared to the ventral LC projecting to the cerebellum and medulla. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro-dendritic close appositions of AT8+ LC neurons, AT8+ long axons of NFT-bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8+ processes of NFT-bearing LC neurons that target the 4th ventricle wall. Our study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans-neuronal spreading of hyperphosphorylated tau. 

  • 25.
    Gong, Ze
    et al.
    Northwestern Polytech Univ Shenzhen, Res & Dev Inst, Shenzhen, Peoples R China.;Northwestern Polytech Univ, Inst Med Res, Xian, Peoples R China..
    Lo, Wai Leung Ambrose
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Rehabil Med, Guangzhou, Peoples R China..
    Wang, Ruoli
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics.
    Li, Le
    Northwestern Polytech Univ Shenzhen, Res & Dev Inst, Shenzhen, Peoples R China.;Northwestern Polytech Univ, Inst Med Res, Xian, Peoples R China..
    Electrical impedance myography combined with quantitative assessment techniques in paretic muscle of stroke survivors: Insights and challenges2023In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 15, article id 1130230Article in journal (Refereed)
    Abstract [en]

    Aging is a non-modifiable risk factor for stroke and the global burden of stroke is continuing to increase due to the aging society. Muscle dysfunction, common sequela of stroke, has long been of research interests. Therefore, how to accurately assess muscle function is particularly important. Electrical impedance myography (EIM) has proven to be feasible to assess muscle impairment in patients with stroke in terms of micro structures, such as muscle membrane integrity, extracellular and intracellular fluids. However, EIM alone is not sufficient to assess muscle function comprehensively given the complex contributors to paretic muscle after an insult. This article discusses the potential to combine EIM and other common quantitative methods as ways to improve the assessment of muscle function in stroke survivors. Clinically, these combined assessments provide not only a distinct advantage for greater accuracy of muscle assessment through cross-validation, but also the physiological explanation on muscle dysfunction at the micro level. Different combinations of assessments are discussed with insights for different purposes. The assessments of morphological, mechanical and contractile properties combined with EIM are focused since changes in muscle structures, tone and strength directly reflect the muscle function of stroke survivors. With advances in computational technology, finite element model and machine learning model that incorporate multi-modal evaluation parameters to enable the establishment of predictive or diagnostic model will be the next step forward to assess muscle function for individual with stroke.

  • 26. Graham, C.
    et al.
    Lewis, S.
    Forbes, J.
    Mead, G.
    Hackett, M. L.
    Hankey, G. J.
    Gommans, J.
    Nguyen, H. T.
    Lundström, E.
    Isaksson, E.
    Näsman, Per
    KTH.
    Rudberg, A. -S
    Dennis, M.
    The FOCUS, AFFINITY and EFFECTS trials studying the effect(s) of fluoxetine in patients with a recent stroke: Statistical and health economic analysis plan for the trials and for the individual patient data meta-analysis2017In: Trials, E-ISSN 1745-6215, Vol. 18, no 1, article id 627Article in journal (Refereed)
    Abstract [en]

    Background: Small trials have suggested that fluoxetine may improve neurological recovery from stroke. FOCUS, AFFINITY and EFFECTS are a family of investigator-led, multicentre, parallel group, randomised, placebo-controlled trials which aim to determine whether the routine administration of fluoxetine (20 mg daily) for six months after an acute stroke improves patients' functional outcome. Methods/Design: The core protocol for the three trials has been published (Mead et al., Trials 20:369, 2015). The trials include patients aged 18 years and older with a clinical diagnosis of stroke and persisting focal neurological deficits at randomisation 2-15 days after stroke onset. Patients are randomised centrally via each trials' web-based randomisation system using a common minimisation algorithm. Patients are allocated fluoxetine 20 mg once daily or matching placebo capsules for six months. The primary outcome measure is the modified Rankin scale (mRS) at six months. Secondary outcomes include: living circumstances; the Stroke Impact Scale; EuroQol (EQ5D-5 L); the vitality subscale of the 36-Item Short Form Health Survey (SF36); diagnosis of depression; adherence to medication; serious adverse events including death and recurrent stroke; and resource use at six and 12 months and the mRS at 12 months. Discussion: Minor variations have been tailored to the national setting in the UK (FOCUS), Australia, New Zealand and Vietnam (AFFINITY) and Sweden (EFFECTS). Each trial is run and funded independently and will report its own results. A prospectively planned individual patient data meta-analysis of all three trials will provide the most precise estimate of the overall effect and establish whether any effects differ between trials or subgroups. This statistical analysis plan describes the core analyses for all three trials and that for the individual patient data meta-analysis. Recruitment and follow-up in the FOCUS trial is expected to be completed by the end of 2018. AFFINITY and EFFECTS are likely to complete follow-up in 2020.

  • 27. Gustafsson, J.
    et al.
    Ternström, Sten
    KTH, School of Computer Science and Communication (CSC), Speech, Music and Hearing, TMH.
    Södersten, M.
    Schalling, E.
    Motor-Learning-Based Adjustment of Ambulatory Feedback on Vocal Loudness for Patients With Parkinson's Disease2016In: Journal of Voice, ISSN 0892-1997, E-ISSN 1873-4588, Vol. 30, no 4, p. 407-415Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate how the direct biofeedback on vocal loudness administered with a portable voice accumulator (VoxLog) should be configured, to facilitate an optimal learning outcome for individuals with Parkinson's disease (PD), on the basis of principles of motor learning. Study Design: Methodologic development in an experimental study. Methods: The portable voice accumulator VoxLog was worn by 20 participants with PD during habitual speech during semistructured conversations. Six different biofeedback configurations were used, in random order, to study which configuration resulted in a feedback frequency closest to 20% as recommended on the basis of previous studies. Results: Activation of feedback when the wearer speaks below a threshold level of 3dB below the speaker's mean voice sound level in habitual speech combined with an activation time of 500ms resulted in a mean feedback frequency of 21.2%. Conclusions: Settings regarding threshold and activation time based on the results from this study are recommended to achieve an optimal learning outcome when administering biofeedback on vocal loudness for individuals with PD using portable voice accumulators.

  • 28. Hernandez, F.
    et al.
    Wu, L. C.
    Yip, M. C.
    Hoffman, A. R.
    Lopez, J.
    Grant, G.
    Kleiven, Svein
    KTH, School of Technology and Health (STH), Medical Engineering, Neuronic Engineering.
    Camarillo, D. B.
    Finite Element Simulation Of Brain Deformation From Six Degree Of Freedom Acceleration Measurements Of Mild Traumatic Brain Injury2014In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 31, no 12, p. A124-A124Article in journal (Other academic)
  • 29.
    Hernando, Sara
    et al.
    Karolinska Inst, Ctr Adv Integrated Med & Engn Sci AIMES, S-17177 Stockholm, Sweden.;KTH Royal Inst Technol, S-17177 Stockholm, Sweden.;Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden.;Univ Basque Country, Sch Pharm, Lab Pharmaceut, NanoBioCel Res Grp,UPV EHU, Vitoria 01006, Spain.;Inst Hlth Carlos III, Biomed Res Networking Ctr Bioengn Biomat & Nanome, Madrid 28029, Spain.;NanoBioCel Res Grp, Bioaraba, Vitoria 01006, Spain..
    Nikolakopoulou, Polyxeni
    KTH, Centres, Center for the Advancement of Integrated Medical and Engineering Sciences, AIMES. Karolinska Inst, Ctr Adv Integrated Med & Engn Sci AIMES, S-17177 Stockholm, Sweden.; Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Voulgaris, Dimitrios
    KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, Centres, Center for the Advancement of Integrated Medical and Engineering Sciences, AIMES. Karolinska Inst, Ctr Adv Integrated Med & Engn Sci AIMES, S-17177 Stockholm, Sweden.; Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Hernandez, Rosa Maria
    Univ Basque Country, Sch Pharm, Lab Pharmaceut, NanoBioCel Res Grp,UPV EHU, Vitoria 01006, Spain.;Inst Hlth Carlos III, Biomed Res Networking Ctr Bioengn Biomat & Nanome, Madrid 28029, Spain.; NanoBioCel Res Grp, Bioaraba, Vitoria 01006, Spain...
    Igartua, Manoli
    Univ Basque Country, Sch Pharm, Lab Pharmaceut, NanoBioCel Res Grp,UPV EHU, Vitoria 01006, Spain.;Inst Hlth Carlos III, Biomed Res Networking Ctr Bioengn Biomat & Nanome, Madrid 28029, Spain.;NanoBioCel Res Grp, Bioaraba, Vitoria 01006, Spain...
    Herland, Anna
    KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Micro and Nanosystems. KTH, Centres, Science for Life Laboratory, SciLifeLab. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology. KTH, Centres, Center for the Advancement of Integrated Medical and Engineering Sciences, AIMES. Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden..
    Dual effect of TAT functionalized DHAH lipid nanoparticles with neurotrophic factors in human BBB and microglia cultures2022In: Fluids and Barriers of the CNS, E-ISSN 2045-8118, Vol. 19, no 1, article id 22Article in journal (Refereed)
    Abstract [en]

    Background

    Neurodegenerative diseases (NDs) are an accelerating global health problem. Nevertheless, the stronghold of the brain- the blood–brain barrier (BBB) prevents drug penetrance and dwindles effective treatments. Therefore, it is crucial to identify Trojan horse-like drug carriers that can effectively cross the blood–brain barrier and reach the brain tissue. We have previously developed polyunsaturated fatty acids (PUFA)-based nanostructured lipid carriers (NLC), namely DHAH-NLC. These carriers are modulated with BBB-permeating compounds such as chitosan (CS) and trans-activating transcriptional activator (TAT) from HIV-1 that can entrap neurotrophic factors (NTF) serving as nanocarriers for NDs treatment. Moreover, microglia are suggested as a key causative factor of the undergoing neuroinflammation of NDs. In this work, we used in vitro models to investigate whether DHAH-NLCs can enter the brain via the BBB and investigate the therapeutic effect of NTF-containing DHAH-NLC and DHAH-NLC itself on lipopolysaccharide-challenged microglia.

    Methods

    We employed human induced pluripotent stem cell-derived brain microvascular endothelial cells (BMECs) to capitalize on the in vivo-like TEER of this BBB model and quantitatively assessed the permeability of DHAH-NLCs. We also used the HMC3 microglia cell line to assess the therapeutic effect of NTF-containing DHAH-NLC upon LPS challenge.

    Results

    TAT-functionalized DHAH-NLCs successfully crossed the in vitro BBB model, which exhibited high transendothelial electrical resistance (TEER) values (≈3000 Ω*cm2). Specifically, the TAT-functionalized DHAH-NLCs showed a permeability of up to 0.4% of the dose. Furthermore, using human microglia (HMC3), we demonstrate that DHAH-NLCs successfully counteracted the inflammatory response in our cultures after LPS challenge. Moreover, the encapsulation of glial cell-derived neurotrophic factor (GNDF)-containing DHAH-NLCs (DHAH-NLC-GNDF) activated the Nrf2/HO-1 pathway, suggesting the triggering of the endogenous anti-oxidative system present in microglia.

    Conclusions

    Overall, this work shows that the TAT-functionalized DHAH-NLCs can cross the BBB, modulate immune responses, and serve as cargo carriers for growth factors; thus, constituting an attractive and promising novel drug delivery approach for the transport of therapeutics through the BBB into the brain.

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  • 30.
    Hogelin, K. Asplund
    et al.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Ruffin, N.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Jiang, X.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Pin, Elisa
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Månberg, Anna
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Hober, Sophia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Technology.
    Gafvelin, G.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Gronlund, H.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Frisell, T.
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Nilsson, Peter
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Khademi, M.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Olsson, T.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Piehl, F.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Al Nimer, F.
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Impact of B-cell depleting treatments on development of humoral and cellular immunological memory against SARS-CoV-22021In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 27, no 2_SUPPL, p. 348-348Article in journal (Other academic)
  • 31.
    Hornung, Maximilian
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Taubmann, O.
    Ditt, H.
    Menze, B.
    Herman, Pawel
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Fransén, Erik
    KTH, School of Electrical Engineering and Computer Science (EECS), Computer Science, Computational Science and Technology (CST).
    Detection of Ischemic Infarct Core in Non-contrast Computed Tomography2020In: Machine Learning in Medical Imaging: 11th International Workshop, MLMI 2020, Held in Conjunction with MICCAI 2020, Lima, Peru, October 4, 2020, Proceedings, Springer Nature , 2020, Vol. 12436, p. 260-269Conference paper (Refereed)
    Abstract [en]

    Fast diagnosis is of critical importance for stroke treatment. In clinical routine, a non-contrast computed tomography scan (NCCT) is typically acquired immediately to determine whether the stroke is ischemic or hemorrhagic and plan therapy accordingly. In case of ischemia, early signs of infarction may appear due to increased water uptake. These signs may be subtle, especially if observed only shortly after symptom onset, but hold the potential to provide a crucial first assessment of the location and extent of the infarction. In this paper, we train a deep neural network to predict the infarct core from NCCT in an image-to-image fashion. To facilitate exploitation of anatomic correspondences, learning is carried out in the standardized coordinate system of a brain atlas to which all images are deformably registered. Apart from binary infarct core masks, perfusion maps such as cerebral blood volume and flow are employed as additional training targets to enrich the physiologic information available to the model. This extension is demonstrated to substantially improve the predictions of our model, which is trained on a data set consisting of 141 cases. It achieves a higher volumetric overlap (statistically significant,) of the predicted core with the reference mask as well as a better localization, although significance could not be shown for the latter. Agreement with human and automatic assessment of affected ASPECTS regions is likewise improved, measured as an increase of the area under the receiver operating characteristic curve from 72.7% to 75.1% and 71.9% to 83.5%, respectively.

  • 32.
    Huang, Yu-Kai
    et al.
    KTH, School of Electrical Engineering and Computer Science (EECS), Electrical Engineering, Electronics and Embedded systems, Electronic and embedded systems.
    Rusu, Ana
    KTH, School of Electrical Engineering and Computer Science (EECS), Electrical Engineering, Electronics and Embedded systems, Integrated devices and circuits.
    Rodriguez, Saul
    KTH, School of Electrical Engineering and Computer Science (EECS), Electrical Engineering, Electronics and Embedded systems, Integrated devices and circuits.
    A 4-Channel NMES IC for Wearable Applications2021In: BioCAS 2021 - IEEE Biomedical Circuits and Systems Conference, Proceedings, Institute of Electrical and Electronics Engineers Inc. , 2021Conference paper (Refereed)
    Abstract [en]

    This paper presents an integrated circuit solution for multi-channel neuromuscular electrical stimulation (NMES). The stimulation waveform is digitally controlled and supports monophasic pulses, and both symmetric and asymmetric biphasic pulses. In addition, the current intensity is programmable, ranging from 0 mA to 31 mA with 5-bit resolution. The integrated circuit occupies an area of 1 mm2and it is designed and simulated in a 180 nm high-voltage CMOS technology. The circuits are powered using standard 1.8 V and 3.3 V power supplies for the digital control and digital-to-analog converter, and a single 40 V power supply for the output drivers. The simulation results show that the design achieves a voltage compliance of up to 35 V, meeting the requirements for NMES applications while offering a very compact and scalable solution.

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  • 33. James, T.
    et al.
    Linden, M.
    Huss, M.
    Brandi, Maya
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Khademi, M.
    Tegner, J.
    Gomez-Cabrero, D.
    Kockum, I.
    Olsson, T.
    Impact of genetic risk loci in multiple sclerosis on expression of proximal genes2014In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 20, p. 250-251Article in journal (Other academic)
  • 34.
    Kaplan, Bernhard A.
    et al.
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    Lansner, Anders
    KTH, School of Computer Science and Communication (CSC), Computational Biology, CB.
    A spiking neural network model of self-organized pattern recognition in the early mammalian olfactory system2014In: Frontiers in Neural Circuits, E-ISSN 1662-5110, Vol. 8, no Feb, p. 5-Article in journal (Refereed)
    Abstract [en]

    Olfactory sensory information passes through several processing stages before an odor percept emerges. The question how the olfactory system learns to create odor representations linking those different levels and how it learns to connect and discriminate between them is largely unresolved. We present a large-scale network model with single and multi-compartmental Hodgkin-Huxley type model neurons representing olfactory receptor neurons (ORNs) in the epithelium, periglomerular cells, mitral/tufted cells and granule cells in the olfactory bulb (OB), and three types of cortical cells in the piriform cortex (PC). Odor patterns are calculated based on affinities between ORNs and odor stimuli derived from physico-chemical descriptors of behaviorally relevant real-world odorants. The properties of ORNs were tuned to show saturated response curves with increasing concentration as seen in experiments. On the level of the OB we explored the possibility of using a fuzzy concentration interval code, which was implemented through dendro-dendritic inhibition leading to winner-take-all like dynamics between mitral/tufted cells belonging to the same glomerulus. The connectivity from mitral/tufted cells to PC neurons was self-organized from a mutual information measure and by using a competitive Hebbian-Bayesian learning algorithm based on the response patterns of mitral/tufted cells to different odors yielding a distributed feed-forward projection to the PC. The PC was implemented as a modular attractor network with a recurrent connectivity that was likewise organized through Hebbian-Bayesian learning. We demonstrate the functionality of the model in a one-sniff-learning and recognition task on a set of 50 odorants. Furthermore, we study its robustness against noise on the receptor level and its ability to perform concentration invariant odor recognition. Moreover, we investigate the pattern completion capabilities of the system and rivalry dynamics for odor mixtures.

  • 35. Karlsson, Bengt
    et al.
    Johansson, Arne V.
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics, Fluid Mechanics and Engineering Acoustics.
    Jokura, Hidefumi
    Petridis, Athanasios
    Düsseldorf; St. Lukes Hospital, Panorama, Thessaloniki, Greece.
    Yang, Huai Che
    Yamamoto, Masaaki
    Martinez, Roberto
    Kawagishi, Jun
    Guo, Wan Yuo
    Chung, Wen Yuh
    Söderman, Michael
    Nga, Vincent
    Risk for Brain Arteriovenous Malformation Rupture During Pregnancy and Puerperium2023In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 93, no 4, p. 918-923Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The hemorrhage risk of unruptured and untreated cerebral arteriovenous malformations (AVMs) has been shown to be higher for female patients than male patients in their child bearing ages. Although it has been neurosurgical practice to advise female patients in their childbearing ages to postpone pregnancy until proven AVM obliteration, there is no literature consensus regarding this potential hemorrhage risk increase. OBJECTIVE: To accurately quantify the risk increase for AVM hemorrhage during pregnancy. METHODS: This study is based on data from previous publications, consisting of known age at the first AVM hemorrhage in 3425 patients. The risk increase during pregnancy could be calculated from the difference in age distribution for the first AVM hemorrhage between male patients and female patients, taking the average pregnancy time per female into account. A comparison was also made with data for all hospital discharges (13 751) in Germany 2008 to 2018 with the diagnosis brain AVM. RESULTS: The average pregnancy and puerperium time was 1.54 years per female in the patient population, which was used to determine the annual AVM hemorrhage risk during pregnancy to be around 9%. The increased risk during pregnancy was further evidenced by analysis of a subgroup of 105 female patients, for which pregnancy status at the time of hemorrhage was known. CONCLUSION: The quantified annual risk for AVM hemorrhage during pregnancy is about 3 times higher than that of male patients at corresponding age. This provides an important basis for advising female patients with patent AVMs about the increased risk for hemorrhage that a pregnancy would entail.

  • 36.
    Karlsson, Bengt
    et al.
    Natl Univ Singapore Hosp, Div Neurosurg, Dept Surg, Singapore, Singapore..
    Johansson, Arne V.
    KTH, School of Engineering Sciences (SCI), Mechanics.
    Yang, Huai-Che
    Vet Gen Hosp, Dept Neurosurg, Taipei, Taiwan..
    Jokura, Hidefumi
    Furukawa Seiryo Hosp, Jiro Suzuki Mem Gamma House, Osaki, Japan..
    Yamamoto, Masaaki
    Katsuta Hosp Mito GammaHouse, Ibaraki, Japan..
    Martinez-Alvarez, Roberto
    Ruber Int Hosp, Madrid, Spain..
    Kawagishi, Jun
    Furukawa Seiryo Hosp, Jiro Suzuki Mem Gamma House, Osaki, Japan..
    Guo, Wan-Yuo
    Vet Gen Hosp, Dept Radiol, Taipei, Taiwan..
    Beute, Guus
    ETZ Elizabeth, Tilburg, Netherlands..
    Pan, David H. C.
    Vet Gen Hosp, Dept Neurosurg, Taipei, Taiwan..
    Chung, Wen-Yuh
    Vet Gen Hosp, Dept Neurosurg, Taipei, Taiwan.;Vet Gen Hosp, Dept Radiol, Taipei, Taiwan..
    Soderman, Michael
    Karolinska Hosp, Stockholm, Sweden..
    Aiyama, Hitoshi
    Katsuta Hosp Mito GammaHouse, Ibaraki, Japan..
    Yeo, Tseng Tsai
    Natl Univ Singapore Hosp, Div Neurosurg, Dept Surg, Singapore, Singapore..
    A novel method to determine the natural course of unruptured brain arteriovenous malformations without the need for follow-up information2018In: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 129, p. 10-16Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE There is a strong clinical need to accurately determine the average annual hemorrhage risk in unruptured brain arteriovenous malformations (AVMs). This need motivated the present initiative to use data from a uniquely large patient population and design a novel methodology to achieve a risk determination with unprecedented accuracy. The authors also aimed to determine the impact of sex, pregnancy, AVM volume, and location on the risk for AVM rupture. METHODS The present study does not consider any specific management of the AVMs, but only uses the age distribution for the first hemorrhage, the shape of which becomes universal for a sufficiently large set of patients. For this purpose, the authors collected observations, including age at first hemorrhage and AVM size and location, in 3425 patients. The average annual risk for hemorrhage could then be determined from the simple relation that the number of patients with their first hemorrhage at a specific age equals the risk for hemorrhage times the number of patients at risk at that age. For a subset of the patients, the information regarding occurrence of AVM hemorrhage after treatment of the first hemorrhage was used for further analysis of the influence on risk from AVM location and pregnancy. RESULTS The age distribution for the first AVM hemorrhage was used to determine the average annual risk for hemorrhage in unruptured AVMs at adult ages (25-60 years). It was concluded to be 3.1% +/- 0.2% and unrelated to AVM volume but influenced by its location, with the highest risk for centrally located AVMs. The hemorrhage risk was found to be significantly higher for females in their fertile years. CONCLUSIONS The present methodology allowed the authors to determine the average annual risk for the first AVM hemorrhage at 3.1% +/- 0.2% without the need for individual patient follow-up. This methodology has potential also for other similar types of investigations. The conclusion that centrally located AVMs carry a higher risk was confirmed by follow-up information. Follow-up information was also used to conclude that pregnancy causes a substantially greater AVM hemorrhage risk. The age distribution for AVM hemorrhage is incompatible with AVMs present at birth having the same hemorrhage risk as AVMs in adults. Plausibly, they instead develop in the early years of life, possibly with a lower hemorrhage risk during that time period.

  • 37. Kavaliunas, Andrius
    et al.
    Manouchehrinia, Ali
    Stawiarz, Leszek
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Agholme, Jonas
    Hedstrom, Anna Karin
    Beiki, Omid
    Glaser, Anna
    Hillert, Jan
    Importance of early treatment initiation in the clinical course of multiple sclerosis2017In: Multiple Sclerosis Journal, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, no 9, p. 1233-1240Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to identify factors influencing the long-term clinical progression of multiple sclerosis (MS). A special objective was to investigate whether early treatment decisions influence outcome. Methods: We included 639 patients diagnosed with MS from 2001 to 2007. The median follow-up time was 99 months (8.25 years). Cox regression models were applied to identify factors correlating with the outcome variable defined as time from treatment start to irreversible score 4 of the Expanded Disability Status Scale (EDSS). Results: Patients initiated on treatment later had a greater risk of reaching EDSS 4 (hazard ratio of 1.074 (95% confidence interval (CI), 1.048-1.101)), increased by 7.4% for every year of delay in treatment start after MS onset. Patients who started treatment after 3 years from MS onset reached the outcome sooner with hazard ratio of 2.64 (95% CI, 1.71-4.08) compared with the patients who started treatment within 1 year from MS onset. Baseline EDSS and age at onset were found to be predictive factors of disability progression. Conclusion: Early treatment initiation was associated with a better clinical outcome. In addition, we confirmed the well-established prognostic factors of late age at onset and early disability.

  • 38. Keimpema, Erik
    et al.
    Zheng, Kang
    Barde, Swapnali Shantaram
    Berghuis, Paul
    Dobszay, Marton B.
    Schnell, Robert
    Mulder, Jan
    KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Institute, Sweden.
    Luiten, Paul G. M.
    Xu, Zhiqing David
    Runesson, Johan
    Langel, Ulo
    Lu, Bai
    Hökfelt, Tomas
    Harkany, Tibor
    GABAergic Terminals Are a Source of Galanin to Modulate Cholinergic Neuron Development in the Neonatal Forebrain2014In: Cerebral Cortex, ISSN 1047-3211, E-ISSN 1460-2199, Vol. 24, no 12, p. 3277-3288Article in journal (Refereed)
    Abstract [en]

    The distribution and (patho-) physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with.-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain.

  • 39.
    Khoonsari, Payam Emami
    et al.
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Shevchenko, Ganna
    Uppsala Univ, Dept Chem BMC, Analyt Chem, Uppsala, Sweden..
    Herman, Stephanie
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Remnestål, Julia
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Affinity Proteomics.
    Giedraitis, Vilmantas
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Brundin, RoseMarie
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Gunnarsson, Malin Degerman
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Kilander, Lena
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Zetterberge, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden.;UK Dementia Res Inst UCL, London, England.;UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England..
    Nilsson, Peter
    KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Lannfelt, Lars
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Ingelsson, Martin
    Uppsala Univ, Dept Publ Hlth & Caring Sci Geriatr, Uppsala, Sweden..
    Kultima, Kim
    Uppsala Univ, Dept Med Sci, Clin Chem, Uppsala, Sweden..
    Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, no 2, p. 639-651Article in journal (Refereed)
    Abstract [en]

    Background: Alzheimer's disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: A beta(42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable. Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCl/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

  • 40.
    Kim, Hyeongju
    et al.
    Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea..
    Lenoir, Sophie
    Univ Grenoble Alpes, CHU Grenoble Alpes, INSERM, U1216,Grenoble Inst Neurosci, Grenoble, France..
    Helfricht, Angela
    ProQR Therapeut NV, Leiden, Netherlands..
    Jung, Taeyang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology. Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea..
    Karneva, Zhana K.
    ProQR Therapeut NV, Leiden, Netherlands..
    Lee, Yejin
    Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea..
    Beumer, Wouter
    ProQR Therapeut NV, Leiden, Netherlands..
    Horst, Geert B. van der
    ProQR Therapeut NV, Leiden, Netherlands..
    Anthonijsz, Herma
    ProQR Therapeut NV, Leiden, Netherlands..
    Buil, Levi C. M.
    ProQR Therapeut NV, Leiden, Netherlands..
    Ham, Frits van der
    ProQR Therapeut NV, Leiden, Netherlands..
    Platenburg, Gerard J.
    ProQR Therapeut NV, Leiden, Netherlands..
    Purhonen, Pasi
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology.
    Hebert, Hans
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Structural Biotechnology. KTH Roual Inst Technol, Dept Biomed Engn & Hlth Syst, S-14152 Huddinge, Sweden..
    Humbert, Sandrine
    Univ Grenoble Alpes, CHU Grenoble Alpes, INSERM, U1216,Grenoble Inst Neurosci, Grenoble, France.;Univ Grenoble Alpes, Grenoble Inst Neurosci, INSERM, U1216,CHU Grenoble Alpes,, F-38000 Grenoble, France..
    Saudou, Frederic
    Univ Grenoble Alpes, CHU Grenoble Alpes, INSERM, U1216,Grenoble Inst Neurosci, Grenoble, France.;Univ Grenoble Alpes, Grenoble Inst Neurosci, INSERM, U1216,CHU Grenoble Alpes,, F-38000 Grenoble, France..
    Klein, Pontus
    ProQR Therapeut NV, Leiden, Netherlands.;ProQR Therapeut NV, NL-2333 CK Leiden, Netherlands..
    Song, Ji-Joon
    Korea Adv Inst Sci & Technol KAIST, Dept Biol Sci, KI BioCentury, Daejeon, South Korea.;291 Daehakro, Daejeon 34141, South Korea..
    A pathogenic proteolysis-resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function2022In: JCI Insight, ISSN 2379-3708, Vol. 7, no 17, article id e154108Article in journal (Refereed)
    Abstract [en]

    Huntington's disease (HD) is a late-onset neurological disorder for which therapeutics are not available. Its key pathological mechanism involves the proteolysis of polyglutamine-expanded (polyQ-expanded) mutant huntingtin (mHTT), which generates N-terminal fragments containing polyQ, a key contributor to HD pathogenesis. Interestingly, a naturally occurring spliced form of HTT mRNA with truncated exon 12 encodes an HTT (HTT & UDelta;12) with a deletion near the caspase-6 cleavage site. In this study, we used a multidisciplinary approach to characterize the therapeutic potential of targeting HTT exon 12. We show that HTT & UDelta;12 was resistant to caspase-6 cleavage in both cell-free and tissue lysate assays. However, HTT & UDelta;12 retained overall biochemical and structural properties similar to those of wt-HTT. We generated mice in which HTT exon 12 was truncated and found that the canonical exon 12 was dispensable for the main physiological functions of HTT, including embryonic development and intracellular trafficking. Finally, we pharmacologically induced HTT & UDelta;12 using the antisense oligonucleotide (ASO) QRX-704. QRX-704 showed predictable pharmacology and efficient biodistribution. In addition, it was stable for several months and inhibited pathogenic proteolysis. Furthermore, QRX-704 treatments resulted in a reduction of HTT aggregation and an increase in dendritic spine count. Thus, ASO-induced HTT exon 12 splice switching from HTT may provide an alternative therapeutic strategy for HD.

  • 41.
    Kizyte, Asta
    et al.
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics.
    Zhang, Haocheng
    Butler Forslund, Emelie
    Gutierrez-Farewik, Elena
    KTH, School of Engineering Sciences (SCI), Engineering Mechanics. KTH, School of Engineering Sciences (SCI), Centres, BioMEx.
    Wang, Ruoli
    KTH, School of Engineering Sciences (SCI), Centres, BioMEx.
    Neuromuscular adaptations in ankle plantar flexor and dorsiflexor in persons with spinal cord injuryManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: Spinal cord injury (SCI) could lead to sensory-motor impairment of varying degree. After the injury, multiple neurophysiological changes occur, altering the neural motor control strategies. This study aims to assess the neuromuscular adaptations in the ankle plantar flexor and dorsiflexor muscles after the SCI by examining the electromyography (EMG) and motor unit parameters during sub-maximal voluntary isometric contractions and comparing these parameters to a control cohort. Methods: High-density EMG (HD-EMG) signals of tibialis anterior and soleus were recorded simultaneously with ankle joint torque during repeated sub-maximal (20% and 50% of the maximal torque) isometric voluntary contractions. Torque parameters such as normalized torque and coefficient of variation of torque during sustained contraction, EMG parameters such as amplitude and intramuscular coherence, as well as motor unit parameters such as motor unit discharge rates, recruitment thresholds, and coefficient of variation of the inter-spike intervals, were analyzed within the SCI and control groups. Results: We found that the SCI group, on average, had significantly weaker plantar flexor but not dorsiflexor muscles than the control group. Despite the increased variation of soleus motor unit inter-spike intervals post-SCI, both groups maintained constant sub-maximal torques with similar variability. However, the SCI group required up to 40.2% higher normalized EMG amplitudes to achieve the same torque level as the control group. Additionally, intramuscular coherence was found to be lower (up to 38.1% in TA and 34.6% in SOL) in the SCI group compared to the control group in the alpha frequency band during sustained sub-maximal isometric contractions. At higher force levels (50% MVC), motor units were recruited and de-recruited at lower thresholds in both muscles and fired at lower rates in the tibialis anterior muscle post-SCI. Conclusion: Through the analysis of these parameters, we observed altered force production and modulation strategies post-SCI. The observed combination of the motor unit and EMG parameter changes may indicate reduced common neural drive within the muscle and a possible shift towards larger motor units and in both TA and SOL muscles. Significance: The results of this study contribute to the knowledge of the neurophysiological modifications in the ankle dorsiflexors and plantar flexors following the SCI, which may aid future research on SCI rehabilitation.

  • 42.
    Kleiven, Svein
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    Predictors for Traumatic Brain Injuries Evaluated through Accident Reconstructions2007In: Stapp Car Crash Journal, ISSN 1532-8546, Vol. 51, p. 81-114Article in journal (Refereed)
    Abstract [en]

    The aim of this study is to evaluate all the 58 available NFL cases and compare various predictors for mild traumatic brain injuries using a detailed and extensively validated finite element model of the human head. Global injury measures such as magnitude in angular and translational acceleration, change in angular velocity, head impact power (HIP) and HIC were also investigated with regard to their ability to predict the intracranial pressure and strains associated with injury. The brain material properties were modeled using a hyperelastic and viscoelastic constitutive law. Also, three different stiffness parameters, encompassing a range of published brain tissue properties, were tested. 8 tissue injury predictors were evaluated for 6 different regions, covering the entire cerebrum, as well as for the whole brain. In addition, 10 head kinematics based predictors were evaluated both for correlation with injury as well as with strain and pressure. When evaluating the results, a statistical correlation between strain, strain rate, product of strain and strain rate, Cumulative Strain Damage Measure (CSDM), strain energy density, maximum pressure, magnitude of minimum pressure, as well as von Mises effective stress, with injury was found when looking into specific regions of the brain. However, the maximal pressure in the gray matter showed a higher correlation with injury than other evaluated measures. On the other hand, it was possible, through the reconstruction of a motocross accident, to re-create the injury pattern in the brain of the injured rider using maximal principal strain. It was also found that a simple linear combination of peak change in rotational velocity and HIC showed a high correlation (R=0.98) with the maximum principal strain in the brain, in addition to being a significant predictor of injury. When applying the rotational and translational kinematics separately for one of the cases, it was found that the translational kinematics contribute very little to the intracranial distortional strains while the rotational kinematics contributes insignificantly to the pressure response. This study underlines that the strain based brain tissue injury predictors are very sensitive to the choice of stiffness for the brain tissue.

  • 43.
    Kleiven, Svein
    KTH, School of Technology and Health (STH), Neuronic Engineering.
    The biomechanics of ‘real’ head protection: New thoughts on preventing TBI2008Conference paper (Other academic)
  • 44.
    Kroon, Martin
    KTH, School of Engineering Sciences (SCI), Solid Mechanics (Dept.).
    Simulation of cerebral aneurysm growth and prediction of evolving rupture risk2011In: Modelling and Simulation in Engineering, ISSN 1687-5591, Vol. 2011, p. 289523-Article in journal (Refereed)
    Abstract [en]

    Cerebral aneurysms are local expansions of blood vessel walls in the brain blood system. The rupture of an aneurysm is a very severe event associated with a high rate of mortality. When cerebral aneurysms are detected, clinicians need to decide if operation is required. The risk of aneurysm rupture is then compared to the risks associated with the medical intervention. In the present paper, a probabilistic framework for a mechanically based rupture risk assessment of cerebral aneurysms is proposed. The method is based on the assumption that the strength of aneurysmal tissues can be described by a statistical distribution. A structural analysis of the aneurysm in question is performed, and the maximum stress experienced by the aneurysm is compared to the strength distribution. The proposed model was compared with clinical results for ruptured aneurysms in terms of rupture density and accumulated rupture risk as a function of aneurysm size. The model was able to reproduce the clinical results well. The proposed framework may potentially be used under in vivo conditions to predict the risk of rupture for diagnosed aneurysms.

  • 45.
    Körner Gustafsson, Joakim
    et al.
    Karolinska Institutet.
    Södersten, Maria
    Karolinska Institutet.
    Ternström, Sten
    KTH, School of Electrical Engineering and Computer Science (EECS), Intelligent systems, Speech, Music and Hearing, TMH, Music Acoustics.
    Schalling, Ellika
    Karolinska Institutet.
    Treatment of Hypophonia in Parkinson’s Disease Through Biofeedback in Daily Life Administered with A Portable Voice Accumulator2021In: Journal of Voice, ISSN 0892-1997, E-ISSN 1873-4588Article in journal (Refereed)
    Abstract [en]

    Objectives

    The purpose of this study was to assess the outcome following continuous tactile biofeedback of voice sound level administered, with a portable voice accumulator to individuals with Parkinson's disease (PD).

    Method

    Nine out of 16 participants with PD completed a 4-week intervention program where biofeedback of voice sound level was administered with the portable voice accumulator VoxLog during speech in daily life. The feedback, a tactile vibration signal from the device, was activated when the wearer used a voice sound level below an individually predetermined threshold level, reminding the wearer to increase voice sound level during speech. Voice use was registered in daily life with the VoxLog during the intervention period as well as during one baseline week, one follow-up week post intervention and 1 week 3 months post intervention. Self-to-other ratio (SOR), which is the difference between voice sound level and environmental noise, was studied in multiple noise ranges.

    Results

    A significant increase in SOR across all noise ranges of 2.28 dB (SD: 0.55) was seen for participants with scores above the cut-off for normal function (>26 points) on the cognitive screening test Montreal Cognitive Assessment (MoCA) (n = 5). No significant increase was seen for the group of participants with MoCA scores below 26 (n = 4). Forty-four percent ended their participation early, all which scored below 26 on MoCA (n = 7).

    Conclusions

    Biofeedback administered in daily life regarding voice level may help individuals with PD to increase their voice sound level in relation to environmental noise in daily life, but only for a limited subset. Only participants with normal cognitive function as screened by MoCA improved their voice sound level in relation to environmental noise.

  • 46. Laic, R. A. G.
    et al.
    Kapeliotis, M.
    Famaey, N.
    Depreitere, B.
    Kleiven, Svein
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Neuronic Engineering.
    Vander Sloten, J.
    Quantifying biovariability in position and diameter of bridging veins to improve acute subdural hematoma prediction in FE head models2022In: Proceedings of Science, Sissa Medialab Srl , 2022, p. 337-352Conference paper (Refereed)
    Abstract [en]

    Bridging veins (BV) rupture is a major cause of Acute Subdural Hematoma. This study aims to quantify their biovariability to better understand their properties and increase the biofidelity of finite element (FE) head models. The number of BV and their measured diameters were manually counted in CT angiograms from 67 patients. A mixed linear model was used for the statistical analysis and the results were implemented in the KTH FE head model. LS-DYNA simulations were used to evaluate the amount of successful BV rupture predictions. The false positive and false negative predictions were also counted. The human brain has a mean of 23,18 BV, with diameters ranging between 0,37 and 3,24 mm. In the initial version of the KTH model two BV mechanical properties datasets gave a 6/8 successful prediction rate with one false positive and one false negative and one dataset gave a 7/8 successful prediction rate with one false negative. For the updated version all sets gave a 7/8 successful prediction rate with one false negative. The number of BV and BV diameter size is segment dependent, but not hemisphere dependent. The implementation of these findings in the FE head model is a good preliminary attempt to increase BV rupture predictability.

  • 47. Larhammar, Martin
    et al.
    Patra, Kalicharan
    Blunder, Martina
    Emilsson, Lina
    Peuckert, Christiane
    Arvidsson, Emma
    Rönnlund, Daniel
    KTH, School of Engineering Sciences (SCI), Applied Physics, Experimental Biomolecular Physics.
    Preobraschenski, Julia
    Birgner, Carolina
    Limbach, Christoph
    Widengren, Jerker
    Blom, Hans
    Jahn, Reinhard
    Wallen-Mackenzie, Asa
    Kullander, Klas
    SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis2015In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, no 6, p. 526-536Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The neuromodulatory transmitters, biogenic amines, have profound effects on multiple neurons and are essential for normal behavior and mental health. Here we report that the orphan transporter SLC10A4, which in the brain is exclusively expressed in presynaptic vesicles of monoaminergic and cholinergic neurons, has a regulatory role in dopamine homeostasis. METHODS: We used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine- regulated behaviors. RESULTS: We show that SLC10A4 is localized on the same synaptic vesicles as either vesicular acetylcholine transporter or vesicular monoamine transporter 2. We did not find evidence for direct transport of dopamine by SLC10A4; however, synaptic vesicle preparations lacking SLC10A4 showed decreased dopamine vesicular uptake efficiency. Furthermore, we observed an increased acidification in synaptic vesicles isolated from mice over-expressing SLC10A4. Loss of SLC10A4 in mice resulted in reduced striatal serotonin, noradrenaline, and dopamine concentrations and a significantly higher dopamine turnover ratio. Absence of SLC10A4 led to slower dopamine clearance rates in vivo, which resulted in accumulation of extracellular dopamine. Finally, whereas SLC10A4 null mutant mice were slightly hypoactive, they displayed hypersensitivity to administration of amphetamine and tranylcypromine. CONCLUSIONS: Our results demonstrate that SLC10A4 is a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo. The discovery of SLC10A4 and its role in dopaminergic signaling reveals a novel mechanism for neuromodulation and represents an unexplored target for the treatment of neurological and mental disorders.

  • 48.
    Leng, Yan
    et al.
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Rehabil Med, Guangzhou, Guangdong, Peoples R China..
    Wang, Zhu
    Sun Yat Sen Univ, Inst Diagnost & Intervent Ultrasound, Affiliated Hosp 1, Dept Med Ultrason, Guangzhou, Guangdong, Peoples R China..
    Bian, Ruihao
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Rehabil Med, Guangzhou, Guangdong, Peoples R China..
    Lo, Wai Leung Ambrose
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Rehabil Med, Guangzhou, Guangdong, Peoples R China..
    Xie, Xiaoyan
    Sun Yat Sen Univ, Inst Diagnost & Intervent Ultrasound, Affiliated Hosp 1, Dept Med Ultrason, Guangzhou, Guangdong, Peoples R China..
    Wang, Ruoli
    KTH, School of Engineering Sciences (SCI), Mechanics. KTH, School of Engineering Sciences (SCI), Centres, BioMEx. Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
    Huang, Dongfeng
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Rehabil Med, Guangzhou, Guangdong, Peoples R China.;Sun Yat Sen Univ, Affiliated Hosp 7, Dept Rehabil Med, Shenzhen, Peoples R China..
    Li, Le
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Rehabil Med, Guangzhou, Guangdong, Peoples R China..
    Alterations of Elastic Property of Spastic Muscle With Its Joint Resistance Evaluated From Shear Wave Elastography and Biomechanical Model2019In: Frontiers in Neurology, E-ISSN 1664-2295, Vol. 10, article id 736Article in journal (Refereed)
    Abstract [en]

    This study aims to quantify passive muscle stiffness of spastic wrist flexors in stroke survivors using shear wave elastography (SWE) and to correlate with neural and non-neural contributors estimated from a biomechanical model to hyper-resistance measured during passive wrist extension. Fifteen hemiplegic individuals after stroke with Modified Ashworth Scale (MAS) score larger than one were recruited. SWE were used to measure Young's modulus of flexor carpi radialis muscle with joint from 0 degrees (at rest) to 50 degrees flexion (passive stretch condition), with 10 degrees interval. The neural (NC) and non-neural components i.e., elasticity component (EC) and viscosity component (VC) of the wrist joint were analyzed from a motorized mechanical device NeuroFlexor (R) (NF). Combining with a validated biomechanical model, the neural reflex and muscle stiffness contribution to the increased resistance can be estimated. MAS and Fugl-Meyer upper limb score were also measured to evaluate the spasticity and motor function of paretic upper limb. Young's modulus was significantly higher in the paretic side of flexor carpi radialis than that of the non-paretic side (p < 0.001) and it increased significantly from 0 degrees to 50 degrees of the paretic side (p < 0.001). NC, EC, and VC on the paretic side were higher than the non-paretic side (p < 0.05). There was moderate significant positive correlation between the Young's Modulus and EC (r = 0.565, p = 0.028) and VC (r = 0.645, p = 0.009) of the paretic forearm flexor muscle. Fugl-Meyer of the paretic forearm flexor has a moderate significant negative correlation with NC (r = -0.578, p = 0.024). No significant correlation between MAS and shear elastic modulus or NF components was observed. This study demonstrated the feasibility of combining SWE and NF as a non-invasive approach to assess spasticity of paretic muscle and joint in stroke clinics. The neural and non-neural components analysis as well as correlation findings of muscle stiffness of SWE might provide understanding of mechanism behind the neuromuscular alterations in stroke survivors and facilitate the design of suitable intervention for them.

  • 49. Li, Fang
    et al.
    Zhu, Huilin
    Xu, Jie
    Gao, Qianqian
    Guo, Huan
    Wu, Shijing
    Li, Xinge
    He, Sailing
    KTH, School of Electrical Engineering and Computer Science (EECS), Electrical Engineering, Electromagnetic Engineering.
    Lie Detection Using fNIRS Monitoring of Inhibition-Related Brain Regions Discriminates Infrequent but not Frequent Liars2018In: Frontiers in Human Neuroscience, E-ISSN 1662-5161, Vol. 12, article id 71Article in journal (Refereed)
    Abstract [en]

    Functional near-infrared spectroscopy (fNIRS) was used to test whether monitoring inhibition-related brain regions is a feasible method for detecting both infrequent liars and frequent liars. Thirty-two participants were divided into two groups: the deceptive group (liars) and the non-deceptive group (ND group, innocents). All the participants were required to undergo a simulated interrogation by a computer. The participants from the deceptive group were instructed to tell a mix of lies and truths and those of the ND group were instructed always to tell the truth. Based on the number of deceptions, the participants of the deceptive group were further divided into a infrequently deceptive group (IFD group, infrequent liars) and a frequently deceptive group (FD group, frequent liars). The infrequent liars exhibited greater neural activities than the frequent liars and the innocents in the left middle frontal gyrus (MFG) when performing the deception detection tasks. While performing deception detection tasks, infrequent liars showed significantly greater neural activation in the left MFG than the baseline, but frequent liars and innocents did not exhibit this pattern of neural activation in any area of inhibition-related brain regions. The results of individual analysis showed an acceptable accuracy of detecting infrequent liars, but an unacceptable accuracy of detecting frequent liars. These results suggest that using fNIRS monitoring of inhibition-related brain regions is feasible for detecting infrequent liars, for whom deception may be more effortful and therefore more physiologically marked, but not frequent liars.

  • 50.
    Li, Xiaogai
    et al.
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Neuronic Engineering.
    Zhou, Zhou
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Neuronic Engineering.
    Kleiven, Svein
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Biomedical Engineering and Health Systems, Neuronic Engineering.
    An anatomically detailed and personalizable head injury model: Significance of brain and white matter tract morphological variability on strain2021In: Biomechanics and Modeling in Mechanobiology, ISSN 1617-7959, E-ISSN 1617-7940Article in journal (Refereed)
    Abstract [en]

    Finite element head (FE) models are important numerical tools to study head injuries and develop protection systems. The generation of anatomically accurate and subject-specific head models with conforming hexahedral meshes remains a significant challenge. The focus of this study is to present two developmental works: first, an anatomically detailed FE head model with conforming hexahedral meshes that has smooth interfaces between the brain and the cerebrospinal fluid, embedded with white matter (WM) fiber tracts; second, a morphing approach for subject-specific head model generation via a new hierarchical image registration pipeline integrating Demons and Dramms deformable registration algorithms. The performance of the head model is evaluated by comparing model predictions with experimental data of brain–skull relative motion, brain strain, and intracranial pressure. To demonstrate the applicability of the head model and the pipeline, six subject-specific head models of largely varying intracranial volume and shape are generated, incorporated with subject-specific WM fiber tracts. DICE similarity coefficients for cranial, brain mask, local brain regions, and lateral ventricles are calculated to evaluate personalization accuracy, demonstrating the efficiency of the pipeline in generating detailed subject-specific head models achieving satisfactory element quality without further mesh repairing. The six head models are then subjected to the same concussive loading to study the sensitivity of brain strain to inter-subject variability of the brain and WM fiber morphology. The simulation results show significant differences in maximum principal strain and axonal strain in local brain regions (one-way ANOVA test, p < 0.001), as well as their locations also vary among the subjects, demonstrating the need to further investigate the significance of subject-specific models. The techniques developed in this study may contribute to better evaluation of individual brain injury and the development of individualized head protection systems in the future. This study also contains general aspects the research community may find useful: on the use of experimental brain strain close to or at injury level for head model validation; the hierarchical image registration pipeline can be used to morph other head models, such as smoothed-voxel models.

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