Publications by authors named "Thomas Grunwald"

107 Publications

A helicase-primase drug candidate with sufficient target tissue exposure affects latent neural herpes simplex virus infections.

Sci Transl Med 2021 Jun;13(598)

Innovative Molecules GmbH, Leopoldshöher Str. 7, 32107 Bad-Salzuflen, Germany.

More than 50% of the world population is chronically infected with herpesviruses. Herpes simplex virus (HSV) infections are the cause of herpes labialis (cold sores), genital herpes, and sight-impairing keratitis. Less frequently, life-threatening disseminated disease (encephalitis and generalized viremia) can also occur, mainly in immunocompromised patients and newborns. After primary infection, HSV persists for life in a latent state in trigeminal or sacral ganglia and, triggered by diverse stimuli, disease recurs in more than 30% of patients up to several times a year. Current therapy with nucleoside analogs targeting the viral polymerase is somewhat effective but limited by poor exposure in the nervous system, and latent infections are not affected by therapy. Here, we report on an inhibitor of HSV helicase-primase with potent in vitro anti-herpes activity, a different mechanism of action, a low frequency of HSV resistance, and a favorable pharmacokinetic and safety profile. Improved target tissue exposure results in superior efficacy in preventing and treating HSV infection and disease in animal models as compared to standard of care. Therapy of primary HSV infections with drug candidate IM-250 {()-2-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)--methyl--(4-methyl-5-(-methylsulfon-imidoyl)thiazol-2-yl)acetamide} not only reduces the duration of disease symptoms or time to healing but also prevents recurrent disease in guinea pigs. Treatment of recurrent infections reduces the frequency of recurrences and viral shedding, and, unlike nucleosidic drugs, IM-250 remains effective for a time after cessation of treatment. Hence, IM-250 has advantages over standard-of-care therapies and represents a promising therapeutic for chronic HSV infection, including nucleoside-resistant HSV.
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http://dx.doi.org/10.1126/scitranslmed.abf8668DOI Listing
June 2021

The Effects of Dynamic and Static Emotional Facial Expressions of Humans and Their Avatars on the EEG: An ERP and ERD/ERS Study.

Front Neurosci 2021 22;15:651044. Epub 2021 Apr 22.

Swiss Epilepsy Center, Zurich, Switzerland.

This study aimed to examine whether the cortical processing of emotional faces is modulated by the computerization of face stimuli ("avatars") in a group of 25 healthy participants. Subjects were passively viewing 128 static and dynamic facial expressions of female and male actors and their respective avatars in neutral or fearful conditions. Event-related potentials (ERPs), as well as alpha and theta event-related synchronization and desynchronization (ERD/ERS), were derived from the EEG that was recorded during the task. All ERP features, except for the very early N100, differed in their response to avatar and actor faces. Whereas the N170 showed differences only for the neutral avatar condition, later potentials (N300 and LPP) differed in both emotional conditions (neutral and fear) and the presented agents (actor and avatar). In addition, we found that the avatar faces elicited significantly stronger reactions than the actor face for theta and alpha oscillations. Especially theta EEG frequencies responded specifically to visual emotional stimulation and were revealed to be sensitive to the emotional content of the face, whereas alpha frequency was modulated by all the stimulus types. We can conclude that the computerized avatar faces affect both, ERP components and ERD/ERS and evoke neural effects that are different from the ones elicited by real faces. This was true, although the avatars were replicas of the human faces and contained similar characteristics in their expression.
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http://dx.doi.org/10.3389/fnins.2021.651044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100234PMC
April 2021

Temporal lobe epilepsy alters neural responses to human and avatar facial expressions in the face perception network.

Brain Behav 2021 Jun 5;11(6):e02140. Epub 2021 May 5.

Swiss Epilepsy Center, Zurich, Switzerland.

Background And Objective: Although avatars are now widely used in advertisement, entertainment, and business today, no study has investigated whether brain lesions in neurological patients interfere with brain activation in response to dynamic avatar facial expressions. The aim of our event-related fMRI study was to compare brain activation differences in people with epilepsy and controls during the processing of fearful and neutral dynamic expressions displayed by human or avatar faces.

Methods: Using functional magnetic resonance imaging (fMRI), we examined brain responses to dynamic facial expressions of trained actors and their avatar look-alikes in 16 people with temporal lobe epilepsy (TLE) and 26 controls. The actors' fearful and neutral expressions were recorded on video and conveyed onto their avatar look-alikes by face tracking.

Results: Our fMRI results show that people with TLE exhibited reduced response differences between fearful and neutral expressions displayed by humans in the right amygdala and the left superior temporal sulcus (STS). Further, TLE was associated with reduced response differences between human and avatar fearful expressions in the dorsal pathway of the face perception network (STS and inferior frontal gyrus) as well as in the medial prefrontal cortex.

Conclusions: Taken together, these findings suggest that brain responses to dynamic facial expressions are altered in people with TLE compared to neurologically healthy individuals-regardless of whether the face is human or computer-generated. In TLE, areas sensitive to dynamic facial features and associated with processes relating to the self and others are particularly affected when processing dynamic human and avatar expressions. Our findings highlight that the impact of TLE on facial emotion processing must be extended to artificial faces and should be considered when applying dynamic avatars in the context of neurological conditions.
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http://dx.doi.org/10.1002/brb3.2140DOI Listing
June 2021

Machine Learning Techniques for Personalized Detection of Epileptic Events in Clinical Video Recordings.

AMIA Annu Symp Proc 2020 25;2020:1003-1011. Epub 2021 Jan 25.

IBM Research - Zurich, Switzerland.

Continuous patient monitoring is essential to achieve an effective and optimal patient treatment in the intensive care unit. In the specific case of epilepsy it is the only way to achieve a correct diagnosis and a subsequent optimal medication plan if possible. In addition to automatic vital sign monitoring, epilepsy patients need manual monitoring by trained personnel, a task that is very difficult to be performed continuously for each patient. Moreover, epileptic manifestations are highly personalized even within the same type of epilepsy. In this work we assess two machine learning methods, dictionary learning and an autoencoder based on long short-term memory (LSTM) cells, on the task of personalized epileptic event detection in videos, with a set of features that were specifically developed with an emphasis on high motion sensitivity. According to the strengths of each method we have selected different types of epilepsy, one with convulsive behaviour and one with very subtle motion. The results on five clinical patients show a highly promising ability of both methods to detect the epileptic events as anomalies deviating from the stable/normal patient status.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075529PMC
June 2021

Dataset of spiking and LFP activity invasively recorded in the human amygdala during aversive dynamic stimuli.

Sci Data 2021 01 14;8(1). Epub 2021 Jan 14.

Klinik für Neurochirurgie, UniversitätsSpital Zürich und Universität Zürich, Zurich, Switzerland.

We present an electrophysiological dataset collected from the amygdalae of nine participants attending a visual dynamic stimulation of emotional aversive content. The participants were patients affected by epilepsy who underwent preoperative invasive monitoring in the mesial temporal lobe. Participants were presented with dynamic visual sequences of fearful faces (aversive condition), interleaved with sequences of neutral landscapes (neutral condition). The dataset contains the simultaneous recording of intracranial EEG (iEEG) and neuronal spike times and waveforms, and localization information for iEEG electrodes. Participant characteristics and trial information are provided. We technically validated this dataset and provide here the spike sorting quality metrics and the spectra of iEEG signals. This dataset allows the investigation of amygdalar response to dynamic aversive stimuli at multiple spatial scales, from the macroscopic EEG to the neuronal firing in the human brain.
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http://dx.doi.org/10.1038/s41597-020-00790-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809031PMC
January 2021

Identification of a large repetitive RTX immunogen in a highly virulent Rodentibacter heylii strain.

Microbes Infect 2021 Mar-Apr;23(2-3):104771. Epub 2020 Oct 23.

Institute of Bacteriology and Mycology, Faculty of Veterinary Medicine, University Leipzig, Leipzig, Germany. Electronic address:

Rodentibacter (R.) heylii is frequently detected in laboratory rodents. Repeats in toxin (RTX) toxins are considered important virulence factors of this major murine pathogen. We evaluated the virulence of a R.heylii strain negative for all known RTX toxin genes and Muribacter (M.) muris, a commensal in mice, in experimental infections of C57BL/6 and BALB/c mice. Experimental intranasal infection with 10 CFU of the pnxI-, pnxII- and pnxIII- R. heylii strain resulted in 75% and 100% mortality in C57BL/6 and BALB/c mice, respectively. In early losses, multiple internal organs were infected and purulent bronchopneumonia was the main pathology. Intranasal application of M. muris did not result in mortality or severe weight loss. Immunoproteomics led to the identification of a surface-associated and specific immunogen, which was designated as R. heylii immunogen A (RhiA) and which was exclusively recognised by sera obtained from mice infected with this R. heylii pathotype. RhiA is a 262.6 kDa large protein containing long imperfect tandem repeats and C-terminal RTX consensus sequences. Immunohistochemical analysis confirmed that this R.heylii pathotype expresses RhiA in the lower respiratory tract. In summary, this study describes a specific immunogen in a virulent R. heylii, strain which is an excellent antigen for pathotype-specific serological screenings and which might carry out RTX-related functions.
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http://dx.doi.org/10.1016/j.micinf.2020.10.007DOI Listing
October 2020

A Recombinant Zika Virus Envelope Protein with Mutations in the Conserved Fusion Loop Leads to Reduced Antibody Cross-Reactivity upon Vaccination.

Vaccines (Basel) 2020 Oct 13;8(4). Epub 2020 Oct 13.

Fraunhofer-Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany.

Zika virus (ZIKV) is a zoonotic, human pathogenic, and mosquito-borne flavivirus. Its distribution is rapidly growing worldwide. Several attempts to develop vaccines for ZIKV are currently ongoing. Central to most vaccination approaches against flavivirus infections is the envelope (E) protein, which is the major target of neutralizing antibodies. Insect-cell derived, recombinantly expressed variants of E from the flaviviruses West Nile and Dengue virus have entered clinical trials in humans. Also for ZIKV, these antigens are promising vaccine candidates. Due to the structural similarity of flaviviruses, cross-reactive antibodies are induced by flavivirus antigens and have been linked to the phenomenon of antibody-dependent enhancement of infection (ADE). Especially the highly conserved fusion loop domain (FL) in the E protein is a target of such cross-reactive antibodies. In areas where different flaviviruses co-circulate and heterologous infections cannot be ruled out, this is of concern. To exclude the possibility that recombinant E proteins of ZIKV might induce ADE in infections with related flaviviruses, we performed an immunization study with an insect-cell derived E protein containing four mutations in and near the FL. Our data show that this mutant antigen elicits antibodies with equal neutralizing capacity as the wildtype equivalent. However, it induces much less serological cross-reactivity and does not cause ADE in vitro. These results indicate that mutated variants of the E protein might lead to ZIKV and other flavivirus vaccines with increased safety profiles.
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http://dx.doi.org/10.3390/vaccines8040603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712286PMC
October 2020

Altered energy partitioning across terrestrial ecosystems in the European drought year 2018.

Philos Trans R Soc Lond B Biol Sci 2020 10 7;375(1810):20190524. Epub 2020 Sep 7.

Institute of Soil Science and Land Evaluation, University of Hohenheim, Emil-Wolff-Straße 27, 70599 Stuttgart, Germany.

Drought and heat events, such as the 2018 European drought, interact with the exchange of energy between the land surface and the atmosphere, potentially affecting albedo, sensible and latent heat fluxes, as well as CO exchange. Each of these quantities may aggravate or mitigate the drought, heat, their side effects on productivity, water scarcity and global warming. We used measurements of 56 eddy covariance sites across Europe to examine the response of fluxes to extreme drought prevailing most of the year 2018 and how the response differed across various ecosystem types (forests, grasslands, croplands and peatlands). Each component of the surface radiation and energy balance observed in 2018 was compared to available data per site during a reference period 2004-2017. Based on anomalies in precipitation and reference evapotranspiration, we classified 46 sites as drought affected. These received on average 9% more solar radiation and released 32% more sensible heat to the atmosphere compared to the mean of the reference period. In general, drought decreased net CO uptake by 17.8%, but did not significantly change net evapotranspiration. The response of these fluxes differed characteristically between ecosystems; in particular, the general increase in the evaporative index was strongest in peatlands and weakest in croplands. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.
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http://dx.doi.org/10.1098/rstb.2019.0524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485107PMC
October 2020

Automated application of low energy electron irradiation enables inactivation of pathogen- and cell-containing liquids in biomedical research and production facilities.

Sci Rep 2020 07 30;10(1):12786. Epub 2020 Jul 30.

Fraunhofer Institute for Cell Therapy and Immunology IZI, Perlickstrasse 1, 04103, Leipzig, Germany.

Ionizing radiation is widely used to inactivate pathogens. It mainly acts by destroying nucleic acids but causes less damage to structural components like proteins. It is therefore highly suited for the sterilization of biological samples or the generation of inactivated vaccines. However, inactivation of viruses or bacteria requires relatively high doses and substantial amounts of radiation energy. Consequently, irradiation is restricted to shielded facilities-protecting personnel and the environment. We have previously shown that low energy electron irradiation (LEEI) has the same capacity to inactivate pathogens in liquids as current irradiation methods, but generates much less secondary X-ray radiation, which enables the use in normal laboratories by self-shielded irradiation equipment. Here, we present concepts for automated LEEI of liquids, in disposable bags or as a continuous process. As the electrons have a limited penetration depth, the liquid is transformed into a thin film. High concentrations of viruses (Influenza, Zika virus and Respiratory Syncytial Virus), bacteria (E. coli, B. cereus) and eukaryotic cells (NK-92 cell line) are efficiently inactivated by LEEI in a throughput suitable for various applications such as sterilization, vaccine manufacturing or cell therapy. Our results validate the premise that for pathogen and cell inactivation in liquids, LEEI represents a suitable and versatile irradiation method for standard biological research and production laboratories.
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http://dx.doi.org/10.1038/s41598-020-69347-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393095PMC
July 2020

Social cognition in an adult epilepsy patient with developmental amnesia.

Neurocase 2020 08 12;26(4):231-240. Epub 2020 Jul 12.

Swiss Epilepsy Center , Zurich, Switzerland.

Reports on social cognition in patients with developmental amnesia resulting from bilateral hippocampal lesions are rare, although the link between social cognition and temporal lobe structures is well established. We present the case of a 23-year-old male epilepsy patient, BM, with developmental amnesia due to perinatal cerebral hypoxia. The patient was examined with neuroimaging and neuropsychological methods and compared to IQ-matched patients with epilepsy to control for effects of epilepsy. In addition, we used a test battery that evaluates emotion recognition and theory of mind to study his social cognition abilities. Structural high-resolution magnetic resonance imaging showed bilateral hippocampal atrophy. The comparison to controls showed that, in addition to the well-documented memory disorders in developmental amnesia, BM showed remarkable deficits in 9 out of 17 social cognitive tasks assessing emotion recognition and theory of mind. In contrast, BM's performance on tasks of executive functions was largely preserved. The relevance of deficits in social cognition for patients with developmental amnesia is discussed.
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http://dx.doi.org/10.1080/13554794.2020.1791904DOI Listing
August 2020

The FLUXNET2015 dataset and the ONEFlux processing pipeline for eddy covariance data.

Sci Data 2020 07 9;7(1):225. Epub 2020 Jul 9.

Department of Sustainable Agro-ecosystems and Bioresources, Research and Innovation Centre, Fondazione Edmund Mach, San Michele All'adige, 38010, Italy.

The FLUXNET2015 dataset provides ecosystem-scale data on CO, water, and energy exchange between the biosphere and the atmosphere, and other meteorological and biological measurements, from 212 sites around the globe (over 1500 site-years, up to and including year 2014). These sites, independently managed and operated, voluntarily contributed their data to create global datasets. Data were quality controlled and processed using uniform methods, to improve consistency and intercomparability across sites. The dataset is already being used in a number of applications, including ecophysiology studies, remote sensing studies, and development of ecosystem and Earth system models. FLUXNET2015 includes derived-data products, such as gap-filled time series, ecosystem respiration and photosynthetic uptake estimates, estimation of uncertainties, and metadata about the measurements, presented for the first time in this paper. In addition, 206 of these sites are for the first time distributed under a Creative Commons (CC-BY 4.0) license. This paper details this enhanced dataset and the processing methods, now made available as open-source codes, making the dataset more accessible, transparent, and reproducible.
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http://dx.doi.org/10.1038/s41597-020-0534-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347557PMC
July 2020

Safety of the paramedian supracerebellar-transtentorial approach for selective amygdalohippocampectomy.

Neurosurg Focus 2020 04;48(4):E4

1Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of Zurich.

Objective: The goal of this study was to assess the reproducibility and safety of the recently introduced paramedian supracerebellar-transtentorial (PST) approach for selective amygdalohippocampectomy (SA).

Methods: The authors performed a retrospective analysis of prospectively collected data originating from their surgical register of patients undergoing SA via a PST approach for lesional medial temporal lobe epilepsy. All patients received thorough pre- and postoperative clinical (neurological, neuropsychological, psychiatric) and instrumental (ictal and long-term EEG, invasive EEG if needed, MRI) workup. Surgery-induced complications were assessed at discharge and at every follow-up thereafter and were classified according to Clavien-Dindo grade (CDG). Epilepsy outcome was defined according to Engel classification. Data were reported according to common descriptive statistical methods.

Results: Between May 2015 and May 2018, 17 patients underwent SA via a PST approach at the authors' institution (hippocampal sclerosis in 13 cases, WHO grade II glioma in 2 cases, and reactive gliosis in 2 cases). The median postoperative follow-up was 7 months (mean 9 months, range 3-19 months). There was no surgery-related mortality and no complication (CDG ≥ 2) in the whole series. Transitory CDG 1 surgical complications occurred in 4 patients and had resolved in all of them by the first postoperative follow-up. One patient showed a deterioration of neuropsychological performance with new slight mnestic deficits. No patient experienced a clinically relevant postoperative visual field defect. No morbidity due to semisitting position was recorded. At last follow-up 13/17 (76.4%) patients were in Engel class I (9/17 [52.9%] were in class IA).

Conclusions: The PST approach is a reproducible and safe surgical route for SA. The achievable complication rate is in line with the best results in the literature. Visual function outcome particularly benefits from this highly selective, neocortex-sparing approach. A larger patient sample and longer follow-up will show in the future if the seizure control rate and neuropsychological outcome also compare better than those achieved with current common surgical techniques.
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http://dx.doi.org/10.3171/2020.1.FOCUS19909DOI Listing
April 2020

Dynamic human and avatar facial expressions elicit differential brain responses.

Soc Cogn Affect Neurosci 2020 05;15(3):303-317

Swiss Epilepsy Center, CH-8008 Zurich, Switzerland.

Computer-generated characters, so-called avatars, are widely used in advertising, entertainment, human-computer interaction or as research tools to investigate human emotion perception. However, brain responses to avatar and human faces have scarcely been studied to date. As such, it remains unclear whether dynamic facial expressions of avatars evoke different brain responses than dynamic facial expressions of humans. In this study, we designed anthropomorphic avatars animated with motion tracking and tested whether the human brain processes fearful and neutral expressions in human and avatar faces differently. Our fMRI results showed that fearful human expressions evoked stronger responses than fearful avatar expressions in the ventral anterior and posterior cingulate gyrus, the anterior insula, the anterior and posterior superior temporal sulcus, and the inferior frontal gyrus. Fearful expressions in human and avatar faces evoked similar responses in the amygdala. We did not find different responses to neutral human and avatar expressions. Our results highlight differences, but also similarities in the processing of fearful human expressions and fearful avatar expressions even if they are designed to be highly anthropomorphic and animated with motion tracking. This has important consequences for research using dynamic avatars, especially when processes are investigated that involve cortical and subcortical regions.
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http://dx.doi.org/10.1093/scan/nsaa039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235958PMC
May 2020

The relation between neuronal firing, local field potentials and hemodynamic activity in the human amygdala in response to aversive dynamic visual stimuli.

Neuroimage 2020 06 10;213:116705. Epub 2020 Mar 10.

Klinik für Neurochirurgie, UniversitätsSpital Zürich und Universität Zürich, Zurich, Switzerland; Zentrum für Neurowissenschaften Zürich, Switzerland. Electronic address:

The amygdala is a central part of networks of brain regions underlying perception and cognition, in particular related to processing of emotionally salient stimuli. Invasive electrophysiological and hemodynamic measurements are commonly used to evaluate functions of the human amygdala, but a comprehensive understanding of their relation is still lacking. Here, we aimed at investigating the link between fast and slow frequency amygdalar oscillations, neuronal firing and hemodynamic responses. To this aim, we recorded intracranial electroencephalography (iEEG), hemodynamic responses and single neuron activity from the amygdala of patients with epilepsy. Patients were presented with dynamic visual sequences of fearful faces (aversive condition), interleaved with sequences of neutral landscapes (neutral condition). Comparing responses to aversive versus neutral stimuli across participants, we observed enhanced high gamma power (HGP, >60 ​Hz) during the first 2 ​s of aversive sequence viewing, and reduced delta power (1-4 ​Hz) lasting up to 18 ​s. In 5 participants with implanted microwires, neuronal firing rates were enhanced following aversive stimuli, and exhibited positive correlation with HGP and hemodynamic responses. Our results show that high gamma power, neuronal firing and BOLD responses from the human amygdala are co-modulated. Our findings provide, for the first time, a comprehensive investigation of amygdalar responses to aversive stimuli, ranging from single-neuron spikes to local field potentials and hemodynamic responses.
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http://dx.doi.org/10.1016/j.neuroimage.2020.116705DOI Listing
June 2020

Low-Energy Electron Irradiation Efficiently Inactivates the Gram-Negative Pathogen -A New Method for the Generation of Bacterial Vaccines with Increased Efficacy.

Vaccines (Basel) 2020 Mar 2;8(1). Epub 2020 Mar 2.

Fraunhofer Institute for Cell Therapy and Immunology IZI, Perlickstrasse 1, 04103 Leipzig, Germany.

Bacterial pathogens cause severe infections worldwide in livestock and in humans, and antibiotic resistance further increases the importance of prophylactic vaccines. Inactivated bacterial vaccines (bacterins) are usually produced via incubation of the pathogen with chemicals such as formaldehyde, which is time consuming and may cause loss of immunogenicity due to the modification of structural components. We evaluated low-energy electron irradiation (LEEI) as an alternative method to generate a bacterin. , an invasive Gram-negative murine pathogen, was inactivated with LEEI and formaldehyde. LEEI resulted in high antigen conservation, and LPS activity was significantly better maintained when compared with formaldehyde treatment. Immunization of mice with LEEI-inactivated elicited a strong immune response with no detectable bacterial burden upon sublethal challenge. The results of this study suggest the inactivation of bacteria with LEEI as an alternative, fast and efficient method to generate bacterial vaccines with increased efficacy.
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http://dx.doi.org/10.3390/vaccines8010113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157226PMC
March 2020

Dataset of human medial temporal lobe neurons, scalp and intracranial EEG during a verbal working memory task.

Sci Data 2020 01 21;7(1):30. Epub 2020 Jan 21.

Klinik für Neurochirurgie, UniversitätsSpital und Universität Zürich, 8091, Zürich, Switzerland.

We present an electrophysiological dataset recorded from nine subjects during a verbal working memory task. Subjects were epilepsy patients undergoing intracranial monitoring for the localization of epileptic seizures. Subjects performed a modified Sternberg task in which the encoding of memory items, maintenance, and recall were temporally separated. The dataset includes simultaneously recorded scalp EEG with the 10-20 system, intracranial EEG (iEEG) recorded with depth electrodes, waveforms and spike times of neurons recorded in the medial temporal lobe, and localization information on the depth electrodes. Subject characteristics and information on each trial (set size, match/mismatch, correct/incorrect, response, and response time) are given. For technical validation of data, we provide spike sorting quality metrics and the spectra of iEEG and scalp EEG signals. This dataset enables the investigation of working memory by providing simultaneous scalp EEG and iEEG recordings, which can be used for connectivity analysis, along with hard-to-obtain neuronal recordings from humans.
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http://dx.doi.org/10.1038/s41597-020-0364-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972902PMC
January 2020

RSV Vaccine Based on Rhabdoviral Vector Protects after Single Immunization.

Vaccines (Basel) 2019 Jul 3;7(3). Epub 2019 Jul 3.

Division of Virology, Medical University of Innsbruck, 6020 Innsbruck, Austria.

The respiratory syncytial virus (RSV) is one major cause of lower respiratory tract infections in childhood and an effective vaccine is still not available. We previously described a new rhabdoviral vector vaccine, VSV-GP, a variant of the vesicular stomatitis virus (VSV), where the VSV glycoprotein G is exchanged by the glycoprotein GP of the lymphocytic choriomeningitis virus. Here, we evaluated VSV-GP as vaccine vector for RSV with the aim to induce RSV neutralizing antibodies. Wild-type F (F) or a codon optimized version (F) were introduced at position 5 into the VSV-GP genome. Both F versions were efficiently expressed in VSV-GP-F infected cells and incorporated into VSV-GP particles. In mice, high titers of RSV neutralizing antibodies were induced already after prime and subsequently boosted by a second immunization. After challenge with RSV, viral loads in the lungs of immunized mice were reduced by 2-3 logs with no signs of an enhanced disease induced by the vaccination. Even a single intranasal immunization significantly reduced viral load by a factor of more than 100-fold. RSV neutralizing antibodies were long lasting and mice were still protected when challenged 20 weeks after the boost. Therefore, VSV-GP is a promising candidate for an effective RSV vaccine.
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http://dx.doi.org/10.3390/vaccines7030059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790003PMC
July 2019

Persistent hippocampal neural firing and hippocampal-cortical coupling predict verbal working memory load.

Sci Adv 2019 03 27;5(3):eaav3687. Epub 2019 Mar 27.

Klinik für Neurochirurgie, UniversitätsSpital und Universität Zürich, 8091 Zürich, Switzerland.

The maintenance of items in working memory relies on persistent neural activity in a widespread network of brain areas. To investigate the influence of load on working memory, we asked human subjects to maintain sets of letters in memory while we recorded single neurons and intracranial encephalography (EEG) in the medial temporal lobe and scalp EEG. Along the periods of a trial, hippocampal neural firing differentiated between success and error trials during stimulus encoding, predicted workload during memory maintenance, and predicted the subjects' behavior during retrieval. During maintenance, neuronal firing was synchronized with intracranial hippocampal EEG. On the network level, synchronization between hippocampal and scalp EEG in the theta-alpha frequency range showed workload dependent oscillatory coupling between hippocampus and cortex. Thus, we found that persistent neural activity in the hippocampus participated in working memory processing that is specific to memory maintenance, load sensitive and synchronized to the cortex.
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http://dx.doi.org/10.1126/sciadv.aav3687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436923PMC
March 2019

Highly sensitive ELISA for the serological detection of murine rotavirus EDIM based on its major immunogen VP6.

J Virol Methods 2018 12 23;262:72-78. Epub 2018 Aug 23.

Institute for Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, Germany; Center for Biotechnology and Biomedicine, Leipzig, Germany. Electronic address:

Precise health monitoring of laboratory animals is a critical factor for surveillance and accuracy of animal experiments. Rotavirus epizootic diarrhea of infant mice (EDIM) leads to infections in mice that can influence animal studies, e.g., by altering the intestinal physiology. Thus, the aim of this study was establishing a highly sensitive and specific ELISA for the serological detection of EDIM infections in rodents. First, virus proteins were separated by SDS-PAGE and immunogenic proteins were visualized by immunoblotting and identified after in-gel digestion by tandem mass spectrometry. Subsequently, the major immunogen VP6 (virus protein 6) was expressed in Escherichia coli in high yields, purified by affinity chromatography, and used to establish an indirect ELISA. The diagnostic sensitivity and specificity were both above 99 % and the selectivity better than 98.7 % for animals infected by other pathogens listed by the Federation of Laboratory Animal Science Associations. Importantly, the Strep-rVP6-His-ELISA was more sensitive than a commercial virus-based ELISA and is a time- and cost-efficient complement to EDIM-specific immune-fluorescence assays. In conclusion, the assay can improve health monitoring by reducing the risk of missed EDIM infections in animal housing facilities, thereby improving animal welfare, reliability of animal studies, and protection of precious mice breeds.
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http://dx.doi.org/10.1016/j.jviromet.2018.07.016DOI Listing
December 2018

Non-human papillomaviruses for gene delivery in vitro and in vivo.

PLoS One 2018 18;13(6):e0198996. Epub 2018 Jun 18.

Department of Immunology, Fraunhofer-Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.

Papillomavirus capsids are known to have the ability to package DNA plasmids and deliver them both in vitro and in vivo. Of all known papillomavirus types, human papillomaviruses (HPVs) are by far the most intensely studied. Although HPVs work well as gene transfer vectors, their use is limited as most individuals are exposed to this virus either through a HPV vaccination or natural infection. To circumvent these constraints, we produced pseudovirions (PsVs) of ten non-human papillomavirus types and tested their transduction efficiencies in vitro. PsVs based on Macaca fascicularis papillomavirus-11 and Puma concolor papillomavirus-1 were further tested in vivo. Intramuscular transduction by PsVs led to months-long expression of a reporter plasmid, indicating that PsVs have potential as gene delivery vectors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198996PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005490PMC
December 2018

Comparative analysis of humoral immune responses and pathologies of BALB/c and C57BL/6 wildtype mice experimentally infected with a highly virulent Rodentibacter pneumotropicus (Pasteurella pneumotropica) strain.

BMC Microbiol 2018 05 30;18(1):45. Epub 2018 May 30.

Institute for Bacteriology and Mycology, Faculty of Veterinary Medicine, University Leipzig, An den Tierkliniken 29, 04103, Leipzig, Germany.

Background: Mice are a natural host for Rodentibacter (R.) pneumotropicus. Despite specific monitoring, it is still one of the most important infectious agents in laboratory animals. The objective of this study was to determine the virulence of a prevalent pathotype of R. pneumotropicus and characterize the host response in a new animal model.

Results: Intranasal infection of C57BL/6 and BALB/c mice with a R. pneumotropicus strain (JF4Ni) bearing the genes of the three known repeats in toxin (RTX) toxins resulted in an unprecedented high mortality and morbidity above 50 and 80%, respectively. Morbidity was associated with severe weight loss as well as conjunctivitis and dyspnea. A main pathology was a catarrhal purulent to necrotic bronchopneumonia. Specific immune globuline (Ig) A was detected in tracheonasal lavages of most surviving mice which were still colonized by R. pneumotropicus. Furthermore, all surviving animals showed a distinct production of IgG antibodies. To differentiate T-helper cell (Th) 1 and Th2 immune responses we used subclasses of IgGs as indicators. Mean ratios of IgG2b to IgG1 were below 0.8 in sera drawn from both mice strains prior infection and from BALB/c mice post infection. In contrast, C57BL/6 mice had a mean IgG2b/IgG1 ratio of 1.6 post infection indicating a Th1 immune response in C57BL/6 versus a Th2 response in BALB/c mice associated with a tenfold higher bacterial load in the lung. In accordance with a Th1 response high antigen-specific IgG2c titers were detected in the majority of surviving C57BL/6 mice.

Conclusions: R. pneumotropicus JF4Ni is a highly virulent strain causing severe pneumonia and septicemia after intranasal infection of C57BL/6 and BALB/c mice. Persisting infections in the two mice strains are associated with Th1 and Th2 immune responses, respectively, and differences in the bacterial burden of the lung. The described model is ideally suited for future vaccination studies using the natural host.
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http://dx.doi.org/10.1186/s12866-018-1186-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977748PMC
May 2018

Immunization with an adjuvanted low-energy electron irradiation inactivated respiratory syncytial virus vaccine shows immunoprotective activity in mice.

Vaccine 2018 03 10;36(12):1561-1569. Epub 2018 Feb 10.

Division of Immunology, Fraunhofer-Institute for Cell Therapy and Immunology IZI, Perlickstrasse 1, 04103 Leipzig, Germany. Electronic address:

Respiratory syncytial virus (RSV) is a pathogen causing severe lower respiratory tract disease in infants and the elderly. In spite of the great need for a vaccine against RSV, currently there is no licensed product on the market. A very early vaccine candidate developed in the 1960s based on formaldehyde inactivation (FI) turned out to instead enhance the disease. Our novel inactivation method applied low-energy electron irradiation (LEEI) to produce a killed RSV vaccine. LEEI yielded inactivated virus particles with a reproducible virus antigen conservation above 70%, while FI resulted in highly variable antigen conservation. Immunization of mice with LEEI-RSV elicited a strong immune response, resulting in a drastic reduction in viral load upon challenge in two independent studies. These results have implications for the development of an RSV vaccine and should be validated in further preclinical and clinical studies.
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http://dx.doi.org/10.1016/j.vaccine.2018.02.014DOI Listing
March 2018

[Non-medical options fort her treatment of drug-resistant epilepsies].

Ther Umsch 2018 ;75(7):448-454

1 Schweizerische Epilepsie-Klinik, Klinik Lengg AG, Zürich.

Non-medical options fort her treatment of drug-resistant epilepsies Abstract. If the first two antiepileptic drugs do not achieve sustained seizure freedom, the probability of reaching this goal with any other medication is only 10 %. In this situation, possible reasons for the failure of antiepileptic drugs should be examined as should be possible chances of epilepsy surgery. If curative epilepsy surgery is not possible, palliative treatments like vagus nerve stimulation (VNS) or deep brain stimulation (DBS) may provide for better seizure control. Ketogenic diet may also be considered as an option especially in severe childhood epilepsies.
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http://dx.doi.org/10.1024/0040-5930/a001023DOI Listing
June 2019

Histopathological Findings in Brain Tissue Obtained during Epilepsy Surgery.

N Engl J Med 2017 10;377(17):1648-1656

From the Departments of Neuropathology (I.B., G.H., R.C., K.K.) and Neurosurgery (K.R.) and the Epilepsy Center (H. Hamer, H.S.), University Hospital Erlangen, Erlangen, the Epilepsy Center Bethel, Krankenhaus Mara, Bielefeld (C.G.B., M.P.), the Departments of Epileptology (C.E., G.W.) and Neuropathology (A.B.), University of Bonn Medical Center, and Medical Faculty, University of Bonn (J.S.), Bonn, the Neuropediatric Clinic, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth (T.P., H. Holthausen, M.K., P.A.W.), the Epilepsy Center Berlin-Brandenburg, Berlin (H.J.M.), the Epilepsy Center (G.H., A.S.-B.) and Department of Neurosurgery (J.Z., D.H.H.), University Hospital, and the Department of Neuroradiology, Medical Center-University of Freiburg, and Faculty of Medicine, University of Freiburg (H.U.) Freiburg, Kork Epilepsy Center, Kehl-Kork (B.J.S., T.B.), the Departments of Neuropathology (S.V.) and Neurology (U.R.), University Hospital Greifswald, Greifswald, the Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen (H.L., Y.W.), the Department of Neurology, University of Ulm, Ulm (H.L., Y.W.), the Epilepsy Center, Department of Neurology, Ludwig-Maximilians-University Hospital, Munich (S.N., E.H., P.A.W.), Sächsisches Epilepsiezentrum Radeberg, Radeberg (T.M., M.L.), Epilepsy Center Frankfurt Rhine-Main and the Department of Neurology, Goethe University, Frankfurt am Main (F.R., A.H.), the Epilepsy Center Hessen-Marburg, Philipps-University Marburg, Marburg (F.R., A.H.), and the Department of Social Medicine, Occupational and Environmental Dermatology, Heidelberg University, Heidelberg (T.L.D.) - all in Germany; the Clinical Epileptology and Experimental Neurophysiology Unit (R.S.) and the Department of Neurophysiology, Epilepsy Center (G.A.), IRCCS Foundation, Neurological Institute C. Besta, and the Claudio Munari Epilepsy Surgery Center, Niguarda Hospital (L.T., G.L.R.), Milan, and the Pediatric Neurology Unit and Laboratories, Children's Hospital A. Meyer-University of Florence, Florence (R.G., C.B.) - all in Italy; Brain Center Rudolf Magnus, Department of Neurology and Neurosurgery (K.P.B., F.L.), and the Department of (Neuro)Pathology (E.A.), University Medical Center Utrecht, Utrecht, the Department of Neurosurgery, VU University Medical Center (J.C.B.), and the Department of (Neuro)Pathology, Academic Medisch Centrum, University of Amsterdam (E.A., A.M.), and the Department of (Neuro)Pathology, VU University Medical Center (E.A., A.M.), Amsterdam, Stichting Epilepsie Instellingen Nederland, Heemstede (E.A.), and the Department of Neurosurgery, Academic Center for Epileptology, Maastricht University Medical Center, Maastricht (O.S.) - all in the Netherlands; the Department of Neurosurgery, Sainte-Anne Hospital, and Paris Descartes University, Paris (F.C.), the Department of Neurology, Michallon Hospital, GIN INSERM Unité 836, Grenoble Alpes University, Grenoble (P. Kahane), and the Department of Clinical Epileptology, Sleep Disorders and Functional Neurology in Children, University Hospitals of Lyon, and the Brain Dynamics and Cognition team, Lyon Neurosciences Research Center, Lyon (A.A., A.U.-C.) - all in France; the Departments of Neuropathology (M.T.) and Clinical and Experimental Epilepsy (M.C.W., S.M.S., J.S.D., A.W.M.), UCL Institute of Neurology, and the Developmental Biology and Cancer Programme (T.S.J.) and Developmental Neurosciences Program (J.H.C.), UCL-Great Ormond Street Institute of Child Health, and the Department of Histopathology, Great Ormond Street Hospital for Children (T.S.J.), London, and Young Epilepsy, Lingfield (J.H.C.) - all in the United Kingdom; the Departments of Neurology (C.Ö.) and Pathology (B.O.), Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey; the Department of Pediatric Neurology, Motol Epilepsy Center, Charles University in Prague, and the 2nd Faculty of Medicine, Motol University Hospital, Prague, Czech Republic (P. Krsek); the Department of Anatomical Pathology, Hospital Pedro Hispano, Matosinhos (M.H.), and the Laboratory of Neuropathology, Department of Neurosciences, Hospital de Santa Maria-Centro Hospitalar de Lisboa Norte, Lisbon (J.P.) - both in Portugal; the Epilepsy Unit, Child Neurology Department, Hospital San Juan de Dios, Barcelona (A.A., A.U.-C.); the Department of Pediatrics, Medical University Vienna, Vienna (M.F., A.M.), the Departments of Neurology (E.T.) and Neurosurgery (P.A.W.), Christian Doppler Medical Center, Paracelsus Medical University, Center for Cognitive Neuroscience, Salzburg, and the Department of Neurology I, Neuromed Campus, Kepler Universitätsklinikum, Linz (T.J.O.) - all in Austria; the Swiss Epilepsy Center and Department of Neurology, University Hospital, Zurich, Switzerland (T.G.); the Department of Neurology, Hospital Ruber Internacional, Madrid (A.G.-N., R.T.D.); and the Neurosurgical Department (B.Z.) and Epilepsy Monitoring Unit (K.G.), St. Luke's Hospital, Thessaloniki, Greece.

Background: Detailed neuropathological information on the structural brain lesions underlying seizures is valuable for understanding drug-resistant focal epilepsy.

Methods: We report the diagnoses made on the basis of resected brain specimens from 9523 patients who underwent epilepsy surgery for drug-resistant seizures in 36 centers from 12 European countries over 25 years. Histopathological diagnoses were determined through examination of the specimens in local hospitals (41%) or at the German Neuropathology Reference Center for Epilepsy Surgery (59%).

Results: The onset of seizures occurred before 18 years of age in 75.9% of patients overall, and 72.5% of the patients underwent surgery as adults. The mean duration of epilepsy before surgical resection was 20.1 years among adults and 5.3 years among children. The temporal lobe was involved in 71.9% of operations. There were 36 histopathological diagnoses in seven major disease categories. The most common categories were hippocampal sclerosis, found in 36.4% of the patients (88.7% of cases were in adults), tumors (mainly ganglioglioma) in 23.6%, and malformations of cortical development in 19.8% (focal cortical dysplasia was the most common type, 52.7% of cases of which were in children). No histopathological diagnosis could be established for 7.7% of the patients.

Conclusions: In patients with drug-resistant focal epilepsy requiring surgery, hippocampal sclerosis was the most common histopathological diagnosis among adults, and focal cortical dysplasia was the most common diagnosis among children. Tumors were the second most common lesion in both groups. (Funded by the European Union and others.).
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http://dx.doi.org/10.1056/NEJMoa1703784DOI Listing
October 2017

Resection of high frequency oscillations predicts seizure outcome in the individual patient.

Sci Rep 2017 10 23;7(1):13836. Epub 2017 Oct 23.

University Hospital Zurich, Neurosurgery Department, Zurich, Switzerland.

High frequency oscillations (HFOs) are recognized as biomarkers for epileptogenic brain tissue. A remaining challenge for epilepsy surgery is the prospective classification of tissue sampled by individual electrode contacts. We analysed long-term invasive recordings of 20 consecutive patients who subsequently underwent epilepsy surgery. HFOs were defined prospectively by a previously validated, automated algorithm in the ripple (80-250 Hz) and the fast ripple (FR, 250-500 Hz) frequency band. Contacts with the highest rate of ripples co-occurring with FR over several five-minute time intervals designated the HFO area. The HFO area was fully included in the resected area in all 13 patients who achieved seizure freedom (specificity 100%) and in 3 patients where seizures reoccurred (negative predictive value 81%). The HFO area was only partially resected in 4 patients suffering from recurrent seizures (positive predictive value 100%, sensitivity 57%). Thus, the resection of the prospectively defined HFO area proved to be highly specific and reproducible in 13/13 patients with seizure freedom, while it may have improved the outcome in 4/7 patients with recurrent seizures. We thus validated the clinical relevance of the HFO area in the individual patient with an automated procedure. This is a prerequisite before HFOs can guide surgical treatment in multicentre studies.
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http://dx.doi.org/10.1038/s41598-017-13064-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653833PMC
October 2017

Comparative analysis of clinics, pathologies and immune responses in BALB/c and C57BL/6 mice infected with Streptobacillus moniliformis.

Microbes Infect 2018 02 10;20(2):101-110. Epub 2017 Oct 10.

Institute for Bacteriology and Mycology, Faculty of Veterinary Medicine, University Leipzig, Leipzig, Germany. Electronic address:

Streptobacillus (S.) moniliformis is a rat-associated zoonotic pathogen that occasionally causes disease in other species. We investigated the working hypothesis that intranasal infection might lead to different immune responses in C57BL/6 and BALB/c mice associated with distinct pathologies. This study confirmed with 75% mortality the known high susceptibility of C57BL/6 mice to Streptobacillus moniliformis infection in comparison to BALB/c mice which did not develop signs of disease. Main pathologies in C57BL/6 mice were purulent to necrotizing lymphadenitis and pneumonia. Significant seroconversion was recorded in surviving mice of both strains. Differentiation of IgG-subclasses revealed mean ratios of IgG2b to IgG1 below 0.5 in sera of all mice prior to infection and of BALB/c mice post infection. In contrast, C57BL/6 mice had a mean IgG2b/IgG1 ratio of 2.5 post infection indicating a Th1 immune response in C57BL/6 versus a Th2 response in BALB/c mice. Evaluation of different sentinel systems revealed that cultural and serological investigations of these animals might not be sufficient to detect infection. In summary, an intranasal S. moniliformis infection model in C57BL/6 mice leading to purulent to necrotizing inflammations in the lung, the lymph nodes and other organs associated with a Th1 immune response is described.
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http://dx.doi.org/10.1016/j.micinf.2017.10.001DOI Listing
February 2018

Prediction of seizure outcome improved by fast ripples detected in low-noise intraoperative corticogram.

Clin Neurophysiol 2017 07 31;128(7):1220-1226. Epub 2017 Mar 31.

University Hospital Zurich, Neurosurgery Department, Zurich, Switzerland; Neuroscience Center Zurich, ETH Zurich, Zurich, Switzerland.

Objective: Fast ripples (FR, 250-500Hz) in the intraoperative corticogram have recently been proposed as specific predictors of surgical outcome in epilepsy patients. However, online FR detection is restricted by their low signal-to-noise ratio. Here we propose the integration of low-noise EEG with unsupervised FR detection.

Methods: Pre- and post-resection ECoG (N=9 patients) was simultaneously recorded by a commercial device (CD) and by a custom-made low-noise amplifier (LNA). FR were analyzed by an automated detector previously validated on visual markings in a different dataset.

Results: Across all recordings, in the FR band the background noise was lower in LNA than in CD (p<0.001). FR rates were higher in LNA than CD recordings (0.9±1.4 vs 0.4±0.9, p<0.001). Comparison between FR rates in post-resection ECoG and surgery outcome resulted in positive predictive value PPV=100% in CD and LNA, and negative predictive value NPV=38% in CD and NPV=50% for LNA. Prediction accuracy was 44% for CD and 67% for LNA.

Conclusions: Prediction of seizure outcome was improved by the optimal integration of low-noise EEG and unsupervised FR detection.

Significance: Accurate, automated and fast FR rating is essential for consideration of FR in the intraoperative setting.
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http://dx.doi.org/10.1016/j.clinph.2017.03.038DOI Listing
July 2017