Biology subjects

Braun, C.

Publications and source records attributed to Braun, C..

33 records · Page 2Linked to original sources

bioRxiv2022

Linking neuronal and hemodynamic network signatures in the resting human brain

Despite several studies investigating the relationship between blood-oxygen-level-dependent functional MRI (BOLD-fMRI) and neuroelectric activity, our understanding is rather incomplete. For instance, the canonical hemodynamic response function (HRF) is commonly used, regardless of brain region, frequency of electric activity and functional networks. We studied this relationship between BOLD-fMRI and electroencephalography (EEG) signal of the human brain in detail using simultaneous fMRI and EEG in healthy awake human subjects at rest. Signals from EEG sensors were filtered into different frequency bands and reconstructed it in the three-dimensional source space. The correlation of the time courses of the two modalities were quantified on a voxel-by-voxel basis on full-brain level as well as separately for each resting state network, with different temporal shifts and EEG frequency bands. We found highly significant correlations between the BOLD-fMRI signal and simultaneously measured EEG, yet with varying time-lags for different frequency bands and different resting state networks. Additionally, we found significant negative correlations with a much longer delay in the fMRI BOLD signal. The positive correlations were mostly around 6-8 seconds delayed in the BOLD time course while the negative correlations were noticed with a BOLD delay of around 20 to 26 seconds. These positive and negative correlation patterns included the commonly reported alpha and gamma bands but also extend in other frequency bands giving characteristic profiles for different resting state networks. Our results confirm recent works that suggest that the relationship between the two modalities is rather brain region / network-specific than a global function and suggest that applying a global canonical HRF for electrophysiological data is probably insufficient to account for the different spatial and temporal dynamics of different brain networks. Moreover, our results suggest that the HRF also varies in different frequency bands giving way to further studies investigating cross-frequency coupling and its interplay with resting state networks.

neuroscience↗

bioRxiv2022

Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress

The transcriptional response to genotoxic stress involves gene expression arrest, followed by recovery of mRNA synthesis (RRS) after DNA repair. Using a small-scale RNA interference screen, we found that the lack of the EXD2 nuclease impaired RRS and decreased cell survival after UV irradiation, without affecting DNA repair. Overexpression of wild-type, but not nuclease-dead EXD2, restored RRS and cell survival. We observed that UV irradiation triggered recruitment of EXD2 to chromatin where the nuclease transiently interacts with RNA Polymerase II (RNAPII) to promote the degradation of nascent mRNAs synthesized at the time of genotoxic attack. Reconstitution of the EXD2-RNAPII partnership on a transcribed DNA template in vitro showed that EXD2 primarily interacts with an elongation-blocked RNAPII and efficiently digest mRNA. Overall, our data highlight a crucial new step in the transcriptional response to genotoxic attack in which EXD2 interacts with elongation-stalled RNAPII on chromatin to degrade the associated nascent mRNA, allowing transcription restart after DNA repair.

molecular biology↗

bioRxiv2021

Localizing spontaneous memory reprocessing during human sleep

Reactivation of newly acquired memories during sleep across hippocampal and neocortical systems is proposed to underlie systems memory consolidation. Here, we investigate spontaneous memory reprocessing during sleep by applying machine learning to source space-transformed magnetoencephalographic data in a two-step exploratory and confirmatory study design. We decode memory-related activity from slow oscillations in hippocampus, frontal cortex and precuneus, indicating parallel memory processing during sleep. Moreover, we show complementary roles of hippocampus and neocortex: while gamma activity indicated memory reprocessing in hippocampus, delta and theta frequencies allowed decoding of memory in neocortex. Neocortex and hippocampus were linked through coherent activity and modulation of high-frequency gamma oscillations by theta, a dynamic similar to memory processing during wakefulness. Overall, we noninvasively demonstrate localized, coordinated memory reprocessing in human sleep.

neuroscience↗

bioRxiv2021

A new adaptive procedure for estimating perceptual thresholds: the effects of observer bias and its correction.

Adaptive threshold estimation procedures sample close to a subjects perceptual threshold by dynamically adapting the stimulation based on the subjects performance. Yet, perceptual thresholds not only depend on the observers sensory capabilities but also on any bias in terms of their expectations and response preferences, thus distorting the precision of the threshold estimates. Using the framework of signal detection theory (SDT), independent estimates of both, an observers sensitivity and internal processing bias can be delineated from threshold estimates. While this approach is commonly available for estimation procedures engaging the method of constant stimuli (MCS), correction procedures for adaptive methods (AM) are only scarcely applied. In this article, we introduce a new AM that takes individual biases into account, and that allows for a bias-corrected assessment of subjects sensitivity. This novel AM is validated with simulations and compared to a typical MCS-procedure, for which the implementation of bias correction has been previously demonstrated. Comparing AM and MCS demonstrates the viability of the presented AM. Besides its feasibility, the results of the simulation reveal both, advantages, and limitations of the proposed AM. The procedure has considerable practical implications, in particular for the design of shaping procedures in sensory training experiments, in which task difficulty has to be constantly adapted to an observers performance, to improve training efficiency.

neuroscience↗

bioRxiv2021

Muscle fatigue revisited - Insights from optically pumped magnetometers

Muscle fatigue is well characterized electromyographically, nevertheless only information about summed potential differences is detectable. In contrast, recently developed quantum sensors optically pumped magnetometers (OPMs) offer the advantage of recording both the electrical current propagation in the muscle as well as its geometry, by measuring the magnetic field generated by the muscular action potentials. Magnetomyographic investigation of muscle fatigue is still lacking and it is an open question whether fatigue is characterized similarly in magnetomyography (MMG) compared to electromyography (EMG). Herein, we investigated the muscle fatigue during a 3x1-min strong isometric contraction of the rectus femoris muscle of 12 healthy subjects using simultaneous EMG-MMG (4-channel surface EMG and 4 OPM along the rectus femoris muscle). Both EMG and MMG showed the characteristic frequency decrease in the signal magnitude during isometric contraction, which is typical for muscle fatigue. In addition, it was shown that the main part of this frequency decrease seems to occur in the circular component of the magnetic field around the muscle fibers and less longitudinally along the muscle fibers. Overall, these results show not only that magnetomyography is capable of reproducing the electromyographic standards in identifying muscular fatigue, but it also adds relevant information about the spatial characterization of the signal. Therefore, OPM-MMG offers new insights for the study of muscular activity and might serve as a new, supplementary neurophysiological method.

physiology↗

bioRxiv2021

Investigation of the temporal and spatial dynamics of muscular action potentials through optically pumped magnetometers.

AimThis study aims to simultaneously record the magnetic and electric components of the propagating muscular action potential. MethodA single-subject study of the monosynaptic stretch reflex of the musculus rectus femoris was performed; the magnetic field generated by the muscular activity was recorded in all three spatial directions by five optically pumped magnetometers. In addition, the electric field was recorded by four invasive fine-wire needle electrodes. The magnetic and electric fields were compared, and modelling and simulations were performed to compare the magnetic field vectors with the underlying muscular anatomy of the rectus femoris muscle. ResultsThe magnetomyography (MMG) signal can reliably be recorded following the stimulation of the monosynaptic stretch reflex. The MMG signal shows several phases of activity inside the muscle, the first of which is the propagating muscular action potential. As predicted by the finite wire model, the magnetic field vectors of the propagating muscular action potential are generated by the current flowing longitudinal to the muscle fiber. Based on the magnetic field vectors, it was possible to reconstruct the pinnation angle in the muscle. The later magnetic components are linked to the activated contractile apparatus. InterpretationMMG allows to analyze the muscle physiology from the propagating muscular action potential to the initiation of the contractile apparatus. At the same time this methods reveal information about muscle fiber direction and extend. With the development of high-resolution magnetic cameras, it will be possible to image the function and structure of any skeletal muscle with high precision. This method could be used in clinical medicine but also in sports and training science. What this paper adds- A robust technique for triggering a muscular action potential that can be recorded by MMG and needle EMG simultaneously - The correlation of the MMG signal with the needle EMG signal - A method for detecting the direction of the propagating muscular action potential - A method for correlating the magnetic field vectors with the pinnation angle of the examined muscle

neuroscience↗

bioRxiv2020

TFIIH kinase CDK7 antagonizes phenotype switching and emergence of drug tolerance in melanoma

Melanoma cells switch back-and-forth between phenotypes of proliferation and invasion in response to changing microenvironment, driving metastatic progression. We show that inhibition of the TFIIH kinase CDK7 (CDK7i) results in a melanocytic to mesenchymal phenotype switching and acquisition of targeted therapy tolerance. We identify a gene expression program controlled by the transcription factor GATA6, which participates in drug tolerance in mesenchymal-like cells and which is antagonized by CDK7 in melanocytic-like cells. This program emerges concomitantly with loss of melanocyte lineage-specific MITF protein following CDK7i. By dissecting the underlying mechanism, we observe that CDK7 accumulates at the super-enhancer regulating MITF to drive its expression. MITF itself binds to a intronic region of GATA6 to transcriptionally repress it. This molecular cascade antagonizes expression of the GATA6 regulon that only emerges in MITF-low cells of metastatic melanoma. Our work reveals a role for CDK7 in counteracting phenotype switching and activation of a gene expression program mediating multidrug tolerance in melanoma cells.

cell biology↗

bioRxiv2020

Optically pumped magnetometers disclose magnetic field components of the muscular action potential.

AimTo track the magnetic field generated by the propagating muscle action potential (MAP). MethodIn this prospective, proof of principle study, the magnetic activity of the intrinsic foot muscle after electric stimulation of the tibial nerve was measured using optically pumped magnetometers (OPMs). A classical biophysical electric dipole model of the propagating MAP was implemented to model the source of the data. ResultsThe signal profile generated by the activity of the intrinsic foot muscles was measured by four OPM devices. Three devices were located above the same muscle to compare the direction and the strength of the magnetic signal while propagating along the muscle. InterpretationOPM devices allow for a new, non-invasive way to study MAP patterns. Since magnetic fields are less altered by the tissue surrounding the dipole source compared to electric activity, a precise analysis of the spatial characteristics and temporal dynamics of the MAP is possible. The classic electric dipole model explains major but not all aspects of the magnetic field. The field has longitudinal components generated by intrinsic structures of the muscle fibre. By understanding these magnetic components, new methods could be developed to analyse the muscular signal transduction pathway in greater detail. What this paper adds- Technological concepts to record and analyse the small magnetic fields generated by electric muscular activity - Model to link the signals measured by the OPM sensors to the underlying physiology - Insights into the propagation of muscle action potential and the sequential control of motor activity

neuroscience↗

bioRxiv2020

Dynamics of nonlinguistic statistical learning: From neural entrainment to the emergence of explicit knowledge

Humans are highly attuned to patterns in the environment. This ability to detect environmental patterns, referred to as statistical learning, plays a key role in many diverse aspects of cognition. However, the spatiotemporal neural mechanisms underlying implicit statistical learning, and how these mechanisms may relate or give rise to explicit learning, remain poorly understood. In the present study, we investigated these different aspects of statistical learning by using an auditory nonlinguistic statistical learning paradigm combined with magnetoencephalography. Twenty-four healthy volunteers were exposed to structured and random tone sequences, and statistical learning was quantified by neural entrainment. Already early during exposure, participants showed strong entrainment to the embedded tone patterns. A significant increase in entrainment over exposure was detected only in the structured condition, reflecting the trajectory of learning. While source reconstruction revealed a wide range of brain areas involved in this process, entrainment in areas around the left pre-central gyrus as well as right temporo-frontal areas significantly predicted behavioral performance. Sensor level results confirmed this relationship between neural entrainment and subsequent explicit knowledge. These results give insights into the dynamic relation between neural entrainment and explicit learning of triplet structures, suggesting that these two aspects are systematically related yet dissociable. Neural entrainment reflects robust, implicit learning of underlying patterns, whereas the emergence of explicit knowledge, likely built on the implicit encoding of structure, varies across individuals and may depend on factors such as sufficient exposure time and attention.

neuroscience↗

bioRxiv2020

Inhibition of fibrosis with multi-agent therapy in pulmonary fibrosis: Results of a drug library screening

AimsSuccessful management of IPF will likely require multi-drug therapy as its pathogenesis is thought to be both driven by both pro-inflammatory and pro-fibrotic pathways. We hypothesized that the available anti-fibrotic agents, pirfenidone and nintedanib, may exhibit synergy in suppressing lung fibroblast extracellular matrix protein generation when administered in combination with other orally active agents. Materials and MethodsA fibroblastic cell line (AKR-2B) was stimulated with TGF-{beta}1 and used to screen a library of over 1500 FDA approved drugs. Extracellular matrix protein generation was assessed via fibronectin ELISA assay and maintenance of cell viability confirmed with XTT assay. ResultsThe screening revealed sixty-two drugs from the repurposed drug-screening library that were shown to significantly suppress fibronectin expression and not result in cell death. Specifically drugs within the category of NSAIDs, steroids, azole antifungal agents, and antipyrine were associated with significant suppression of fibronectin on ELISA analysis. Surprisingly, we observed anti-fibrotic activity across a number of the azole antifungal compounds. We next assessed whether combination of azoles would exhibit synergy when combined with current anti-fibrotic therapies in the stimulated fibroblasts. As proof of concept, we demonstrated in vitro synergy between oxiconazole and nintedanib in suppressing fibroblast generation of extracellular matrix fibronectin. ConclusionsThese results suggest an approach to identify potential combinations of therapy that may improve patient outcomes by reducing cost and potential toxicities during treatment.

cell biology↗

bioRxiv2020

Stimulation Artifact Source Separation (SASS) for assessing electric brain oscillations during transcranial alternating current stimulation (tACS)

Brain oscillations, e.g. measured by electro- or magnetoencephalography (EEG/MEG), are causally linked to brain functions that are fundamental for perception, cognition and learning. Recent advances in neurotechnology provide means to non-invasively target these oscillations using frequency-tuned amplitude-modulated transcranial alternating current stimulation (AM-tACS). However, online adaptation of stimulation parameters to ongoing brain oscillations remains an unsolved problem due to stimulation artifacts that impede such adaptation, particularly at the target frequency. Here, we introduce a real-time compatible artifact rejection algorithm (Stimulation Artifact Source Separation, SASS) that overcomes this limitation. SASS is a spatial filter (linear projection) removing EEG signal components that are maximally different in the presence versus absence of stimulation. This enables the reliable removal of stimulation-specific signal components, while leaving physiological signal components unaffected. For validation of SASS, we evoked brain activity with known phase and amplitude using 10 Hz visual flickers across 7 healthy human volunteers. 64-channel EEG was recorded during and in absence of 10 Hz AM-tACS targeting the visual cortex. Phase differences between AM-tACS and the visual stimuli were randomized, so that steady-state visually evoked potentials (SSVEPs) were phase-locked to the visual stimuli but not to the AM-tACS signal. For validation, distributions of single-trial amplitude and phase of EEG signals recorded during and in absence of AM-tACS were compared for each participant. When no artifact rejection method was applied, AM-tACS stimulation artifacts impeded assessment of single-trial SSVEP amplitude and phase. Using SASS, amplitude and phase of single trials recorded during and in absence of AM-tACS were comparable. These results indicate that SASS can be used to establish adaptive (closed-loop) AM-tACS, a potentially powerful tool to target various brain functions, and to investigate how AM-tACS interacts with electric brain oscillations. Highlights- Stimulation Artifact Source Separation (SASS), a real-time compatible signal decomposition algorithm for separating electric brain activity and stimulation signal artifacts related to amplitude-modulated transcranial alternating current stimulation (AM-tACS), is introduced - Employing SASS, phase and amplitude of single-trial steady state visual evoked potentials (SSVEPs) were reliably recovered from electroencephalography (EEG) recordings at the frequency targeted with AM-tACS - SASS enables assessment of single-trial oscillatory brain activity at the target frequency during stimulation and paves the way for online adaptation of stimulation parameters to ongoing brain oscillations

neuroscience↗

bioRxiv2019

HUMANS USE A LOCAL CODE FOR TACTILE PERCEPTION

Humans are classically thought to use either spectral decomposition or averaging to identify vibrotactile signals. These are general purpose global codes that require integration of the signal over long stretches of time. Natural vibrotactile signals, however, likely contain short signature events that can be detected and used for inference of textures, instantaneously, with minimal integration, suggesting a hitherto ignored local code. Here, by employing pulsatile stimuli and a change detection psychophysical task, we studied whether humans make use of local cues. We compared three local cues based on instantaneous skin position and its derivatives, as well as six global cues, calculated as summed powers (with exponents 1,2, and 3) of velocity and acceleration. Deliberate manipulation of pulse width and amplitude (local+global) as well as pulse frequency (global) allowed us to disentangle local from global codes. The results singled out maximum velocity, an instantaneous code, as a likely and dominant coding variable that humans rely on to perform the task. Comparing stimuli containing versus lacking local cues, demonstrated that performances exclusively using global cues are rather poor compared to situations where local ones are available as well. Our results are in line with the notion that humans not only do use local cues but that local cues may even play a dominant role in perception. Our results parallel previous results in rodents, pointing to the possibility that quite similar coding strategies evolved in whisker and finger tactile systems. Significance statementThe brain is believed to select coding symbols in sensory signals that would most efficiently convey functionally relevant information about the world. For instance, the visual system is widely believed to use spatially local features, like edge orientation, to delineate a visual scene. For the tactile system only global, general purpose coding schemes have been discussed so far. Based on the insight that moving contacts, characteristic for active touch, feature short-lived stick-slip events, frictional movements that transfer fair amounts of texture information, one should expect the brain to use a temporally local code, extracting and instantaneously analyzing short snippets of skin movement. Here, we provide the first analytical psychophysical evidence in humans that this indeed is the case.

neuroscience↗

bioRxiv2018

Mutant Screen Reveals the Piccolo’s Control over Depression and Brain-Gonad Crosstalk

Successful sexual reproduction involves complex, genetically encoded interplay between animal physiology and behavior. The rat provides a highly fecund mammalian model for studying how the brain impacts reproduction. Here, we report a forward genetics screen in rats to identify genes that affect reproduction. A panel of 18 distinct rat strains harboring Sleeping Beauty gene trap mutations were analyzed for the ability to reproduce. As expected, our mutant screen identified genes where reproductive failure was connected to gametogenesis (Btrc, Pan3, Spaca6, Ube2k) and embryogenesis (Alk3, Exoc6b, Slc1a3, Tmx4, Zmynd8). In addition, we identified Ata13 (longevity) and Pclo (neuronal disorders), previously not associated with an inability to conceive. Neurologically, Pclo is known to regulate the size of presynaptic vesicle pools. Here, dominant traits in Pclo mutant rats caused epileptiform activity and affected genes supporting GABAergic synaptic transmission (Gabra6, Gabrg3). Recessive traits in Pclo mutant rats transmitted altered reproductive behavior, as homozygous Pclo mutant rats produced gametes but neither sex would mate with wildtype rats. Pclo mutant rat behavior was linked to endophenotypes signifying compromised brain-gonad crosstalk via disturbed GnRH signaling and allelic markers for major depressive disorder in humans (Grm5, Htr2a, Sorcs3, Negr1, Drd2). Thus, by rat genetics, we identified Pclo as a candidate presynaptic factor required for reproduction. Author SummaryPiccolo gene mutations have previously been identified in human cohorts diagnosed with behavioral syndromes that impact ones emotions, including depression and bipolar disorder. Although studies in human populations implicate changes to Piccolos DNA sequence to enhanced susceptibility for behavioral disorders, studies in mouse models have yet to link Piccolo mutations to altered behavior. Here, by a novel genetics approach, we report Piccolo mutation-dependent effects on reproductive behavior in rats, a finding that may turn out to be relevant to the behavioral effects that are associated with human Piccolo gene mutations. Thus, research aimed at understanding how Piccolo functions to regulate reproduction in rats could prove pivotal in our ability to understand neurological mechanisms that influence human emotions.

genetics↗

bioRxiv2018

Functional dynamics underlying near-threshold perception of facial emotions: a magnetoencephalography investigation.

Conscious perception of emotional valence of faces has been proposed to involve top-down and bottom-up information processing. Yet, the underlying neuronal mechanisms of these two processes and the implementation of their cooperation is still unclear. We hypothesized that the networks activated during the interaction of top-down and bottom-up processes are the key substrates responsible for perception. We assessed the participation of neural networks involved in conscious perception of emotional stimuli near the perceptual threshold using a visual-backward-masking paradigm in 12 healthy individuals using magnetoencephalography. Providing visual stimulation near the perceptual threshold enabled us to compare correctly and incorrectly recognized facial emotions and assess differences in top-down modulation for these stimuli using coherence analysis. We found a fronto-parietal network oscillating in the lower gamma band and exerting top-down control as determined by the causality measure of phase slope index. We demonstrated that correct recognition of facial emotions involved high-beta and low-gamma activity in parietal networks, Incorrect recognition was associated with enhanced coupling in the gamma band between left frontal and right parietal regions. Our results indicate that fronto-parietal control of the perception of emotional face stimuli relies on the right-hemispheric dominance of synchronized gamma band activity.

neuroscience↗

bioRxiv2017

Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo

Epigenetic mechanisms and transcription factor networks essential for differentiation of cardiac myocytes have been uncovered. However, reshaping of the epigenome of these terminally differentiated cells during fetal development, postnatal maturation and in disease remains unknown. Thus, the aim of this study was to determine the dynamics of the cardiac myocyte epigenome during development and in chronic heart failure. Prenatal development and postnatal maturation are characterized by a cooperation of active CpG methylation and histone marks at cis-regulatory and genic regions to shape the cardiac myocyte transcriptome. In contrast, pathological gene expression in terminal heart failure is accompanied by changes in active histone marks without major alterations in CpG methylation and repressive chromatin marks. Notably, cis-regulatory regions in cardiac myocytes are significantly enriched for cardiovascular disease-associated variants. This study uncovers distinct layers of epigenetic regulation not only during prenatal development and postnatal maturation but also in diseased human cardiac myocytes.

genomics↗