Peter Tass

All Publications

• Information processing in tree networks of excitable elements. Physical review. E Khaledi-Nasab, A., Chauhan, K., Tass, P. A., Neiman, A. B. 2021; 103 (1-1): 012308

  Abstract

  We study the collective response of small random tree networks of diffusively coupled excitable elements to stimuli applied to leaf nodes. Such networks model the morphology of certain sensory neurons that possess branched myelinated dendrites with excitable nodes of Ranvier at every branch point and at leaf nodes. Leaf nodes receive random inputs along with a stimulus and initiate action potentials that propagate through the tree. We quantify the collective response registered at the central node using mutual information. We show that in the strong-coupling limit, the statistics of the number of nodes and leaves determines the mutual information. At the same time, the collective response is insensitive to particular node connectivity and distribution of stimulus over leaf nodes. However, for intermediate coupling, the mutual information may strongly depend on the stimulus distribution among leaf nodes. We identify a mechanism behind the competition of leaf nodes that leads to nonmonotonous dependence of mutual information on coupling strength. We show that a localized stimulus given to a tree branch can be occluded by the background firing of unstimulated branches, thus suppressing mutual information. Nonetheless, the mutual information can be enhanced by a proper stimulus localization and tuning of coupling strength.

  View details for DOI 10.1103/PhysRevE.103.012308

  View details for PubMedID 33601542

• Accumbens coordinated reset stimulation in mice exhibits ameliorating aftereffects on binge alcohol drinking. Brain stimulation Ho, A. L., Feng, A. Y., Barbosa, D. A., Wu, H., Smith, M. L., Malenka, R. C., Tass, P. A., Halpern, C. H. 2021

  Abstract

  Alcohol use disorder (AUD) affects nearly 5% of the world's adult population. Despite treatment, AUD often manifests with relapse to binge drinking, which has been associated with corticostriatal hypersynchrony involving the nucleus accumbens (NAc).A modified "Drinking in the Dark" protocol was used to provoke binge-like alcohol drinking. We implemented Coordinated Reset Stimulation (CRS), a computationally designed, spatio-temporal stimulation algorithm, to desynchronize abnormal neuronal activity via a deep brain stimulation (DBS) electrode in the NAc of mice exhibiting binge-like alcohol drinking. Integral CRS charge injected would be 2.5% of that of conventional high-frequency DBS.NAc CRS delivery during only the initial phase of exposure to alcohol and prior to the exposure (but not during) significantly reduced binge-like drinking without interfering with social behavior or locomotor activity.NAc CRS ameliorates binge-like alcohol drinking and preliminarily exhibits sustained aftereffects that are suggestive of an unlearning of hypersynchrony.

  View details for DOI 10.1016/j.brs.2021.01.015

  View details for PubMedID 33524612

• A Single Case Feasibility Study of Sensorimotor Rhythm Neurofeedback in Parkinson's Disease. Frontiers in neuroscience Cook, A. J., Pfeifer, K. J., Tass, P. A. 2021; 15: 623317

  Abstract

  Electroencephalographic activity over the sensorimotor cortex has been one of the best studied targets for neurofeedback therapy. Parkinson's disease patients display abnormal brain rhythms in the motor cortex caused by increased synchrony in the basal ganglia-cortical pathway. Few studies have examined the effects of sensorimotor-based neurofeedback therapy in humans with PD. In this pilot study, one patient, diagnosed with Parkinson's disease 10 years prior, participated in two consecutive days of EEG neurofeedback training to increase sensorimotor rhythm (SMR) power over the motor cortex. Using a visual display connected to ongoing EEG, the patient voluntarily manipulated SMR power, and he/she was awarded with points to positively reinforce successful increases over a predefined threshold. Recorded EEG data were source localized and analyzed for the occurrence of high amplitude bursts of SMR activity as well as bursts in the beta frequency band in the precentral cortex. The rate of SMR bursts increased with each subsequent training session, while the rate of beta bursts only increased on the final session. Relative power in the beta band, a marker of PD symptom severity, decreased over the motor cortex in the later session. These results provide first evidence for the feasibility of SMR neurofeedback training as a non-invasive therapy for reducing Parkinson's disease related activity and upregulating SMR in the human motor cortex.

  View details for DOI 10.3389/fnins.2021.623317

  View details for PubMedID 33613185

• Entrainment of a network of interacting neurons with minimum stimulating charge PHYSICAL REVIEW E Pyragas, K., Fedaravicius, A. P., Pyragiene, T., Tass, P. A. 2020; 102 (1): 012221

  Abstract

  Periodic pulse train stimulation is generically used to study the function of the nervous system and to counteract disease-related neuronal activity, e.g., collective periodic neuronal oscillations. The efficient control of neuronal dynamics without compromising brain tissue is key to research and clinical purposes. We here adapt the minimum charge control theory, recently developed for a single neuron, to a network of interacting neurons exhibiting collective periodic oscillations. We present a general expression for the optimal waveform, which provides an entrainment of a neural network to the stimulation frequency with a minimum absolute value of the stimulating current. As in the case of a single neuron, the optimal waveform is of bang-off-bang type, but its parameters are now determined by the parameters of the effective phase response curve of the entire network, rather than of a single neuron. The theoretical results are confirmed by three specific examples: two small-scale networks of FitzHugh-Nagumo neurons with synaptic and electric couplings, as well as a large-scale network of synaptically coupled quadratic integrate-and-fire neurons.

  View details for DOI 10.1103/PhysRevE.102.012221

  View details for Web of Science ID 000555098400008

  View details for PubMedID 32795011

• Long-Lasting Desynchronization of Plastic Neural Networks by Random Reset Stimulation. Frontiers in physiology Khaledi-Nasab, A., Kromer, J. A., Tass, P. A. 2020; 11: 622620

  Abstract

  Excessive neuronal synchrony is a hallmark of neurological disorders such as epilepsy and Parkinson's disease. An established treatment for medically refractory Parkinson's disease is high-frequency (HF) deep brain stimulation (DBS). However, symptoms return shortly after cessation of HF-DBS. Recently developed decoupling stimulation approaches, such as Random Reset (RR) stimulation, specifically target pathological connections to achieve long-lasting desynchronization. During RR stimulation, a temporally and spatially randomized stimulus pattern is administered. However, spatial randomization, as presented so far, may be difficult to realize in a DBS-like setup due to insufficient spatial resolution. Motivated by recently developed segmented DBS electrodes with multiple stimulation sites, we present a RR stimulation protocol that copes with the limited spatial resolution of currently available depth electrodes for DBS. Specifically, spatial randomization is realized by delivering stimuli simultaneously to L randomly selected stimulation sites out of a total of M stimulation sites, which will be called L/M-RR stimulation. We study decoupling by L/M-RR stimulation in networks of excitatory integrate-and-fire neurons with spike-timing dependent plasticity by means of theoretical and computational analysis. We find that L/M-RR stimulation yields parameter-robust decoupling and long-lasting desynchronization. Furthermore, our theory reveals that strong high-frequency stimulation is not suitable for inducing long-lasting desynchronization effects. As a consequence, low and high frequency L/M-RR stimulation affect synaptic weights in qualitatively different ways. Our simulations confirm these predictions and show that qualitative differences between low and high frequency L/M-RR stimulation are present across a wide range of stimulation parameters, rendering stimulation with intermediate frequencies most efficient. Remarkably, we find that L/M-RR stimulation does not rely on a high spatial resolution, characterized by the density of stimulation sites in a target area, corresponding to a large M. In fact, L/M-RR stimulation with low resolution performs even better at low stimulation amplitudes. Our results provide computational evidence that L/M-RR stimulation may present a way to exploit modern segmented lead electrodes for long-lasting therapeutic effects.

  View details for DOI 10.3389/fphys.2020.622620

  View details for PubMedID 33613303

  View details for PubMedCentralID PMC7893102

• Impact of number of stimulation sites on long-lasting desynchronization effects of coordinated reset stimulation CHAOS Kromer, J. A., Khaledi-Nasab, A., Tass, P. A. 2020; 30

  View details for DOI 10.1063/5.0015196

• Information processing in tree networks of excitable elements Information processing in tree networks of excitable elements Khaledi Nasab , A., Chauhan , K., Tass, P., Neiman , A. 2020; 103: 012308

  Abstract

  We study the collective response of small random tree networks of diffusively coupled excitable elements to stimuli applied to leaf nodes. Such networks model the morphology of certain sensory neurons that possess branched myelinated dendrites with excitable nodes of Ranvier at every branch point and at leaf nodes. Leaf nodes receive random inputs along with a stimulus and initiate action potentials that propagate through the tree. We quantify the collective response registered at the central node using mutual information. We show that in the strong-coupling limit, the statistics of the number of nodes and leaves determines the mutual information. At the same time, the collective response is insensitive to particular node connectivity and distribution of stimulus over leaf nodes. However, for intermediate coupling, the mutual information may strongly depend on the stimulus distribution among leaf nodes. We identify a mechanism behind the competition of leaf nodes that leads to nonmonotonous dependence of mutual information on coupling strength. We show that a localized stimulus given to a tree branch can be occluded by the background firing of unstimulated branches, thus suppressing mutual information. Nonetheless, the mutual information can be enhanced by a proper stimulus localization and tuning of coupling strength.

  View details for DOI 10.1103/PhysRevE.103.012308

• Long-lasting desynchronization by decoupling stimulation PHYSICAL REVIEW RESEARCH Kromer, J. A., Tass, P. A. 2020; 2 (3)

  View details for DOI 10.1103/PhysRevResearch.2.033101

• Technology of deep brain stimulation: current status and future directions. Nature reviews. Neurology Krauss, J. K., Lipsman, N., Aziz, T., Boutet, A., Brown, P., Chang, J. W., Davidson, B., Grill, W. M., Hariz, M. I., Horn, A., Schulder, M., Mammis, A., Tass, P. A., Volkmann, J., Lozano, A. M. 2020

  Abstract

  Deep brain stimulation (DBS) is a neurosurgical procedure that allows targeted circuit-based neuromodulation. DBS is a standard of care in Parkinson disease, essential tremor and dystonia, and is also under active investigation for other conditions linked to pathological circuitry, including major depressive disorder and Alzheimer disease. Modern DBS systems, borrowed from the cardiac field, consist of an intracranial electrode, an extension wire and a pulse generator, and have evolved slowly over the past two decades. Advances in engineering and imaging along with an improved understanding of brain disorders are poised to reshape how DBS is viewed and delivered to patients. Breakthroughs in electrode and battery designs, stimulation paradigms, closed-loop and on-demand stimulation, and sensing technologies are expected to enhance the efficacy and tolerability of DBS. In this Review, we provide a comprehensive overview of the technical development of DBS, from its origins to its future. Understanding the evolution of DBS technology helps put the currently available systems in perspective and allows us to predict the next major technological advances and hurdles in the field.

  View details for DOI 10.1038/s41582-020-00426-z

  View details for PubMedID 33244188

• Brain-Responsive Neurostimulation for Loss of Control Eating: Early Feasibility Study. Neurosurgery Wu, H., Adler, S., Azagury, D. E., Bohon, C., Safer, D. L., Barbosa, D. A., Bhati, M. T., Williams, N. R., Dunn, L. B., Tass, P. A., Knutson, B. D., Yutsis, M., Fraser, A., Cunningham, T., Richardson, K., Skarpaas, T. L., Tcheng, T. K., Morrell, M. J., Roberts, L. W., Malenka, R. C., Lock, J. D., Halpern, C. H. 2020

  Abstract

  Loss of control (LOC) is a pervasive feature of binge eating, which contributes significantly to the growing epidemic of obesity; approximately 80 million US adults are obese. Brain-responsive neurostimulation guided by the delta band was previously found to block binge-eating behavior in mice. Following novel preclinical work and a human case study demonstrating an association between the delta band and reward anticipation, the US Food and Drug Administration approved an Investigational Device Exemption for a first-in-human study.To assess feasibility, safety, and nonfutility of brain-responsive neurostimulation for LOC eating in treatment-refractory obesity.This is a single-site, early feasibility study with a randomized, single-blinded, staggered-onset design. Six subjects will undergo bilateral brain-responsive neurostimulation of the nucleus accumbens for LOC eating using the RNS® System (NeuroPace Inc). Eligible participants must have treatment-refractory obesity with body mass index ≥ 45 kg/m2. Electrophysiological signals of LOC will be characterized using real-time recording capabilities coupled with synchronized video monitoring. Effects on other eating disorder pathology, mood, neuropsychological profile, metabolic syndrome, and nutrition will also be assessed.Safety/feasibility of brain-responsive neurostimulation of the nucleus accumbens will be examined. The primary success criterion is a decrease of ≥1 LOC eating episode/week based on a 28-d average in ≥50% of subjects after 6 mo of responsive neurostimulation.This study is the first to use brain-responsive neurostimulation for obesity; this approach represents a paradigm shift for intractable mental health disorders.

  View details for DOI 10.1093/neuros/nyaa300

  View details for PubMedID 32717033

• Adaptive delivery of continuous and delayed feedback deep brain stimulation - a computational study. Scientific reports Popovych, O. V., Tass, P. A. 2019; 9 (1): 10585

  Abstract

  Adaptive deep brain stimulation (aDBS) is a closed-loop method, where high-frequency DBS is turned on and off according to a feedback signal, whereas conventional high-frequency DBS (cDBS) is delivered permanently. Using a computational model of subthalamic nucleus and external globus pallidus, we extend the concept of adaptive stimulation by adaptively controlling not only continuous, but also demand-controlled stimulation. Apart from aDBS and cDBS, we consider continuous pulsatile linear delayed feedback stimulation (cpLDF), specifically designed to induce desynchronization. Additionally, we combine adaptive on-off delivery with continuous delayed feedback modulation by introducing adaptive pulsatile linear delayed feedback stimulation (apLDF), where cpLDF is turned on and off using pre-defined amplitude thresholds. By varying the stimulation parameters of cDBS, aDBS, cpLDF, and apLDF we obtain optimal parameter ranges. We reveal a simple relation between the thresholds of the local field potential (LFP) for aDBS and apLDF, the extent of the stimulation-induced desynchronization, and the integral stimulation time required. We find that aDBS and apLDF can be more efficient in suppressing abnormal synchronization than continuous simulation. However, apLDF still remains more efficient and also causes a stronger reduction of the LFP beta burst length. Hence, adaptive on-off delivery may further improve the intrinsically demand-controlled pLDF.

  View details for DOI 10.1038/s41598-019-47036-4

  View details for PubMedID 31332226

• Acoustic coordinated reset therapy for tinnitus with perceptually relevant frequency spacing and levels Scientific Reports Tass, P. A., Silchenko, A. N., Popelka, G. R. 2019; 9: 13607

  View details for DOI 10.1038/s41598-019-49945-w

• Dendritic and Axonal Propagation Delays May Shape Neuronal Networks With Plastic Synapses FRONTIERS IN PHYSIOLOGY Asl, M., Valizadeh, A., Tass, P. A. 2018; 9

  View details for DOI 10.3389/fphys.2018.01849

  View details for Web of Science ID 000453895900001

• Optimal waveform for entrainment of a spiking neuron with minimum stimulating charge PHYSICAL REVIEW E Pyragas, K., Fedaravicius, A. P., Pyragiene, T., Tass, P. A. 2018; 98 (4)

  View details for DOI 10.1103/PhysRevE.98.042216

  View details for Web of Science ID 000448928700006

• Propagation delays determine neuronal activity and synaptic connectivity patterns emerging in plastic neuronal networks. Chaos (Woodbury, N.Y.) Madadi Asl, M., Valizadeh, A., Tass, P. A. 2018; 28 (10): 106308

  Abstract

  In plastic neuronal networks, the synaptic strengths are adapted to the neuronal activity. Specifically, spike-timing-dependent plasticity (STDP) is a fundamental mechanism that modifies the synaptic strengths based on the relative timing of pre- and postsynaptic spikes, taking into account the spikes' temporal order. In many studies, propagation delays were neglected to avoid additional dynamic complexity or computational costs. So far, networks equipped with a classic STDP rule typically rule out bidirectional couplings (i.e., either loops or uncoupled states) and are, hence, not able to reproduce fundamental experimental findings. In this review paper, we consider additional features, e.g., extensions of the classic STDP rule or additional aspects like noise, in order to overcome the contradictions between theory and experiment. In addition, we review in detail recent studies showing that a classic STDP rule combined with realistic propagation patterns is able to capture relevant experimental findings. In two coupled oscillatory neurons with propagation delays, bidirectional synapses can be preserved and potentiated. This result also holds for large networks of type-II phase oscillators. In addition, not only the mean of the initial distribution of synaptic weights, but also its standard deviation crucially determines the emergent structural connectivity, i.e., the mean final synaptic weight, the number of two-neuron loops, and the symmetry of the final connectivity pattern. The latter is affected by the firing rates, where more symmetric synaptic configurations emerge at higher firing rates. Finally, we discuss these findings in the context of the computational neuroscience-based development of desynchronizing brain stimulation techniques.

  View details for PubMedID 30384625

• Propagation delays determine neuronal activity and synaptic connectivity patterns emerging in plastic neuronal networks CHAOS Asl, M., Valizadeh, A., Tass, P. A. 2018; 28 (10)

  View details for DOI 10.1063/1.5037309

  View details for Web of Science ID 000448974600036

• Periodic flashing coordinated reset stimulation paradigm reduces sensitivity to ON and OFF period durations PLOS ONE Tyulmankov, D., Tass, P. A., Bokil, H. 2018; 13 (9): e0203782

  Abstract

  Pathological synchronization in the basal ganglia network has been considered an important component of Parkinson's disease pathophysiology. An established treatment for some patients with Parkinson's disease is deep brain stimulation, in which a tonic high-frequency pulse train is delivered to target regions of the brain. In recent years, a novel neuromodulation paradigm called coordinated reset stimulation has been proposed, which aims to reverse the pathological synchrony by sequentially delivering short high-frequency bursts to distinct sub-regions of the pathologically synchronized network, with an average intra-burst interval for each sub-region corresponding to period of the pathological oscillation. It has further been proposed that the resultant desynchronization can be enhanced when stimulation is interrupted periodically, and that it is particularly beneficial to precisely tune the stimulation ON and OFF time-windows to the underlying pathological frequency. Pre-clinical and clinical studies of coordinated reset stimulation have relied on these proposals for their stimulation protocols. In this study, we present a modified ON-OFF coordinated reset stimulation paradigm called periodic flashing and study its behavior through computational modeling using the Kuramoto coupled phase oscillator model. We demonstrate that in contrast to conventional coordinated reset stimulation, the periodic flashing variation does not exhibit a need for precise turning of the ON-OFF periods to the pathological frequency, and demonstrates desynchronization for a wide range of ON and OFF periods. We provide a mechanistic explanation for the previously observed sensitivities and demonstrate that they are an artifact of the specific ON-OFF cycling paradigm used. As a practical consequence, the periodic flashing paradigm simplifies the tuning of optimal stimulation parameters by decreasing the dimension of the search space. It also suggests new, more flexible ways of delivering coordinated reset stimulation.

  View details for PubMedID 30192855

• Delay-Induced Multistability and Loop Formation in Neuronal Networks with Spike-Timing-Dependent Plasticity SCIENTIFIC REPORTS Asl, M., Valizadeh, A., Tass, P. A. 2018; 8: 12068

  Abstract

  Spike-timing-dependent plasticity (STDP) adjusts synaptic strengths according to the precise timing of pre- and postsynaptic spike pairs. Theoretical and computational studies have revealed that STDP may contribute to the emergence of a variety of structural and dynamical states in plastic neuronal populations. In this manuscript, we show that by incorporating dendritic and axonal propagation delays in recurrent networks of oscillatory neurons, the asymptotic connectivity displays multistability, where different structures emerge depending on the initial distribution of the synaptic strengths. In particular, we show that the standard deviation of the initial distribution of synaptic weights, besides its mean, determines the main properties of the emergent structural connectivity such as the mean final synaptic weight, the number of two-neuron loops and the symmetry of the final structure. We also show that the firing rates of the neurons affect the evolution of the network, and a more symmetric configuration of the synapses emerges at higher firing rates. We justify the network results based on a two-neuron framework and show how the results translate to large recurrent networks.

  View details for PubMedID 30104713

• Computationally Developed Sham Stimulation Protocol for Multichannel Desynchronizing Stimulation FRONTIERS IN PHYSIOLOGY Zeitler, M., Tass, P. A. 2018; 9: 512

  Abstract

  A characteristic pattern of abnormal brain activity is abnormally strong neuronal synchronization, as found in several brain disorders, such as tinnitus, Parkinson's disease, and epilepsy. As observed in several diseases, different therapeutic interventions may induce a placebo effect that may be strong and hinder reliable clinical evaluations. Hence, to distinguish between specific, neuromodulation-induced effects and unspecific, placebo effects, it is important to mimic the therapeutic procedure as precisely as possibly, thereby providing controls that actually lack specific effects. Coordinated Reset (CR) stimulation has been developed to specifically counteract abnormally strong synchronization by desynchronization. CR is a spatio-temporally patterned multichannel stimulation which reduces the extent of coincident neuronal activity and aims at an anti-kindling, i.e., an unlearning of both synaptic connectivity and neuronal synchrony. Apart from acute desynchronizing effects, CR may cause sustained, long-lasting desynchronizing effects, as already demonstrated in pre-clinical and clinical proof of concept studies. In this computational study, we set out to computationally develop a sham stimulation protocol for multichannel desynchronizing stimulation. To this end, we compare acute effects and long-lasting effects of six different spatio-temporally patterned stimulation protocols, including three variants of CR, using a no-stimulation condition as additional control. This is to provide an inventory of different stimulation algorithms with similar fundamental stimulation parameters (e.g., mean stimulation rates) but qualitatively different acute and/or long-lasting effects. Stimulation protocols sharing basic parameters, but inducing nevertheless completely different or even no acute effects and/or after-effects, might serve as controls to validate the specific effects of particular desynchronizing protocols such as CR. In particular, based on our computational findings we propose a multichannel sham (i.e., inactive) stimulation protocol as control condition for phase 2 and phase 3 studies with desynchronizing multichannel stimulation techniques.

  View details for PubMedID 29867556

• How stimulation frequency and intensity impact on the long-lasting effects of coordinated reset stimulation PLOS COMPUTATIONAL BIOLOGY Manos, T., Zeitler, M., Tass, P. A. 2018; 14 (5): e1006113

  Abstract

  Several brain diseases are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was computationally designed to specifically counteract abnormal neuronal synchronization processes by desynchronization. In the presence of spike-timing-dependent plasticity (STDP) this may lead to a decrease of synaptic excitatory weights and ultimately to an anti-kindling, i.e. unlearning of abnormal synaptic connectivity and abnormal neuronal synchrony. The long-lasting desynchronizing impact of CR stimulation has been verified in pre-clinical and clinical proof of concept studies. However, as yet it is unclear how to optimally choose the CR stimulation frequency, i.e. the repetition rate at which the CR stimuli are delivered. This work presents the first computational study on the dependence of the acute and long-term outcome on the CR stimulation frequency in neuronal networks with STDP. For this purpose, CR stimulation was applied with Rapidly Varying Sequences (RVS) as well as with Slowly Varying Sequences (SVS) in a wide range of stimulation frequencies and intensities. Our findings demonstrate that acute desynchronization, achieved during stimulation, does not necessarily lead to long-term desynchronization after cessation of stimulation. By comparing the long-term effects of the two different CR protocols, the RVS CR stimulation turned out to be more robust against variations of the stimulation frequency. However, SVS CR stimulation can obtain stronger anti-kindling effects. We revealed specific parameter ranges that are favorable for long-term desynchronization. For instance, RVS CR stimulation at weak intensities and with stimulation frequencies in the range of the neuronal firing rates turned out to be effective and robust, in particular, if no closed loop adaptation of stimulation parameters is (technically) available. From a clinical standpoint, this may be relevant in the context of both invasive as well as non-invasive CR stimulation.

  View details for PubMedID 29746458

• Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization FRONTIERS IN PHYSIOLOGY Manos, T., Zeitler, M., Tass, P. A. 2018; 9: 376

  Abstract

  In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long-term desynchronization at comparably short stimulation duration and low integral stimulation duration. Currently, clinical proof of concept is available for deep brain CR stimulation for Parkinson's therapy and acoustic CR stimulation for tinnitus therapy. Promising first in human data is available for vibrotactile CR stimulation for Parkinson's treatment. For the clinical development of these treatments it is mandatory to perform dose-finding studies to reveal optimal stimulation parameters and dosage regimens. Our findings can straightforwardly be tested in human dose-finding studies.

  View details for PubMedID 29706900

• Multisite Delayed Feedback for Electrical Brain Stimulation FRONTIERS IN PHYSIOLOGY Popovych, O. V., Tass, P. A. 2018; 9: 46

  Abstract

  Demand-controlled deep brain stimulation (DBS) appears to be a promising approach for the treatment of Parkinson's disease (PD) as revealed by computational, pre-clinical and clinical studies. Stimulation delivery is adapted to brain activity, for example, to the amount of neuronal activity considered to be abnormal. Such a closed-loop stimulation setup might help to reduce the amount of stimulation current, thereby maintaining therapeutic efficacy. In the context of the development of stimulation techniques that aim to restore desynchronized neuronal activity on a long-term basis, specific closed-loop stimulation protocols were designed computationally. These feedback techniques, e.g., pulsatile linear delayed feedback (LDF) or pulsatile nonlinear delayed feedback (NDF), were computationally developed to counteract abnormal neuronal synchronization characteristic for PD and other neurological disorders. By design, these techniques are intrinsically demand-controlled methods, where the amplitude of the stimulation signal is reduced when the desired desynchronized regime is reached. We here introduce a novel demand-controlled stimulation method, pulsatile multisite linear delayed feedback (MLDF), by employing MLDF to modulate the pulse amplitude of high-frequency (HF) DBS, in this way aiming at a specific, MLDF-related desynchronizing impact, while maintaining safety requirements with the charge-balanced HF DBS. Previously, MLDF was computationally developed for the control of spatio-temporal synchronized patterns and cluster states in neuronal populations. Here, in a physiologically motivated model network comprising neurons from subthalamic nucleus (STN) and external globus pallidus (GPe), we compare pulsatile MLDF to pulsatile LDF for the case where the smooth feedback signals are used to modulate the amplitude of charge-balanced HF DBS and suggest a modification of pulsatile MLDF which enables a pronounced desynchronizing impact. Our results may contribute to further clinical development of closed-loop DBS techniques.

  View details for PubMedID 29449814

• Neuronal connectivity in major depressive disorder: a systematic review NEUROPSYCHIATRIC DISEASE AND TREATMENT Helm, K., Viol, K., Weiger, T. M., Tass, P. A., Grefkes, C., del Monte, D., Schiepek, G. 2018; 14: 2715–37

  View details for DOI 10.2147/NDT.S170989

  View details for Web of Science ID 000447518000001

• Letter: Electric Beats Open New Frontiers for Deep Brain Stimulation. Neurosurgery Halpern, C. H., Miller, K. J., Wu, H., Tass, P. A. 2018; 82 (1): E19–E20

  View details for PubMedID 29029326

• Neuronal connectivity in major depressive disorder: a systematic review. Neuropsychiatric disease and treatment Helm, K., Viol, K., Weiger, T. M., Tass, P. A., Grefkes, C., Del Monte, D., Schiepek, G. 2018; 14: 2715–37

  Abstract

  The causes of major depressive disorder (MDD), as one of the most common psychiatric disorders, still remain unclear. Neuroimaging has substantially contributed to understanding the putative neuronal mechanisms underlying depressed mood and motivational as well as cognitive impairments in depressed individuals. In particular, analyses addressing changes in interregional connectivity seem to be a promising approach to capture the effects of MDD at a systems level. However, a plethora of different, sometimes contradicting results have been published so far, making general conclusions difficult. Here we provide a systematic overview about connectivity studies published in the field over the last decade considering different methodological as well as clinical issues.A systematic review was conducted extracting neuronal connectivity results from studies published between 2002 and 2015. The findings were summarized in tables and were graphically visualized.The review supports and summarizes the notion of an altered frontolimbic mood regulation circuitry in MDD patients, but also stresses the heterogeneity of the findings. The brain regions that are most consistently affected across studies are the orbitomedial prefrontal cortex, anterior cingulate cortex, amygdala, hippocampus, cerebellum and the basal ganglia.The results on connectivity in MDD are very heterogeneous, partly due to different methods and study designs, but also due to the temporal dynamics of connectivity. While connectivity research is an important step toward a complex systems approach to brain functioning, future research should focus on the dynamics of functional and effective connectivity.

  View details for PubMedID 30425491

  View details for PubMedCentralID PMC6200438

• Dendritic and Axonal Propagation Delays May Shape Neuronal Networks With Plastic Synapses. Frontiers in physiology Madadi Asl, M., Valizadeh, A., Tass, P. A. 2018; 9: 1849

  Abstract

  Biological neuronal networks are highly adaptive and plastic. For instance, spike-timing-dependent plasticity (STDP) is a core mechanism which adapts the synaptic strengths based on the relative timing of pre- and postsynaptic spikes. In various fields of physiology, time delays cause a plethora of biologically relevant dynamical phenomena. However, time delays increase the complexity of model systems together with the computational and theoretical analysis burden. Accordingly, in computational neuronal network studies propagation delays were often neglected. As a downside, a classic STDP rule in oscillatory neurons without propagation delays is unable to give rise to bidirectional synaptic couplings, i.e., loops or uncoupled states. This is at variance with basic experimental results. In this mini review, we focus on recent theoretical studies focusing on how things change in the presence of propagation delays. Realistic propagation delays may lead to the emergence of neuronal activity and synaptic connectivity patterns, which cannot be captured by classic STDP models. In fact, propagation delays determine the inventory of attractor states and shape their basins of attractions. The results reviewed here enable to overcome fundamental discrepancies between theory and experiments. Furthermore, these findings are relevant for the development of therapeutic brain stimulation techniques aiming at shifting the diseased brain to more favorable attractor states.

  View details for PubMedID 30618847

  View details for PubMedCentralID PMC6307091

• Coordinated Reset Vibrotactile Stimulation Shows Prolonged Improvement in Parkinson's Disease MOVEMENT DISORDERS Syrkin-Nikolau, J., Neuville, R., O'Day, J., Anidi, C., Koop, M., Martin, T., Tass, P. A., Bronte-Stewart, H. 2018; 33 (1): 179–80

  View details for PubMedID 29150859

  View details for PubMedCentralID PMC5836884

• Letter: Electric Beats Open New Frontiers for Deep Brain Stimulation NEUROSURGERY Halpern, C. H., Miller, K. J., Wu, H., Tass, P. A. 2018; 82 (1): E19–E20

  View details for DOI 10.1093/neuros/nyx482

  View details for Web of Science ID 000424223500008

• Closed-loop deep brain stimulation by pulsatile delayed feedback with increased gap between pulse phases SCIENTIFIC REPORTS Popovych, O. V., Lysyansky, B., Tass, P. A. 2017; 7

  Abstract

  Computationally it was shown that desynchronizing delayed feedback stimulation methods are effective closed-loop techniques for the control of synchronization in ensembles of interacting oscillators. We here computationally design stimulation signals for electrical stimulation of neuronal tissue that preserve the desynchronizing delayed feedback characteristics and comply with mandatory charge deposit-related safety requirements. For this, the amplitude of the high-frequency (HF) train of biphasic charge-balanced pulses used by the standard HF deep brain stimulation (DBS) is modulated by the smooth feedback signals. In this way we combine the desynchronizing delayed feedback approach with the HF DBS technique. We show that such a pulsatile delayed feedback stimulation can effectively and robustly desynchronize a network of model neurons comprising subthalamic nucleus and globus pallidus external and suggest this approach for desynchronizing closed-loop DBS. Intriguingly, an interphase gap introduced between the recharging phases of the charge-balanced biphasic pulses can significantly improve the stimulation-induced desynchronization and reduce the amount of the administered stimulation. In view of the recent experimental and clinical studies indicating a superiority of the closed-loop DBS to open-loop HF DBS, our results may contribute to a further development of effective stimulation methods for the treatment of neurological disorders characterized by abnormal neuronal synchronization.

  View details for DOI 10.1038/s41598-017-01067-x

  View details for Web of Science ID 000399972900032

  View details for PubMedID 28432303

• Pulsatile desynchronizing delayed feedback for closed-loop deep brain stimulation PLOS ONE Popovych, O. V., Lysyansky, B., Rosenblum, M., Pikovsky, A., Tass, P. A. 2017; 12 (3): e0173363

  View details for DOI 10.1371/journal.pone.0173363

• Acute effects and after-effects of acoustic coordinated reset neuromodulation in patients with chronic subjective tinnitus. NeuroImage. Clinical Adamchic, I., Toth, T., Hauptmann, C., Walger, M., Langguth, B., Klingmann, I., Tass, P. A. 2017; 15: 541–58

  Abstract

  Chronic subjective tinnitus is an auditory phantom phenomenon characterized by abnormal neuronal synchrony in the central auditory system. As shown computationally, acoustic coordinated reset (CR) neuromodulation causes a long-lasting desynchronization of pathological synchrony by downregulating abnormal synaptic connectivity. In a previous proof of concept study acoustic CR neuromodulation, employing stimulation tone patterns tailored to the dominant tinnitus frequency, was compared to noisy CR-like stimulation, a CR version significantly detuned by sparing the tinnitus-related pitch range and including substantial random variability of the tone spacing on the frequency axis. Both stimulation protocols caused an acute relief as measured with visual analogue scale scores for tinnitus loudness (VAS-L) and annoyance (VAS-A) in the stimulation-ON condition (i.e. 15 min after stimulation onset), but only acoustic CR neuromodulation had sustained long-lasting therapeutic effects after 12 weeks of treatment as assessed with VAS-L, VAS-A scores and a tinnitus questionnaire (TQ) in the stimulation-OFF condition (i.e. with patients being off stimulation for at least 2.5 h). To understand the source of the long-lasting therapeutic effects, we here study whether acoustic CR neuromodulation has different electrophysiological effects on oscillatory brain activity as compared to noisy CR-like stimulation under stimulation-ON conditions and immediately after cessation of stimulation. To this end, we used a single-blind, single application, cross over design in 18 patients with chronic tonal subjective tinnitus and administered three different 16-minute stimulation protocols: acoustic CR neuromodulation, noisy CR-like stimulation and low frequency range (LFR) stimulation, a CR type stimulation with deliberately detuned pitch and repetition rate of stimulation tones, as control stimulation. We measured VAS-L and VAS-A scores together with spontaneous EEG activity pre-, during- and post-stimulation. Under stimulation-ON conditions acoustic CR neuromodulation and noisy CR-like stimulation had similar effects: a reduction of VAS-L and VAS-A scores together with a decrease of auditory delta power and an increase of auditory alpha and gamma power, without significant differences. In contrast, LFR stimulation had significantly weaker EEG effects and no significant clinical effects under stimulation-ON conditions. The distinguishing feature between acoustic CR neuromodulation and noisy CR-like stimulation were the electrophysiological after-effects. Acoustic CR neuromodulation caused the longest significant reduction of delta and gamma and increase of alpha power in the auditory cortex region. Noisy CR-like stimulation had weaker and LFR stimulation hardly any electrophysiological after-effects. This qualitative difference further supports the assertion that long-term effects of acoustic CR neuromodulation on tinnitus are mediated by a specific disruption of synchronous neural activity. Furthermore, our results indicate that acute electrophysiological after-effects might serve as a marker to further improve desynchronizing sound stimulation.

  View details for PubMedID 28652968

  View details for PubMedCentralID PMC5476468

• Sensorimotor rhythm neurofeedback as adjunct therapy for Parkinson's disease. Annals of clinical and translational neurology Philippens, I. H., Wubben, J. A., Vanwersch, R. A., Estevao, D. L., Tass, P. A. 2017; 4 (8): 585–90

  Abstract

  Neurofeedback may enhance compensatory brain mechanisms. EEG-based sensorimotor rhythm neurofeedback training was suggested to be beneficial in Parkinson's disease. In a placebo-controlled study in parkinsonian nonhuman primates we here show that sensorimotor rhythm neurofeedback training reduces MPTP-induced parkinsonian symptoms and both ON and OFF scores during classical L-DOPA treatment. Our findings encourage further development of sensorimotor rhythm neurofeedback training as adjunct therapy for Parkinson's disease which might help reduce L-DOPA-induced side effects.

  View details for PubMedID 28812048

  View details for PubMedCentralID PMC5553225

• Vibrotactile Coordinated Reset Stimulation for the Treatment of Neurological Diseases: Concepts and Device Specifications. Cureus Tass, P. A. 2017; 9 (8): e1535

  Abstract

  Coordinated reset stimulation (CRS) consists of spatiotemporal sequences of stimuli delivered to different sites in the brain. Computationally, it was shown that by achieving an unlearning of abnormal synaptic connectivity, CRS can cause a long-lasting reduction of pathological synchronization, a hallmark feature of Parkinson's disease and other brain disorders. Pre-clinical and proof of concept clinical studies in parkinsonian monkeys and patients showed that CRS applied through deep brain stimulation electrodes implanted in the subthalamic nucleus resulted in cumulative and long-lasting therapeutic effects along with a reduction of beta band oscillations. To apply CRS noninvasively by vibrotactile stimulation delivered to different fingertips, we present three different possible stimulation concepts. These different CRS approaches target different mechanoreceptors and related stimulus mechanisms. The different approaches are based on the diverse physiology of mechanoreceptors and dynamic CRS principles. Required stimulation parameters and specifications provide a guideline for technically implementing vibrotactile CRS during clinical tests.

  View details for PubMedID 28983444

  View details for PubMedCentralID PMC5624565

• Dendritic and Axonal Propagation Delays Determine Emergent Structures of Neuronal Networks with Plastic Synapses Scientific Reports Madadi Asl, M., Valizadeh, A., Tass, P. A. 2017; 7: 39682

  View details for DOI 10.1038/srep39682

• Validation of a Mobile Device for Acoustic Coordinated Reset Neuromodulation Tinnitus Therapy JOURNAL OF THE AMERICAN ACADEMY OF AUDIOLOGY Hauptmann, C., Wegener, A., Poppe, H., Williams, M., Popelka, G., Tass, P. A. 2016; 27 (9): 720-731

  Abstract

  Sound-based tinnitus intervention stimuli include broad-band noise signals with subjectively adjusted bandwidths used as maskers delivered by commercial devices or hearing aids, environmental sounds broadly described and delivered by both consumer devices and hearing aids, music recordings specifically modified and delivered in a variety of different ways, and other stimuli. Acoustic coordinated reset neuromodulation therapy for tinnitus reduction has unique and more stringent requirements compared to all other sound-based tinnitus interventions. These include precise characterization of tinnitus pitch and loudness, and effective provision of patient-controlled daily therapy signals at defined frequencies, levels, and durations outside of the clinic.The purpose of this study was to evaluate an approach to accommodate these requirements including evaluation of a mobile device, validation of an automated tinnitus pitch-matching algorithm and assessment of a patient's ability to control stimuli and collect repeated outcome measures.The experimental design involved direct laboratory measurements of the sound delivery capabilities of a mobile device, comparison of an automated, adaptive pitch-matching method to a traditional manual method and measures of a patient's ability to understand and manipulate a mobile device graphic user interface to both deliver the therapy signals and collect the outcome measures.This study consisted of 5 samples of a common mobile device for the laboratory measures and a total of 30 adult participants: 15 randomly selected normal-hearing participants with simulated tinnitus for validation of a tinnitus pitch-matching algorithm and 15 sequentially selected patients already undergoing tinnitus therapy for evaluation of patient usability.No tinnitus intervention(s) were specifically studied as a component of this study.Data collection involved laboratory measures of mobile devices, comparison of manual and automated adaptive tinnitus pitch-matching psychoacoustic procedures in the same participant analyzed for absolute differences (t test), variance differences (f test), and range comparisons, and assessment of patient usability including questionnaire measures and logs of patient observations.Mobile devices are able to reliably and accurately deliver the acoustic therapy signals. There was no difference in mean pitch matches (t test, p > 0.05) between an automated adaptive method compared to a traditional manual pitch-matching method. However, the variability of the automated pitch-matching method was much less (f test, p < 0.05) with twice as many matches within the predefined error range (±5%) compared to the manual pitch-matching method (80% versus 40%). After a short initial training, all participants were able to use the mobile device effectively and to perform the required tasks without further professional assistance.

  View details for DOI 10.3766/jaaa.15082

  View details for Web of Science ID 000384630200005

  View details for PubMedID 27718349

• Capacitive Feedthroughs for Medical Implants FRONTIERS IN NEUROSCIENCE Grob, S., Tass, P. A., Hauptmann, C. 2016; 10

  Abstract

  Important technological advances in the last decades paved the road to a great success story for electrically stimulating medical implants, including cochlear implants or implants for deep brain stimulation. However, there are still many challenges in reducing side effects and improving functionality and comfort for the patient. Two of the main challenges are the wish for smaller implants on one hand, and the demand for more stimulation channels on the other hand. But these two aims lead to a conflict of interests. This paper presents a novel design for an electrical feedthrough, the so called capacitive feedthrough, which allows both reducing the size, and increasing the number of included channels. Capacitive feedthroughs combine the functionality of a coupling capacitor and an electrical feedthrough within one and the same structure. The paper also discusses the progress and the challenges of the first produced demonstrators. The concept bears a high potential in improving current feedthrough technology, and could be applied on all kinds of electrical medical implants, even if its implementation might be challenging.

  View details for DOI 10.3389/fnins.2016.00404

  View details for Web of Science ID 000382912800001

  View details for PubMedID 27660602

  View details for PubMedCentralID PMC5014865

• Anti-kindling Induced by Two-Stage Coordinated Reset Stimulation with Weak Onset Intensity FRONTIERS IN COMPUTATIONAL NEUROSCIENCE Zeitler, M., Tass, P. A. 2016; 10

  Abstract

  Abnormal neuronal synchrony plays an important role in a number of brain diseases. To specifically counteract abnormal neuronal synchrony by desynchronization, Coordinated Reset (CR) stimulation, a spatiotemporally patterned stimulation technique, was designed with computational means. In neuronal networks with spike timing-dependent plasticity CR stimulation causes a decrease of synaptic weights and finally anti-kindling, i.e., unlearning of abnormally strong synaptic connectivity and abnormal neuronal synchrony. Long-lasting desynchronizing aftereffects of CR stimulation have been verified in pre-clinical and clinical proof of concept studies. In general, for different neuromodulation approaches, both invasive and non-invasive, it is desirable to enable effective stimulation at reduced stimulation intensities, thereby avoiding side effects. For the first time, we here present a two-stage CR stimulation protocol, where two qualitatively different types of CR stimulation are delivered one after another, and the first stage comes at a particularly weak stimulation intensity. Numerical simulations show that a two-stage CR stimulation can induce the same degree of anti-kindling as a single-stage CR stimulation with intermediate stimulation intensity. This stimulation approach might be clinically beneficial in patients suffering from brain diseases characterized by abnormal neuronal synchrony where a first treatment stage should be performed at particularly weak stimulation intensities in order to avoid side effects. This might, e.g., be relevant in the context of acoustic CR stimulation in tinnitus patients with hyperacusis or in the case of electrical deep brain CR stimulation with sub-optimally positioned leads or side effects caused by stimulation of the target itself. We discuss how to apply our method in first in man and proof of concept studies.

  View details for DOI 10.3389/fncom.2016.00044

  View details for Web of Science ID 000375840700001

  View details for PubMedID 27242500

  View details for PubMedCentralID PMC4868855

• Noise-enhanced coupling between two oscillators with long-term plasticity PHYSICAL REVIEW E Luecken, L., Popovych, O. V., Tass, P. A., Yanchuk, S. 2016; 93 (3)

  Abstract

  Spike timing-dependent plasticity is a fundamental adaptation mechanism of the nervous system. It induces structural changes of synaptic connectivity by regulation of coupling strengths between individual cells depending on their spiking behavior. As a biophysical process its functioning is constantly subjected to natural fluctuations. We study theoretically the influence of noise on a microscopic level by considering only two coupled neurons. Adopting a phase description for the neurons we derive a two-dimensional system which describes the averaged dynamics of the coupling strengths. We show that a multistability of several coupling configurations is possible, where some configurations are not found in systems without noise. Intriguingly, it is possible that a strong bidirectional coupling, which is not present in the noise-free situation, can be stabilized by the noise. This means that increased noise, which is normally expected to desynchronize the neurons, can be the reason for an antagonistic response of the system, which organizes itself into a state of stronger coupling and counteracts the impact of noise. This mechanism, as well as a high potential for multistability, is also demonstrated numerically for a coupled pair of Hodgkin-Huxley neurons.

  View details for DOI 10.1103/PhysRevE.93.032210

  View details for Web of Science ID 000371745300003

  View details for PubMedID 27078347

• SUPPRESSION OF SPONTANEOUS OSCILLATIONS IN HIGH- FREQUENCY STIMULATED NEURON MODELS LITHUANIAN JOURNAL OF PHYSICS Pyragas, K., Tass, P. A. 2016; 56 (4): 223-238

  View details for Web of Science ID 000392688800005

• The Spacing Principle for Unlearning Abnormal Neuronal Synchrony PLOS ONE Popovych, O. V., Xenakis, M. N., Tass, P. A. 2015; 10 (2)

  Abstract

  Desynchronizing stimulation techniques were developed to specifically counteract abnormal neuronal synchronization relevant to several neurological and psychiatric disorders. The goal of our approach is to achieve an anti-kindling, where the affected neural networks unlearn abnormal synaptic connectivity and, hence, abnormal neuronal synchrony, by means of desynchronizing stimulation, in particular, Coordinated Reset (CR) stimulation. As known from neuroscience, psychology and education, learning effects can be enhanced by means of the spacing principle, i.e. by delivering repeated stimuli spaced by pauses as opposed to delivering a massed stimulus (in a single long stimulation session). To illustrate that the spacing principle may boost the anti-kindling effect of CR neuromodulation, in this computational study we carry this approach to extremes. To this end, we deliver spaced CR neuromodulation at particularly weak intensities which render permanently delivered CR neuromodulation ineffective. Intriguingly, spaced CR neuromodulation at these particularly weak intensities effectively induces an anti-kindling. In fact, the spacing principle enables the neuronal population to successively hop from one attractor to another one, finally approaching attractors characterized by down-regulated synaptic connectivity and synchrony. Our computational results might open up novel opportunities to effectively induce sustained desynchronization at particularly weak stimulation intensities, thereby avoiding side effects, e.g., in the case of deep brain stimulation.

  View details for DOI 10.1371/journal.pone.0117205

  View details for Web of Science ID 000350168700030

  View details for PubMedID 25714553

  View details for PubMedCentralID PMC4340932

• Maladaptive neual synchrony in tinnitus: origin and restoration FRONTIERS IN NEUROLOGY Eggermont, J. J., Tass, P. A. 2015; 6

  Abstract

  Tinnitus is the conscious perception of sound heard in the absence of physical sound sources external or internal to the body, reflected in aberrant neural synchrony of spontaneous or resting-state brain activity. Neural synchrony is generated by the nearly simultaneous firing of individual neurons, of the synchronization of membrane-potential changes in local neural groups as reflected in the local field potentials, resulting in the presence of oscillatory brain waves in the EEG. Noise-induced hearing loss, often resulting in tinnitus, causes a reorganization of the tonotopic map in auditory cortex and increased spontaneous firing rates and neural synchrony. Spontaneous brain rhythms rely on neural synchrony. Abnormal neural synchrony in tinnitus appears to be confined to specific frequency bands of brain rhythms. Increases in delta-band activity are generated by deafferented/deprived neuronal networks resulting from hearing loss. Coordinated reset (CR) stimulation was developed in order to specifically counteract such abnormal neuronal synchrony by desynchronization. The goal of acoustic CR neuromodulation is to desynchronize tinnitus-related abnormal delta-band oscillations. CR neuromodulation does not require permanent stimulus delivery in order to achieve long-lasting desynchronization or even a full-blown anti-kindling but may have cumulative effects, i.e., the effect of different CR epochs separated by pauses may accumulate. Unlike other approaches, acoustic CR neuromodulation does not intend to reduce tinnitus-related neuronal activity by employing lateral inhibition. The potential efficacy of acoustic CR modulation was shown in a clinical proof of concept trial, where effects achieved in 12 weeks of treatment delivered 4-6 h/day persisted through a preplanned 4-week therapy pause and showed sustained long-term effects after 10 months of therapy, leading to 75% responders.

  View details for DOI 10.3389/fneur.2015.00029

  View details for Web of Science ID 000363758800001

  View details for PubMedID 25741316

  View details for PubMedCentralID PMC4330892

• Mathematical modeling of chemotaxis and glial scarring around implanted electrodes NEW JOURNAL OF PHYSICS Silchenko, A. N., Tass, P. A. 2015; 17

  View details for DOI 10.1088/1367-2630/17/2/023009

  View details for Web of Science ID 000352864600009

• Acoustic Coordinated Reset Neuromodulation in a Real Life Patient Population with Chronic Tonal Tinnitus. BioMed research international Hauptmann, C., Ströbel, A., Williams, M., Patel, N., Wurzer, H., von Stackelberg, T., Brinkmann, U., Langguth, B., Tass, P. A. 2015; 2015: 569052-?

  Abstract

  Primary tinnitus has a severe negative influence on the quality of life of a significant portion of the general population. Acoustic coordinated reset neuromodulation is designed to induce a long-lasting reduction of tinnitus symptoms. To test acoustic coordinated reset neuromodulation as a treatment for chronic, tonal tinnitus under real life conditions, an outpatient study "RESET Real Life" was commissioned by ANM GmbH. Herein we present the results of this study.In a prospective, open-label, nonrandomized, noncontrolled multicenter clinical study with 200 chronic tinnitus patients, tinnitus questionnaire TBF-12 and Global Clinical Improvement-Impression Scale (CGI-I7) are used to study the safety and efficacy of acoustic coordinated reset neuromodulation. 189 patients completed the last 12-month visit, 11 patients dropped out (8 because of nontreatment related reasons; 2 because tinnitus did not change; and 1 because tinnitus got louder).Acoustic coordinated reset neuromodulation caused a statistically and clinically significant decrease in TBF-12 scores as well as in CGI-I7 after 12 months of therapy under real life conditions. There were no persistent adverse events reported that were related to the therapy.The field study "RESET Real Life" provides evidence for safety and efficacy of acoustic coordinated reset neuromodulation in a prospective, open-label, real life setting.

  View details for DOI 10.1155/2015/569052

  View details for PubMedID 26568958

  View details for PubMedCentralID PMC4629059

• Augmented brain function by coordinated reset stimulation with slowly varying sequences. Frontiers in systems neuroscience Zeitler, M., Tass, P. A. 2015; 9: 49-?

  Abstract

  Several brain disorders are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was developed to selectively counteract abnormal neuronal synchrony by desynchronization. For this, phase resetting stimuli are delivered to different subpopulations in a timely coordinated way. In neural networks with spike timing-dependent plasticity CR stimulation may eventually lead to an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and abnormal synchrony. The spatiotemporal sequence by which all stimulation sites are stimulated exactly once is called the stimulation site sequence, or briefly sequence. So far, in simulations, pre-clinical and clinical applications CR was applied either with fixed sequences or rapidly varying sequences (RVS). In this computational study we show that appropriate repetition of the sequence with occasional random switching to the next sequence may significantly improve the anti-kindling effect of CR. To this end, a sequence is applied many times before randomly switching to the next sequence. This new method is called SVS CR stimulation, i.e., CR with slowly varying sequences. In a neuronal network with strong short-range excitatory and weak long-range inhibitory dynamic couplings SVS CR stimulation turns out to be superior to CR stimulation with fixed sequences or RVS.

  View details for DOI 10.3389/fnsys.2015.00049

  View details for PubMedID 25873867

  View details for PubMedCentralID PMC4379899

• Acoustic Coordinated Reset Neuromodulation in a Real Life Patient Population with Chronic Tonal Tinnitus BIOMED RESEARCH INTERNATIONAL Hauptmann, C., Stroebel, A., Williams, M., Patel, N., Wurzer, H., von Stackelberg, T., Brinkmann, U., Langguth, B., Tass, P. A. 2015

  Abstract

  Primary tinnitus has a severe negative influence on the quality of life of a significant portion of the general population. Acoustic coordinated reset neuromodulation is designed to induce a long-lasting reduction of tinnitus symptoms. To test acoustic coordinated reset neuromodulation as a treatment for chronic, tonal tinnitus under real life conditions, an outpatient study "RESET Real Life" was commissioned by ANM GmbH. Herein we present the results of this study.In a prospective, open-label, nonrandomized, noncontrolled multicenter clinical study with 200 chronic tinnitus patients, tinnitus questionnaire TBF-12 and Global Clinical Improvement-Impression Scale (CGI-I7) are used to study the safety and efficacy of acoustic coordinated reset neuromodulation. 189 patients completed the last 12-month visit, 11 patients dropped out (8 because of nontreatment related reasons; 2 because tinnitus did not change; and 1 because tinnitus got louder).Acoustic coordinated reset neuromodulation caused a statistically and clinically significant decrease in TBF-12 scores as well as in CGI-I7 after 12 months of therapy under real life conditions. There were no persistent adverse events reported that were related to the therapy.The field study "RESET Real Life" provides evidence for safety and efficacy of acoustic coordinated reset neuromodulation in a prospective, open-label, real life setting.

  View details for DOI 10.1155/2015/569052

  View details for Web of Science ID 000364067900001

  View details for PubMedCentralID PMC4629059

• Coordinated reset stimulation in a large-scale model of the STN-GPe circuit FRONTIERS IN COMPUTATIONAL NEUROSCIENCE Ebert, M., Hauptmann, C., Tass, P. A. 2014; 8

  Abstract

  Synchronization of populations of neurons is a hallmark of several brain diseases. Coordinated reset (CR) stimulation is a model-based stimulation technique which specifically counteracts abnormal synchrony by desynchronization. Electrical CR stimulation, e.g., for the treatment of Parkinson's disease (PD), is administered via depth electrodes. In order to get a deeper understanding of this technique, we extended the top-down approach of previous studies and constructed a large-scale computational model of the respective brain areas. Furthermore, we took into account the spatial anatomical properties of the simulated brain structures and incorporated a detailed numerical representation of 2 · 10(4) simulated neurons. We simulated the subthalamic nucleus (STN) and the globus pallidus externus (GPe). Connections within the STN were governed by spike-timing dependent plasticity (STDP). In this way, we modeled the physiological and pathological activity of the considered brain structures. In particular, we investigated how plasticity could be exploited and how the model could be shifted from strongly synchronized (pathological) activity to strongly desynchronized (healthy) activity of the neuronal populations via CR stimulation of the STN neurons. Furthermore, we investigated the impact of specific stimulation parameters especially the electrode position on the stimulation outcome. Our model provides a step forward toward a biophysically realistic model of the brain areas relevant to the emergence of pathological neuronal activity in PD. Furthermore, our model constitutes a test bench for the optimization of both stimulation parameters and novel electrode geometries for efficient CR stimulation.

  View details for DOI 10.3389/fncom.2014.00154

  View details for Web of Science ID 000346835800001

  View details for PubMedID 25505882

  View details for PubMedCentralID PMC4245901

• Coordinated Reset Neuromodulation for Parkinson's Disease: Proof-of-Concept Study MOVEMENT DISORDERS Adamchic, I., Hauptmann, C., Barnikol, U., Pawelczyk, N., Popovych, O., Barnikol, T., Silchenko, A., Volkmann, J., Deuschl, G., Meissner, W. G., Maarouf, M., Sturm, V., Freund, H., Tass, P. 2014; 29 (13): 1679–84

  Abstract

  The discovery of abnormal synchronization of neuronal activity in the basal ganglia in Parkinson's disease (PD) has prompted the development of novel neuromodulation paradigms. Coordinated reset neuromodulation intends to specifically counteract excessive synchronization and to induce cumulative unlearning of pathological synaptic connectivity and neuronal synchrony.In this prospective case series, six PD patients were evaluated before and after coordinated reset neuromodulation according to a standardized protocol that included both electrophysiological recordings and clinical assessments.Coordinated reset neuromodulation of the subthalamic nucleus (STN) applied to six PD patients in an externalized setting during three stimulation days induced a significant and cumulative reduction of beta band activity that correlated with a significant improvement of motor function.These results highlight the potential effects of coordinated reset neuromodulation of the STN in PD patients and encourage further development of this approach as an alternative to conventional high-frequency deep brain stimulation in PD.

  View details for DOI 10.1002/mds.25923

  View details for Web of Science ID 000344648400016

  View details for PubMedID 24976001

  View details for PubMedCentralID PMC4282372

• Interoperable atlases of the human brain NEUROIMAGE Amunts, K., Hawrylycz, M. J., Van Essen, D. C., Van Horn, J. D., Harel, N., Poline, J., De Martino, F., Bjaalie, J. G., Dehaene-Lambertz, G., Dehaene, S., Valdes-Sosa, P., Thirion, B., Zilles, K., Hill, S. L., Abrams, M. B., Tass, P. A., Vanduffel, W., Evans, A. C., Eickhoff, S. B. 2014; 99: 525-532

  Abstract

  The last two decades have seen an unprecedented development of human brain mapping approaches at various spatial and temporal scales. Together, these have provided a large fundus of information on many different aspects of the human brain including micro- and macrostructural segregation, regional specialization of function, connectivity, and temporal dynamics. Atlases are central in order to integrate such diverse information in a topographically meaningful way. It is noteworthy, that the brain mapping field has been developed along several major lines such as structure vs. function, postmortem vs. in vivo, individual features of the brain vs. population-based aspects, or slow vs. fast dynamics. In order to understand human brain organization, however, it seems inevitable that these different lines are integrated and combined into a multimodal human brain model. To this aim, we held a workshop to determine the constraints of a multi-modal human brain model that are needed to enable (i) an integration of different spatial and temporal scales and data modalities into a common reference system, and (ii) efficient data exchange and analysis. As detailed in this report, to arrive at fully interoperable atlases of the human brain will still require much work at the frontiers of data acquisition, analysis, and representation. Among them, the latter may provide the most challenging task, in particular when it comes to representing features of vastly different scales of space, time and abstraction. The potential benefits of such endeavor, however, clearly outweigh the problems, as only such kind of multi-modal human brain atlas may provide a starting point from which the complex relationships between structure, function, and connectivity may be explored.

  View details for DOI 10.1016/j.neuroimage.2014.06.010

  View details for Web of Science ID 000339860000051

  View details for PubMedID 24936682

• Abnormal cross-frequency coupling in the tinnitus network FRONTIERS IN NEUROSCIENCE Adamchic, I., Langguth, B., Hauptmann, C., Tass, P. A. 2014; 8

  Abstract

  Neuroimaging studies have identified networks of brain areas and oscillations associated with tinnitus perception. However, how these regions relate to perceptual characteristics of tinnitus, and how oscillations in various frequency bands are associated with communications within the tinnitus network is still incompletely understood. Recent evidence suggests that apart from changes of the tinnitus severity the changes of tinnitus dominant pitch also have modulating effect on the underlying neuronal activity in a number of brain areas within the tinnitus network. Therefore, in a re-analysis of an existing dataset, we sought to determine how the oscillations in the tinnitus network in the various frequency bands interact. We also investigate how changes of tinnitus loudness, annoyance and pitch affect cross-frequency interaction both within and between nodes of the tinnitus network. Results of this study provide, to our knowledge, the first evidence that in tinnitus patients, aside from the previously described changes of oscillatory activity, there are also changes of cross-frequency coupling (CFC); phase-amplitude CFC was increased in tinnitus patients within the auditory cortex and the dorsolateral prefrontal regions between the phase of delta-theta and the amplitude of gamma oscillations (Modulation Index [MI] 0.17 in tinnitus patients vs. 0.08 in tinnitus free controls). Moreover, theta phase in the anterior cingulate region modulated gamma in the auditory (MI 0.1) and dorsolateral prefrontal regions (MI 0.19). Reduction of tinnitus severity after acoustic coordinated reset therapy led to a partial normalization of abnormal CFC. Also treatment induced changes in tinnitus pitch significantly modulated changes in CFC. Thus, tinnitus perception is associated with a more pronounced CFC within and between nodes of the tinnitus network. CFC can coordinate tinnitus-relevant activity in the tinnitus network providing a mechanism for effective communication between nodes of this network.

  View details for DOI 10.3389/fnins.2014.00284

  View details for Web of Science ID 000346533300001

  View details for PubMedID 25309309

  View details for PubMedCentralID PMC4174755

• Reversing pathologically increased EEG power by acoustic coordinated reset neuromodulation HUMAN BRAIN MAPPING Adamchic, I., Toth, T., Hauptmann, C., Tass, P. 2014; 35 (5): 2099–2118

  Abstract

  Acoustic Coordinated Reset (CR) neuromodulation is a patterned stimulation with tones adjusted to the patient's dominant tinnitus frequency, which aims at desynchronizing pathological neuronal synchronization. In a recent proof-of-concept study, CR therapy, delivered 4-6 h/day more than 12 weeks, induced a significant clinical improvement along with a significant long-lasting decrease of pathological oscillatory power in the low frequency as well as γ band and an increase of the α power in a network of tinnitus-related brain areas. As yet, it remains unclear whether CR shifts the brain activity toward physiological levels or whether it induces clinically beneficial, but nonetheless abnormal electroencephalographic (EEG) patterns, for example excessively decreased δ and/or γ. Here, we compared the patients' spontaneous EEG data at baseline as well as after 12 weeks of CR therapy with the spontaneous EEG of healthy controls by means of Brain Electrical Source Analysis source montage and standardized low-resolution brain electromagnetic tomography techniques. The relationship between changes in EEG power and clinical scores was investigated using a partial least squares approach. In this way, we show that acoustic CR neuromodulation leads to a normalization of the oscillatory power in the tinnitus-related network of brain areas, most prominently in temporal regions. A positive association was found between the changes in tinnitus severity and the normalization of δ and γ power in the temporal, parietal, and cingulate cortical regions. Our findings demonstrate a widespread CR-induced normalization of EEG power, significantly associated with a reduction of tinnitus severity.

  View details for DOI 10.1002/hbm.22314

  View details for Web of Science ID 000334012100022

  View details for PubMedID 23907785

  View details for PubMedCentralID PMC4216412

• Control of abnormal synchronization in neurological disorders FRONTIERS IN NEUROLOGY Popovych, O., Tass, P. A. 2014; 5

  Abstract

  In the nervous system, synchronization processes play an important role, e.g., in the context of information processing and motor control. However, pathological, excessive synchronization may strongly impair brain function and is a hallmark of several neurological disorders. This focused review addresses the question of how an abnormal neuronal synchronization can specifically be counteracted by invasive and non-invasive brain stimulation as, for instance, by deep brain stimulation for the treatment of Parkinson's disease, or by acoustic stimulation for the treatment of tinnitus. On the example of coordinated reset (CR) neuromodulation, we illustrate how insights into the dynamics of complex systems contribute to successful model-based approaches, which use methods from synergetics, non-linear dynamics, and statistical physics, for the development of novel therapies for normalization of brain function and synaptic connectivity. Based on the intrinsic multistability of the neuronal populations induced by spike timing-dependent plasticity (STDP), CR neuromodulation utilizes the mutual interdependence between synaptic connectivity and dynamics of the neuronal networks in order to restore more physiological patterns of connectivity via desynchronization of neuronal activity. The very goal is to shift the neuronal population by stimulation from an abnormally coupled and synchronized state to a desynchronized regime with normalized synaptic connectivity, which significantly outlasts the stimulation cessation, so that long-lasting therapeutic effects can be achieved.

  View details for DOI 10.3389/fneur.2014.00268

  View details for Web of Science ID 000209629300251

  View details for PubMedCentralID PMC4267271

• Control of abnormal synchronization in neurological disorders. Frontiers in neurology Popovych, O. V., Tass, P. A. 2014; 5: 268-?

  Abstract

  In the nervous system, synchronization processes play an important role, e.g., in the context of information processing and motor control. However, pathological, excessive synchronization may strongly impair brain function and is a hallmark of several neurological disorders. This focused review addresses the question of how an abnormal neuronal synchronization can specifically be counteracted by invasive and non-invasive brain stimulation as, for instance, by deep brain stimulation for the treatment of Parkinson's disease, or by acoustic stimulation for the treatment of tinnitus. On the example of coordinated reset (CR) neuromodulation, we illustrate how insights into the dynamics of complex systems contribute to successful model-based approaches, which use methods from synergetics, non-linear dynamics, and statistical physics, for the development of novel therapies for normalization of brain function and synaptic connectivity. Based on the intrinsic multistability of the neuronal populations induced by spike timing-dependent plasticity (STDP), CR neuromodulation utilizes the mutual interdependence between synaptic connectivity and dynamics of the neuronal networks in order to restore more physiological patterns of connectivity via desynchronization of neuronal activity. The very goal is to shift the neuronal population by stimulation from an abnormally coupled and synchronized state to a desynchronized regime with normalized synaptic connectivity, which significantly outlasts the stimulation cessation, so that long-lasting therapeutic effects can be achieved.

  View details for DOI 10.3389/fneur.2014.00268

  View details for PubMedID 25566174

  View details for PubMedCentralID PMC4267271

• Mechanism of suppression of sustained neuronal spiking under high-frequency stimulation BIOLOGICAL CYBERNETICS Pyragas, K., Novicenko, V., Tass, P. 2013; 107 (6): 669–84

  Abstract

  Using Hodgkin-Huxley and isolated subthalamic nucleus (STN) model neurons as examples, we show that electrical high-frequency stimulation (HFS) suppresses sustained neuronal spiking. The mechanism of suppression is explained on the basis of averaged equations derived from the original neuron equations in the limit of high frequencies. We show that for frequencies considerably greater than the reciprocal of the neuron's characteristic time scale, the result of action of HFS is defined by the ratio between the amplitude and the frequency of the stimulating signal. The effect of suppression emerges due to a stabilization of the neuron's resting state or due to a stabilization of a low-amplitude subthreshold oscillation of its membrane potential. Intriguingly, although we neglect synaptic dynamics, neural circuity as well as contribution of glial cells, the results obtained with the isolated high-frequency stimulated STN model neuron resemble the clinically observed relations between stimulation amplitude and stimulation frequency required to suppress Parkinsonian tremor.

  View details for DOI 10.1007/s00422-013-0567-1

  View details for Web of Science ID 000328202200004

  View details for PubMedID 24146294

  View details for PubMedCentralID PMC3840296

• Self-organized noise resistance of oscillatory neural networks with spike timing-dependent plasticity SCIENTIFIC REPORTS Popovych, O. V., Yanchuk, S., Tass, P. A. 2013; 3: 2926

  Abstract

  Intuitively one might expect independent noise to be a powerful tool for desynchronizing a population of synchronized neurons. We here show that, intriguingly, for oscillatory neural populations with adaptive synaptic weights governed by spike timing-dependent plasticity (STDP) the opposite is true. We found that the mean synaptic coupling in such systems increases dynamically in response to the increase of the noise intensity, and there is an optimal noise level, where the amount of synaptic coupling gets maximal in a resonance-like manner as found for the stochastic or coherence resonances, although the mechanism in our case is different. This constitutes a noise-induced self-organization of the synaptic connectivity, which effectively counteracts the desynchronizing impact of independent noise over a wide range of the noise intensity. Given the attempts to counteract neural synchrony underlying tinnitus with noisers and maskers, our results may be of clinical relevance.

  View details for DOI 10.1038/srep02926

  View details for Web of Science ID 000325536600005

  View details for PubMedID 24113385

  View details for PubMedCentralID PMC4070574

• Computational modeling of chemotactic signaling and aggregation of microglia around implantation site during deep brain stimulation EUROPEAN PHYSICAL JOURNAL-SPECIAL TOPICS Silchenko, A. N., Tass, P. A. 2013; 222 (10): 2647–53

  View details for DOI 10.1140/epjst/e2013-02044-5

  View details for Web of Science ID 000326166600023

• Impact of acoustic coordinated reset neuromodulation on effective connectivity in a neural network of phantom sound NEUROIMAGE Silchenko, A. N., Adamchic, I., Hauptmann, C., Tass, P. A. 2013; 77: 133–47

  Abstract

  Chronic subjective tinnitus is an auditory phantom phenomenon characterized by abnormal neuronal synchrony in the central auditory system. As recently shown in a proof of concept clinical trial, acoustic coordinated reset (CR) neuromodulation causes a significant relief of tinnitus symptoms combined with a significant decrease of pathological oscillatory activity in a network comprising auditory and non-auditory brain areas. The objective of the present study was to analyze whether CR therapy caused an alteration of the effective connectivity in a tinnitus related network of localized EEG brain sources. To determine which connections matter, in a first step, we considered a larger network of brain sources previously associated with tinnitus. To that network we applied a data-driven approach, combining empirical mode decomposition and partial directed coherence analysis, in patients with bilateral tinnitus before and after 12 weeks of CR therapy as well as in healthy controls. To increase the signal-to-noise ratio, we focused on the good responders, classified by a reliable-change-index (RCI). Prior to CR therapy and compared to the healthy controls, the good responders showed a significantly increased connectivity between the left primary cortex auditory cortex and the posterior cingulate cortex in the gamma and delta bands together with a significantly decreased effective connectivity between the right primary auditory cortex and the dorsolateral prefrontal cortex in the alpha band. Intriguingly, after 12 weeks of CR therapy most of the pathological interactions were gone, so that the connectivity patterns of good responders and healthy controls became statistically indistinguishable. In addition, we used dynamic causal modeling (DCM) to examine the types of interactions which were altered by CR therapy. Our DCM results show that CR therapy specifically counteracted the imbalance of excitation and inhibition. CR significantly weakened the excitatory connection between posterior cingulate cortex and primary auditory cortex and significantly strengthened inhibitory connections between auditory cortices and the dorsolateral prefrontal cortex. The overall impact of CR therapy on the entire tinnitus-related network showed up as a qualitative transformation of its spectral response, in terms of a drastic change of the shape of its averaged transfer function. Based on our findings we hypothesize that CR therapy restores a silence based cognitive auditory comparator function of the posterior cingulate cortex.

  View details for DOI 10.1016/j.neuroimage.2013.03.013

  View details for Web of Science ID 000320073900013

  View details for PubMedID 23528923

• Desynchronization boost by non-uniform coordinated reset stimulation in ensembles of pulse-coupled neurons FRONTIERS IN COMPUTATIONAL NEUROSCIENCE Luecken, L., Yanchuk, S., Popovych, O. V., Tass, P. A. 2013; 7: 63

  Abstract

  Several brain diseases are characterized by abnormal neuronal synchronization. Desynchronization of abnormal neural synchrony is theoretically compelling because of the complex dynamical mechanisms involved. We here present a novel type of coordinated reset (CR) stimulation. CR means to deliver phase resetting stimuli at different neuronal sub-populations sequentially, i.e., at times equidistantly distributed in a stimulation cycle. This uniform timing pattern seems to be intuitive and actually applies to the neural network models used for the study of CR so far. CR resets the population to an unstable cluster state from where it passes through a desynchronized transient, eventually resynchronizing if left unperturbed. In contrast, we show that the optimal stimulation times are non-uniform. Using the model of weakly pulse-coupled neurons with phase response curves, we provide an approach that enables to determine optimal stimulation timing patterns that substantially maximize the desynchronized transient time following the application of CR stimulation. This approach includes an optimization search for clusters in a low-dimensional pulse coupled map. As a consequence, model-specific non-uniformly spaced cluster states cause considerably longer desynchronization transients. Intriguingly, such a desynchronization boost with non-uniform CR stimulation can already be achieved by only slight modifications of the uniform CR timing pattern. Our results suggest that the non-uniformness of the stimulation times can be a medically valuable parameter in the calibration procedure for CR stimulation, where the latter has successfully been used in clinical and pre-clinical studies for the treatment of Parkinson's disease and tinnitus.

  View details for DOI 10.3389/fncom.2013.00063

  View details for Web of Science ID 000319733300001

  View details for PubMedID 23750134

  View details for PubMedCentralID PMC3656351

• Neuromodulation: selected approaches and challenges JOURNAL OF NEUROCHEMISTRY Parpura, V., Silva, G. A., Tass, P. A., Bennet, K. E., Meyyappan, M., Koehne, J., Lee, K. H., Andrews, R. J. 2013; 124 (4): 436–53

  Abstract

  The brain operates through complex interactions in the flow of information and signal processing within neural networks. The 'wiring' of such networks, being neuronal or glial, can physically and/or functionally go rogue in various pathological states. Neuromodulation, as a multidisciplinary venture, attempts to correct such faulty nets. In this review, selected approaches and challenges in neuromodulation are discussed. The use of water-dispersible carbon nanotubes has been proven effective in the modulation of neurite outgrowth in culture and in aiding regeneration after spinal cord injury in vivo. Studying neural circuits using computational biology and analytical engineering approaches brings to light geometrical mapping of dynamics within neural networks, much needed information for stimulation interventions in medical practice. Indeed, sophisticated desynchronization approaches used for brain stimulation have been successful in coaxing 'misfiring' neuronal circuits to resume productive firing patterns in various human disorders. Devices have been developed for the real-time measurement of various neurotransmitters as well as electrical activity in the human brain during electrical deep brain stimulation. Such devices can establish the dynamics of electrochemical changes in the brain during stimulation. With increasing application of nanomaterials in devices for electrical and chemical recording and stimulating in the brain, the era of cellular, and even intracellular, precision neuromodulation will soon be upon us.

  View details for DOI 10.1111/jnc.12105

  View details for Web of Science ID 000314186300003

  View details for PubMedID 23190025

  View details for PubMedCentralID PMC3557763

• Rebuttal to reply by G. Rucker and G. Antes on Tass et al. "Counteracting tinnitus by acoustic coordinated reset neuromodulation", Restorative Neurology and Neuroscience Vol. 30(2), 2012 RESTORATIVE NEUROLOGY AND NEUROSCIENCE Tass, P. A., Adamchic, I., Freund, H., von Stackelberg, T., Hauptmann, C. 2013; 31 (3): 235–37

  View details for DOI 10.3233/RNN-121123

  View details for Web of Science ID 000318266400002

  View details for PubMedID 23314005

• optimal number of stimulation contacts for coordinated reset neuromodulation Frontiers in neuroengineering Lysyansky, B., Popovych, O., Tass, P. A. 2013; 6: 5
• Psychometric Evaluation of Visual Analog Scale for the Assessment of Chronic Tinnitus AMERICAN JOURNAL OF AUDIOLOGY Adamchic, I., Langguth, B., Hauptmann, C., Tass, P. 2012; 21 (2): 215–25

  Abstract

  The development of therapeutic interventions for chronic tinnitus requires sensitive and clinically responsive tools to measure treatment-induced changes in tinnitus loudness and annoyance. In this study, the authors evaluated the psychometric properties of patient-reported visual analog scales (VAS) for measuring subjectively perceived tinnitus loudness and annoyance.The authors analyzed data from a single-blind, randomized, placebo-controlled study of acoustic coordinated reset (CR) neuromodulation in patients with chronic tinnitus (trial registration: "Randomized Evaluation of Sound Evoked Treatment of Tinnitus [RESET] study"; ClinicalTrials.gov identifier: NCT00927121) to assess the reliability, validity, and minimally clinically identifiable difference (MCID) of the VAS loudness and VAS annoyance. The VAS loudness and VAS annoyance were completed at screening, at baseline, and at 5 visits during the 16 weeks of the clinical study. Data were analyzed with respect to test-retest reliability, validity, and MCID.VAS loudness and VAS annoyance showed good test-retest reliability of .8 and .79, respectively. In terms of convergent validity, VAS loudness and VAS annoyance correlated well with the tinnitus questionnaire at all clinical visits (max r = .67, p < .05). MCID estimates clustered between 10 and 15 points.VAS loudness and VAS annoyance are valid and effective measurements for capturing reductions in tinnitus severity in patients with chronic tinnitus.

  View details for DOI 10.1044/1059-0889(2012/12-0010)

  View details for Web of Science ID 000314455400011

  View details for PubMedID 22846637

• Coordinated reset has sustained aftereffects in Parkinsonian monkeys ANNALS OF NEUROLOGY Tass, P. A., Qin, L., Hauptmann, C., Dovero, S., Bezard, E., Boraud, T., Meissner, W. G. 2012; 72 (5): 816–20

  Abstract

  Coordinated reset neuromodulation consists of the application of consecutive brief high-frequency pulse trains through the different contacts of the stimulation electrode. In theoretical studies, by achieving unlearning of abnormal connectivity between neurons, coordinated reset neuromodulation reduces pathological synchronization, a hallmark feature of Parkinson's disease pathophysiology. Here we show that coordinated reset neuromodulation of the subthalamic nucleus has both acute and sustained long-lasting aftereffects on motor function in parkinsonian nonhuman primates. Long-lasting aftereffects were not observed with classical deep brain stimulation. These observations encourage further development of coordinated reset neuromodulation for treating motor symptoms in Parkinson disease patients.

  View details for DOI 10.1002/ana.23663

  View details for Web of Science ID 000312940300020

  View details for PubMedID 23280797

• Linking the Tinnitus Questionnaire and the subjective Clinical Global Impression: Which differences are clinically important? HEALTH AND QUALITY OF LIFE OUTCOMES Adamchic, I., Tass, P., Langguth, B., Hauptmann, C., Koller, M., Schecklmann, M., Zeman, F., Landgrebe, M. 2012; 10: 79

  Abstract

  Development of new tinnitus treatments requires prospective placebo-controlled randomized trials to prove their efficacy. The Tinnitus Questionnaire (TQ) is a validated and commonly used instrument for assessment of tinnitus severity and has been used in many clinical studies. Defining the Minimal Clinically Important Difference (MCID) for TQ changes is an important step to a better interpretation of the clinical relevance of changes observed in clinical trials. In this study we aimed to estimate the minimum change of the TQ score that could be considered clinically relevant.757 patients with chronic tinnitus were pooled from the TRI database and the RESET study. An anchor-based approach using the Clinical Global Impression (CGI) scale and distributional approaches were used to estimate MCID. Receiver Operating Characteristic (ROC) curves were calculated to define optimal TQ change cutoffs discriminating between minimally changed and unchanged subjects.The relationship between TQ change scores and CGI ratings of change was good (r = 0.52, p < 0.05). Mean change scores associated with minimally better and minimally worse CGI categories were -6.65 and +2.72 respectively. According to the ROC method MCID for improvement was -5 points and for deterioration +1 points.Distribution and anchor-based methods yielded comparable results in identifying MCIDs. ΔTQ scores of -5 and +1 points were identified as the minimal clinically relevant change for improvement and worsening respectively. The asymmetry of the MCIDs for improvement and worsening may be related to expectation effects.

  View details for DOI 10.1186/1477-7525-10-79

  View details for Web of Science ID 000311250500001

  View details for PubMedID 22781703

  View details for PubMedCentralID PMC3487915

• Desynchronizing electrical and sensory coordinated reset neuromodulation FRONTIERS IN HUMAN NEUROSCIENCE Popovych, O. V., Tass, P. A. 2012; 6: 58

  Abstract

  Coordinated reset (CR) stimulation is a desynchronizing stimulation technique based on timely coordinated phase resets of sub-populations of a synchronized neuronal ensemble. It has initially been computationally developed for electrical deep brain stimulation (DBS), to enable an effective desynchronization and unlearning of pathological synchrony and connectivity (anti-kindling). Here we computationally show for ensembles of spiking and bursting model neurons interacting via excitatory and inhibitory adaptive synapses that a phase reset of neuronal populations as well as a desynchronization and an anti-kindling can robustly be achieved by direct electrical stimulation or indirect (synaptically-mediated) excitatory and inhibitory stimulation. Our findings are relevant for DBS as well as for sensory stimulation in neurological disorders characterized by pathological neuronal synchrony. Based on the obtained results, we may expect that the local effects in the vicinity of a depth electrode (realized by direct stimulation of the neurons' somata or stimulation of axon terminals) and the non-local CR effects (realized by stimulation of excitatory or inhibitory efferent fibers) of deep brain CR neuromodulation may be similar or even identical. Furthermore, our results indicate that an effective desynchronization and anti-kindling can even be achieved by non-invasive, sensory CR neuromodulation. We discuss the concept of sensory CR neuromodulation in the context of neurological disorders.

  View details for DOI 10.3389/fnhum.2012.00058

  View details for Web of Science ID 000302710400002

  View details for PubMedID 22454622

  View details for PubMedCentralID PMC3308339

• Unlearning tinnitus-related cerebral synchrony with acoustic coordinated reset stimulation: theoretical concept and modelling BIOLOGICAL CYBERNETICS Tass, P. A., Popovych, O. V. 2012; 106 (1): 27–36

  Abstract

  Tinnitus is a deafferentation-induced phantom phenomenon characterized by abnormal cerebral synchrony and connectivity. Computationally, we show that desynchronizing acoustic coordinated reset (CR) stimulation can effectively counteract both up-regulated synchrony and connectivity. CR stimulation has initially been developed for the application to electrical deep brain stimulation. We here adapt this approach to non-invasive, acoustic CR stimulation. For this, we use the tonotopic organization of the central auditory system and replace electrical stimulation bursts applied to different brain sites by acoustically delivered tones of different pitch. Based on our simulations, we propose non-invasive acoustic CR stimulation as a possible novel therapy for tinnitus.

  View details for DOI 10.1007/s00422-012-0479-5

  View details for Web of Science ID 000302644100003

  View details for PubMedID 22350536

• Changes of oscillatory activity in pitch processing network and related tinnitus relief induced by acoustic CR neuromodulation FRONTIERS IN SYSTEMS NEUROSCIENCE Adamchic, L., Hauptmann, C., Tass, P. A. 2012; 6: 18

  Abstract

  Chronic subjective tinnitus is characterized by abnormal neuronal synchronization in the central auditory system. As shown in a controlled clinical trial, acoustic coordinated reset (CR) neuromodulation causes a significant relief of tinnitus symptoms along with a significant decrease of pathological oscillatory activity in a network comprising auditory and non-auditory brain areas, which is often accompanied with a significant tinnitus pitch change. Here we studied if the tinnitus pitch change correlates with a reduction of tinnitus loudness and/or annoyance as assessed by visual analog scale (VAS) scores. Furthermore, we studied if the changes of the pattern of brain synchrony in tinnitus patients induced by 12 weeks of CR therapy depend on whether or not the patients undergo a pronounced tinnitus pitch change. Therefore, we applied standardized low-resolution brain electromagnetic tomography (sLORETA) to EEG recordings from two groups of patients with a sustained CR-induced relief of tinnitus symptoms with and without tinnitus pitch change. We found that absolute changes of VAS loudness and VAS annoyance scores significantly correlate with the modulus, i.e., the absolute value, of the tinnitus pitch change. Moreover, as opposed to patients with small or no pitch change we found a significantly stronger decrease in gamma power in patients with pronounced tinnitus pitch change in right parietal cortex (Brodmann area, BA 40), right frontal cortex (BA 9, 46), left temporal cortex (BA 22, 42), and left frontal cortex (BA 4, 6), combined with a significantly stronger increase of alpha (10-12 Hz) activity in the right and left anterior cingulate cortex (ACC; BA 32, 24). In addition, we revealed a significantly lower functional connectivity in the gamma band between the right dorsolateral prefrontal cortex (BA 46) and the right ACC (BA 32) after 12 weeks of CR therapy in patients with pronounced pitch change. Our results indicate a substantial, CR-induced reduction of tinnitus-related auditory binding in a pitch processing network.

  View details for DOI 10.3389/fnsys.2012.00018

  View details for Web of Science ID 000214847700018

  View details for PubMedID 22493570

  View details for PubMedCentralID PMC3319974

• Counteracting tinnitus by acoustic coordinated reset neuromodulation RESTORATIVE NEUROLOGY AND NEUROSCIENCE Tass, P. A., Adamchic, I., Freund, H., von Stackelberg, T., Hauptmann, C. 2012; 30 (2): 137–59

  Abstract

  Subjective tinnitus is associated with pathologic enhanced neuronal synchronization. We used a model based desynchronization technique, acoustic coordinated reset (CR) neuromodulation, to specifically counteract tinnitus-related neuronal synchrony thereby inducing an unlearning of pathological synaptic connectivity and neuronal synchrony.In a prospective, randomized, single blind, placebo-controlled trial in 63 patients with chronic tonal tinnitus and up to 50 dB hearing loss we studied safety and efficacy of different doses of acoustic CR neuromodulation. We measured visual analogue scale and tinnitus questionnaire (TQ) scores and spontaneous EEG.CR treatment was safe, well-tolerated and caused a significant decrease of tinnitus loudness and symptoms. Placebo treatment did not lead to any significant changes. Effects gained in 12 weeks of treatment persisted through a preplanned 4-week therapy pause and showed sustained long-term effects after 10 months of therapy: response, i.e. a reduction of at least 6 TQ points, was obtained in 75% of patients with a mean TQ reduction of 50% among responders. CR therapy significantly lowered tinnitus frequency and reversed the tinnitus related EEG alterations.The CR-induced reduction of tinnitus and underlying neuronal characteristics indicates a new non-invasive therapy which might also be applicable to other conditions with neuronal hypersynchrony.

  View details for DOI 10.3233/RNN-2012-110218

  View details for Web of Science ID 000302459100006

  View details for PubMedID 22414611

• Variability of spatio-temporal patterns in non-homogeneous rings of spiking neurons CHAOS Yanchuk, S., Perlikowski, P., Popovych, O. V., Tass, P. A. 2011; 21 (4): 047511

  Abstract

  We show that a ring of unidirectionally delay-coupled spiking neurons may possess a multitude of stable spiking patterns and provide a constructive algorithm for generating a desired spiking pattern. More specifically, for a given time-periodic pattern, in which each neuron fires once within the pattern period at a predefined time moment, we provide the coupling delays and/or coupling strengths leading to this particular pattern. The considered homogeneous networks demonstrate a great multistability of various travelling time- and space-periodic waves which can propagate either along the direction of coupling or in opposite direction. Such a multistability significantly enhances the variability of possible spatio-temporal patterns and potentially increases the coding capability of oscillatory neuronal loops. We illustrate our results using FitzHugh-Nagumo neurons interacting via excitatory chemical synapses as well as limit-cycle oscillators.

  View details for DOI 10.1063/1.3665200

  View details for Web of Science ID 000298639100056

  View details for PubMedID 22225385

• Delay- and Coupling-Induced Firing Patterns in Oscillatory Neural Loops PHYSICAL REVIEW LETTERS Popovych, O. V., Yanchuk, S., Tass, P. A. 2011; 107 (22): 228102

  Abstract

  For a feedforward loop of oscillatory Hodgkin-Huxley neurons interacting via excitatory chemical synapses, we show that a great variety of spatiotemporal periodic firing patterns can be encoded by properly chosen communication delays and synaptic weights, which contributes to the concept of temporal coding by spikes. These patterns can be obtained by a modulation of the multiple coexisting stable in-phase synchronized states or traveling waves propagating along or against the direction of coupling. We derive explicit conditions for the network parameters allowing us to achieve a desired pattern. Interestingly, whereas the delays directly affect the time differences between spikes of interacting neurons, the synaptic weights control the phase differences. Our results show that already such a simple neural circuit may unfold an impressive spike coding capability.

  View details for DOI 10.1103/PhysRevLett.107.228102

  View details for Web of Science ID 000297292000017

  View details for PubMedID 22182043

• Desynchronizing anti-resonance effect of m: n ON-OFF coordinated reset stimulation JOURNAL OF NEURAL ENGINEERING Lysyansky, B., Popovych, O. V., Tass, P. A. 2011; 8 (3): 036019

  Abstract

  This computational study is devoted to the optimal parameter calibration for coordinated reset (CR) stimulation, a stimulation technique suggested for an effective desynchronization of pathological neuronal synchronization. We present a detailed study of the parameter space of the CR stimulation method and show that CR stimulation can induce cluster states, desynchronization and oscillation death. The stimulation-induced cluster states (at CR offset) cause the longest desynchronizing post-stimulus transients, which constitute an essential part of the CR stimulation effect. We discover a desynchronization-related anti-resonance response of the stimulated oscillators induced by a periodic ON-OFF CR stimulation protocol with m cycles ON stimulation followed by n cycles OFF stimulation. The undesired collective oscillations are effectively desynchronized if the stimulation is administered at resonant frequencies of the controlled ensemble, which is in complete contrast to the typical effect of the usual periodic forcing.

  View details for DOI 10.1088/1741-2560/8/3/036019

  View details for Web of Science ID 000291035100031

  View details for PubMedID 21555848

• Macroscopic entrainment of periodically forced oscillatory ensembles PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY Popovych, O. V., Tass, P. A. 2011; 105 (1-2): 98–108

  Abstract

  Large-amplitude oscillations of macroscopic neuronal signals, such as local field potentials and electroencephalography or magnetoencephalography signals, are commonly considered as being generated by a population of mutually synchronized neurons. In a computational study in generic networks of phase oscillators and bursting neurons, however, we show that this common belief may be wrong if the neuronal population receives an external rhythmic input. The latter may stem from another neuronal population or an external, e.g., sensory or electrical, source. In that case the population field potential may be entrained by the rhythmic input, whereas the individual neurons are phase desynchronized both mutually and with their field potential. Intriguingly, the corresponding large-amplitude oscillations of the population mean field are generated by pairwise desynchronized neurons oscillating at frequencies shifted far away from the frequency of the macroscopic field potential.

  View details for DOI 10.1016/j.pbiomolbio.2010.09.018

  View details for Web of Science ID 000288635300010

  View details for PubMedID 20875831

• Multi-frequency activation of neuronal networks by coordinated reset stimulation INTERFACE FOCUS Lysyansky, B., Popovych, O. V., Tass, P. A. 2011; 1 (1): 75–85

  Abstract

  We computationally study whether it is possible to stimulate a neuronal population in such a way that its mean firing rate increases without an increase of the population's net synchronization. For this, we use coordinated reset (CR) stimulation, which has previously been developed to desynchronize populations of oscillatory neurons. Intriguingly, delivered to a population of predominantly silent FitzHugh-Nagumo or Hindmarsh-Rose neurons at sufficient stimulation amplitudes, CR robustly causes a multi-frequency activation: different Arnold tongues such as 1 : 1 or n : m entrained neuronal clusters emerge, which consist of phase-shifted sub clusters. Owing to the clustering pattern the neurons' timing is well balanced, so that in total there is no synchronization. Our findings may contribute to the development of novel and safe stimulation treatments that specifically counteract cerebral hypo-activity without promoting pathological synchronization or inducing epileptic seizures.

  View details for DOI 10.1098/rsfs.2010.0010

  View details for Web of Science ID 000297272400009

  View details for PubMedID 22419975

  View details for PubMedCentralID PMC3262242

• The Translational Value of the MPTP Non-Human Primate Model of Parkinsonism for Deep Brain Stimulation Research Tass, P. A., Qin, L., Hauptmann, C., Dovero, S., Bezard, E., Boraud, T., Meissner, W. G., IEEE IEEE. 2011: 663–66

  Abstract

  Deep brain stimulation (DBS) has been applied in more than 70000 patients worldwide during the last two decades. The main target is the subthalamic nucleus (STN) for the treatment of motor complications in late stage Parkinson's disease (PD). Positive results in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated non-human primates have set the grounds for its successful translation to PD patients. Since then, this model has allowed gaining significant insights in the underlying mechanisms of action of DBS and is currently being used for the development of new stimulation techniques. Altogether, this underpins the high potential of this preclinical model for future translation of DBS research in PD.

  View details for Web of Science ID 000298810000159

  View details for PubMedID 22254396

• Modeling of a segmented electrode for desynchronizing deep brain stimulation Frontiers in neuroengineering Buhlmann, J., Hofmann, L., Tass, P. A., Hauptmann, C. 2011; 4: 15
• Modified pulse shapes for effective neural stimulation Frontiers in neuroengineering Hofmann, L., Ebert, M., Tass, P. A., Hauptmann, C., et al 2011; 4: 9
• Desynchronization (computational neuroscience) Scholarpedia Popovych, O. V., Tass, P. A., Hauptmann, C. 2011; 6 (10): 1325
• Chimera states induced by spatially modulated delayed feedback PHYSICAL REVIEW E Omel'chenko, O. E., Maistrenko, Y. L., Tass, P. A. 2010; 82 (6): 066201

  Abstract

  Recently, we have presented spatially modulated delayed feedback as a novel mechanism, which generically generates chimera states, remarkable spatiotemporal patterns in which coherence coexists with incoherence [O. E. Omel'chenko, Phys. Rev. Lett. 100, 044105 (2008)]. Remarkably, such chimera states serve as a natural link between completely coherent states and completely incoherent states. So far, we have studied this mechanism with a self-consistency-based numerical analysis only. In contrast, in this paper we perform a thorough dynamical description and, in particular, a stability analysis of the emerging chimera states. For this, we apply a recently developed reduction procedure [A. Pikovsky and M. Rosenblum, Phys. Rev. Lett. 101, 264103 (2008)]. By combining analytical and numerical approaches, we systematically describe the relationship between the parameters of the delayed feedback on one hand and the properties of the chimera states on the other hand. We provide the general rules for an effective control and manipulation of the chimera states.

  View details for DOI 10.1103/PhysRevE.82.066201

  View details for Web of Science ID 000286738900004

  View details for PubMedID 21230717

• Phase-locking swallows in coupled oscillators with delayed feedback PHYSICAL REVIEW E Popovych, O. V., Krachkovskyi, V., Tass, P. A. 2010; 82 (4): 046203

  Abstract

  We show that a nonlinear coupling with delayed feedback between two limit-cycle oscillators can lead to phase-locked, periodically modulated, and chaotic phase synchronization as well as to desynchronization. Parameter regions with stable phase-locked states attain the well-known form of the swallows or shrimps found and studied for nonlinear maps. We demonstrate that the swallow regions can be accompanied by a different bifurcation scenario where the periodic orbits of the phase-locked states undergo a torus bifurcation instead of a previously reported period-doubling bifurcation. This property has an impact on the spatial organization of the swallows in the parameter space. The swallow regions contribute to the synchronization domain of the considered system, and we analytically approximate the parameter synchronization threshold.

  View details for DOI 10.1103/PhysRevE.82.046203

  View details for Web of Science ID 000282425500003

  View details for PubMedID 21230361

• Restoration of segregated, physiological neuronal connectivity by desynchronizing stimulation JOURNAL OF NEURAL ENGINEERING Hauptmann, C., Tass, P. A. 2010; 7 (5): 056008

  Abstract

  The loss of segregation of neuronal signal processing pathways is an important hypothesis for explaining the origin of functional deficits as associated with Parkinson's disease. Here we use a modeling approach which is utilized to study the influence of deep brain stimulation on the restoration of segregated activity in the target structures. Besides the spontaneous activity of the target network, the model considers a weak sensory input mimicking signal processing tasks, electrical deep brain stimulation delivered through a standard DBS electrode and synaptic plasticity. We demonstrate that the sensory input is capable of inducing a modification of the network structure which results in segregated microcircuits if the network is initialized in the healthy, desynchronized state. Depending on the strength and coverage, the sensory input is capable of restoring the functional sub-circuits even if the network is initialized in the synchronized, pathological state. Weak coordinated reset stimulation, applied to a network featuring a loss of segregation caused by global synchronization, is able to restore the segregated activity and to truncate the pathological, synchronized activity.

  View details for DOI 10.1088/1741-2560/7/5/056008

  View details for Web of Science ID 000282097500008

  View details for PubMedID 20811089

• Periodic patterns in a ring of delay-coupled oscillators PHYSICAL REVIEW E Perlikowski, P., Yanchuk, S., Popovych, O. V., Tass, P. A. 2010; 82 (3): 036208

  Abstract

  We describe the appearance and stability of spatiotemporal periodic patterns (rotating waves) in unidirectional rings of coupled oscillators with delayed couplings. We show how delays in the coupling lead to the splitting of each rotating wave into several new ones. The appearance of rotating waves is mediated by the Hopf bifurcations of the symmetric equilibrium. We also conclude that the coupling delays can be effectively replaced by increasing the number of oscillators in the chain. The phenomena are shown for the Stuart-Landau oscillators as well as for the coupled FitzHugh-Nagumo systems modeling an ensemble of spiking neurons interacting via excitatory chemical synapses.

  View details for DOI 10.1103/PhysRevE.82.036208

  View details for Web of Science ID 000282052700002

  View details for PubMedID 21230162

• Data-driven approach to the estimation of connectivity and time delays in the coupling of interacting neuronal subsystems JOURNAL OF NEUROSCIENCE METHODS Silchenko, A. N., Adamchic, I., Pawelczyk, N., Hauptmann, C., Maarouf, M., Sturm, V., Tass, P. A. 2010; 191 (1): 32–44

  Abstract

  One of the challenges in neuroscience is the detection of directionality between signals reflecting neural activity. To reveal the directionality of coupling and time delays between interacting multi-scale signals, we use a combination of a data-driven technique called empirical mode decomposition (EMD) and partial directed coherence (PDC) together with the instantaneous causality test (ICT). EMD is used to separate multiple processes associated with different frequency bands, while PDC and ICT allow to explore directionality and characteristic time delays, respectively. We computationally validate our approach for the cases of both stochastic and chaotic oscillatory systems with different types of coupling. Moreover, we apply our approach to the analysis of the connectivity in different frequency bands between local field potentials (LFPs) bilaterally recorded from the left and right of subthalamic nucleus (STN) in patients with Parkinson's disease (PD). We reveal a bidirectional coupling between the left and right STN in the beta-band (10-30 Hz) for an akinetic PD patient and in the tremor band (3-5 Hz) for a tremor-dominant PD patient. We detect a short time delay, most probably reflecting the inter-hemispheric transmission time. Additionally, in both patients we observe a long time delay of approximately a mean period of the beta-band activity in the akinetic PD patient or the tremor band activity in the tremor-dominant PD patient. These long delays may emerge in subcortico-thalamic loops or longer pathways, comprising reflex loops, respectively. We show that the replacement of EMD by conventional bandpass filtering complicates the detection of directionality and leads to a spurious detection of time delays.

  View details for DOI 10.1016/j.jneumeth.2010.06.004

  View details for Web of Science ID 000280973300005

  View details for PubMedID 20542060

• Synchronization control of interacting oscillatory ensembles by mixed nonlinear delayed feedback PHYSICAL REVIEW E Popovych, O. V., Tass, P. A. 2010; 82 (2): 026204

  Abstract

  We propose a method for the control of synchronization in two oscillator populations interacting according to a drive-response coupling scheme. The response ensemble of oscillators, which gets synchronized because of a strong forcing by the intrinsically synchronized driving ensemble, is controlled by mixed nonlinear delayed feedback. The stimulation signal is constructed from the mixed macroscopic activities of both ensembles. We show that the suggested method can effectively decouple the interacting ensembles from each other, where the natural desynchronous dynamics can be recovered in a demand-controlled way either in the stimulated ensemble, or, intriguingly, in both stimulated and not stimulated populations. We discuss possible therapeutic applications in the context of the control of abnormal brain synchrony in loops of affected neuronal populations.

  View details for DOI 10.1103/PhysRevE.82.026204

  View details for Web of Science ID 000280757800003

  View details for PubMedID 20866890

• Changes in Apraxia After Deep Brain Stimulation of the Nucleus Basalis Meynert in a Patient With Parkinson Dementia Syndrome MOVEMENT DISORDERS Barnikol, T. T., Pawelczyk, N. A., Barnikol, U. B., Kuhn, J., Lenartz, D., Sturm, V., Tass, P. A., Freund, H. 2010; 25 (10): 1519–20

  View details for DOI 10.1002/mds.23141

  View details for Web of Science ID 000280753200036

  View details for PubMedID 20629167

• STDP in oscillatory recurrent networks: theoretical conditions for desynchronization and applications to deep brain stimulation FRONTIERS IN COMPUTATIONAL NEUROSCIENCE Pfister, J., Tass, P. A. 2010; 4

  Abstract

  Highly synchronized neural networks can be the source of various pathologies such as Parkinson's disease or essential tremor. Therefore, it is crucial to better understand the dynamics of such networks and the conditions under which a high level of synchronization can be observed. One of the key factors that influences the level of synchronization is the type of learning rule that governs synaptic plasticity. Most of the existing work on synchronization in recurrent networks with synaptic plasticity are based on numerical simulations and there is a clear lack of a theoretical framework for studying the effects of various synaptic plasticity rules. In this paper we derive analytically the conditions for spike-timing dependent plasticity (STDP) to lead a network into a synchronized or a desynchronized state. We also show that under appropriate conditions bistability occurs in recurrent networks governed by STDP. Indeed, a pathological regime with strong connections and therefore strong synchronized activity, as well as a physiological regime with weaker connections and lower levels of synchronization are found to coexist. Furthermore, we show that with appropriate stimulation, the network dynamics can be pushed to the low synchronization stable state. This type of therapeutical stimulation is very different from the existing high-frequency stimulation for deep brain stimulation since once the stimulation is stopped the network stays in the low synchronization regime.

  View details for DOI 10.3389/fncom.2010.00022

  View details for Web of Science ID 000283734200005

  View details for PubMedID 20802859

  View details for PubMedCentralID PMC2928668

• The causal relationship between subcortical local field potential oscillations and Parkinsonian resting tremor JOURNAL OF NEURAL ENGINEERING Tass, P., Smirnov, D., Karavaev, A., Barnikol, U., Barnikol, T., Adamchic, I., Hauptmann, C., Pawelcyzk, N., Maarouf, M., Sturm, V., Freund, H., Bezruchko, B. 2010; 7 (1): 16009

  Abstract

  To study the dynamical mechanism which generates Parkinsonian resting tremor, we apply coupling directionality analysis to local field potentials (LFP) and accelerometer signals recorded in an ensemble of 48 tremor epochs in four Parkinsonian patients with depth electrodes implanted in the ventro-intermediate nucleus of the thalamus (VIM) or the subthalmic nucleus (STN). Apart from the traditional linear Granger causality method we use two nonlinear techniques: phase dynamics modelling and nonlinear Granger causality. We detect a bidirectional coupling between the subcortical (VIM or STN) oscillation and the tremor, in the theta range (around 5 Hz) as well as broadband (>2 Hz). In particular, we show that the theta band LFP oscillations definitely play an efferent role in tremor generation, while beta band LFP oscillations might additionally contribute. The brain-->tremor driving is a complex, nonlinear mechanism, which is reliably detected with the two nonlinear techniques only. In contrast, the tremor-->brain driving is detected with any of the techniques including the linear one, though the latter is less sensitive. The phase dynamics modelling (applied to theta band oscillations) consistently reveals a long delay in the order of 1-2 mean tremor periods for the brain-->tremor driving and a small delay, compatible with the neural transmission time, for the proprioceptive feedback. Granger causality estimation (applied to broadband signals) does not provide reliable estimates of the delay times, but is even more sensitive to detect the brain-->tremor influence than the phase dynamics modelling.

  View details for DOI 10.1088/1741-2560/7/1/016009

  View details for Web of Science ID 000275479000009

  View details for PubMedID 20083863

• External trial deep brain stimulation device for the application of desynchronizing stimulation techniques JOURNAL OF NEURAL ENGINEERING Hauptmann, C., Roulet, J., Niederhauser, J. J., Doell, W., Kirlangic, M. E., Lysyansky, B., Krachkovskyi, V., Bhatti, M. A., Barnikol, U. B., Sasse, L., Buehrle, C. P., Speckmann, E., Goetz, M., Sturm, V., Freund, H., Schnell, U., Tass, P. A. 2009; 6 (6): 066003

  Abstract

  In the past decade deep brain stimulation (DBS)-the application of electrical stimulation to specific target structures via implanted depth electrodes-has become the standard treatment for medically refractory Parkinson's disease and essential tremor. These diseases are characterized by pathological synchronized neuronal activity in particular brain areas. We present an external trial DBS device capable of administering effectively desynchronizing stimulation techniques developed with methods from nonlinear dynamics and statistical physics according to a model-based approach. These techniques exploit either stochastic phase resetting principles or complex delayed-feedback mechanisms. We explain how these methods are implemented into a safe and user-friendly device.

  View details for DOI 10.1088/1741-2560/6/6/066003

  View details for Web of Science ID 000272077900012

  View details for PubMedID 19837998

• Long-lasting desynchronization in rat hippocampal slice induced by coordinated reset stimulation PHYSICAL REVIEW E Tass, P. A., Silchenko, A. N., Hauptmann, C., Barnikol, U. B., Speckmann, E. 2009; 80 (1): 011902

  Abstract

  In computational models it has been shown that appropriate stimulation protocols may reshape the connectivity pattern of neural or oscillator networks with synaptic plasticity in a way that the network learns or unlearns strong synchronization. The underlying mechanism is that a network is shifted from one attractor to another, so that long-lasting stimulation effects are caused which persist after the cessation of stimulation. Here we study long-lasting effects of multisite electrical stimulation in a rat hippocampal slice rendered epileptic by magnesium withdrawal. We show that desynchronizing coordinated reset stimulation causes a long-lasting desynchronization between hippocampal neuronal populations together with a widespread decrease in the amplitude of the epileptiform activity. In contrast, periodic stimulation induces a long-lasting increase in both synchronization and amplitude.

  View details for DOI 10.1103/PhysRevE.80.011902

  View details for Web of Science ID 000268616300090

  View details for PubMedID 19658724

• Cumulative and after-effects of short and weak coordinated reset stimulation: a modeling study JOURNAL OF NEURAL ENGINEERING Hauptmann, C., Tass, P. A. 2009; 6 (1): 016004

  Abstract

  We show that the dynamical multistability of a network of bursting subthalamic neurons, caused by synaptic plasticity has a strong impact on the stimulus-response properties when exposed to weak and short desynchronizing stimuli. Intriguingly, such stimuli can reliably shift the network from a stable state with pathological synchrony and connectivity to a stable desynchronized state with down-regulated connectivity. However, unlike in the case of stronger coordinated reset stimulation, after termination of weaker stimulation the network may undergo a transient rebound of synchrony. When the coordinated reset stimulation is even weaker and/or shorter, so that a single stimulation epoch is not effective, the network dynamics and connectivity can still be reshaped in a cumulative manner by repetitive stimulation delivery.

  View details for DOI 10.1088/1741-2560/6/1/016004

  View details for Web of Science ID 000263341700006

  View details for PubMedID 19141875

• Anti-kindling achieved by stimulation targeting slow synaptic dynamics RESTORATIVE NEUROLOGY AND NEUROSCIENCE Tass, P. A., Hauptmann, C. 2009; 27 (6): 589–609

  Abstract

  Different stimulation techniques are introduced which specifically modulate the slow synaptic dynamics in a neuronal network model of the subthalamic nucleus with activity dependent synaptic plasticity.A modeling approach is utilized to investigate the effects of the different stimulation techniques. In particular, the short-term and long-term outcome is studied in a mathematical model for a population of bursting STN neurons subject to synaptic plasticity with symmetric spike timing characteristics. In our mathematical model in the absence of stimulation synchronized network states with strong connectivity (modeling disease states) as well as desynchronized states with weak connectivity (modeling healthy states) are stable.We demonstrate that different stimulation techniques induce an anti-kindling by shifting the target population to a weakly connected, desynchronized state. Intriguingly, long-term anti-kindling can even be achieved although during stimulus delivery the neuronal synchrony hardly decreases or even slightly increases. The therapeutic index and the impact of inhibition, calculated to compare the different stimulation techniques, indicate that coordinated rest stimulation might be particularly robust and reliable.The presented stimulation strategies and the results of our modeling study might have strong implications in the context of deep brain stimulation.

  View details for DOI 10.3233/RNN-2009-0484

  View details for Web of Science ID 000273329700002

  View details for PubMedID 20042784

• Tremor entrainment by patterned low-frequency stimulation PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES Barnikol, U. B., Popovych, O. V., Hauptmann, C., Sturm, V., Freund, H., Tass, P. A. 2008; 366 (1880): 3545–73

  Abstract

  High-frequency test stimulation for tremor suppression is a standard procedure for functional target localization during deep brain stimulation. This method does not work in cases where tremor vanishes intraoperatively, for example, due to general anaesthesia or due to an insertional effect. To overcome this difficulty, we developed a stimulation technique that effectively evokes tremor in a well-defined and quantifiable manner. For this, we used patterned low-frequency stimulation (PLFS), i.e. brief high-frequency pulse trains administered at pulse rates similar to neurons' preferred burst frequency. Unlike periodic single-pulse stimulation, PLFS enables one to convey effective and considerably greater integral charge densities without violation of safety requirements. In a computational investigation of an oscillatory neuronal network temporarily rendered inactive, we found that PLFS evokes synchronized activity, phase locked to the stimulus. While a stronger increase in the amount of synchrony in the neuronal population requires higher stimulus intensities, the portion of synchronously active neurons nevertheless becomes strongly phase locked to PLFS already at weak stimulus intensities. The phase entrainment effect of PLFS turned out to be robust against variations in the stimulation frequency, whereas enhancement of synchrony required precisely tuned stimulation frequencies. We applied PLFS to a patient with spinocerebellar ataxia type 2 (SCA2) with pronounced tremor that disappeared intraoperatively under general anaesthesia. In accordance with our computational results, PLFS evoked tremor, phase locked to the stimulus. In particular, weak PLFS caused low-amplitude, but strongly phase-locked tremor. PLFS test stimulations provided the only functional information about target localization. Optimal target point selection was confirmed by excellent post-operative tremor suppression.

  View details for DOI 10.1098/rsta.2008.0104

  View details for Web of Science ID 000258866400007

  View details for PubMedID 18632457

• Theme issue 'biomedical applications of systems biology and biological physics' - Preface PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES Mosekilde, E., Tass, P. A. 2008; 366 (1880): 3437–44

  View details for DOI 10.1098/rsta.2008.0130

  View details for Web of Science ID 000258866400001

  View details for PubMedID 18632456

• Coexistence of numerous synchronized and desynchronized states in a model of two phase oscillators coupled with delay INTERNATIONAL JOURNAL OF BIFURCATION AND CHAOS Lysyansky, B., Maistrenko, Y. L., Tass, P. A. 2008; 18 (6): 1791–1800

  View details for DOI 10.1142/S0218127408021373

  View details for Web of Science ID 000258879500016

• Collective dynamics of globally coupled phase oscillators under multisite delayed feedback stimulation PHYSICA D-NONLINEAR PHENOMENA Omel'chenko, O. E., Hauptmann, C., Maistrenko, Y. L., Tass, P. A. 2008; 237 (3): 365–84

  View details for DOI 10.1016/j.physd.2007.09.019

  View details for Web of Science ID 000254107600009

• Modeling nonlinear oscillatory systems and diagnostics of coupling between them using chaotic time series analysis: applications in neurophysiology Bezruchko, B. P., Ponomarenko, V. I., Prokhorov, M. D., Smirnov, D. A., Tass, P. A. TURPION LTD. 2008: 304–10

  View details for DOI 10.1070/PU2008v051n03ABEH006494

  View details for Web of Science ID 000257460000007

• Chimera states: The natural link between coherence and incoherence PHYSICAL REVIEW LETTERS Omel'chenko, O. E., Maistrenko, Y. L., Tass, P. A. 2008; 100 (4): 044105

  Abstract

  Chimera states are remarkable spatiotemporal patterns in which coherence coexists with incoherence. As yet, chimera states have been considered as nongeneric, since they emerge only for particular initial conditions. In contrast, we show here that in a network of globally coupled oscillators delayed feedback stimulation with realistic (i.e., spatially decaying) stimulation profile generically induces chimera states. Intriguingly, a bifurcation analysis reveals that these chimera states are the natural link between the coherent and the incoherent states.

  View details for DOI 10.1103/PhysRevLett.100.044105

  View details for Web of Science ID 000252863400039

  View details for PubMedID 18352280

• Computational modeling of paroxysmal depolarization shifts in neurons induced by the glutamate release from astrocytes BIOLOGICAL CYBERNETICS Silchenko, A. N., Tass, P. A. 2008; 98 (1): 61–74

  Abstract

  Recent experimental studies have shown that astrocytes respond to external stimuli with a transient increase of the intracellular calcium concentration or can exhibit self-sustained spontaneous activity. Both evoked and spontaneous astrocytic calcium oscillations are accompanied by exocytosis of glutamate caged in astrocytes leading to paroxysmal depolarization shifts (PDS) in neighboring neurons. Here, we present a simple mathematical model of the interaction between astrocytes and neurons that is able to numerically reproduce the experimental results concerning the initiation of the PDS. The timing of glutamate release from the astrocyte is studied by means of a combined modeling of a vesicle cycle and the dynamics of SNARE-proteins. The neuronal slow inward currents (SICs), induced by the astrocytic glutamate and leading to PDS, are modeled via the activation of presynaptic glutamate receptors. The dependence of the bidirectional communication between neurons and astrocytes on the concentration of glutamate transporters is analyzed, as well. Our numerical results are in line with experimental findings showing that astrocyte can induce synchronous PDSs in neighboring neurons, resulting in a transient synchronous spiking activity.

  View details for DOI 10.1007/s00422-007-0196-7

  View details for Web of Science ID 000252160000006

  View details for PubMedID 18064484

• The generation of Parkinsonian tremor as revealed by directional coupling analysis EPL Smirnov, D. A., Barnikol, U. B., Barnikol, T. T., Bezruchko, B. P., Hauptmann, C., Buehrle, C., Maarouf, M., Sturm, V., Freund, H. J., Tass, P. A. 2008; 83 (2)

  View details for DOI 10.1209/0295-5075/83/20003

  View details for Web of Science ID 000259021200032

• Impact of Nonlinear Delayed Feedback on Synchronized Oscillators JOURNAL OF BIOLOGICAL PHYSICS Popovych, O. V., Hauptmann, C., Tass, P. A. 2008; 34 (3-4): 367–79

  Abstract

  We show that synchronization processes can effectively be controlled with nonlinear delayed feedback. We demonstrate that nonlinear delayed feedback can have a twofold impact on the collective dynamics of large ensembles of coupled oscillators: synchronizing and, mostly, desynchronizing effects. By means of a model equation for the mean field, we explore the existence and stability of the feedback-induced desynchronized states, their multistability and dynamical properties. We propose nonlinear delayed feedback stimulation for the therapy of neurological diseases characterized by abnormal synchrony.

  View details for DOI 10.1007/s10867-008-9068-1

  View details for Web of Science ID 000262824400010

  View details for PubMedID 19669477

  View details for PubMedCentralID PMC2585627

• Control of spatially patterned synchrony with multisite delayed feedback PHYSICAL REVIEW E Hauptmann, C., Omel'chenko, O., Popovych, O. V., Maistrenko, Y., Tass, P. A. 2007; 76 (6): 066209

  Abstract

  We present an analytical study describing a method for the control of spatiotemporal patterns of synchrony in networks of coupled oscillators. Delayed feedback applied through a small number of electrodes effectively induces spatiotemporal dynamics at minimal stimulation intensities. Different arrangements of the delays cause different spatial patterns of synchrony, comparable to central pattern generators (CPGs), i.e., interacting clusters of oscillatory neurons producing patterned output, e.g., for motor control. Multisite delayed feedback stimulation might be used to restore CPG activity in patients with incomplete spinal cord injury or gait ignition disorders.

  View details for DOI 10.1103/PhysRevE.76.066209

  View details for Web of Science ID 000251985800019

  View details for PubMedID 18233906

• Timing of V1/V2 and V5+ activations during coherent motion of dots: An MEG study NEUROIMAGE Prieto, E., Barnikol, U. B., Soler, E., Dolan, K., Hesselmann, G., Mohlberg, H., Amunts, K., Zilles, K., Niedeggen, M., Tass, P. A. 2007; 37 (4): 1384–95

  Abstract

  In order to study the temporal activation course of visual areas V1 and V5 in response to a motion stimulus, a random dots kinematogram paradigm was applied to eight subjects while magnetic fields were recorded using magnetoencephalography (MEG). Sources generating the registered magnetic fields were localized with Magnetic Field Tomography (MFT). Anatomical identification of cytoarchitectonically defined areas V1/V2 and V5 was achieved by means of probabilistic cytoarchitectonic maps. We found that the areas V1/V2 and V5+ (V5 and other adjacent motion sensitive areas) exhibited two main activations peaks at 100-130 ms and at 140-200 ms after motion onset. The first peak found for V1/V2, which corresponds to the visual evoked field (VEF) M1, always preceded the peak found in V5+. Additionally, the V5+ peak was correlated significantly and positively with the second V1/V2 peak. This result supports the idea that the M1 component is generated not only by the visual area V1/V2 (as it is usually proposed), but also by V5+. It reflects a forward connection between both structures, and a feedback projection to V1/V2, which provokes a second activation in V1/V2 around 200 ms. This second V1/V2 activation (corresponding to motion VEF M2) appeared earlier than the second V5+ activation but both peaked simultaneously. This result supports the hypothesis that both areas also generate the M2 component, which reflects a feedback input from V5+ to V1/V2 and a crosstalk between both structures. Our study indicates that during visual motion analysis, V1/V2 and V5+ are activated repeatedly through forward and feedback connections and both contribute to m-VEFs M1 and M2.

  View details for DOI 10.1016/j.neuroimage.2007.03.080

  View details for Web of Science ID 000249773600042

  View details for PubMedID 17689986

• Desynchronizing the abnormally synchronized neural activity in the subthalamic nucleus: a modeling study EXPERT REVIEW OF MEDICAL DEVICES Hauptmann, C., Popovych, O., Tass, P. A. 2007; 4 (5): 633–50

  Abstract

  A mathematical model of a target area for deep brain stimulation was used to investigate the effects of electrical stimulation on pathologically synchronized clusters of neurons. In total, three newly developed stimulation techniques based on multisite coordinated reset and delayed feedback were tested and compared with a high-frequency stimulation method that is currently used as a standard stimulation protocol for deep brain stimulation. By modeling both excitatory and inhibitory actions of the electrical stimulation, we revealed the desynchronization impacts of the novel stimulation techniques. This contrasts with standard high-frequency stimulation, which failed to desynchronize the target population and whose inhibitory effects blocked all neuronal activity. We also explored the demand-controlled character of the proposed methods, and demonstrated that the amount of stimulation current required was considerably smaller than that for high-frequency stimulation. These novel stimulation methods appear to be superior to standard high-frequency stimulation techniques, and we propose the methods now be used for deep brain stimulation.

  View details for DOI 10.1586/17434440.4.5.633

  View details for Web of Science ID 000249914800009

  View details for PubMedID 17850198

• Response clustering in transient stochastic synchronization and desynchronization of coupled neuronal bursters PHYSICAL REVIEW E Neiman, A. B., Russell, D. F., Yakusheva, T. A., DiLullo, A., Tass, P. A. 2007; 76 (2): 021908

  Abstract

  We studied the transient dynamics of synchronized coupled neuronal bursters subjected to repeatedly applied stimuli, using a hybrid neuroelectronic system of paddlefish electroreceptors. We show experimentally that the system characteristically undergoes poststimulus transients, in which the relative phases of the oscillators may be grouped in several clusters, traversing alternate phase trajectories. These signature transient dynamics can be detected and characterized quantitatively using specific statistical measures based on a stochastic approach to transient oscillator responses.

  View details for DOI 10.1103/PhysRevE.76.021908

  View details for Web of Science ID 000249154600072

  View details for PubMedID 17930066

• Twofold impact of delayed feedback on coupled oscillators INTERNATIONAL JOURNAL OF BIFURCATION AND CHAOS Popovych, O. V., Krachkovskyi, V., Tass, P. A. 2007; 17 (7): 2517–30

  View details for DOI 10.1142/S0218127407018592

  View details for Web of Science ID 000252021900026

• Demand-controlled desynchronization of oscillatory networks by means of a multisite delayed feedback stimulation COMPUTING AND VISUALIZATION IN SCIENCE Hauptmann, C., Popovych, O., Tass, P. A. 2007; 10 (2): 71–78

  View details for DOI 10.1007/s00791-006-0034-9

  View details for Web of Science ID 000217919700002

• Multistability in the Kuramoto model with synaptic plasticity PHYSICAL REVIEW E Maistrenko, Y. L., Lysyansky, B., Hauptmann, C., Burylko, O., Tass, P. A. 2007; 75 (6): 066207

  Abstract

  We present a simplified phase model for neuronal dynamics with spike timing-dependent plasticity (STDP). For asymmetric, experimentally observed STDP we find multistability: a coexistence of a fully synchronized, a fully desynchronized, and a variety of cluster states in a wide enough range of the parameter space. We show that multistability can occur only for asymmetric STDP, and we study how the coexistence of synchronization and desynchronization and clustering depends on the distribution of the eigenfrequencies. We test the efficacy of the proposed method on the Kuramoto model which is, de facto, one of the sample models for a description of the phase dynamics in neuronal ensembles.

  View details for DOI 10.1103/PhysRevE.75.066207

  View details for Web of Science ID 000247624100029

  View details for PubMedID 17677340

• Therapeutic rewiring by means of desynchronizing brain stimulation Hauptmann, C., Tass, P. A. ELSEVIER SCI LTD. 2007: 173–81

  Abstract

  We study possible anti-kindling effects of the standard high-frequency deep brain stimulation (HFDBS) and of a desynchronizing multisite coordinated reset stimulation (MCRS) theoretically in a mathematical model of the subthalamic nucleus (STN). The latter is an effective target for deep brain stimulation (DBS) in patients suffering from Parkinson's disease (PD). Depending on the structures being activated, electrical pulses may have excitatory and/or inhibitory impact. According to our simulation results MCRS may achieve robust long-term anti-kindling (i.e., curative) effects, irrespectively, of the ratio between excitatory and inhibitory impact. This means, that during MCRS the STN unlearns its pathologic synaptic connections and reestablishes a physiological level of connectivity. In contrast, HFDBS has anti-kindling effects only if its impact is predominantly excitatory. Our results are relevant for selecting appropriate locations for DBS electrodes. In fact, even with HFDBS we may expect anti-kindling effects, provided the target is properly chosen.

  View details for DOI 10.1016/j.biosystems.2006.04.015

  View details for Web of Science ID 000247057900025

  View details for PubMedID 17184901

• Subthalamic-thalamic DBS in a case with spinocerebellar ataxia type 2 and severe tremor - A unusual clinical benefit MOVEMENT DISORDERS Freund, H., Barnikol, U. B., Nolte, D., Treuer, H., Auburger, G., Tass, P. A., Samii, M., Sturm, V. 2007; 22 (5): 732–35

  Abstract

  This is a single case report of a patient with spinocerebellar ataxia type 2 (SCA2) and severe tremor. Whereas disease progression with prevailing ataxia and dysmetria was slow over the first symptomatic 6 years, 6 months prior to operation were characterized by the development of a severe, debilitating postural tremor rendering the patient unable to independently sit, stand, speak, or swallow. Deep brain stimulation (DBS) at a subthalamic-thalamic electrode position almost completely arrested her tremor. The patient regained the functional state prior to her rapid disease progression allowing a restricted range of daily activities. Her condition has remained approximately stable over the two postoperative years to date. In addition to the efficacy of DBS on cerebellar tremor, the results illustrate a remarkable improvement of the patient's general condition and independence.

  View details for DOI 10.1002/mds.21338

  View details for Web of Science ID 000246213100024

  View details for PubMedID 17265523

• swLORETA: a novel approach to robust source localization and synchronization tomography PHYSICS IN MEDICINE AND BIOLOGY Palmero-Soler, E., Dolan, K., Hadamschek, V., Tass, P. A. 2007; 52 (7): 1783–1800

  Abstract

  Standardized low-resolution brain electromagnetic tomography (sLORETA) is a widely used technique for source localization. However, this technique still has some limitations, especially under realistic noisy conditions and in the case of deep sources. To overcome these problems, we present here swLORETA, an improved version of sLORETA, obtained by incorporating a singular value decomposition-based lead field weighting. We show that the precision of the source localization can further be improved by a tomographic phase synchronization analysis based on swLORETA. The phase synchronization analysis turns out to be superior to a standard linear coherence analysis, since the latter cannot distinguish between real phase locking and signal mixing.

  View details for DOI 10.1088/0031-9155/52/7/002

  View details for Web of Science ID 000246162200004

  View details for PubMedID 17374911

• Therapeutic modulation of synaptic connectivity with desynchronizing brain stimulation INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY Tass, P. A., Hauptmann, C. 2007; 64 (1): 53–61

  Abstract

  In a modeling study, we show that synaptic connectivity can effectively be reshaped by an appropriate modulation of neuronal dynamics. To this end, we incorporate synaptic plasticity with symmetric spike-timing characteristics into a population of bursting neurons, which are interacting via chemical synapses. Under spontaneous conditions, qualitatively different stable dynamical states may coexist. We observe states characterized either by pathological synchrony or by uncorrelated activity. Suitably designed stimulation protocols enable to shift the neuronal population from one dynamical state to another. Due to low-frequency periodic pulse train stimulation, the population learns pathologically strong interactions, as known from the kindling phenomenon. In contrast, desynchronizing stimulation, e.g., multi-site coordinated reset stimulation, enables the network to unlearn pathologically strong synaptic interactions, so that a powerful long-term anti-kindling is achieved. We demonstrate that anti-kindling can be achieved even with weak and/or short desynchronizing stimuli, which are not able to cause a complete desynchronization in the course of the stimulation. Our results show that desynchronizing stimulation may serve as a novel curative approach for the therapy of neurological diseases connected with pathological cerebral synchrony.

  View details for DOI 10.1016/j.ijpsycho.2006.07.013

  View details for Web of Science ID 000246091900008

  View details for PubMedID 16997408

• A new toolbox for combining magnetoencephalographic source analysis and cyto architectonic probabilistic data for anatomical classification of dynamic brain activity NEUROIMAGE Dammers, J., Mohlberg, H., Boers, F., Tass, P., Amunts, K., Mathiak, K. 2007; 34 (4): 1577–87

  Abstract

  Size and location of activated cortical areas are often identified in relation to their surrounding macro-anatomical landmarks such as gyri and sulci. The sulcal pattern, however, is highly variable. In addition, many cortical areas are not linked to well defined landmarks, which in turn do not have a fixed relationship to functional and cytoarchitectonic boundaries. Therefore, it is difficult to unambiguously attribute localized neuronal activity to the corresponding cortical areas in the living human brain. Here we present new methods that are implemented in a toolbox for the objective anatomical identification of neuromagnetic activity with respect to cortical areas. The toolbox enables the platform independent integration of many types of source analysis obtained from magnetoencephalography (MEG) together with probabilistic cytoarchitectonic maps obtained in postmortem brains. The probability maps provide information about the relative frequency of a given cortical area being located at a given position in the brain. In the new software, the neuromagnetic data are analyzed with respect to cytoarchitectonic maps that have been transformed to the individual subject brain space. A number of measures define the degree of overlap between and distance from the activated areas and the corresponding cytoarchitectonic maps. The implemented algorithms enable the investigator to quantify how much of the reconstructed current density can be attributed to distinct cortical areas. Dynamic correspondence patterns between the millisecond-resolved MEG data and the static cytoarchitectonic maps are obtained. We show examples for auditory and visual activation patterns. However, size and location of the postmortem brain areas as well as the inverse method applied to the neuromagnetic data bias the anatomical classification. Therefore, the adaptation to the respective application and a combination of the objective quantities are discussed.

  View details for DOI 10.1016/j.neuroimage.2006.09.040

  View details for Web of Science ID 000244349900024

  View details for PubMedID 17187996

• Controlling synchrony in oscillatory networks with a separate stimulation-registration setup EPL Pyragas, K., Popovych, O. V., Tass, P. A. 2007; 80 (4)

  View details for DOI 10.1209/0295-5075/80/40002

  View details for Web of Science ID 000251647700002

• Control of Synchronization in Oscillatory Neural Networks Handbook of Chaos Control Tass, P. A., Hauptmann, C., Popovych, O. V. Wiley Online Library. 2007; 2nd : 653–682
• Phase resetting in medicine and biology: stochastic modelling and data analysis Tass, P. A. Springer Science & Business Media. 2007
• Desynchronization in networks of globally coupled neurons with dendritic dynamics JOURNAL OF BIOLOGICAL PHYSICS Majtanik, M., Dolan, K., Tass, P. A. 2006; 32 (3-4): 307–33

  Abstract

  Effective desynchronization can be exploited as a tool for probing the functional significance of synchronized neural activity underlying perceptual and cognitive processes or as a mild treatment for neurological disorders like Parkinson's disease. In this article we show that pulse-based desynchronization techniques, originally developed for networks of globally coupled oscillators (Kuramoto model), can be adapted to networks of coupled neurons with dendritic dynamics. Compared to the Kuramoto model, the dendritic dynamics significantly alters the response of the neuron to the stimulation. Under medium stimulation amplitude a bistability of the response of a single neuron is observed. When stimulated at some initial phases, the neuron displays only modulations of its firing, whereas at other initial phases it stops oscillating entirely. Significant alterations in the duration of stimulation-induced transients are also observed. These transients endure after the end of the stimulation and cause maximal desynchronization to occur not during the stimulation, but with some delay after the stimulation has been turned off. To account for this delayed desynchronization effect, we have designed a new calibration procedure for finding the stimulation parameters that result in optimal desynchronization. We have also developed a new desynchronization technique by low frequency entrainment. The stimulation techniques originally developed for the Kuramoto model, when using the new calibration procedure, can also be applied to networks with dendritic dynamics. However, the mechanism by which desynchronization is achieved is substantially different than for the network of Kuramoto oscillators. In particular, the addition of dendritic dynamics significantly changes the timing of the stimulation required to obtain desynchronization. We propose desynchronization stimulation for experimental analysis of synchronized neural processes and for the therapy of movement disorders.

  View details for DOI 10.1007/s10867-006-9018-8

  View details for Web of Science ID 000242325600008

  View details for PubMedID 19669469

  View details for PubMedCentralID PMC2651528

• Control of neuronal synchrony by nonlinear delayed feedback BIOLOGICAL CYBERNETICS Popovych, O. V., Hauptmann, C., Tass, P. A. 2006; 95 (1): 69–85

  Abstract

  We present nonlinear delayed feedback stimulation as a technique for effective desynchronization. This method is intriguingly robust with respect to system and stimulation parameter variations. We demonstrate its broad applicability by applying it to different generic oscillator networks as well as to a population of bursting neurons. Nonlinear delayed feedback specifically counteracts abnormal interactions and, thus, restores the natural frequencies of the individual oscillatory units. Nevertheless, nonlinear delayed feedback enables to strongly detune the macroscopic frequency of the collective oscillation. We propose nonlinear delayed feedback stimulation for the therapy of neurological diseases characterized by abnormal synchrony.

  View details for DOI 10.1007/s00422-006-0066-8

  View details for Web of Science ID 000238739800005

  View details for PubMedID 16614837

• Development of therapeutic brain stimulation techniques with methods from nonlinear dynamics and statistical physics INTERNATIONAL JOURNAL OF BIFURCATION AND CHAOS Tass, P. A., Hauptmann, C., Popovych, O. V. 2006; 16 (7): 1889–1911

  View details for DOI 10.1142/S0218127406015787

  View details for Web of Science ID 000240860400002

• Desynchronization and decoupling of interacting oscillators by nonlinear delayed feedback INTERNATIONAL JOURNAL OF BIFURCATION AND CHAOS Popovych, O. V., Hauptmann, C., Tass, P. A. 2006; 16 (7): 1977–87

  View details for DOI 10.1142/S0218127406015830

  View details for Web of Science ID 000240860400007

• Stimulus-locked responses of two phase oscillators coupled with delayed feedback PHYSICAL REVIEW E Krachkovskyi, V., Popovych, O. V., Tass, P. A. 2006; 73 (6): 066220

  Abstract

  For a system of two phase oscillators coupled with delayed self-feedback we study the impact of pulsatile stimulation administered to both oscillators. This system models the dynamics of two coupled phase-locked loops (PLLs) with a finite internal delay within each loop. The delayed self-feedback leads to a rich variety of dynamical regimes, ranging from phase-locked and periodically modulated synchronized states to chaotic phase synchronization and desynchronization. Remarkably, for large coupling strength the two PLLs are completely desynchronized. We study stimulus-locked responses emerging in the different dynamical regimes. Simple phase resets may be followed by a response clustering, which is intimately connected with long poststimulus resynchronization. Intriguingly, a maximal perturbation (i.e., maximal response clustering and maximal resynchronization time) occurs, if the system gets trapped at a stable manifold of an unstable saddle fixed point due to appropriately calibrated stimulus. Also, single stimuli with suitable parameters can shift the system from a stable synchronized state to a stable desynchronized state or vice versa. Our result show that appropriately calibrated single pulse stimuli may cause pronounced transient and/or long-lasting changes of the oscillators' dynamics. Pulse stimulation may, hence, constitute an effective approach for the control of coupled oscillators, which might be relevant to both physical and medical applications.

  View details for DOI 10.1103/PhysRevE.73.066220

  View details for Web of Science ID 000238694200070

  View details for PubMedID 16906959

• Pattern reversal visual evoked responses of V1/V2 and V5/MT as revealed by MEG combined with probabilistic cytoarchitectonic maps NEUROIMAGE Barnikol, U. B., Amunts, K., Dammers, J., Mohlberg, H., Fieseler, T., Malikovic, A., Zilles, K., Niedeggen, M., Tass, P. A. 2006; 31 (1): 86–108

  Abstract

  Pattern reversal stimulation provides an established tool for assessing the integrity of the visual pathway and for studying early visual processing. Numerous magnetoencephalographic (MEG) and electroencephalographic (EEG) studies have revealed a three-phasic waveform of the averaged pattern reversal visual evoked potential/magnetic field, with components N75(m), P100(m), and N145(m). However, the anatomical assignment of these components to distinct cortical generators is still a matter of debate, which has inter alia connected with considerable interindividual variations of the human striate and extrastriate cortex. The anatomical variability can be compensated for by means of probabilistic cytoarchitectonic maps, which are three-dimensional maps obtained by an observer-independent statistical mapping in a sample of ten postmortem brains. Transformed onto a subject's brain under consideration, these maps provide the probability with which a given voxel of the subject's brain belongs to a particular cytoarchitectonic area. We optimize the spatial selectivity of the probability maps for V1 and V2 with a probability threshold which optimizes the self- vs. cross-overlap in the population of postmortem brains used for deriving the probabilistic cytoarchitectonic maps. For the first time, we use probabilistic cytoarchitectonic maps of visual cortical areas in order to anatomically identify active cortical generators underlying pattern reversal visual evoked magnetic fields as revealed by MEG. The generators are determined with magnetic field tomography (MFT), which reconstructs the current source density in each voxel. In all seven subjects, our approach reveals generators in V1/V2 (with a greater overlap with V1) and in V5 unilaterally (right V5 in three subjects, left V5 in four subjects) and consistent time courses of their stimulus-locked activations, with three peak activations in V1/V2 (contributing to C1m/N75m, P100m, and N145m) and two peak activations in V5 (contributing to P100m and N145m). The reverberating V1/V2 and V5 activations demonstrate the effect of recurrent activation mechanisms including V1 and extrastriate areas and/or corticofugal feedback loops. Our results demonstrate that the combined investigation of MEG signals with MFT and probabilistic cytoarchitectonic maps significantly improves the anatomical identification of active brain areas.

  View details for DOI 10.1016/j.neuroimage.2005.11.045

  View details for Web of Science ID 000238012200009

  View details for PubMedID 16480895

• Long-term anti-kindling effects of desynchronizing brain stimulation: a theoretical study BIOLOGICAL CYBERNETICS Tass, P. A., Majtanik, M. 2006; 94 (1): 58–66

  Abstract

  In a modeling study we show that desynchronization stimulation may have powerful anti-kindling effects. For this, we incorporate spike-timing-dependent plasticity into a generic network of coupled phase oscillators, which serves as a model network of synaptically interacting neurons. Two states may coexist under spontaneous conditions: a state of uncorrelated firing and a state of pathological synchrony. Appropriate stimulation protocols make the network learn or unlearn the pathological synaptic interactions, respectively. Low-frequency periodic pulse train stimulation causes a kindling. Permanent high-frequency stimulation, used as golden standard for deep brain stimulation in medically refractory movement disorders, basically freezes the synaptic weights. In contrast, desynchronization stimulation, e.g., by means of a multi-site coordinated reset, has powerful long-term anti-kindling effects and enables the network to unlearn pathologically strong synaptic interactions. We propose desynchronization stimulation for the therapy of movement disorders and epilepsies.

  View details for DOI 10.1007/s00422-005-0028-6

  View details for Web of Science ID 000234274100007

  View details for PubMedID 16284784

• Long-term anti-kindling effects induced by short-term, weak desynchronizing stimulation Nonlinear Phenomena in Complex Systems Tass, P., Hauptmann, C., et al 2006; 9: 298-312
• Effectively desynchronizing deep brain stimulation based on a coordinated delayed feedback stimulation via several sites: a computational study BIOLOGICAL CYBERNETICS Hauptmann, C., Popovych, O., Tass, P. A. 2005; 93 (6): 463–70

  Abstract

  In detailed simulations we present a coordinated delayed feedback stimulation as a particularly robust and mild technique for desynchronization. We feed back the measured and band-pass filtered local filed potential via several or multiple sites with different delays, respectively. This yields a resounding desynchronization in a naturally demand-controlled way. Our novel approach is superior to previously developed techniques: It is robust against variations of system parameters, e.g., the mean firing rate. It does not require time-consuming calibration. It also prevents intermittent resynchronization typically caused by all methods employing repetitive administration of shocks. We suggest our novel technique to be used for deep brain stimulation in patients suffering from neurological diseases with pathological synchronization, such as Parkinsonian tremor, essential tremor or epilepsy.

  View details for DOI 10.1007/s00422-005-0020-1

  View details for Web of Science ID 000233719600007

  View details for PubMedID 16240125

• Phase resetting and transient desynchronization in networks of globally coupled phase oscillators with inertia PHYSICA D-NONLINEAR PHENOMENA Dolan, K., Majtanik, M., Tass, P. A. 2005; 211 (1-2): 128–38

  View details for DOI 10.1016/j.physd.2005.08.009

  View details for Web of Science ID 000232727200009

• Chaotic attractor in the Kuramoto model INTERNATIONAL JOURNAL OF BIFURCATION AND CHAOS Maistrenko, Y. L., Popovych, O. V., Tass, P. A. 2005; 15 (11): 3457–66

  View details for DOI 10.1142/S0218127405014155

  View details for Web of Science ID 000235355800005

• Delayed feedback control of synchronization in locally coupled neuronal networks Hauptmann, C., Popovych, O., Tass, P. A. ELSEVIER SCIENCE BV. 2005: 759–67

  View details for DOI 10.1016/j.neucom.2004.10.072

  View details for Web of Science ID 000229663600098

• Multisite coordinated delayed feedback for an effective desynchronization of neuronal networks Hauptmann, C., Popovych, O., Tass, P. A. WORLD SCIENTIFIC PUBL CO PTE LTD. 2005: 307–19

  View details for DOI 10.1142/S0219493705001420

  View details for Web of Science ID 000231609000015

• Phase chaos in coupled oscillators PHYSICAL REVIEW E Popovych, O. V., Maistrenko, Y. L., Tass, P. A. 2005; 71 (6): 065201

  Abstract

  A complex high-dimensional chaotic behavior, phase chaos, is found in the finite-dimensional Kuramoto model of coupled phase oscillators. This type of chaos is characterized by half of the spectrum of Lyapunov exponents being positive and the Lyapunov dimension equaling almost the total system dimension. Intriguingly, the strongest phase chaos occurs for intermediate-size ensembles. Phase chaos is a common property of networks of oscillators of very different natures, such as phase oscillators, limit-cycle oscillators, and chaotic oscillators, e.g., Rössler systems.

  View details for DOI 10.1103/PhysRevE.71.065201

  View details for Web of Science ID 000230275000007

  View details for PubMedID 16089804

• Desynchronization of coupled electrochemical oscillators with pulse stimulations PHYSICAL REVIEW E Zhai, Y. M., Kiss, I. Z., Tass, P. A., Hudson, J. L. 2005; 71 (6): 065202

  Abstract

  Various stimulation desynchronization techniques are explored in a laboratory experiment on electrochemical oscillators, a system that exhibits transient dynamics, heterogeneities, and inherent noise. Stimulation with a short, single pulse applied at a vulnerable phase can effectively desynchronize a cluster. A double pulse method, that can be applied at any phase, can be improved either by adding an extra weak pulse between the original two pulses or by adding noise to the first pulse.

  View details for DOI 10.1103/PhysRevE.71.065202

  View details for Web of Science ID 000230275000008

  View details for PubMedID 16089805

• Estimation of the transmission time of stimulus-locked responses: modelling and stochastic phase resetting analysis PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Tass, P. A. 2005; 360 (1457): 995–99

  Abstract

  A model of two coupled phase oscillators is studied, where both oscillators are subject to random forces but only one oscillator is repetitively stimulated with a pulsatile stimulus. A pulse causes a reset, which is transmitted to the other oscillator via the coupling. The transmission time of the cross-trial (CT) averaged responses, i.e. the difference in time between the maxima of the CT averaged responses of both oscillators differs from the time difference between the maxima of the oscillators' resets. In fact, the transmission time of the CT averaged responses directly corresponds to the phase difference in the stable synchronized state with integer multiples of the oscillators' mean period added to it. With CT averaged responses it is impossible to reliably estimate the time elapsing, owing to the stimulus' action being transmitted between the two oscillators.

  View details for DOI 10.1098/rstb.2005.1635

  View details for Web of Science ID 000230676700013

  View details for PubMedID 16087443

  View details for PubMedCentralID PMC1854919

• Effective desynchronization by nonlinear delayed feedback PHYSICAL REVIEW LETTERS Popovych, O. V., Hauptmann, C., Tass, P. A. 2005; 94 (16): 164102

  Abstract

  We show that nonlinear delayed feedback opens up novel means for the control of synchronization. In particular, we propose a demand-controlled method for powerful desynchronization, which does not require any time-consuming calibration. Our technique distinguishes itself by its robustness against variations of system parameters, even in strongly coupled ensembles of oscillators. We suggest our method for mild and effective deep brain stimulation in neurological diseases characterized by pathological cerebral synchronization.

  View details for DOI 10.1103/PhysRevLett.94.164102

  View details for Web of Science ID 000228763800033

  View details for PubMedID 15904229

• Desynchronization and chaos in the Kuramoto model Maistrenko, Y. L., Popovych, O., Tass, P. A., Chazottes, Fernandez, B. SPRINGER-VERLAG BERLIN. 2005: 285–306

  View details for Web of Science ID 000231040300012

• Transmission of stimulus-locked responses in two oscillators with bistable coupling BIOLOGICAL CYBERNETICS Tass, P. A. 2004; 91 (4): 203–11

  Abstract

  Numerous electroencephalography (EEG) and magnetoencephalography (MEG) studies aim at identifying the chronological order of activation of brain areas. This paper demonstrates that the timing sequence obtained with the gold standard for EEG/MEG analysis (averaging across trials) may not correlate at all with the actual transmission of a stimulus' effect within a pathway formed by connected brain areas. This is shown by studying transmission of stimulus-locked responses in a model that shares basic features with stimulated neuronal rhythms: in two phase oscillators with bistable coupling and noise one oscillator is stimulated. The model presents a mechanism that causes a response clustering, i.e., a switching between two different responses across trials, without extinction of the averaged response (calculated over all trials). Transmission times are calculated for all trials as well as for the two clusters separately with standard averaged responses and with a stochastic phase resetting analysis. The stochastic phase resetting analysis provides reliable estimates of the transmission time. In contrast, transmission times calculated by averaging across trials correspond to the phase difference in the different stable synchronized states (when calculated for the two clusters separately) or their weighted superposition (when calculated over all trials). The standard method does not detect the time elapsing during the transmission of the stimulus' action. The results presented here call into question many findings reported in the evoked response literature.

  View details for DOI 10.1007/s00422-004-0512-4

  View details for Web of Science ID 000224617700001

  View details for PubMedID 15378377

• Mechanism of desynchronization in the finite-dimensional Kuramoto model PHYSICAL REVIEW LETTERS Maistrenko, Y., Popovych, O., Burylko, O., Tass, P. A. 2004; 93 (8): 084102

  Abstract

  We study how a decrease of the coupling strength causes a desynchronization in the Kuramoto model of N globally coupled phase oscillators. We show that, if the natural frequencies are distributed uniformly or close to that, the synchronized state can robustly split into any number of phase clusters with different average frequencies, even culminating in complete desynchronization. In the simplest case of N=3 phase oscillators, the course of the splitting is controlled by a Cherry flow. The general N-dimensional desynchronization mechanism is numerically illustrated for N=5.

  View details for DOI 10.1103/PhysRevLett.93.084102

  View details for Web of Science ID 000223472400034

  View details for PubMedID 15447191

• Transmission of stimulus-locked responses in two coupled phase oscillators PHYSICAL REVIEW E Tass, P. A. 2004; 69 (5): 051909

  Abstract

  A model of two n:m coupled phase oscillators is studied, where both oscillators are subject to random forces, but only one oscillator is repetitively stimulated with a pulsatile stimulus. The focus of the paper is on transmission of transient responses as well as transient synchronization and desynchronization, which are stimulus locked, i.e., tightly time locked to the stimulus. A bistability or multistability of stable synchronized states of the two-phase oscillators (modulo 2pi ) occurs due to the n:m coupling. Accordingly, after stimulation the two oscillators may tend to qualitatively different stable states, which leads to a cross-trial (CT) response clustering (i.e., a switching between qualitatively different poststimulus responses across trials) of either one of the oscillators or both. A stochastic CT phase resetting analysis allows one to detect such transient responses and provides a reliable estimation of the transmission time. In contrast, CT averaging (averaging over an ensemble of responses), CT standard deviation, and CT cross correlation fail in studying the transmission of such stimulus-locked responses, even in the simpler case of 1:1 coupling. In particular, even though being used as golden standard for the analysis of evoked responses in medicine and neuroscience, CT averaging typically causes severe artifacts and misinterpretations.

  View details for DOI 10.1103/PhysRevE.69.051909

  View details for Web of Science ID 000221813100053

  View details for PubMedID 15244849

• Transmission times of stimulus-locked responses of oscillators cannot be estimated by averaging across trials FLUCTUATION AND NOISE LETTERS Tass, P. A. 2004; 4 (1): L119–L128

  View details for DOI 10.1142/S0219477504001720

  View details for Web of Science ID 000222204900014

• A model of desynchronizing deep brain stimulation with a demand-controlled coordinated reset of neural subpopulations BIOLOGICAL CYBERNETICS Tass, P. A. 2003; 89 (2): 81–88

  Abstract

  The coordinated reset of neural subpopulations is introduced as an effectively desynchronizing stimulation technique. For this, short sequences of high-frequency pulse trains are administered at different sites in a coordinated way. Desynchronization is easily maintained by performing a coordinated reset with demand-controlled timing or by periodically administering resetting high-frequency pulse trains of demand-controlled length. Unlike previously developed methods, this novel approach is robust against variations of model parameters and does not require time-consuming calibration. The novel technique is suggested to be used for demand-controlled deep brain stimulation in patients suffering from Parkinson's disease or essential tremor. It might even be applicable to diseases with intermittently emerging synchronized neural oscillations like epilepsy.

  View details for DOI 10.1007/s00422-003-0425-7

  View details for Web of Science ID 000185256200001

  View details for PubMedID 12905037

• Obsessive-compulsive disorder: Development of demand controlled deep brain stimulation with methods from Stochastic phase resetting Tass, P. A., Klosterkotter, J., Schneider, F., Lenartz, D., Koulousakis, A., Sturm NATURE PUBLISHING GROUP. 2003: S27–S34

  Abstract

  Synchronization of neuronal firing is a hallmark of several neurological diseases. Recently, stimulation techniques have been developed which make it possible to desynchronize oscillatory neuronal activity in a mild and effective way, without suppressing the neurons' firing. As yet, these techniques are being used to establish demand-controlled deep brain stimulation (DBS) techniques for the therapy of movement disorders like severe Parkinson's disease or essential tremor. We here present a first conceptualization suggesting that the nucleus accumbens is a promising target for the standard, that is, permanent high-frequency, DBS in patients with severe and chronic obsessive-compulsive disorder (OCD). In addition, we explain how demand-controlled DBS techniques may be applied to the therapy of OCD in those cases that are refractory to behavioral therapies and pharmacological treatment.

  View details for DOI 10.1038/sj.npp.1300144

  View details for Web of Science ID 000183888600006

  View details for PubMedID 12827141

• Stochastic phase resetting of two coupled phase oscillators stimulated at different times PHYSICAL REVIEW E Tass, P. A. 2003; 67 (5): 051902

  Abstract

  A model of two coupled phase oscillators is presented, where the oscillators are subject to random forces and are stimulated at different times. Transient phase dynamics, synchronization, and desynchronization, which are stimulus locked (i.e., tightly time locked to a repetitively administered stimulus), are investigated. Complex coordinated responses, in terms of a noise-induced switching across trials between qualitatively different responses, may occur when the two oscillators are reset close to an unstable fixed point of their relative phases. This can be achieved with an appropriately chosen delay between the two stimuli. The switching of the responses shows up as a coordinated cross-trial (CT) response clustering of the oscillators, where the two oscillators produce two different pairs of responses. By varying noise amplitude and coupling strength we observe a stochastic resonance and a coupling-mediated resonance of the CT response clustering, respectively. The presented data analysis method makes it possible to detect such processes in numerical and experimental signals. Its time resolution is enormous, since it is only restricted by the time resolution of the preprocessing necessary for extracting the phases from experimental data. In contrast, standard data analysis tools applied across trials relative to stimulus onset, such as CT averaging (where an ensemble of poststimulus responses is simply averaged), CT standard deviation, and CT cross correlation, fail in detecting complex coordinated responses and lead to severe misinterpretations and artifacts. The consequences for the analysis of evoked responses in medicine and neuroscience are significant and are discussed in detail.

  View details for DOI 10.1103/PhysRevE.67.051902

  View details for Web of Science ID 000183482200055

  View details for PubMedID 12786173

• Tapping in to the brain PHYSICS WORLD [Anonymous] 2003; 16 (4): 3

  View details for Web of Science ID 000182613600001

• Neurology - Lockstep neurons caught in the act NEW SCIENTIST Mullins, J. 2003; 177 (2387): 26

  View details for Web of Science ID 000181746200022

• Stochastic phase resetting of stimulus-locked responses of two coupled oscillators: Transient response clustering, synchronization, and desynchronization Tass, P. A. AMER INST PHYSICS. 2003: 364–76

  Abstract

  Transient phase dynamics, synchronization, and desynchronization which are stimulus-locked (i.e., tightly time-locked to a repetitively administered stimulus) are studied in two coupled phase oscillators in the presence of noise. The presented method makes it possible to detect such processes in numerical and experimental signals. The time resolution is enormous, since it is only restricted by the sampling rate. Stochastic stimulus locking of the phases or the n:m phase difference at a particular time t relative to stimulus onset is defined by the presence of one or more prominent peaks in the cross-trial distribution of the phases or the n:m phase difference at time t relative to stimulus onset in an ensemble of poststimulus responses. The oscillators' coupling may cause a transient cross-trial response clustering of the poststimulus responses. In particular, the mechanism by which intrinsic noise induces symmetric antiphase cross-trial response clustering in coupled detuned oscillators is a stochastic resonance. Unlike the presented approach, both cross-trial averaging (where an ensemble of poststimulus responses is simply averaged) and cross-trial cross correlation (CTCC) lead to severe misinterpretations: Triggered averaging cannot distinguish a cross-trial response clustering or decorrelation from a mean amplitude decrease of the single responses. CTCC not only depends on the oscillators' phase difference but also on their phases and, thus, inevitably displays "artificial" oscillations that are not related to synchronization or desynchronization.

  View details for DOI 10.1063/1.1505813

  View details for Web of Science ID 000181202400039

  View details for PubMedID 12675443

• Synchronization tomography: A method for three-dimensional localization of phase synchronized neuronal populations in the human brain using magnetoencephalography PHYSICAL REVIEW LETTERS Tass, P. A., Fieseler, T., Dammers, J., Dolan, K., Morosan, P., Majtanik, M., Boers, F., Muren, A., Zilles, K., Fink, G. R. 2003; 90 (8): 088101

  Abstract

  We present a noninvasive technique which allows the anatomical localization of phase synchronized neuronal populations in the human brain with magnetoencephalography. We study phase synchronization between the reconstructed current source density (CSD) of different brain areas as well as between the CSD and muscular activity. We asked four subjects to tap their fingers in synchrony with a rhythmic tone, and to continue tapping at the same rate after the tone was switched off. The phase synchronization behavior of brain areas relevant for movement coordination, inner voice, and time estimation changes drastically when the transition to internal pacing occurs, while their averaged amplitudes remain unchanged. Information of this kind cannot be derived with standard neuroimaging techniques like functional magnetic resonance imaging or positron emission tomography.

  View details for DOI 10.1103/PhysRevLett.90.088101

  View details for Web of Science ID 000181289300050

  View details for PubMedID 12633462

• Desynchronization by means of a coordinated reset of neural sub-populations - A novel technique for demand-controlled deep brain stimulation Tass, P. A. PROGRESS THEORETICAL PHYSICS PUBLICATION OFFICE. 2003: 281–96

  View details for Web of Science ID 000185853500024

• Development of bipolar deep brain stimulation techniques based on stochastic phase resetting Nonlinear Dynamics and the Spatiotemporal Principles of Biology Tass, P. 2003; 88: 207-224
• Inferring asymmetric relations between interacting neuronal oscillators Cimponeriu, L., Rosenblum, M. G., Fieseler, T., Dammers, J., Schiek, M., Majtanik, M., Morosan, P., Bezerianos, A., Tass, P. A. PROGRESS THEORETICAL PHYSICS PUBLICATION OFFICE. 2003: 22–36

  View details for Web of Science ID 000185853500004

• Effective desynchronization with bipolar double-pulse stimulation PHYSICAL REVIEW E Tass, P. A. 2002; 66 (3): 036226

  Abstract

  This paper is devoted to the desynchronizing effects of bipolar stimuli on a synchronized cluster of globally coupled phase oscillators. The bipolar pulses considered here are symmetrical and consist of a positive and a negative monopolar pulse. A bipolar single pulse with the right intensity and duration desynchronizes a synchronized cluster provided the stimulus is administered at a vulnerable initial phase of the cluster's order parameter. A considerably more effective desynchronization is achieved with a bipolar double pulse consisting of two qualitatively different bipolar pulses. The first bipolar pulse is stronger and resets the cluster, so that the second bipolar pulse, which follows after a constant delay, hits the cluster in a vulnerable state and desynchronizes it. A bipolar double pulse desynchronizes the cluster independently of the cluster's dynamical state at the beginning of the stimulation. The dynamics of the order parameter during a bipolar single pulse or a bipolar double pulse is different from the dynamics during a monopolar single pulse or a monopolar double pulse. Nevertheless, concerning their desynchronizing effects the monopolar and the bipolar stimuli are comparable, respectively. This is significant for applications where bipolar stimulation is required. For example, in medicine and physiology charge-balanced stimulation is typically necessary in order to avoid tissue damage. Based on the results presented here, demand-controlled bipolar double-pulse stimulation is suggested as a milder and more efficient therapy compared to the standard permanent high-frequency deep brain stimulation in neurological patients.

  View details for DOI 10.1103/PhysRevE.66.036226

  View details for Web of Science ID 000178624100075

  View details for PubMedID 12366243

• Desynchronization of brain rhythms with soft phase-resetting techniques BIOLOGICAL CYBERNETICS Tass, P. A. 2002; 87 (2): 102–15

  Abstract

  Composite stimulation techniques are presented here which are based on a soft (i.e., slow and mild) reset. They effectively desynchronize a cluster of globally coupled phase oscillators in the presence of noise. A composite stimulus contains two qualitatively different stimuli. The first stimulus is either a periodic pulse train or a smooth, sinusoidal periodic stimulus with an entraining frequency close to the cluster's natural frequency. In the course of several periods of the entrainment, the cluster's dynamics is reset (restarted), independently of its initial dynamic state. The second stimulus, a single pulse, is administered with a fixed delay after the first stimulus in order to desynchronize the cluster by hitting it in a vulnerable state. The incoherent state is unstable, and thus the desynchronized cluster starts to resynchronize. Nevertheless, resynchronization can effectively be blocked by repeatedly delivering the same composite stimulus. Previously designed stimulation techniques essentially rely on a hard (i.e., abrupt) reset. With the composite stimulation techniques based on a soft reset, an effective desynchronization can be achieved even if strong, quickly resetting stimuli are not available or not tolerated. Accordingly, the soft methods are very promising for applications in biology and medicine requiring mild stimulation. In particular, it can be applied to effectively maintain incoherency in a population of oscillatory neurons which try to synchronize their firing. Accordingly, it is explained how to use the soft techniques for (i). an improved, milder, and demand-controlled deep brain stimulation for patients with Parkinson's disease or essential tremor, and for (ii). selectively blocking gamma activity in order to manipulate visual binding.

  View details for DOI 10.1007/s00422-002-0322-5

  View details for Web of Science ID 000177747400003

  View details for PubMedID 12181586

• Stimulus-locked transient phase dynamics, synchronization and desynchronization of two oscillators EUROPHYSICS LETTERS Tass, P. A. 2002; 59 (2): 199–205

  View details for DOI 10.1209/epl/i2002-00226-8

  View details for Web of Science ID 000176877200007

• Effective desynchronization with a stimulation technique based on soft phase resetting EUROPHYSICS LETTERS Tass, P. A. 2002; 57 (2): 164–70

  View details for DOI 10.1209/epl/i2002-00557-x

  View details for Web of Science ID 000173821100003

• Synchronization Tomography: A Method for Three-Dimensional Localization of Phase Synchronized Neuronal Populations in the Human Brain using Magnetoencephalography Synchronization Tomography: A Method for Three-Dimensional Localization of Phase Synchronized Neuronal Populations in the Human Brain using Magnetoencephalography Tass, P., et al 2002; 90 (8): 088101-1-4
• Estimation of synchronization from noisy data with application to human brain activity Stochastic Processes in Physics, Chemistry, and Biology Rosenblum, M. G., Tass, P. A., Kurths, J. Springer. 2002: 202–211
• Synergetics of the nervous system: from basic principles to therapy Synergetics of the nervous system: from basic principles to therapy Tass, P. A. 2002; 5 (4): 470-478
• Desynchronizing double-pulse phase resetting and application to deep brain stimulation BIOLOGICAL CYBERNETICS Tass, P. A. 2001; 85 (5): 343–54

  Abstract

  Based on a stochastic phase-resetting approach, three different double-pulse stimulation techniques are presented here which make it possible to effectively desynchronize a population of phase oscillators in the presence of noise. In the three sorts of double pulses the first, stronger pulse restarts the cluster independent of its initial dynamic state. The three methods differ with respect to the mechanism through which the second, weaker pulse desynchronizes the cluster. Both first and second pulses are delivered to the same site. Because of the oscillators' global couplings in the model under consideration, the incoherent state is unstable, so that after the desynchronization the cluster tends to resynchronize. However, resynchronization is effectively blocked by repeated administration of a double pulse. The experimental application of double-pulse stimulation is explained in detail. In particular, demand-controlled deep brain double-pulse stimulation is suggested for the therapy of patients suffering from Parkinson's disease or essential tremor.

  View details for DOI 10.1007/s004220100268

  View details for Web of Science ID 000171813600003

  View details for PubMedID 11721989

• Effective desynchronization with a resetting pulse train followed by a single pulse EUROPHYSICS LETTERS Tass, P. A. 2001; 55 (2): 171–77

  View details for DOI 10.1209/epl/i2001-00397-8

  View details for Web of Science ID 000169987000005

• New treatment for Parkinson's disease PHYSICS WORLD Cartlidge, E. 2001; 14 (3): 6

  View details for Web of Science ID 000167314000006

• Effective desynchronization by means of double-pulse phase resetting EUROPHYSICS LETTERS Tass, P. A. 2001; 53 (1): 15–21

  View details for DOI 10.1209/epl/i2001-00117-6

  View details for Web of Science ID 000166795300003

• Phase synchronization: from theory to data analysis Handbook of biological physics Rosenblum, M. G., Pikovsky, A., Schafer, C., Kurths, J., Tass, P. A. 2001; 4: 93-94
• Cortico-muscular synchronization during isometric muscle contraction in humans as revealed by magnetoencephalography JOURNAL OF PHYSIOLOGY-LONDON Gross, J., Tass, P. A., Salenius, S., Hari, R., Freund, H. J., Schnitzler, A. 2000; 527 (3): 623–31

  Abstract

  Magnetoencephalographic (MEG) and electromyographic (EMG) signals were recorded from six subjects during isometric contraction of four different muscles. Cortical sources were located from the MEG signal which was averaged time-locked to the onset of motor unit potentials. A spatial filtering algorithm was used to estimate the source activity. Sources were found in the primary motor cortex (M1) contralateral to the contracted muscle. Significant coherence between rectified EMG and M1 activity was seen in the 20 Hz frequency range in all subjects. Interactions between the motor cortex and spinal motoneuron pool were investigated by separately studying the non-stationary phase and amplitude dynamics of M1 and EMG signals. Delays between M1 and EMG signals, computed from their phase difference, were found to be in agreement with conduction times from the primary motor cortex to the respective muscle. The time-dependent cortico-muscular phase synchronization was found to be correlated with the time course of both M1 and EMG signals. The findings demonstrate that the coupling between the primary motor cortex and motoneuron pool is at least partly due to phase synchronization of 20 Hz oscillations which varies over time. Furthermore, the consistent phase lag between M1 and EMG signals, compatible with conduction time between M1 and the respective muscle with the M1 activity preceding EMG activity, supports the conjecture that the motor cortex drives the motoneuron pool.

  View details for DOI 10.1111/j.1469-7793.2000.00623.x

  View details for Web of Science ID 000089438600018

  View details for PubMedID 10990546

  View details for PubMedCentralID PMC2270094

• Stochastic phase resetting: A theory for deep brain stimulation Tass, P. A. PROGRESS THEORETICAL PHYSICS PUBLICATION OFFICE. 2000: 301–13

  View details for Web of Science ID 000088239700026

• Phase synchronization may reveal communication pathways in brain activity PHYSICS TODAY Fitzgerald, R. 1999; 52 (3): 17–19

  View details for DOI 10.1063/1.882606

  View details for Web of Science ID 000078965100008

• The role of ventral medial wall motor areas in bimanual co-ordination - A combined lesion and activation study BRAIN Stephan, K. M., Binkofski, F., Halsband, U., Dohle, C., Wunderlich, G., Schnitzler, A., Tass, P., Posse, S., Herzog, H., Sturm, Zilles, K., Seitz, R. J., Freund, H. J. 1999; 122: 351–68

  Abstract

  Two patients with midline tumours and disturbances of bimanual co-ordination as the presenting symptoms were examined. Both reported difficulties whenever the two hands had to act together simultaneously, whereas they had no problems with unimanual dexterity or the use of both hands sequentially. In the first patient the lesion was confined to the cingulate gyrus; in the second it also invaded the corpus callosum and the supplementary motor area. Kinematic analysis of bimanual in-phase and anti-phase movements revealed an impairment of both the temporal adjustment between the hands and the independence of movements between the two hands. A functional imaging study in six volunteers, who performed the same bimanual in-phase and anti-phase tasks, showed strong activations of midline areas including the cingulate and ventral supplementary motor area. The prominent activation of the ventral medial wall motor areas in the volunteers in conjunction with the bimanual co-ordination disorder in the two patients with lesions compromising their function is evidence for their pivotal role in bimanual co-ordination.

  View details for DOI 10.1093/brain/122.2.351

  View details for Web of Science ID 000078756900017

  View details for PubMedID 10071062

• Synchronization in noisy systems and cardiorespiratory interaction IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE Rosenblum, M. G., Kurths, J., Pikovsky, A., Schafer, C., Tass, P., Abel, H. H. 1998; 17 (6): 46–53

  View details for DOI 10.1109/51.731320

  View details for Web of Science ID 000076934600011

  View details for PubMedID 9824761

• Detection of n : m phase locking from noisy data: Application to magnetoencephalography PHYSICAL REVIEW LETTERS Tass, P., Rosenblum, M. G., Weule, J., Kurths, J., Pikovsky, A., Volkmann, J., Schnitzler, A., Freund, H. J. 1998; 81 (15): 3291–94

  View details for DOI 10.1103/PhysRevLett.81.3291

  View details for Web of Science ID 000076369400061

• Phase and frequency shifts in a population of phase oscillators PHYSICAL REVIEW E Tass, P. 1997; 56 (2): 2043–60

  View details for DOI 10.1103/PhysRevE.56.2043

  View details for Web of Science ID A1997XR16000098

• Oscillatory cortical activity during visual hallucinations JOURNAL OF BIOLOGICAL PHYSICS Tass, P. 1997; 23 (1): 21–66

  Abstract

  From a theoretical point of view we investigate cortical activity patterns causing dynamic visual hallucinations. For this reason we analyze an oscillatory instability of the dynamics ofthe activator-inhibitor model of Ermentrout and Cowan.Such an oscillatory instability occurs as a result of several disease mechanisms.We explicitly derive the order parameter equation. By means of the averaging theorem, we obtain the averaged order parameter equation.The latter enables us to determine stable and unstable bifurcating cortical activity patterns analytically in lowest order.Depending on model parameters as well as on initial conditions two types of cortical activity patterns occur: travelling waves and 'blinking rolls', i.e.standing waves oscillating with the same frequency and with a phase shift of π/2. In contrast to cortical activitypatterns caused by non-oscillatory instabilitiesanalyzed by Ermentrout and Cowan and by the author the travelling waves and the blinking rolls lead to a variety of dynamic visual hallucinations which are discussed indetail.

  View details for DOI 10.1023/A:1004990707739

  View details for Web of Science ID A1997XA76300003

  View details for PubMedID 23345648

  View details for PubMedCentralID PMC3456268

• Delay-induced transitions in visually guided movements PHYSICAL REVIEW E Tass, P., Kurths, J., Rosenblum, M. G., Guasti, G., Hefter, H. 1996; 54 (3): R2224–R2227

  View details for DOI 10.1103/PhysRevE.54.R2224

  View details for Web of Science ID A1996VK26500012

• Synchronization in networks of limit cycle oscillators ZEITSCHRIFT FUR PHYSIK B-CONDENSED MATTER Tass, P., Haken, H. 1996; 100 (2): 303–20

  View details for DOI 10.1007/s002570050126

  View details for Web of Science ID A1996UP72700021

• Resetting biological oscillators - A stochastic approach JOURNAL OF BIOLOGICAL PHYSICS Tass, P. 1996; 22 (1): 27–64

  View details for DOI 10.1007/BF00383820

  View details for Web of Science ID A1996VD49100003

• Synchronized oscillations in the visual cortex - A synergetic model BIOLOGICAL CYBERNETICS Tass, P., Haken, H. 1996; 74 (1): 31–39

  Abstract

  We present an oscillator network model for the synchronization of oscillatory neuronal activity underlying visual processing. The single neuron is modeled by means of a limit cycle oscillator with an eigenfrequency corresponding to visual stimulation. The eigenfrequency may be time dependent. The mutual coupling strengths are unsymmetrical and activity dependent, and they scatter within the network. Synchronized clusters (groups) of neurons emerge in the network due to the visual stimulation. The different clusters correspond to different visual stimuli. There is no limitation of the number of stimuli. Distinct clusters do not perturb each other, although the coupling strength between all model neurons is of the same order of magnitude. Our analysis is not restricted to weak coupling strength. The scatter of the couplings causes shifts of the cluster frequencies. The model's behavior is compared with the experimental findings. The coupling mechanism is extended in order to model the influence of bicucullin upon the neural network. We additionally investigate repulsive couplings, which lead to constant phase differences between clusters of the same frequency. Finally, we consider the problem of selective attention from the viewpoint of our model.

  View details for DOI 10.1007/BF00199135

  View details for Web of Science ID A1996TM23500004

  View details for PubMedID 8573651

• Phase resetting associated with changes of burst shape JOURNAL OF BIOLOGICAL PHYSICS Tass, P. 1996; 22 (3): 125–55

  View details for DOI 10.1007/BF00417647

  View details for Web of Science ID A1996WD38700001

• Phase and frequency shifts of two nonlinearly coupled oscillators ZEITSCHRIFT FUR PHYSIK B-CONDENSED MATTER Tass, P. 1995; 99 (1): 111–21

  View details for DOI 10.1007/s002570050017

  View details for Web of Science ID 000202952900017

• Cortical pattern formation during visual hallucinations JOURNAL OF BIOLOGICAL PHYSICS Tass, P. 1995; 21 (3): 177–210

  View details for DOI 10.1007/BF00712345

  View details for Web of Science ID A1995TM54000003

• A THEORETICAL-MODEL OF SINUSOIDAL FOREARM TRACKING WITH DELAYED VISUAL FEEDBACK JOURNAL OF BIOLOGICAL PHYSICS TASS, P., WUNDERLIN, A., SCHANZ, M. 1995; 21 (2): 83–112

  View details for DOI 10.1007/BF00705593

  View details for Web of Science ID A1995TA85900001