Recent Submissions

  • Journal Article

    The self-organized learning of noisy environmental stimuli requires distinct phases of plasticity 

    Krüppel, Steffen; Tetzlaff, Christian
    Network Neuroscience 2020; 4(1) p.174-199
    Along sensory pathways, representations of environmental stimuli become increasingly sparse and expanded. If additionally the feed-forward synaptic weights are structured according to the inherent organization of stimuli, the increase in sparseness and expansion leads to a reduction of sensory noise. However, it is unknown how the synapses in the brain form the required structure, especially given the omnipresent noise of environmental stimuli. Here, we employ a combination of synaptic plasticity and intrinsic plasticity-adapting the excitability of each neuron individually-and present stimuli with an inherent organization to a feed-forward network. We observe that intrinsic plasticity maintains the sparseness of the neural code and thereby allows synaptic plasticity to learn the organization of stimuli in low-noise environments. Nevertheless, even high levels of noise can be handled after a subsequent phase of readaptation of the neuronal excitabilities by intrinsic plasticity. Interestingly, during this phase the synaptic structure has to be maintained. These results demonstrate that learning and recalling in the presence of noise requires the coordinated interplay between plasticity mechanisms adapting different properties of the neuronal circuit.
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  • Journal Article

    Microtiming Deviations and Swing Feel in Jazz 

    Datseris, George; Ziereis, Annika; Albrecht, Thorsten; Hagmayer, York; Priesemann, Viola; Geisel, Theo
    Scientific Reports 2019; 9(1): Art. 19824
    Jazz music that swings has the fascinating power to elicit a pleasant sensation of flow in listeners and the desire to synchronize body movements with the music. Whether microtiming deviations (MTDs), i.e. small timing deviations below the bar or phrase level, enhance the swing feel is highly debated in the current literature. Studies on other groove related genres did not find evidence for a positive impact of MTDs. The present study addresses jazz music and swing in particular, as there is some evidence that microtiming patterns are genre-specific. We recorded twelve piano jazz standards played by a professional pianist and manipulated the natural MTDs of the recordings in systematic ways by quantizing, expanding and inverting them. MTDs were defined with respect to a grid determined by the average swing ratio. The original and manipulated versions were presented in an online survey and evaluated by 160 listeners with various musical skill levels and backgrounds. Across pieces the quantized versions (without MTDs) were rated slightly higher and versions with expanded MTDs were rated lower with regard to swing than the original recordings. Unexpectedly, inversion had no impact on swing ratings except for two pieces. Our results suggest that naturally fluctuating MTDs are not an essential factor for the swing feel.
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  • Journal Article

    Emergence and suppression of cooperation by action visibility in transparent games 

    Unakafov, Anton M.; Schultze, Thomas; Gail, Alexander; Moeller, Sebastian; Kagan, Igor; Eule, Stephan; Wolf, Fred
    PLOS Computational Biology 2020; 16(1): Art. e1007588
    Real-world agents, humans as well as animals, observe each other during interactions and choose their own actions taking the partners' ongoing behaviour into account. Yet, classical game theory assumes that players act either strictly sequentially or strictly simultaneously without knowing each other's current choices. To account for action visibility and provide a more realistic model of interactions under time constraints, we introduce a new game-theoretic setting called transparent games, where each player has a certain probability of observing the partner's choice before deciding on its own action. By means of evolutionary simulations, we demonstrate that even a small probability of seeing the partner's choice before one's own decision substantially changes the evolutionary successful strategies. Action visibility enhances cooperation in an iterated coordination game, but reduces cooperation in a more competitive iterated Prisoner's Dilemma. In both games, "Win-stay, lose-shift" and "Tit-for-tat" strategies are predominant for moderate transparency, while a "Leader-Follower" strategy emerges for high transparency. Our results have implications for studies of human and animal social behaviour, especially for the analysis of dyadic and group interactions.
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  • Journal Article

    In vivo optochemical control of cell contractility at single‐cell resolution 

    Kong, Deqing; Lv, Zhiyi; Häring, Matthias; Lin, Benjamin; Wolf, Fred; Großhans, Jörg
    EMBO reports 2019; 20(12): Art. e47755
    The spatial and temporal dynamics of cell contractility plays a key role in tissue morphogenesis, wound healing, and cancer invasion. Here, we report a simple optochemical method to induce cell contractions in vivo during Drosophila morphogenesis at single-cell resolution. We employed the photolabile Ca2+ chelator o-nitrophenyl EGTA to induce bursts of intracellular free Ca2+ by laser photolysis in the epithelial tissue. Ca2+ bursts appear within seconds and are restricted to individual target cells. Cell contraction reliably followed within a minute, causing an approximately 50% drop in the cross-sectional area. Increased Ca2+ levels are reversible, and the target cells further participated in tissue morphogenesis. Depending on Rho kinase (ROCK) activity but not RhoGEF2, cell contractions are paralleled with non-muscle myosin II accumulation in the apico-medial cortex, indicating that Ca2+ bursts trigger non-muscle myosin II activation. Our approach can be, in principle, adapted to many experimental systems and species, as no specific genetic elements are required.
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  • Journal Article

    Quantifying Information Modification in Developing Neural Networks via Partial Information Decomposition 

    Wibral, Michael; Finn, Conor; Wollstadt, Patricia; Lizier, Joseph; Priesemann, Viola
    Entropy 2017; 19(9): Art. 494
    Information processing performed by any system can be conceptually decomposed into the transfer, storage and modification of information—an idea dating all the way back to the work of Alan Turing. However, formal information theoretic definitions until very recently were only available for information transfer and storage, not for modification. This has changed with the extension of Shannon information theory via the decomposition of the mutual information between inputs to and the output of a process into unique, shared and synergistic contributions from the inputs, called a partial information decomposition (PID). The synergistic contribution in particular has been identified as the basis for a definition of information modification. We here review the requirements for a functional definition of information modification in neuroscience, and apply a recently proposed measure of information modification to investigate the developmental trajectory of information modification in a culture of neurons vitro, using partial information decomposition. We found that modification rose with maturation, but ultimately collapsed when redundant information among neurons took over. This indicates that this particular developing neural system initially developed intricate processing capabilities, but ultimately displayed information processing that was highly similar across neurons, possibly due to a lack of external inputs. We close by pointing out the enormous promise PID and the analysis of information modification hold for the understanding of neural systems.
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  • Journal Article

    Adaptive Control Strategies for Interlimb Coordination in Legged Robots: A Review 

    Aoi, Shinya; Manoonpong, Poramate; Ambe, Yuichi; Matsuno, Fumitoshi; Wörgötter, Florentin
    Frontiers in Neurorobotics 2017; 11: Art. 39
    Walking animals produce adaptive interlimb coordination during locomotion in accordance with their situation. Interlimb coordination is generated through the dynamic interactions of the neural system, the musculoskeletal system, and the environment, although the underlying mechanisms remain unclear. Recently, investigations of the adaptation mechanisms of living beings have attracted attention, and bio-inspired control systems based on neurophysiological findings regarding sensorimotor interactions are being developed for legged robots. In this review, we introduce adaptive interlimb coordination for legged robots induced by various factors (locomotion speed, environmental situation, body properties, and task). In addition, we show characteristic properties of adaptive interlimb coordination, such as gait hysteresis and different time-scale adaptations. We also discuss the underlying mechanisms and control strategies to achieve adaptive interlimb coordination and the design principle for the control system of legged robots.
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  • Journal Article

    Diversity in spatial scope of contrast adaptation among mouse retinal ganglion cells 

    Khani, Mohammad Hossein; Gollisch, Tim
    Journal of Neurophysiology 2017; 118(6) p.3024-3043
    Retinal ganglion cells adapt to changes in visual contrast by adjusting their response kinetics and sensitivity. While much work has focused on the time scales of these adaptation processes, less is known about the spatial scale of contrast adaptation. For example, do small, localized contrast changes affect a cell's signal processing across its entire receptive field? Previous investigations have provided conflicting evidence, suggesting that contrast adaptation occurs either locally within subregions of a ganglion cell's receptive field or globally over the receptive field in its entirety. Here, we investigated the spatial extent of contrast adaptation in ganglion cells of the isolated mouse retina through multielectrode-array recordings. We applied visual stimuli so that ganglion cell receptive fields contained regions where the average contrast level changed periodically as well as regions with constant average contrast level. This allowed us to analyze temporal stimulus integration and sensitivity separately for stimulus regions with and without contrast changes. We found that the spatial scope of contrast adaptation depends strongly on cell identity, with some ganglion cells displaying clear local adaptation, whereas others, in particular large transient ganglion cells, adapted globally to contrast changes. Thus, the spatial scope of contrast adaptation in mouse retinal ganglion cells appears to be cell-type specific. This could reflect differences in mechanisms of contrast adaptation and may contribute to the functional diversity of different ganglion cell types.NEW & NOTEWORTHY Understanding whether adaptation of a neuron in a sensory system can occur locally inside the receptive field or whether it always globally affects the entire receptive field is important for understanding how the neuron processes complex sensory stimuli. For mouse retinal ganglion cells, we here show that both local and global contrast adaptation exist and that this diversity in spatial scope can contribute to the functional diversity of retinal ganglion cell types.
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  • Journal Article

    Comparing Open-Source Toolboxes for Processing and Analysis of Spike and Local Field Potentials Data 

    Unakafova, Valentina A.; Gail, Alexander
    Frontiers in Neuroinformatics 2019; 13: Art. 57
    Analysis of spike and local field potential (LFP) data is an essential part of neuroscientific research. Today there exist many open-source toolboxes for spike and LFP data analysis implementing various functionality. Here we aim to provide a practical guidance for neuroscientists in the choice of an open-source toolbox best satisfying their needs. We overview major open-source toolboxes for spike and LFP data analysis as well as toolboxes with tools for connectivity analysis, dimensionality reduction and generalized linear modeling. We focus on comparing toolboxes functionality, statistical and visualization tools, documentation and support quality. To give a better insight, we compare and illustrate functionality of the toolboxes on open-access dataset or simulated data and make corresponding MATLAB scripts publicly available.
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  • Journal Article

    Library of actions: Implementing a generic robot execution framework by using manipulation action semantics 

    Aein, Mohamad Javad; Aksoy, Eren Erdal; Wörgötter, Florentin
    The International Journal of Robotics Research 2019; 38(8) p.910-934
    When a robot has to imitate an observed action sequence, it must first understand the inherent characteristic features of the individual actions. Such features need to reflect the semantics of the action with a high degree of invariance between different demonstrations of the same action. At the same time the machine needs to be able to execute the action sequence in any appropriate situation. In this study, we introduce a new library of actions, which is a generic framework for executing manipulation actions on robotic systems by combining features that capture action semantics with a framework for execution. We focus on manipulation actions and first create a generic representation consisting of symbolic and subsymbolic components. To link these two domains we introduce a finite state machine allowing for sequential execution with error handling. The framework is developed from observing humans which provides us with a high degree of grounding. To quantitatively evaluate the scalability of the proposed approach, we conducted a large set of experiments involving different actions performed either individually or sequentially with various types of objects in different scene contexts.
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  • Journal Article

    Local field potentials are induced by visually evoked spiking activity in macaque cortical area MT 

    Esghaei, Moein; Daliri, Mohammad Reza; Treue, Stefan
    Scientific Reports 2017; 7(1)
    Local field potentials (LFP) have been the focus of many recent studies in systems neuroscience. However, the exact neural basis of these signals remains unclear. To address this question, we determined the relationship between LFP signals and another, much better understood, signature of neural activity: action potentials. Specifically, we focused on the relationship between the amplitude of stimulus-induced LFPs and the magnitude of spiking activity in visual cortex of non-human primates. Our trial-by-trial correlation analyses between these two components of extracellular signals in macaque visual cortex show that the spike rate is coupled to the LFP amplitude with a surprisingly long latency, typically 50 ms. Our analysis shows that the neural spike rate is a significant predictor of the LFP amplitude. This limits the functional interpretation of LFP signals beyond that based on spiking activities.
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  • Journal Article

    Spontaneous termination of chaotic spiral wave dynamics in human cardiac ion channel models 

    Aron, Marcel; Herzog, Sebastian; Parlitz, Ulrich; Luther, Stefan; Lilienkamp, Thomas
    PLOS ONE 2019; 14(8): Art. e0221401
    Chaotic spiral or scroll wave dynamics can be found in diverse systems. In cardiac dynamics, spiral or scroll waves of electrical excitation determine the dynamics during life-threatening arrhythmias like ventricular fibrillation. In numerical studies it was found that chaotic episodes of spiral and scroll waves can be transient, thus they terminate spontaneously. We show in this study that this behavior can also be observed using models which describe the ion channel dynamics of human cardiomyocytes (Bueno-Orovio-Cherry-Fenton model and the Ten Tusscher-Noble-Noble-Panfilov model). For both models we find that the average lifetime of the chaotic transients grows exponentially with the system size. With this behavior, we classify the systems into the group of type-II supertransients. We observe a significant difference of the breakup behavior between the models, which results in a distinct dynamics during the final phase just before the termination. The observation of a (temporally) stable single-spiral state affects the prevailing description of the dynamics of type-II supertransients as being "quasi-stationary" and also the feasibility of predicting the spontaneous termination of the spiral wave dynamics. In the long term, the relation between the breakup behavior of spiral waves and properties of chaotic transients like predictability or average transient lifetime may contribute to an improved understanding and classification of cardiac arrhythmias.
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  • Journal Article

    Strategic deployment of feature-based attentional gain in primate visual cortex 

    Kozyrev, Vladislav; Daliri, Mohammad Reza; Schwedhelm, Philipp; Treue, Stefan
    PLOS Biology 2019; 17(8): Art. e3000387
    Attending to visual stimuli enhances the gain of those neurons in primate visual cortex that preferentially respond to the matching locations and features (on-target gain). Although this is well suited to enhance the neuronal representation of attended stimuli, it is nonoptimal under difficult discrimination conditions, as in the presence of similar distractors. In such cases, directing attention to neighboring neuronal populations (off-target gain) has been shown to be the most efficient strategy, but although such a strategic deployment of attention has been shown behaviorally, its underlying neural mechanisms are unknown. Here, we investigated how attention affects the population responses of neurons in the middle temporal (MT) visual area of rhesus monkeys to bidirectional movement inside the neurons' receptive field (RF). The monkeys were trained to focus their attention onto the fixation spot or to detect a direction or speed change in one of the motion directions (the "target"), ignoring the distractor motion. Population activity profiles were determined by systematically varying the patterns' directions while maintaining a constant angle between them. As expected, the response profiles show a peak for each of the 2 motion directions. Switching spatial attention from the fixation spot into the RF enhanced the peak representing the attended stimulus and suppressed the distractor representation. Importantly, the population data show a direction-dependent attentional modulation that does not peak at the target feature but rather along the slopes of the activity profile representing the target direction. Our results show that attentional gains are strategically deployed to optimize the discriminability of target stimuli, in line with an optimal gain mechanism proposed by Navalpakkam and Itti.
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  • Journal Article

    Antibody-driven capture of synaptic vesicle proteins on the plasma membrane enables the analysis of their interactions with other synaptic proteins 

    Richter, Katharina N.; Patzelt, Christina; Phan, Nhu T. N.; Rizzoli, Silvio O.
    Scientific Reports 2019; 9(1): Art. 9231
    Many organelles from the secretory pathway fuse to the plasma membrane, to exocytose different cargoes. Their proteins are then retrieved from the plasma membrane by endocytosis, and the organelles are re-formed. It is generally unclear whether the organelle proteins colocalize when they are on the plasma membrane, or whether they disperse. To address this, we generated here a new approach, which we tested on synaptic vesicles, organelles that are known to exo- and endocytose frequently. We tagged the synaptotagmin molecules of newly exocytosed vesicles using clusters of primary and secondary antibodies targeted against the luminal domains of these molecules. The antibody clusters are too large for endocytosis, and thus sequestered the synaptotagmin molecules on the plasma membrane. Immunostainings for other synaptic molecules then revealed whether they colocalized with the sequestered synaptotagmin molecules. We suggest that such assays may be in the future extended to other cell types and other organelles.
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  • Journal Article

    Ultrafast optogenetic stimulation of the auditory pathway by targeting‐optimized Chronos 

    Keppeler, Daniel; Merino, Ricardo Martins; Lopez de la Morena, David; Bali, Burak; Huet, Antoine Tarquin; Gehrt, Anna; Wrobel, Christian; Subramanian, Swati; Dombrowski, Tobias; Wolf, Fred; et al.
    Rankovic, VladanNeef, AndreasMoser, Tobias
    The EMBO Journal 2018; 37(24): Art. e99649
    Optogenetic tools, providing non‐invasive control over selected cells, have the potential to revolutionize sensory prostheses for humans. Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in cochlear implants. However, most channelrhodopsins do not support the high temporal fidelity pertinent to auditory coding because they require milliseconds to close after light‐off. Here, we biophysically characterized the fast channelrhodopsin Chronos and revealed a deactivation time constant of less than a millisecond at body temperature. In order to enhance neural expression, we improved its trafficking to the plasma membrane (Chronos‐ES/TS). Following efficient transduction of SGNs using early postnatal injection of the adeno‐associated virus AAV‐PHP.B into the mouse cochlea, fiber‐based optical stimulation elicited optical auditory brainstem responses (oABR) with minimal latencies of 1 ms, thresholds of 5 μJ and 100 μs per pulse, and sizable amplitudes even at 1,000 Hz of stimulation. Recordings from single SGNs demonstrated good temporal precision of light‐evoked spiking. In conclusion, efficient virus‐mediated expression of targeting‐optimized Chronos‐ES/TS achieves ultrafast optogenetic control of neurons.
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  • Journal Article

    A Theoretical Framework to Derive Simple, Firing-Rate-Dependent Mathematical Models of Synaptic Plasticity 

    Lappalainen, Janne; Herpich, Juliane; Tetzlaff, Christian
    Frontiers in Computational Neuroscience 2019; 13: Art. 26
    Synaptic plasticity serves as an essential mechanism underlying cognitive processes as learning and memory. For a better understanding detailed theoretical models combine experimental underpinnings of synaptic plasticity and match experimental results. However, these models are mathematically complex impeding the comprehensive investigation of their link to cognitive processes generally executed on the neuronal network level. Here, we derive a mathematical framework enabling the simplification of such detailed models of synaptic plasticity facilitating further mathematical analyses. By this framework we obtain a compact, firing-rate-dependent mathematical formulation, which includes the essential dynamics of the detailed model and, thus, of experimentally verified properties of synaptic plasticity. Amongst others, by testing our framework by abstracting the dynamics of two well-established calcium-dependent synaptic plasticity models, we derived that the synaptic changes depend on the square of the presynaptic firing rate, which is in contrast to previous assumptions. Thus, the here-presented framework enables the derivation of biologically plausible but simple mathematical models of synaptic plasticity allowing to analyze the underlying dependencies of synaptic dynamics from neuronal properties such as the firing rate and to investigate their implications in complex neuronal networks.
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  • Journal Article

    Dementia with Lewy bodies: an update and outlook 

    Outeiro, Tiago Fleming; Koss, David J.; Erskine, Daniel; Walker, Lauren; Kurzawa-Akanbi, Marzena; Burn, David; Donaghy, Paul; Morris, Christopher; Taylor, John-Paul; Thomas, Alan; et al.
    Attems, JohannesMcKeith, Ian
    Molecular Neurodegeneration 2019; 14(1): Art. 5
    Dementia with Lewy bodies (DLB) is an age-associated neurodegenerative disorder producing progressive cognitive decline that interferes with normal life and daily activities. Neuropathologically, DLB is characterised by the accumulation of aggregated α-synuclein protein in Lewy bodies and Lewy neurites, similar to Parkinson's disease (PD). Extrapyramidal motor features characteristic of PD, are common in DLB patients, but are not essential for the clinical diagnosis of DLB. Since many PD patients develop dementia as disease progresses, there has been controversy about the separation of DLB from PD dementia (PDD) and consensus reports have put forward guidelines to assist clinicians in the identification and management of both syndromes. Here, we present basic concepts and definitions, based on our current understanding, that should guide the community to address open questions that will, hopefully, lead us towards improved diagnosis and novel therapeutic strategies for DLB and other synucleinopathies.
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  • Journal Article

    Peri-hand space expands beyond reach in the context of walk-and-reach movements 

    Berger, Michael; Neumann, Peter; Gail, Alexander
    Scientific Reports 2019; 9(1): Art. 3013
    The brain incorporates sensory information across modalities to be able to interact with our environment. The peripersonal space (PPS), defined by a high level of crossmodal interaction, is centered on the relevant body part, e.g. the hand, but can spatially expand to encompass tools or reach targets during goal-directed behavior. Previous studies considered expansion of the PPS towards goals within immediate or tool-mediated reach, but not the translocation of the body as during walking. Here, we used the crossmodal congruency effect (CCE) to quantify the extension of the PPS and test if PPS can also expand further to include far located walk-and-reach targets accessible only by translocation of the body. We tested for orientation specificity of the hand-centered reference frame, asking if the CCE inverts with inversion of the hand orientation during reach. We show a high CCE with onset of the movement not only towards reach targets but also walk-and-reach targets. When participants must change hand orientation, the CCE decreases, if not vanishes, and does not simply invert. We conclude that the PPS can expand to the action space beyond immediate or tool-mediated reaching distance but is not purely hand-centered with respect to orientation.
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  • Journal Article

    Technical challenges of quantitative chest MRI data analysis in a large cohort pediatric study 

    Nguyen, Anh H.; Perez-Rovira, Adria; Wielopolski, Piotr A.; Hernandez Tamames, Juan A.; Duijts, Liesbeth; de Bruijne, Marleen; Aliverti, Andrea; Pennati, Francesca; Ivanovska, Tetyana; Tiddens, Harm A. W. M.; et al.
    Ciet, Pierluigi
    European Radiology
    OBJECTIVES: This study was conducted in order to evaluate the effect of geometric distortion (GD) on MRI lung volume quantification and evaluate available manual, semi-automated, and fully automated methods for lung segmentation. METHODS: A phantom was scanned with MRI and CT. GD was quantified as the difference in phantom's volume between MRI and CT, with CT as gold standard. Dice scores were used to measure overlap in shapes. Furthermore, 11 subjects from a prospective population-based cohort study each underwent four chest MRI acquisitions. The resulting 44 MRI scans with 2D and 3D Gradwarp were used to test five segmentation methods. Intraclass correlation coefficient, Bland-Altman plots, Wilcoxon, Mann-Whitney U, and paired t tests were used for statistics. RESULTS: Using phantoms, volume differences between CT and MRI varied according to MRI positions and 2D and 3D Gradwarp correction. With the phantom located at the isocenter, MRI overestimated the volume relative to CT by 5.56 ± 1.16 to 6.99 ± 0.22% with body and torso coils, respectively. Higher Dice scores and smaller intraobject differences were found for 3D Gradwarp MR images. In subjects, semi-automated and fully automated segmentation tools showed high agreement with manual segmentations (ICC = 0.971-0.993 for end-inspiratory scans; ICC = 0.992-0.995 for end-expiratory scans). Manual segmentation time per scan was approximately 3-4 h and 2-3 min for fully automated methods. CONCLUSIONS: Volume overestimation of MRI due to GD can be quantified. Semi-automated and fully automated segmentation methods allow accurate, reproducible, and fast lung volume quantification. Chest MRI can be a valid radiation-free imaging modality for lung segmentation and volume quantification in large cohort studies. KEY POINTS: • Geometric distortion varies according to MRI setting and patient positioning. • Automated segmentation methods allow fast and accurate lung volume quantification. • MRI is a valid radiation-free alternative to CT for quantitative data analysis.
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  • Journal Article

    Activity Correlations between Direction-Selective Retinal Ganglion Cells Synergistically Enhance Motion Decoding from Complex Visual Scenes 

    Kühn, Norma Krystyna; Gollisch, Tim
    Neuron 2019; 101(5): Art. 976.e7
    Neurons in sensory systems are often tuned to particular stimulus features. During complex naturalistic stimulation, however, multiple features may simultaneously affect neuronal responses, which complicates the readout of individual features. To investigate feature representation under complex stimulation, we studied how direction-selective ganglion cells in salamander retina respond to texture motion where direction, velocity, and spatial pattern inside the receptive field continuously change. We found that the cells preserve their direction preference under this stimulation, yet their direction encoding becomes ambiguous due to simultaneous activation by luminance changes. The ambiguities can be resolved by considering populations of direction-selective cells with different preferred directions. This gives rise to synergistic motion decoding, yielding more information from the population than the summed information from single-cell responses. Strong positive response correlations between cells with different preferred directions amplify this synergy. Our results show how correlated population activity can enhance feature extraction in complex visual scenes.
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  • Journal Article

    Precisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions. 

    Fornasiero, Eugenio F.; Mandad, Sunit; Wildhagen, Hanna; Alevra, Mihai; Rammner, Burkhard; Keihani, Sarva; Opazo, Felipe; Urban, Inga; Ischebeck, Till; Sakib, M. Sadman; et al.
    Fard, Maryam K.Kirli, KorayCenteno, Tonatiuh PenaVidal, Ramon O.Rahman, Raza-UrBenito, EvaFischer, AndréDennerlein, SvenRehling, PeterFeussner, IvoBonn, StefanSimons, MikaelUrlaub, HenningRizzoli, Silvio O.
    Nature Communications 2018; 9(1): Art. 4230
    The turnover of brain proteins is critical for organism survival, and its perturbations are linked to pathology. Nevertheless, protein lifetimes have been difficult to obtain in vivo. They are readily measured in vitro by feeding cells with isotopically labeled amino acids, followed by mass spectrometry analyses. In vivo proteins are generated from at least two sources: labeled amino acids from the diet, and non-labeled amino acids from the degradation of pre-existing proteins. This renders measurements difficult. Here we solved this problem rigorously with a workflow that combines mouse in vivo isotopic labeling, mass spectrometry, and mathematical modeling. We also established several independent approaches to test and validate the results. This enabled us to measure the accurate lifetimes of ~3500 brain proteins. The high precision of our data provided a large set of biologically significant observations, including pathway-, organelle-, organ-, or cell-specific effects, along with a comprehensive catalog of extremely long-lived proteins (ELLPs).
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