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D’Anna, E., Valle, G., Mazzoni, A., Strauss, I., Iberite, F., Patton, J., Petrini, F., Raspopovic, S., Granata, G., Di Iorio, R., Controzzi, M., Cipriani, C., Stieglitz, T., Rossini, P.M., Micera, S.
A closed-loop hand prosthesis with simultaneous intraneural tactile and position feedback
2019 Sci Robotics, volume: 4(27)
Show abstract
Current myoelectric prostheses allow transradial amputees to regain voluntary motor control of their artificial limb by exploiting residual muscle function in the forearm. However, the overreliance on visual cues resulting from a lack of sensory feedback is a common complaint. Recently, several groups have provided tactile feedback in upper limb amputees using implanted electrodes, surface nerve stimulation, or sensory substitution. These approaches have led to improved function and prosthesis embodiment. Nevertheless, the provided information remains limited to a subset of the rich sensory cues available to healthy individuals. More specifically, proprioception, the sense of limb position and movement, is predominantly absent from current systems. Here, we show that sensory substitution based on intraneural stimulation can deliver position feedback in real time and in conjunction with somatotopic tactile feedback. This approach allowed two transradial amputees to regain high and close-to-natural remapped proprioceptive acuity, with a median joint angle reproduction precision of 9.1° and a median threshold to detection of passive movements of 9.5°, which was comparable with results obtained in healthy participants. The simultaneous delivery of position information and somatotopic tactile feedback allowed both amputees to discriminate the size and compliance of four objects with high levels of performance (75.5%). These results demonstrate that tactile information delivered via somatotopic neural stimulation and position information delivered via sensory substitution can be exploited simultaneously and efficiently by transradial amputees. This study paves a way to more sophisticated bidirectional bionic limbs conveying richer, multimodal sensations.
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A. Müller, M. C. Wapler, U. Wallrabe
A quick and accurate method to determine the Poisson’s ratio and the coefficient of thermal expansion of PDMS
2019 Soft Matter, volume: 15, page(s): 779 - 784
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Kuhner, D., Fiederer, L., Aldinger, J., Burget, F., Völker, M., Schirrmeister, R., Do, C., Boedecker, J., Nebel, B., Ball, T. and Burgard, W.
A service assistant combining autonomous robotics, flexible goal formulation, and deep-learning-based brain–computer interfacing
2019 Robotics and Autonomous Systems, volume: 116, page(s): 98 - 113
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Wülfing Jan M, Kumar Sreedhar S, Boedecker Joschka, Riedmiller Martin, Egert Ulrich
Adaptive Long-term Control of Biological Neural Networks with Deep Reinforcement Learning
2019 Neurocomputing, volume: 342, page(s): 66 - 74
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Castaño-Candamil Sebastián, Piroth Tobias, Reinacher Peter, Sajonz Bastian, Coenen Volker, Tangermann Michael
An Easy-to-Use and Fast Assessment of Patient-Specific DBS-induced Changes in Hand Motor Control in Parkinson’s Disease
2019 IEEE Transactions on Neural Systems and Rehabilitation Engineering, volume: In print
Open publication
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Lagzi F, Atay FM, Rotter S
Bifurcation analysis of the dynamics of interacting subnetworks of a spiking network
2019 Scientific Reports
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Heining K, Kilias A, Janz P, Häussler U, Kumar A, Haas CA, Egert U
Bursts with high and low load of epileptiform spikes show context-dependent correlations in epileptic mice
2019 eNeuro, volume: 6, issue: 5, page(s): 1 - 14
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Eich S, Müller O, Schulze-Bonhage A
Changes in self-perception in patients treated with neurostimulating devices.
2019 Epilepsy Behav, volume: 90, page(s): 25 - 30
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Barz., F., Trouillet, V., Paul, O. and Ruther, P.
CMOS-compatible, Flexible, Intracortical Neural Probes
2019 IEEE Transactions on Biomedical Engineering
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E. Galindo-Leon, I. Stitt, F. Pieper, E. Fiedler, T. Stieglitz, G. Engler, and A.K. Engel
Context-specific modulation of intrinsic coupling modes shapes multisensory processing
2019 Science Advances, volume: 5, issue: 4, page(s): eaar7633
Show abstract
Intrinsically generated patterns of coupled neuronal activity are associated with the dynamics of specific brain states. Sensory inputs are extrinsic factors that can perturb these intrinsic coupling modes, creating a complex scenario in which forthcoming stimuli are processed. Studying this intrinsic-extrinsic interplay is necessary to better understand perceptual integration and selection. Here, we show that this interplay leads to a reconfiguration of functional cortical connectivity that acts as a mechanism to facilitate stimulus processing. Using audiovisual stimulation in anesthetized ferrets, we found that this reconfiguration of coupling modes is context specific, depending on long-term modulation by repetitive sensory inputs. These reconfigured coupling modes lead to changes in latencies and power of local field potential responses that support multisensory integration. Our study demonstrates that this interplay extends across multiple time scales and involves different types of intrinsic coupling. These results suggest a previously unknown large-scale mechanism that facilitates multisensory integration.
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Edgar E. Galindo-Leon, Iain Stitt, Florian Pieper, Eva Fiedler, Thomas Stieglitz, Gerhard Engler and Andreas. K. Engel
Context-specific modulation of intrinsic coupling modes shapes multisensory processing.
2019 Science Advances, volume: 5, issue: 4, page(s): eaar7633
Show abstract
Intrinsically generated patterns of coupled neuronal activity are associated with the dynamics of specific brain states. Sensory inputs are extrinsic factors that can perturb these intrinsic coupling modes, creating a complex scenario in which forthcoming stimuli are processed. Studying this intrinsic-extrinsic interplay is necessary to better understand perceptual integration and selection. Here, we show that this interplay leads to a reconfiguration of functional cortical connectivity that acts as a mechanism to facilitate stimulus processing. Using audiovisual stimulation in anesthetized ferrets, we found that this reconfiguration of coupling modes is context specific, depending on long-term modulation by repetitive sensory inputs. These reconfigured coupling modes lead to changes in latencies and power of local field potential responses that support multisensory integration. Our study demonstrates that this interplay extends across multiple time scales and involves different types of intrinsic coupling. These results suggest a previously unknown large-scale mechanism that facilitates multisensory integration.
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C. Elgueta and M. Bartos
Dendritic inhibition differentially regulates excitability of dentate gyrus parvalbumin-expressing interneurons and granule cells
2019 Nature Comm, volume: 10, issue: 5561
Show abstract
Fast-spiking parvalbumin-expressing interneurons (PVIs) and granule cells (GCs) of the dentate gyrus receive layer-specific dendritic inhibition. Its impact on PVI and GC excitability is, however, unknown. By applying whole-cell recordings, GABA uncaging and single-cell-modeling, we show that proximal dendritic inhibition in PVIs is less efficient in lowering perforant path-mediated subthreshold depolarization than distal inhibition but both are highly efficient in silencing PVIs. These inhibitory effects can be explained by proximal shunting and distal strong hyperpolarizing inhibition. In contrast, GC proximal but not distal inhibition is the primary regulator of their excitability and recruitment. In GCs inhibition is hyperpolarizing along the entire somato-dendritic axis with similar strength. Thus, dendritic inhibition differentially controls input-output transformations in PVIs and GCs. Dendritic inhibition in PVIs is suited to balance PVI discharges in dependence on global network activity thereby providing strong and tuned perisomatic inhibition that contributes to the sparse representation of information in GC assemblies.
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T. Hainmüller and M. Bartos
Dentate gyrus circuits for encoding, retrieval and discrimination of episodice memories
2019 Nat Rev Neurosci, volume: in press
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Robinson JT, Pohlmeyer E, Gather MC, Kemere C, Kitching JE, Malliaras GG, Marblestone A, Shepard KL, Stieglitz T, Xie C
Developing Next-Generation Brain Sensing Technologies—A Review
2019 IEEE Sens J, volume: 19, issue: 22, page(s): 10163 - 10175
Show abstract
Advances in sensing technology raise the possibility of creating neural interfaces that can more effectively restore or repair neural function and reveal fundamental properties of neural information processing. To realize the potential of these bioelectronic devices, it is necessary to understand the capabilities of emerging technologies and identify the best strategies to translate these technologies into products and therapies that will improve the lives of patients with neurological and other disorders. Here, we discuss emerging technologies for sensing brain activity, anticipated challenges for translation, and perspectives for how to best transition these technologies from academic research labs to useful products for neuroscience researchers and human patients.
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Filipovic, M., Ketzef, M., Reig, R., Aertsen, A., Silberberg, G. and Kumar, A.
Direct Pathway Neurons in Mouse Dorsolateral Striatum In Vivo Receive Stronger Synaptic Input than Indirect Pathway Neurons
2019 Journal of Neurophysiology
Show abstract
Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1 or D2 type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modelling of the striatal network has predicted that under healthy conditions dMSNs should receive more total input than iMSNs. To test this prediction, we analyzed in vivo whole-cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (6OHDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials, we found that dMSNs depolarized towards the spike threshold significantly faster than iMSNs did. Together, these findings (in particular the STA analysis) corroborate the theoretical prediction that direct-pathway MSNs receive stronger total input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question how the lack of dopamine may lead to behavioral deficits associated with Parkinson's disease.
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Dümpelmann M
Early seizure detection for closed loop direct neurostimulation devices in epilepsy.
2019 J. Neural Eng., volume: 16, issue: 4, page(s): 041001
Show abstract
Current treatment concepts for epilepsy are based on continuous drug delivery or electrical stimulation to prevent the occurrence of seizures, exposing the brain and body to a mostly unneeded risk of adverse effects. To address the infrequent occurrence and short duration of epileptic seizures, intelligent implantable closed-loop devices are needed which are based on a refined analysis of ongoing brain activity with highly specific and fast detection algorithms to allow for timely, ictal interventions. Since the development and FDA approval of a first closed loop neurostimulation device relying on simple threshold-based approaches, machine learning approaches became widely available, probably outperformed in the near future by deep convolutional neural networks, which already showed to be extremely successful in pattern recognition in images and partly in signal analysis. Handcrafted features or rules defined by experts become replaced by systematic feature selection procedures and systematic hyperparameter search approaches. Training of these classifiers augments the need of large databases with intracranial EEG recordings, which is partly given by existing databases but potentially can be replaced by continuously transferring data from implanted devices and their publication for research purposes. Already in early design states, the final target hardware must be taken into account for algorithm development. Size, power consumption and, as a consequence, limited computational resources given by low power microcontrollers, FPGAs and ASICS limit the complexity of feature computation, classifier complexity, and the numbers and complexity of layers of deep neuronal networks. Novel approaches for early seizure detection will be a key module for new generations of closed-loop devices together with improved low power implant hardware and will provide together with more efficient intervention paradigms new treatment options for patients with difficult to treat epilepsy.
Open publication
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Koch, J., Schuettler, M., Pasluosta, C. Stieglitz, T.
Electrical connectors for neural implants: design, state of the art and future challenges of an underestimated component.
2019 Journal of Neural Engineering, volume: 16, issue: 6, page(s): 061002
Show abstract
Technological advances in electrically active implantable devices have increased the complexity of hardware design. In particular, the increasing number of stimulation and recording channels requires innovative approaches for connectors that interface electrodes with the implant circuitry. This work aims to provide a common theoretical ground for implantable connector development with a focus on neural applications. Aspects and experiences from several disciplines are compiled from an engineering perspective to discuss the state of the art of connector solutions. Whenever available, we also present general design guidelines. Degradation mechanisms, material stability and design rules in terms of biocompatibility and biostability are introduced. Considering contact physics, we address the design and characterization of the contact zone and review contaminants, wear and contact degradation. For high-channel counts and body-like environments, insulation can be even more crucial than the electrical connection itself. Therefore, we also introduce the requirements for electrical insulation to prevent signal loss and distortion and discuss its impact on the practical implementation. A final review is dedicated to the state of the art connector concepts, their mechanical setup, electrical performance and the interface to other implant components. We conclude with an outlook for possible approaches for the future generations of implants.
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Kleber C, Lienkamp K, Ruhe J, Asplund M
Electrochemically Controlled Drug Release from a Conducting Polymer Hydrogel (PDMAAp/PEDOT) for Local Therapy and Bioelectronics.
2019 Adv Healthc Mater, page(s): e1801488
Show abstract
In this study, the release of fluorescein from a photo‐crosslinked conducting polymer hydrogel made from a hydrogel precursor poly(dimethylacrylamide‐co‐4‐methacryloyloxy benzophenone (5%)‐co‐4‐styrenesulfonate (2.5%)) (PDMAAp) and the conducting polymer poly(3,4‐ethylenedioxythiophene) (PEDOT) is investigated. Fluorescein, here used as a model for a drug, is actively released through application of an electrical trigger signal. The detected quantity is more than six times higher in comparison to that released from a conventional PEDOT/polysterene sulfonate (PSS) system. Release profiles, drug dose, and timing can be tailored by the application of different trigger signals and pretreatments. To demonstrate that the novel drug release system can be used for a drug relevant for local delivery to a neural interface, experiments are furthermore performed with the anti‐inflammatory drug dexamethasone (Dex). The conducting polymer hydrogel facilitates the active release of Dex, in comparison to the previously used PEDOT/Dex. It is suggested that PEDOT/PDMAAp is an interesting alternative for conducting polymer based drug release systems, with the potential to offer more volume for storage, yet retaining the excellent electrochemical properties known for PEDOT electrodes.
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Petrini FM, Valle G, Bumbasirevic M, Barberi F, Bortolotti D, Cvancara P, Hiairrassary A, Mijovic P, Sverrisson AO, Pedrocchi A, Divoux JL, Popovic I, Lechler K, Mijovic B, Guiraud D, Stieglitz T, Alexandersson A, Micera S, Lesic A, Raspopovic S
Enhancing functional abilities and cognitive integration of the lower limb prosthesis.
2019 Sci Transl Med, volume: 11, issue: 512
Show abstract
Lower limb amputation (LLA) destroys the sensory communication between the brain and the external world during standing and walking. Current prostheses do not restore sensory feedback to amputees, who, relying on very limited haptic information from the stump-socket interaction, are forced to deal with serious issues: the risk of falls, decreased mobility, prosthesis being perceived as an external object (low embodiment), and increased cognitive burden. Poor mobility is one of the causes of eventual device abandonment. Restoring sensory feedback from the missing leg of above-knee (transfemoral) amputees and integrating the sensory feedback into the sensorimotor loop would markedly improve the life of patients. In this study, we developed a leg neuroprosthesis, which provided real-time tactile and emulated proprioceptive feedback to three transfemoral amputees through nerve stimulation. The feedback was exploited in active tasks, which proved that our approach promoted improved mobility, fall prevention, and agility. We also showed increased embodiment of the lower limb prosthesis (LLP), through phantom leg displacement perception and questionnaires, and ease of the cognitive effort during a dual-task paradigm, through electroencephalographic recordings. Our results demonstrate that induced sensory feedback can be integrated at supraspinal levels to restore functional abilities of the missing leg. This work paves the way for further investigations about how the brain interprets different artificial feedback strategies and for the development of fully implantable sensory-enhanced leg neuroprostheses, which could drastically ameliorate life quality in people with disability.
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P. Kellmeyer, N. Biller-Andorno and G. Meynen
Ethical Tensions in Virtual Reality Treatment in Vulnerable Patients
2019 Nature Medicine, page(s): 1185 - 1188
Show abstract
Emerging virtual reality systems offer intriguing therapeutic possibilities, but their development and use should be guided by ethical priorities that account for the specific vulnerabilities of patients.
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Tulke S, Haas CA, Häussler U
Expression of brain-derived neurotrophic factor and structural plasticity in the dentate gyrus and CA2 region correlate with epileptiform activity
2019 Epilepsia, volume: 60, issue: 6, page(s): 1234 - 1247
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Schumacher, F., Schumacher, L., Schelter, B. and Kaller, C.
Functionally dissociating ventro-dorsal components within the rostro-caudal hierarchical organization of the human prefrontal cortex
2019 NeuroImage, volume: 185, page(s): 398 - 407
Show abstract
Cognitive control is proposed to rely on a rostral-to-caudal hierarchy of neural processing within the prefrontal cortex (PFC), with more rostral parts exerting control over more caudal parts. Anatomical and functional data suggest that this hierarchical organization of the PFC may be separated into a ventral and a dorsal component. Furthermore, recent studies indicate that the apex of the hierarchy resides within the mid-lateral rather the rostral PFC. However, investigating the hierarchical aspect of rostro-to-caudal processing requires quantification of the directed interactions between PFC regions. Using functional near-infrared spectroscopy (fNIRS) in a sample of healthy young adults we analyzed directed interactions between rostral and caudal PFC during passive watching of nature documentaries. Directed coherence (DC) as a measure of directed interaction was computed pairwise between 38 channels evenly distributed over the lateral prefrontal convexity. Results revealed an overall predominance of rostral-to-caudal directed interactions in the PFC that further dissociated along a ventro-dorsal axis: Dorsal regions exerted stronger rostro-caudally directed interactions on dorsal than on ventral regions and vice versa. Interactions between ventral and dorsal PFC were stronger from ventral to dorsal areas than vice versa. Results further support the notion that the mid-dorsolateral PFC constitutes the apex of the prefrontal hierarchy. Taken together these data provide novel evidence for parallel dorsal and ventral streams within the rostro-caudal hierarchical organization of the PFC. FNIRS-based analyses of directed interactions put forward a new perspective on the functional architecture of the prefrontal hierarchy and complement previous insights from functional magnetic resonance imaging.
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J. Hartmann, F. Thalheimer, F. Höpfner, T. Kerzel, K. Khodosevich, D. García-González, H. Monyer, I. Diester, H. Büning, J. E. Carette, P. Fries and C. J. Buchholz
GluA4-targeted AAV vectors deliver genes selectively to interneurons while relying onthe AAV receptor for entry
2019 Molecular Therapy - Methods and Clinical Development, volume: 14, page(s): 252 - 260
Show abstract
Selective gene delivery into subtypes of interneurons remains an important challenge in vector development. Adeno-associated virus (AAV) vector particles are especially promising for intracerebral injections. For cell entry, AAV2 particles are supposed to attach to heparan-sulfate proteoglycans (HSPGs) followed by endocytosis via the AAV receptor (AAVR). Here, we assessed engineered AAV particles deficient in HSPG attachment but competent in recognizing the glutamate receptor 4 (GluA4, also known as GluRD or GRIA4) through a displayed GluA4-specific DARPin (designed ankyrin repeat protein). When injected into the mouse brain, histological evaluation revealed that in various regions, more than 90% of the transduced cells were interneurons, mainly of the parvalbumin-positive subtype. Although part of the selectivity was mediated by the DARPin, the chosen spleen focus-forming virus (SFFV) promoter had contributed as well. Further analysis revealed that the DARPin mediated selective attachment to GluA4-positive cells, whereas gene delivery required expression of AAVR. Our data suggest that cell selectivity of AAV particles can be modified rationally and efficiently through DARPins, but expression of the AAV entry receptor remains essential.
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E. Fuhrer, M. Jouda, C. O. Klein, M. Wilhelm and J. G. Korvink
Gradient-induced mechanical vibration of neural interfaces during MRI
2019 IEEE Transactions on Biomedical Engineering
Show abstract
Objective: Resonant vibrations of implanted structures during an MRI procedure pose a risk to the patient in the form of soft tissue irritation and degradation of the implant. In this study, the mechanical behaviour of implant structures in air, water, and viscoelastic materials was explored. Methods: The static and dynamic transfer functions of various test samples in air, and immersed in both water and hydrogels, were analysed. The laser-based acquisition method allowed for high angular resolution (10 μDeg) and high dynamic range (0 to 6 kHz) measurements. Additional MRI experiments were conducted to investigate the dependence of vibration strength on MR sequence parameters in combination with the obtained transfer functions. Results: The largest forces were found to be in the μN to mN range, which is comparable to forces applied during implantation. Of additional concern was the damping introduced by viscoelastic tissue, which was less than expected, leading to an underdamped system. In contrast to current wisdom, the imaging experiments demonstrated drastically different vibration amplitudes for identical gradient slope but different timing parameters TR, mainly due to resonant amplification. Conclusion: The results showed that a safe, force-free MR procedure depends not only on the gradient slope, but also and more drastically on the choice of secure timing parameters. Significance: These findings delineate design improvements to achieve longevity of implants, and will lead to increased patient safety during MRI. A prudent choice of mechanical characteristics of implanted structures is sufficient to avoid resonant excitation due to mismatched MR sequence parameters.
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M. Kern, S. Bert, O. Glanz, A. Schulze-Bonhage and T. Ball
Human motor cortex relies on sparse and action-specific activation during laughing, smiling and speech production
2019 Communications biology, volume: 2, issue: 1
Show abstract
Smiling, laughing, and overt speech production are fundamental to human everyday communication. However, little is known about how the human brain achieves the highly accurate and differentiated control of such orofacial movement during natural conditions. Here, we utilized the high spatiotemporal resolution of subdural recordings to elucidate how human motor cortex is functionally engaged during control of real-life orofacial motor behaviour. For each investigated movement class—lip licking, speech production, laughing and smiling—our findings reveal a characteristic brain activity pattern within the mouth motor cortex with both spatial segregation and overlap between classes. Our findings thus show that motor cortex relies on sparse and action-specific activation during real-life orofacial behaviour, apparently organized in distinct but overlapping subareas that control different types of natural orofacial movements.
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Fiederer, L. D., Völker, M., Schirrmeister, R. T., Burgard, W., Boedecker, J., Ball, T.
Hybrid Brain-Computer-Interfacing for Human-Compliant Robots: Inferring Continuous Subjective Ratings with Deep Regression
2019 Front Neurorobotics, page(s): 13 - 76
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Okujeni Samora, Egert Ulrich
Inhomogeneities in network structure and excitability govern initiation and propagation of spontaneous burst activity
2019 Frontiers in Neuroscience, volume: 13, page(s): 543
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Clemente, F., Valle, G., Controzzi, M., Strauss, I., Iberite, F., Stieglitz, T., Granata, G., Rossini, P.M., Petrini, F., Micera, D., Cipriani, C.
Intraneural sensory feedback restores grip force control and motor coordination while using a prosthetic hand
2019 Journal of Neural Engineering, volume: 16, issue: 2, page(s): 026034
Show abstract
Objective. Tactile afferents in the human hand provide fundamental information about hand-environment interactions, which is used by the brain to adapt the motor output to the physical properties of the object being manipulated. A hand amputation disrupts both afferent and efferent pathways from/to the hand, completely invalidating the individual's motor repertoire. Although motor functions may be partially recovered by using a myoelectric prosthesis, providing functionally effective sensory feedback to users of prosthetics is a largely unsolved challenge. While past studies using invasive stimulation suggested that sensory feedback may help in handling fragile objects, none explored the underpinning, relearned, motor coordination during grasping. In this study, we aimed at showing for the first time that intraneural sensory feedback of the grip force (GF) improves the sensorimotor control of a transradial amputee controlling a myoelectric prosthesis. Approach. We performed a longitudinal study testing a single subject (clinical trial registration number NCT02848846). A stacking cups test (CUP) performed over two weeks aimed at measuring the subject's ability to finely regulate the GF applied with the prosthesis. A pick and lift test (PLT), performed at the end of the study, measured the level of motor coordination, and whether the subject transferred the motor skills learned in the CUP to an alien task. Main results. The results show that intraneural sensory feedback increases the subject's ability in regulating the GF and allows for improved performance over time. Additionally, the PLT demonstrated that the subject was able to generalize and transfer her manipulation skills to an unknown task and to improve her motor coordination. Significance. Our findings suggest that intraneural sensory feedback holds the potential of restoring functionally effective tactile feedback. This opens up new possibilities to improve the quality of life of amputees using a neural prosthesis.
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Erhardt, J.B., Lottner, T., Martinez, J., Özen, A.C., Schuettler, M., Stieglitz, T., Ennis, D.B., Bock, M.
It's the little things: On the complexity of planar electrode heating in MRI.
2019 Neuroimage, volume: 195, page(s): 272 - 284
Show abstract
Neurological disorders are increasingly analysed and treated with implantable electrodes, and patients with such electrodes are studied with MRI despite the risk of radio-frequency (RF) induced heating during the MRI exam. Recent clinical research suggests that electrodes with smaller diameters of the electrical interface between implant and tissue are beneficial; however, the influence of this electrode contact diameter on RF-induced heating has not been investigated. In this work, electrode contact diameters between 0.3 and 4 mm of implantable electrodes appropriate for stimulation and electrocorticography were evaluated in a 1.5 T MRI system. In situ temperature measurements adapted from the ASTM standard test method were performed and complemented by simulations of the specific absorption rate (SAR) to assess local SAR values, temperature increase and the distribution of dissipated power. Measurements showed temperature changes between 0.8 K and 53 K for different electrode contact diameters, which is well above the legal limit of 1 K. Systematic errors in the temperature measurements are to be expected, as the temperature sensors may disturb the heating pattern near small electrodes. Compared to large electrodes, simulations suggest that small electrodes are subject to less dissipated power, but more localized power density. Thus, smaller electrodes might be classified as safe in current certification procedures but may be more likely to burn adjacent tissue. To assess these local heating phenomena, smaller temperature sensors or new non-invasive temperature sensing methods are needed.
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Kolkhorst Henrich, Burgard Wolfram, Tangermann Michael
Learning User Preferences for Trajectories from Brain Signals
2019 arXiv:1909.01039 [cs, stat]
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De la Oliva, N., Del Valle, J., Delgado-Martinez, I., Mueller, M., Stieglitz, T., Navarro, X.
Long-Term Functionality of Transversal Intraneural Electrodes Is Improved by Dexamethasone Treatment.
2019 IEEE Trans Neural Systems and Rehabilitation Engineering, volume: 27, issue: 3, page(s): 457 - 464
Show abstract
Neuroprostheses aimed to restore lost functions after a limb amputation are based on the interaction with the nervous system by means of neural interfaces. Among the different designs, intraneural electrodes implanted in peripheral nerves represent a good strategy to stimulate nerve fibers to send sensory feedback and to record nerve signals to control the prosthetic limb. However, intraneural electrodes, as any device implanted in the body, induce a foreign body reaction (FBR) that results in the tissue encapsulation of the device. The FBR causes a progressive decline of the electrode functionality over time due to the physical separation between the electrode active sites and the axons to interface. Modulation of the inflammatory response has arisen as a good strategy to reduce the FBR and maintain electrode functionality. In this study transversal intraneural multi-channel electrodes (TIMEs) were implanted in the rat sciatic nerve and tested for 3 months to evaluate stimulation and recording capabilities under chronic administration of dexamethasone. Dexamethasone treatment significantly reduced the threshold for evoking muscle responses during the follow-up compared to saline-treated animals, without affecting the selectivity of stimulation. However, dexamethasone treatment did not improve the signal-to-noise ratio of the recorded neural signals. Dexamethasone treatment allowed to maintain more working active sites along time than saline treatment. Thus, systemic administration of dexamethasone appears as a useful treatment in chronically implanted animals with neural electrodes as it increases the number of functioning contacts of the implanted TIME and reduces the intensity needed to stimulate the nerve.
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Meinel Andreas, Kolkhorst Henrich, Tangermann Michael
Mining within-trial oscillatory brain dynamics to address the variability of optimized spatial filters
2019 IEEE Transactions on Neural Systems and Rehabilitation Engineering, volume: 27, issue: 3, page(s): 378 - 388
Open publication
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Lu H, Gallinaro J, Rotter S
Network remodeling induced by transcranial brain stimulation: A computational model of tDCS-triggered cell assembly formation
2019 Network Neuroscience, page(s): 1 - 21
Show abstract
Transcranial direct current stimulation (tDCS) is a variant of noninvasive neuromodulation, which promises treatment for brain diseases like major depressive disorder. In experiments, long-lasting aftereffects were observed, suggesting that persistent plastic changes are induced. The mechanism underlying the emergence of lasting aftereffects, however, remains elusive. Here we propose a model, which assumes that tDCS triggers a homeostatic response of the network involving growth and decay of synapses. The cortical tissue exposed to tDCS is conceived as a recurrent network of excitatory and inhibitory neurons, with synapses subject to homeostatically regulated structural plasticity. We systematically tested various aspects of stimulation, including electrode size and montage, as well as stimulation intensity and duration. Our results suggest that transcranial stimulation perturbs the homeostatic equilibrium and leads to a pronounced growth response of the network. The stimulated population eventually eliminates excitatory synapses with the unstimulated population, and new synapses among stimulated neurons are grown to form a cell assembly. Strong focal stimulation tends to enhance the connectivity within new cell assemblies, and repetitive stimulation with well-chosen duty cycles can increase the impact of stimulation even further. One long-term goal of our work is to help in optimizing the use of tDCS in clinical applications.
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Lu, Han and Gallinaro, Júlia V. and Rotter, Stefan
Network remodeling induced by transcranial brain stimulation: A computational model of tDCS-triggered cell assembly formation
2019 Network Neuroscience, volume: 3, issue: 4, page(s): 924 - 943
Show abstract
Transcranial direct current stimulation (tDCS) is a variant of noninvasive neuromodulation, which promises treatment for brain diseases like major depressive disorder. In experiments, long-lasting aftereffects were observed, suggesting that persistent plastic changes are induced. The mechanism underlying the emergence of lasting aftereffects, however, remains elusive. Here we propose a model, which assumes that tDCS triggers a homeostatic response of the network involving growth and decay of synapses. The cortical tissue exposed to tDCS is conceived as a recurrent network of excitatory and inhibitory neurons, with synapses subject to homeostatically regulated structural plasticity. We systematically tested various aspects of stimulation, including electrode size and montage, as well as stimulation intensity and duration. Our results suggest that transcranial stimulation perturbs the homeostatic equilibrium and leads to a pronounced growth response of the network. The stimulated population eventually eliminates excitatory synapses with the unstimulated population, and new synapses among stimulated neurons are grown to form a cell assembly. Strong focal stimulation tends to enhance the connectivity within new cell assemblies, and repetitive stimulation with well-chosen duty cycles can increase the impact of stimulation even further. One long-term goal of our work is to help in optimizing the use of tDCS in clinical applications.
Open publication
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A. Dressing, C. P. Kaller, K. Nitschke, L. Beume, D. Kuemmerer, C. S. M. Schmidt, T. Bormann, R. M. Umarova, K. Egger, M. Rijntjes, C. Weiller, and M. Martin
Neural correlates of acute apraxia: Evidence from lesion data and functional MRI in stroke patients
2019 Cortex, volume: 120, page(s): 1 - 2
Show abstract
Behavioral deficits after stroke like apraxia can be related to structural lesions and to a functional state of the underlying network - three factors, reciprocally influencing each other. Combining lesion data, behavioral performance and passive functional activation of the network-of-interest, this study aims to disentangle those mutual influences and to identify 1) activation patterns associated with the presence or absence of acute apraxia in tool-associated actions and 2) the specific impact of lesion location on those activation patterns. Brain activity of 48 patients (63.31 ± 13.68 years, 35 male) was assessed in a fMRI paradigm with observation of tool-related actions during the acute phase after first-ever left-hemispheric stroke (4.83 ± 2.04 days). Behavioral assessment of apraxia in tool-related tasks was obtained independently. Brain activation was compared between patients versus healthy controls and between patient with versus without apraxia. Interaction effects of lesion location (frontal vs parietal) and behavioral performance (apraxia vs no apraxia) were assessed in a 2 × 2 factorial design. Action observation activated the ventro-dorsal parts of the network for cognitive motor function; activation was globally downregulated after stroke. Apraxic compared to non-apraxic patients showed relatively increased activity in bilateral posterior middle temporal gyrus and middle frontal gyrus/superior frontal sulcus. Altered activation occurred in regions for tool-related cognition, corroborating known functions of the ventro-dorsal and ventral streams for praxis, and comprised domain-general areas, functionally related to cognitive control. The interaction analyses revealed different levels of activation in the left anterior middle temporal gyrus in the ventral stream in apraxic patients with frontal compared to parietal lesions, suggesting a modulation of network activation in relation to behavioral performance and lesion location as separate factors. By detecting apraxia-specific activation patterns modulated by lesion location, this study underlines the necessity to combine structural lesion information, behavioral parameters and functional activation to comprehensively examine cognitive functions in acute stroke patients.
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Claret CR, Herget GW, Kouba L, Wiest D, Adler J, von Tscharner V, Stieglitz T, Pasluosta C
Neuromuscular adaptations and sensorimotor integration following a unilateral transfemoral amputation.
2019 J Neuroeng Rehabil, volume: 16, issue: 1, page(s): 115
Show abstract
Background: Following an amputation, the human postural control system develops neuromuscular adaptations to regain an effective postural control. We investigated the compensatory mechanisms behind these adaptations and how sensorimotor integration is affected after a lower-limb transfemoral amputation.
METHODS:
Center of pressure (CoP) data of 12 unilateral transfemoral amputees and 12 age-matched able-bodied subjects were recorded during quiet standing with eyes open (EO) and closed (EC). CoP adjustments under each leg were recorded to study their contribution to posture control. The spatial structure of the CoP displacements was characterized by measuring the mean distance, the mean velocity of the CoP adjustments, and the sway area. The Entropic Half-Life (EnHL) quantifies the temporal structure of the CoP adjustments and was used to infer disrupted sensory feedback loops in amputees. We expanded the analysis with measures of weight-bearing imbalance and asymmetry, and with two standardized balance assessments, the Berg Balance Scale (BBS) and Timed Up-and-Go (TUG).
RESULTS:
There was no difference in the EnHL values of amputees and controls when combining the contributions of both limbs (p = 0.754). However, amputees presented significant differences between the EnHL values of the intact and prosthetic limb (p < 0.001). Suppressing vision reduced the EnHL values of the intact (p = 0.001) and both legs (p = 0.028), but not in controls. Vision feedback in amputees also had a significant effect (increase) on the mean CoP distance (p < 0.001), CoP velocity (p < 0.001) and sway area (p = 0.007). Amputees presented an asymmetrical stance. The EnHL values of the intact limb in amputees were positively correlated to the BBS scores (EO: ρ = 0.43, EC: ρ = 0.44) and negatively correlated to the TUG times (EO: ρ = - 0.59, EC: ρ = - 0.69).
CONCLUSION:
These results suggest that besides the asymmetry in load distribution, there exist neuromuscular adaptations after an amputation, possibly related to the loss of sensory feedback and an altered sensorimotor integration. The EnHL values suggest that the somatosensory system predominates in the control of the intact leg. Further, suppressing the visual system caused instability in amputees, but had a minimal impact on the CoP dynamics of controls. These findings points toward the importance of providing somatosensory feedback in lower-limb prosthesis to reestablish a normal postural control.
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A. Weltin, D. Ganatra, K. König, K. Joseph, U.G. Hofmann, G.A. Urban, J. Kieninger
New life for old wires: electrochemical sensor method for neural implants
2019 Journal of Neural Engineering, volume: 17, issue: 1, page(s): 016007
Show abstract
Objective. Electrochemical microsensors based on noble metals can give essential information on their microenvironment with high spatio-temporal resolution. However, most advanced chemo- and biosensors lack the long-term stability for physiological monitoring of brain tissue beyond an acute application. Noble metal electrodes are widely used as neural interfaces, particularly for stimulating in the central nervous system. Our goal was to recruit already deployed, unmodified noble metal electrodes (Pt, Pt/Ir) as in situ chemical sensors. Approach. With advanced electrochemical sensor methods, we investigated electrode surface processes, oxidizable species and oxygen as an indicator for tissue mass transport. We developed a unique, multi-step, amperometric/potentiometric sensing procedure derived from the investigation of Pt surface processes by chronocoulometry providing fundamental characterization of the electrode itself. Main results. The resulting electrochemical protocol preconditions the electrode, measures oxidizable and reducible species, and the open circuit potential (OCP). A linear, stable sensor performance was demonstrated, also in the presence of proteins, validating signal stability of our cyclic protocol in complex environments. We investigated our sensor protocol with microelectrodes on custom Pt/Ir-wire tetrodes by in vivo measurements in the rat brain for up to four weeks. Results showed that catalytic activity of the electrode is lost over time, but our protocol is repeatedly able to both quantify and restore electrode sensitivity in vivo. Significance. Our approach is highly relevant because it can be applied to any existing Pt electrode. Current methods to assess the brain/electrode microenvironment mainly rely on imaging techniques, histology and analysis of explanted devices, which are often end-point methods. Our procedure delivers online and time-transient information on the chemical microenvironment directly at the electrode/tissue interface of neural implants, gives new insight into the charge transfer processes, and delivers information on the state of the electrode itself addressing long-term electrode degradation.
Open publication
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Weltin A, Ganatra D, König K, Joseph K, Hofmann UG, Urban G, Kieninger J
New life for old wires: Electrochemical sensor method for neural implants
2019 J Neural Eng
Show abstract
Objective. Electrochemical microsensors based on noble metals can give essential information on their microenvironment with high spatio‐temporal resolution. However, most advanced chemo‐ and biosensors lack the long‐term stability for physiological monitoring of brain tissue beyond an acute application. Noble metal electrodes are widely used as neural interfaces, particularly for stimulating in the central nervous system. Our goal was to recruit already deployed, unmodified noble metal electrodes (Pt, Pt/Ir) as in situ chemical sensors. Approach. With advanced electrochemical sensor methods, we investigated electrode surface processes, oxidizable species and oxygen as an indicator for tissue mass transport. We developed a unique, multi‐step, amperometric/potentiometric sensing procedure derived from the investigation of Pt surface processes by chronocoulometry providing fundamental characterization of the electrode itself. Main results. The resulting electrochemical protocol preconditions the electrode, measures oxidizable and reducible species, and the open circuit potential. A linear, stable sensor performance was demonstrated, also in the presence of proteins, validating signal stability of our cyclic protocol in complex environments. We investigated our sensor protocol with microelectrodes on custom Pt/Ir‐wire tetrodes by in vivo measurements in the rat brain for up to four weeks. Results showed that catalytic activity of the electrode is lost over time, but our protocol is repeatedly able to both quantify and restore electrode sensitivity in vivo. Significance. Our approach is highly relevant because it can be applied to any existing Pt electrode. Current methods to assess the brain/electrode microenvironment mainly rely on imaging techniques, histology and analysis of explanted devices, which are often end‐point methods. Our procedure delivers online and time‐transient information on the chemical microenvironment directly at the electrode/tissue interface of neural implants, gives new insight into the charge transfer processes, and delivers information on the state of the electrode itself addressing long‐term electrode degradation.
Open publication
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Donkels C, Peters M, Fariña Núñez MT, Nakagawa JM, Kirsch M, Vlachos A, Scheiwe C, Schulze-Bonhage H, Prinz M, Beck J, Haas CA
Oligodendrocyte lineage and myelination are compromised in the gray matter of focal cortical dysplasia type IIa
2019 Epilepsia
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Risso G., Valle G., Iberite F., Strauss I., Stieglitz T., Controzzi M., Clemente F., Granata G., Rossini P.M., Micera S., Baud-Bovy G.
Optimal integration of intraneural somatosensory feedback with visual information: a single-case study.
2019 Scientific Reports, volume: 9, issue: 1, page(s): 7916
Show abstract
Providing somatosensory feedback to amputees is a long-standing objective in prosthesis research. Recently, implantable neural interfaces have yielded promising results in this direction. There is now considerable evidence that the nervous system integrates redundant signals optimally, weighting each signal according to its reliability. One question of interest is whether artificial sensory feedback is combined with other sensory information in a natural manner. In this single-case study, we show that an amputee with a bidirectional prosthesis integrated artificial somatosensory feedback and blurred visual information in a statistically optimal fashion when estimating the size of a hand-held object. The patient controlled the opening and closing of the prosthetic hand through surface electromyography, and received intraneural stimulation proportional to the object’s size in the ulnar nerve when closing the robotic hand on the object. The intraneural stimulation elicited a vibration sensation in the phantom hand that substituted the missing haptic feedback. This result indicates that sensory substitution based on intraneural feedback can be integrated with visual feedback and make way for a promising method to investigate multimodal integration processes.
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Deubner, J., Coulon, P. and Diester, I.
Optogenetic approaches to study the mammalian brain.
2019 Current opinion in structural biology, volume: 57, page(s): 157 - 163
Show abstract
Optogenetics has revolutionized neurobiological research by allowing to disentangle intricate neuronal circuits at a spatio-temporal precision unmatched by other techniques. Here, we review current advances of optogenetic applications in mammals, especially focusing on freely moving animals. State-of-the-art strategies allow the targeted expression of opsins in neuronal subpopulations, defined either by genetic cell type or neuronal projection pattern. Optogenetic manipulations of these subpopulations become particularly powerful when combined with behavioral paradigms and neurophysiological readout techniques. Thereby, specific roles can be assigned to identified cells. All-optical approaches with the opportunity to write complex three dimensional patterns into neuronal networks have recently emerged. While clinical implications of the new tool set seem tempting, we emphasize here the role of optogenetics for basic research.
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J. Behncke, M. Kern, J. Ruescher, A. Schulze-Bonhage, and T. Ball
Probabilistic neuroanatomical assignment of intracranial electrodes using the ELAS toolbox
2019 J Neurosci Methods, volume: 327, page(s): 108396
Show abstract
BACKGROUND:
Intracranial electroencephalography (iEEG) is increasingly used in neuroscientific research. However, the position of the implanted electrodes varies greatly between patients, which makes group analyses particularly difficult. Therefore, an assignment procedure is needed that enables the neuroanatomical information to be obtained for each individual electrode contact.
NEW METHOD:
Here, we present a MATLAB-based electrode assignment approach for iEEG electrode contacts, implemented in the open-source toolbox ELAS, that allows a hierarchical probabilistic assignment of individual electrode contacts to cytoarchitectonically-defined brain areas. The here presented ELAS consists of two major steps: (I) a pre-assignment to the cerebral lobes and (II) a following probabilistic assignment based on lobe-specific probability maps of the SPM Anatomy Toolbox.
RESULTS:
We analyzed iEEG data obtained in 14 epilepsy patients with a total of 783 intracranial electrode contacts. The neuroanatomical assignment to cortical brain areas was possible in 72.5% of the electrode contacts that were located on the lateral cortical convexity.
COMPARISON WITH EXISTING METHODS:
This assignment procedure is to our knowledge the first approach that combines both individual macro-anatomical and cytoarchitectonic probabilistic information. Due to the integration of information about individual anatomical landmarks, incorrect assignments could be avoided in approx. 7% of electrode contacts.
CONCLUSION:
The present study demonstrates how probabilistic assignment procedures developed for the analysis of neuroimaging data can be adapted to iEEG, which is especially helpful for group analyses. The presented assignment approach is freely available via the open-source toolbox ELAS, including a 3D visualization and a file export for virtual reality setups.
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Merkt B, Schüßler F, Rotter S
Propagation of orientation selectivity in a spiking network model of layered primary visual cortex
2019 Plos Comput Biol, volume: 15, issue: 7, page(s): e1007080
Show abstract
Neurons in different layers of sensory cortex generally have different functional properties. But what determines firing rates and tuning properties of neurons in different layers? Orientation selectivity in primary visual cortex (V1) is an interesting case to study these questions. Thalamic projections essentially determine the preferred orientation of neurons that receive direct input. But how is this tuning propagated though layers, and how can selective responses emerge in layers that do not have direct access to the thalamus? Here we combine numerical simulations with mathematical analyses to address this problem. We find that a large-scale network, which just accounts for experimentally measured layer and cell-type specific connection probabilities, yields firing rates and orientation selectivities matching electrophysiological recordings in rodent V1 surprisingly well. Further analysis, however, is complicated by the fact that neuronal responses emerge in a dynamic fashion and cannot be directly inferred from static neuroanatomy, as some connections tend to have unintuitive effects due to recurrent interactions and strong feedback loops. These emergent phenomena can be understood by linearizing and coarse-graining. In fact, we were able to derive a low-dimensional linear dynamical system effectively describing stimulus-driven activity layer by layer. This low-dimensional system explains layer-specific firing rates and orientation tuning by accounting for the different gain factors of the aggregate system. Our theory can also be used to design novel optogenetic stimulation experiments, thus facilitating further exploration of the interplay between connectivity and function.
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Eickenscheidt, M., Singler, E., Stieglitz, T.
Pulsed electropolymerization of PEDOT enabling controlled branching.
2019 Polymer Journal, volume: 51, issue: 10, page(s): 1029 - 1036
Show abstract
Controlling the growth of conductive polymers via electrolysis enables defined surface modifications and can be used as a rapid prototyping process. In this study, the controlled dendritic growth of poly(3,4-ethylenedioxythiophene) (PEDOT) in a two-electrode setup was investigated by pulsed voltage-driven electropolymerization of the precursor EDOT and a low concentration of tetrabutylammonium perchlorate dissolved in acetonitrile. Rapid growth of different polymeric shapes was reliably achieved by varying the reduction voltage and duty factor. The obtained structures were optically examined and quantified using fractal dimensions. Their shapes ranged from solid coatings over branched fractals to straight fibers without requiring any template. These rapid and controllable electropolymerization processes were further combined to increase conductor complexity.
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Böhm T, Joseph K, Kirsch M, Moroni R, Hilger A, Osenberg M, Manke I, Johnston M, Stieglitz T, Hofmann UG, Haas CA, Thiele S
Quantitative synchrotron X‐ray tomography of the material‐tissue interface in rat cortex implanted with neural probes
2019 Sci Rep-uk, volume: 9, page(s): 7646
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Karvat, G., Schneider, A., Alyahyaey, M., Steenbergen, F. and Diester, I.
Real-time detection of neural oscillation bursts allows behaviourally relevant neurofeedback
2019 bioRxiv, Cold Spring Harbor Laboratory
Show abstract
Neural oscillations are increasingly interpreted as transient bursts, yet a method to measure these short-lived events in real-time is missing. Here we present a real-time data analysis system, capable to detect short and narrowband bursts, and demonstrate its usefulness for volitional increase of beta-band burst-rate in rats. This neurofeedback-training induced changes in overall oscillatory power, and bursts could be decoded from the movement of the rats, thus enabling future investigation of the role of oscillatory bursts.
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Okujeni S, Egert U
Self-organization of modular network architecture by activity-dependent neuronal migration and outgrowth
2019 Elife, volume: 8, page(s): e47996
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A. Valada, R. Mohan and W. Burgard
Self-Supervised Model Adaptation for Multimodal Semantic Segmentation
2019 International Journal of Computer Vision, page(s): 1 - 47
Show abstract
Learning to reliably perceive and understand the scene is an integral enabler for robots to operate in the real-world. This problem is inherently challenging due to the multitude of object types as well as appearance changes caused by varying illumination and weather conditions. Leveraging complementary modalities can enable learning of semantically richer representations that are resilient to such perturbations. Despite the tremendous progress in recent years, most multimodal convolutional neural network approaches directly concatenate feature maps from individual modality streams rendering the model incapable of focusing only on the relevant complementary information for fusion. To address this limitation, we propose a mutimodal semantic segmentation framework that dynamically adapts the fusion of modality-specific features while being sensitive to the object category, spatial location and scene context in a self-supervised manner. Specifically, we propose an architecture consisting of two modality-specific encoder streams that fuse intermediate encoder representations into a single decoder using our proposed self-supervised model adaptation fusion mechanism which optimally combines complementary features. As intermediate representations are not aligned across modalities, we introduce an attention scheme for better correlation. In addition, we propose a computationally efficient unimodal segmentation architecture termed AdapNet++ that incorporates a new encoder with multiscale residual units and an efficient atrous spatial pyramid pooling that has a larger effective receptive field with more than 10× fewer parameters, complemented with a strong decoder with a multi-resolution supervision scheme that recovers high-resolution details. Comprehensive empirical evaluations on Cityscapes, Synthia, SUN RGB-D, ScanNet and Freiburg Forest benchmarks demonstrate that both our unimodal and multimodal architectures achieve state-of-the-art performance while simultaneously being efficient in terms of parameters and inference time as well as demonstrating substantial robustness in adverse perceptual conditions.
Open publication
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F. P. Petrini, M. Bumbasirevic, G. Valle, V. Ilic, P. Mijovic, P. Cvancara, F. Barberi, D. Bortolotti, D. Andreu, J.-L. Divoux, K. Lechler, A. Lesic, S. Mazic, B. Mijovic, D. Guiraud, T. Stieglitz, A. Asgeir, S. Micera and S. Raspopovic
Sensory feedback restoration in leg amputees improves walking speed, metabolic cost and phantom pain
2019 Nature Medicine, volume: 25, page(s): 1356 - 1363
Show abstract
Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to above-knee amputees, thereby reducing confidence and walking speed in the users that is associated with high mental and physical fatigue1,2,3,4. The lack of physiological feedback from the remaining extremity to the brain also contributes to the generation of phantom limb pain from the missing leg5,6. To determine whether neural sensory feedback restoration addresses these issues, we conducted a study with two transfemoral amputees, implanted with four intraneural stimulation electrodes7 in the remaining tibial nerve (ClinicalTrials.gov identifier NCT03350061). Participants were evaluated while using a neuroprosthetic device consisting of a prosthetic leg equipped with foot and knee sensors. These sensors drive neural stimulation, which elicits sensations of knee motion and the sole of the foot touching the ground. We found that walking speed and self-reported confidence increased while mental and physical fatigue decreased for both participants during neural sensory feedback compared to the no stimulation trials. Furthermore, participants exhibited reduced phantom limb pain with neural sensory feedback. The results from these proof-of-concept cases provide the rationale for larger population studies investigating the clinical utility of neuroprostheses that restore sensory feedback.
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Petrini, F.M., Bumbasirevic, M., Valle, G., Ilic, V., Mijovic, P., Cvancara, P., Barberi, F., Bortolotti, D., Andreu, D., Divoux, J.-L., Lechler, K., Lesic, A., Mazic, S., Mijovic, B., Guiraud, D., Stieglitz, T., Asgeir, A., Micera, S., Raspopovic, S.
Sensory feedback restoration in leg amputees improves walking speed, metabolic cost and phantom pain.
2019 Nature Medicine, volume: 25, page(s): 1356 - 1363
Show abstract
Conventional leg prostheses do not convey sensory information about motion or interaction with the ground to above-knee amputees, thereby reducing confidence and walking speed in the users that is associated with high mental and physical fatigue1,2,3,4. The lack of physiological feedback from the remaining extremity to the brain also contributes to the generation of phantom limb pain from the missing leg5,6. To determine whether neural sensory feedback restoration addresses these issues, we conducted a study with two transfemoral amputees, implanted with four intraneural stimulation electrodes7 in the remaining tibial nerve (ClinicalTrials.gov identifier NCT03350061). Participants were evaluated while using a neuroprosthetic device consisting of a prosthetic leg equipped with foot and knee sensors. These sensors drive neural stimulation, which elicits sensations of knee motion and the sole of the foot touching the ground. We found that walking speed and self-reported confidence increased while mental and physical fatigue decreased for both participants during neural sensory feedback compared to the no stimulation trials. Furthermore, participants exhibited reduced phantom limb pain with neural sensory feedback. The results from these proof-of-concept cases provide the rationale for larger population studies investigating the clinical utility of neuroprostheses that restore sensory feedback.
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Jordao MJC, Sankowski R, Brendecke SM, Sagar, Locatelli G, Tai YH, Tay TL, Schramm E, Armbruster S, Hagemeyer N, Gross O, Mai D, Cicek O, Falk T, Kerschensteiner M, Grun D, Prinz M
Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation.
2019 Science, volume: 363, issue: 6425
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Petrini, F. M., Valle, G., Strauss, I., Granata, G., Di Iorio, R., DAnna, E., Cvancara, P., Mueller, M., Carpaneto, J., Clemente, F., Controzzi, M., Bisoni, L., Carboni, C., Barbaro, M., Iodice, F., Andreu, D., Hiairrassary, A., Divoux, J.-L., Cipriani, C
Six-Month Assessment of a Hand Prosthesis with Intraneural Tactile Feedback.
2019 Annals of neurology, volume: 85, page(s): 137 - 154
Show abstract
OBJECTIVE: Hand amputation is a highly disabling event, which significantly affects quality of life. An effective hand replacement can be achieved if the user, in addition to motor functions, is provided with the sensations that are naturally perceived while grasping and moving. Intraneural peripheral electrodes have shown promising results toward the restoration of the sense of touch. However, the long-term usability and clinical relevance of intraneural sensory feedback have not yet been clearly demonstrated. METHODS: To this aim, we performed a 6-month clinical study with 3 transradial amputees who received implants of transverse intrafascicular multichannel electrodes (TIMEs) in their median and ulnar nerves. After calibration, electrical stimulation was delivered through the TIMEs connected to artificial sensors in the digits of a prosthesis to generate sensory feedback, which was then used by the subjects while performing different grasping tasks. RESULTS: All subjects, notwithstanding their important clinical differences, reported stimulation-induced sensations from the phantom hand for the whole duration of the trial. They also successfully integrated the sensory feedback into their motor control strategies while performing experimental tests simulating tasks of real life (with and without the support of vision). Finally, they reported a decrement of their phantom limb pain and a general improvement in mood state. INTERPRETATION: The promising results achieved with all subjects show the feasibility of the use of intraneural stimulation in clinical settings. ANN NEUROL 2019;85:137-154.
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Boehler C, Oberueber F, Asplund M
Tuning drug delivery from conducting polymer films for accurately controlled release of charged molecules.
2019 J Control Release, volume: 304, page(s): 173 - 180
Show abstract
Spatio-temporally controlled drug release based on conducting polymer films offers a powerful technology to improve the tissue integration for implantable neuroprobes. We here explore the release efficiency of such systems in order to improve the understanding of the release mechanism and allow for optimized implementation of this technology into future drug release applications. By exposing drug loaded PEDOT coatings of different thicknesses to a multitude of release signals, along with optimizing the steps during the polymer synthesis, we could identify a highly reproducible electrostatically controlled drug release next to a slow diffusion driven release component. The release efficiency was moreover observed to be higher for a cyclic voltammetry signal in comparison to release driven by a constant potential. Biphasic current pulses, as used during neural stimulation, did not allow for long enough diffusion times to yield efficient active drug expulsion from the polymer films. A quantitative analysis could confirm an overall linear dependency between drug release and film thickness. The amount of drug released in response to the trigger signals was however not linearly correlated with the amount of charge applied. By combining these findings we could develop a model which accurately describes the drug release mechanism from a PEDOT film. The proposed model thereby points the way for how actively controlled, and diffusion related, release can be tuned for obtaining delivery dynamics tailored to specific applications.
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Falk T, Mai D, Bensch R, Çiçek Ö, Abdulkadir A, Marrakchi Y, Böhm A, Deubner J, Jäckel Z, Seiwald K, Dovzhenko A, Tietz O, Dal Bosco C, Walsh S, Saltukoglu D, Tay TL, Prinz M, Palme K, Simons M, Diester I, Brox T, Ronneberger O
U-Net: deep learning for cell counting, detection, and morphometry.
2019 Nat Methods, volume: 16, issue: 1, page(s): 67 - 70
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J. Zhang, L. Tai, P. Yun, Y. Xiong, M. Liu, J. Boedecker, W. Burgard
Vr-goggles for robots: Real-to-sim domain adaptation for visual control
2019 IEEE Robotics and Automation Letters, volume: 4, issue: 2, page(s): 1148 - 1155
Show abstract
In this letter, we deal with the reality gap from a novel perspective, targeting transferring deep reinforcement learning (DRL) policies learned in simulated environments to the real-world domain for visual control tasks. Instead of adopting the common solutions to the problem by increasing the visual fidelity of synthetic images output from simulators during the training phase, we seek to tackle the problem by translating the real-world image streams back to the synthetic domain during the deployment phase, to make the robot feel at home. We propose this as a lightweight, flexible, and efficient solution for visual control, as first, no extra transfer steps are required during the expensive training of DRL agents in simulation; second, the trained DRL agents will not be constrained to being deployable in only one specific real-world environment; and third, the policy training and the transfer operations are decoupled, and can be conducted in parallel. Besides this, we propose a simple yet effective shift loss that is agnostic to the downstream task, to constrain the consistency between subsequent frames which is important for consistent policy outputs. We validate the shift loss for artistic style transfer for videos and domain adaptation, and validate our visual control approach in indoor and outdoor robotics experiments.
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Kleber C, Lienkamp K, Rühe J, Asplund M
Wafer‐Scale Fabrication of Conducting Polymer Hydrogels for Microelectrodes and Flexible Bioelectronics
2019 Advanced Biosystems, volume: 3, issue: 8
Show abstract
Future‐oriented directions in neural interface technologies point towards the development of multimodal devices that combine different functionalities such as neural stimulation, neurotransmitter sensing, and drug release within one platform. Conducting polymer hydrogels (CPHs) are suggested as materials for the coating of standard metal electrodes to add functionalities such as local delivery of therapeutic drugs. However, to make such coatings truly useful for multimodal devices, it is necessary to develop process technologies that allow the micropatterning of CPHs onto selected electrode sites. In this study, a wafer‐scale fabrication procedure is presented, which is used to coat the CPH, based on the hydrogel P(DMAA‐co‐5%MABP‐co‐2,5%SSNa) and the conducting polymer poly(3,4‐ethylenedioxythiophene) (PEDOT), onto flexible neural probes. The resulting material has favorable properties for the generation of recording electrodes and in addition offers a convenient platform for biofunctionalization. By controlling the PEDOT content within the hydrogel matrix, charge injection limits of up to 3.7 mC cm−2 are obtained. Long‐term stability is tested by immersing coated samples in phosphate‐buffered saline solution at 37 °C for 1 year. Non‐cytotoxicity of the coatings is confirmed with a direct cell culture test using a fluorescent neuroblastoma cell line.
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Stieglitz, T.
Why Neurotechnologies ? About the Purposes, Opportunities and Limitations of Neurotechnologies in Clinical Applications.
2019 Neuroethics, page(s): 1 - 12
Show abstract
Neurotechnologies describe a field of science and engineering in which the nervous system is interfaced with technical devices. Fundamental research is conducted to explore functions of the brain, decipher the neural code and get a better understanding of diseases and disorders. Risk benefit assessment has been well established in all medical disciplines to treat patients best possible while minimizing jeopardizing their lives by the interventions. Is this set of assessment rules sufficient when the brain will be interfaced with a technical system and is this assessment enough? How will these new technologies change personality and society? This article will shortly review different stakeholders’ opinions and their expectation in the field, assembles information the state-of-the art in medical applications of neurotechnological implants and describes and assesses the fundamental technologies that are used to build up these implants starting with essential requirements of technical materials in contact with living tissue. The different paragraphs guide the reader through the main aspects of neurotechnologies and lay a foundation of knowledge to be able to contribute to the discussion in which cases implants will be beneficial and in which cases we should express serious concerns.