Peter A. Tass, MD, PhD

All Publications

• 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 DOI 10.1063/1.5037309

  View details for PubMedID 30384625

• 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 DOI 10.1371/journal.pone.0203782

  View details for Web of Science ID 000444093600142

  View details for PubMedID 30192855

  View details for PubMedCentralID PMC6128645

• 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 DOI 10.1038/s41598-018-30565-9

  View details for Web of Science ID 000441444100015

  View details for PubMedID 30104713

  View details for PubMedCentralID PMC6089910

• 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 DOI 10.3389/fphys.2018.00512

  View details for Web of Science ID 000431696900001

  View details for PubMedID 29867556

  View details for PubMedCentralID PMC5952302

• 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 DOI 10.1371/journal.pcbi.1006113

  View details for Web of Science ID 000434012100011

  View details for PubMedID 29746458

  View details for PubMedCentralID PMC5963814

• 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 DOI 10.3389/fphys.2018.00376

  View details for Web of Science ID 000429829800001

  View details for PubMedID 29706900

  View details for PubMedCentralID PMC5906576

• 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 DOI 10.3389/fphys.2018.00046

  View details for Web of Science ID 000423823500001

  View details for PubMedID 29449814

  View details for PubMedCentralID PMC5799832

• 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

• 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 DOI 10.1002/mds.27223

  View details for Web of Science ID 000419963500030

  View details for PubMedID 29150859

  View details for PubMedCentralID PMC5836884

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

  View details for DOI 10.1155/2015/569052

  View details for Web of Science ID 000364067900001

• 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

• 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

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

  View details for DOI 10.3389/fneur.2014.00268

  View details for Web of Science ID 000209629300251

• 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