Randomised controlled trial of interventions for bothersome tinnitus: DesyncraTM versus cognitive behavioural therapy.

OBJECTIVE: Compare the relative efficacy of DesyncraTM and Cognitive Behavioural Therapy (CBT). DESIGN AND STUDY SAMPLE: Sixty-one participants were randomly assigned to receive either DesyncraTM (n = 29) or CBT (n = 32). Randomisation included stratification regarding current hearing aid (HA) use. Depending on group assignment, participants attended approximately 7-12 visits. Tinnitus distress was measured using the Tinnitus Questionnaire (TQ). RESULTS: Mean TQ scores decreased post-baseline from 5-15 points across treatment arms and strata. Model-based findings for the no-HA stratum showed a difference of -2.0 TQ points favouring Desyncra at 24-weeks, with a 90% posterior interval varying from -5.4 points favouring Desyncra to 0.8 TQ points favouring CBT. For the HA stratum, results show a difference of -1.0 TQ points favouring Desyncra, with a 90% posterior interval ranging from -4.7 points favouring Desyncra to 2.9 points favouring CBT. CONCLUSIONS: The difference between Desyncra and CBT on average showed greater improvement with Desyncra in the no-HA stratum by about 2 TQ points. To the extent that the study sample represents a clinical population and recognising the assumptions in the design and analysis, these results suggest Desyncra is just as effective or more so than CBT in reducing tinnitus distress.

Reversing pathologically increased EEG power by acoustic coordinated reset neuromodulation.

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.

Coordinated reset neuromodulation for Parkinson's disease: proof-of-concept study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Impact of acoustic coordinated reset neuromodulation on effective connectivity in a neural network of phantom sound.

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.

Coordinated reset has sustained aftereffects in Parkinsonian monkeys.

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.

Linking the Tinnitus Questionnaire and the subjective Clinical Global Impression: which differences are clinically important?

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Tackling the Waves of COVID-19: A Planning Model for Intrahospital Resource Allocation.

Background: The current pandemic requires hospitals to ensure care not only for the growing number of COVID-19 patients but also regular patients. Hospital resources must be allocated accordingly. Objective: To provide hospitals with a planning model to optimally allocate resources to intensive care units given a certain incidence of COVID-19 cases. Methods: The analysis included 334 cases from four adjacent counties south-west of Munich. From length of stay and type of ward [general ward (NOR), intensive care unit (ICU)] probabilities of case numbers within a hospital at a certain time point were derived. The epidemiological situation was simulated by the effective reproduction number R, the infection rates in mid-August 2020 in the counties, and the German hospitalization rate. Simulation results are compared with real data from 2nd and 3rd wave (September 2020-May 2021). Results: With R = 2, a hospitalization rate of 17%, mitigation measures implemented on day 9 (i.e., 7-day incidence surpassing 50/100,000), the peak occupancy was reached on day 22 (155.1 beds) for the normal ward and on day 25 (44.9 beds) for the intensive care unit. A higher R led to higher occupancy rates. Simulated number of infections and intensive care unit occupancy was concordant in validation with real data obtained from the 2nd and 3rd waves in Germany. Conclusion: Hospitals could expect a peak occupancy of normal ward and intensive care unit within ~5-11 days after infections reached their peak and critical resources could be allocated accordingly. This delay (in particular for the peak of intensive care unit occupancy) might give options for timely preparation of additional intensive care unit resources.

A Matlab toolbox for analyzing repetitive movements: application in gait and tapping experiments.

Coordination and timing in repetitive movements have been intensively investigated in diverse experimental settings for understanding the underlying basic mechanisms in healthy controls. On this basic research side, there are mainly two theoretical models: the Wing-Kristofferson (WK) model and the Haken-Kelso-Bunz (HKB) model. On the clinical side of the research, several efforts have been spent on quantitatively assessing gait and other repetitive movements such as tapping, especially as an outcome measure of clinical trials in diverse neurological disorders. Nevertheless, Parkinson's disease (PD) remains the predominant disorder in the clinical literature in this context, as the tremor activity and the changes in the gait are both common symptoms in PD. Although there are motion recording systems for data acquisition in clinical settings, the tools for analysis and quantification of the extracted time-series offered by these systems are severely restricted. Therefore, we introduce a toolbox which enables the analysis of repetitive movements within the framework of the two main theoretical models of motor coordination, which explicitly focuses on varying clinical and experimental settings such as self-paced vs. cued or uni-manual vs. bi-manual measurements. The toolbox contains particular pipelines for digital signal processing. Licensed under the GNU General Public License (GNU-GPL), the open source toolbox is freely available and can be downloaded from the Github link: https://github.com/MehmetEylemKirlangic/RepetitiveMovementAnalysis. We illustrate the application of the toolbox on sample experiments of gait and tapping with a control subject, as well as with a Parkinson's patient. The patient has gone through a brain surgery for deep brain stimulation (DBS); hence, we present the results for both stimulation ON and stimulation OFF modes. Sample data are freely accessible at: https://github.com/MehmetEylemKirlangic/DATA.

Adapted Acoustic CR Neuromodulation in Patients With Chronic Tonal Tinnitus and Hearing Loss.

Chronic tonal tinnitus is often accompanied by sensorineural hearing loss which is associated with altered tuning curves and bandwidth of alternating masking. In this feasibility study the so-called hearing threshold adapted coordinated reset (HTA-CR) neuromodulation was investigated. This method is based on CR neuromodulation, which has been demonstrated to be an effective treatment for chronic tonal tinnitus. It applies four stimulation tones that are determined by the patient's individual tinnitus frequency and hearing impairment. The HTA-CR neuromodulation was programmed to the Desyncra™ for Tinnitus Therapy System and treatment was applied to 25 patients for 4 months on average and 4 h daily. Regular check-ups were done every 4-6 weeks. Therapy outcome was assessed by the tinnitus questionnaire (Tinnitusfragebogen, TF) as per Goebel and Hiller. After 4 months the mean TF score was reduced by 27.4%. A reduction of ≥ 15 points was found in 40% of the patients while for further 32% of the patients a reduction of 6-14 points was found. Thus, a positive response rate of 72% was observed after 4 months of HTA-CR neuromodulation. Our results suggest that HTA-CR neuromodulation might be at least comparable to standard CR neuromodulation providing another effective therapeutic option for the treatment of chronic tonal tinnitus.

Therapeutic modulation of synaptic connectivity with desynchronizing brain stimulation.

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.

Multistability in the Kuramoto model with synaptic plasticity.

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.

Therapeutic rewiring by means of desynchronizing brain stimulation.

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.

Desynchronizing the abnormally synchronized neural activity in the subthalamic nucleus: a modeling study.

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.

Technical Feasibility of Acoustic Coordinated Reset Therapy for Tinnitus Delivered via Hearing Aids: A Case Study.

Primary tinnitus has a severe negative influence on the quality of life of a substantial portion of the general population. When acoustic coordinated reset (CR) neuromodulation stimuli are delivered for several hours per day over several weeks a clinically significant symptom reduction in patients with primary tonal tinnitus has been reported by several clinical sites. Here, we reported the first case where CR neuromodulation was delivered through a hearing aid. A 52-year-old man with chronic primary tonal tinnitus was previously considered untreatable with sound therapy. He initially received the classic CR treatment protocol with signals delivered with the separate proprietary device with his hearing aids removed during treatment. He was subsequently treated with the therapy being deployed through a set of contemporary hearing aids. After 5 months of classic CR treatment with the separate custom device, the THI and VASL/A scores worsened by 57% and 13%/14%, respectively. Using the hearing aid without CR treatment for 5 months no change in tinnitus symptoms was observed. However, after three months of CR treatment delivered through the hearing aids, the THI and VASL/A scores were reduced by 70% and 32%/32%, respectively.

Acute effects and after-effects of acoustic coordinated reset neuromodulation in patients with chronic subjective tinnitus.

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.

Capacitive Feedthroughs for Medical Implants.

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.

Validation of a Mobile Device for Acoustic Coordinated Reset Neuromodulation Tinnitus Therapy.

BACKGROUND: 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. PURPOSE: 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. RESEARCH DESIGN: 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. STUDY SAMPLE: 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. INTERVENTION: No tinnitus intervention(s) were specifically studied as a component of this study. DATA COLLECTION AND ANALYSIS: 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. RESULTS: 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.

Acoustic CR Neuromodulation Therapy for Subjective Tonal Tinnitus: A Review of Clinical Outcomes in an Independent Audiology Practice Setting.

OBJECTIVE: To describe the quantitative treatment outcomes of patients undergoing acoustic coordinated reset (CR) neuromodulation at a single independent audiology practice over a 22- to 26-week period as part of an open label, non-randomized, non-controlled observational study. METHODS: Sixty-six patients with subjective tonal tinnitus were treated with acoustic CR neuromodulation with a retrospective review of patient records being performed in order to identify changes of visual analog scale (VAS, n = 66) and in the score of the tinnitus handicap questionnaire (THQ, n = 51). Patients had their tinnitus severity recorded prior to the initiation of therapy using the tinnitus handicap inventory in order to categorize patients into slight up to catastrophic impact categories. THQ and VAS for tinnitus loudness/annoyance were obtained at the patient's initial visit, at 10-14 and 22-26 weeks. RESULTS: Visual analog scale scores were significantly improved, demonstrating a 25.8% mean reduction in tinnitus loudness and a 32% mean reduction in tinnitus annoyance with a clinically significant reduction in percept loudness and annoyance being recorded in 59.1 and 72.7% of the patient group. THQ scores were significantly improved by 19.4% after 22-26 weeks of therapy compared to baseline. CONCLUSION: Acoustic CR neuromodulation therapy appears to be a practical and promising treatment for subjective tonal tinnitus. However, due to the lack of a control group it is difficult to reach an absolute conclusion regarding to what extent the observed effects are related directly to the acoustic CR neuromodulation therapy. Also, as the observed patient group was made up of paying clients it is unknown as to whether this could have caused any additional placebo like effects to influence the final results.

Acoustic Coordinated Reset Neuromodulation in a Real Life Patient Population with Chronic Tonal Tinnitus.

PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Coordinated reset stimulation in a large-scale model of the STN-GPe circuit.

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.