Coordinated Reset Neuromodulation Research Articles

T125. Neural oscillatory changes by the co-ordinated multifocal transcranial magnetic burst stimulation in the motor cortex

Abnormal neural oscillation in human brains such as overt synchronous beta oscillation in Parkinson’s disease can be one of the neural pathological signatures. How to desynchronize the abnormal oscillation is an important issue for treating the Parkinson’s disease. Therefore, neurologists tried to adopt multiple external oscillatory stimulation to desynchronize the neuronal oscillation of the target frequency as clinical treatment. The concept has been approved by coordinated reset neuromodulation in the deep brain stimulation setting. However, it’s unclear if similar effect can be made through noninvasive stimulation. The noninvasive Co-Ordinated Multifocal Burst Stimulation (COMBS) method by utilizing multiple transcranial magnetic stimulation is proposed in this study for investigating the neural oscillatory changes in the motor cortex. Five healthy volunteer subjects including four females were recruited. Three independent figure of eight coils surrounded the motor hot-spot of extensor indicis proprius (EIP) muscle in the left primary motor cortex. We conducted 50 Hz bursts composed of three pulses with 80% active motor threshold intensity of EIP. To desynchronize the target frequency around 6 Hz, we set one stimulation cycle as every coil firing once randomly, with total duration last for 172.5 ms. Three cycles composed one stimulation block. Total 65 blocks with 315 ms pause between each block were conducted. We implemented finger rapid alternative movement task, which was consisted of three behavioral states including preparation, movement, and resting state. Each subject performed 40 trials before and after COMBS session. EEG signal were collected through 64 EEG channels Neuroscan amplifier system. EEG signal processing contained (1) power spectrum density analysis on the C3 or FC3 channel corresponding to the motor cortex, (2) comparison of the event-related synchronization (ERS) or desynchronization (ERD) before and after the COMBS protocol. The experiment results showed the increasing frequency power from 5 to 20 Hz in the C3 and FC3 electrodes after the COMBS. However, the target frequency around 6 Hz was not desynchronized after stimulation. Consistent ERD and ERS of both α and β frequency during the task were observed. Whereas after COMBS, both α and β frequency spectrum power increased in all behavioral states, without changing desynchronization or synchronization ratio. This study proposed an innovative Co-Ordinated Multifocal Burst Stimulation (COMBS). Experimental findings revealed that the neural oscillation change in the target frequency cannot be decreased effectively by COMBS on healthy motor cortex, but it can increase the power spectrum in the 5–20 Hz frequency composition. In the future work, we will adopt this paradigm on the Parkinson’s disease patients for understanding the further neural oscillation changes on the motor cortex.

Acoustic Coordinated Reset Neuromodulation: A Systematic Review of a Novel Therapy for Tinnitus.

There are growing technological advances in the development of sound-based methods for the treatment of tinnitus. Most of these methods intend to affect the speculated underlying neurological causes of tinnitus. Acoustic coordinated reset (CR) neuromodulation is one of them. A novel method that as of yet seems inadequately reviewed. To evaluate the current evidence on acoustic CR neuromodulation as a method for the treatment of tinnitus and to assess whether the method can be implemented in daily clinical practice. A systematic literature search was performed in 13 databases in the period from February 1, 2015 to May 1, 2016. Studies regarding acoustic CR neuromodulation as a treatment method for tinnitus were included in the present review. A total of 8 studies were eligible for being reviewed comprising a total of 329 patients. Overall, the evidence level of the published literature was low. The main findings in the included studies were that acoustic CR neuromodulation was safe and well tolerated and most patients reported reduction of tinnitus symptoms. The neurophysiological basis of the method was claimed to be desynchronization, anti-kindling, and change of abnormal frequency couplings in a widespread tinnitus network comprising both auditory and non/auditory brain areas based on EEG analyses. The available evidence is insufficient for clinical implementation of acoustic CR neuromodulation. The limited level of evidence suggests that acoustic CR neuromodulation may have positive effects on tinnitus symptoms. Preliminary electroencephalographic data are compatible with the claim that tinnitus reduction after CR treatment is mediated by a desynchronizing effect. However, a proof for this claim is still lacking.

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.

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

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.

EP 47. Three new techniques for improving DBS therapy: Controversies

Question Steering DBS, adaptive DBS and coordinated reset neuromodulation the last fifteen years have been proposed as new techniques to improve the effect of DBS. Application of these techniques strongly depends on the design of the electronic devices. Why has the design of conventional pulse generators not changed up till now? Methods Steering DBS opens the possibility to steer the DBS current into a specific direction after implantation. A special high-density DBS lead and a multichannel programmable device is required. Adaptive DBS has the advantage of the adjustment of the stimulation amplitude depending on local field potential parameters. This requires a sensing possibility of the DBS equipment. Coordinated reset neuromodulation includes a different stimulation protocol with independent asynchronous stimulation on different contact points. Results All three new techniques have been tested experimentally per-operatively or shortly after neurosurgery. However, data on chronic stimulation are lacking since appropriate implantable pulse generators are missing. But also there is still uncertainty about how to implement these new techniques. More studies are needed on the advantage of steering DBS, on which local field potential parameters are most suitable for feedback ( Fig. 1 ) and on what is the best protocol to take optimum advantage of coordinated reset. Conclusions Very promising new techniques for DBS therapy are under development which have the potential of making DBS more efficient, leading to much smaller batteries and giving more possibilities on automatic adjustment of temporal and spatial stimulus parameters ( [Contarino et al., 2014] , [Bour et al., 2015] , [Lourens et al., 2015] , [Adamchic et al., 2014] , [Little et al., 2015] ).

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.

The spacing principle for unlearning abnormal neuronal synchrony.

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.

Maladaptive neural synchrony in tinnitus: origin and restoration.

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.

Control of abnormal synchronization in neurological disorders.

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.

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

BackgroundThe 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.MethodsIn 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.ResultsCoordinated 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.ConclusionsThese 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. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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. Hum Brain Mapp 35:2099–2118, 2014. © 2013 The Authors Human Brain Mapping published by Wiley Periodicals, Inc.

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.

Reply to Tass et al. on “Counteracting tinnitus by acoustic coordinated reset neuromodulation” Restorative Neurology and Neuroscience Vol. 30 (2), 2012

Dear Sir, In a published study, Tass et al. brought up the scientific question whether a special treatment is associated with relief of symptoms of tinnitus over time (Tass et al., 2012). The study design was a prospective, randomized, single blind, placebo-controlled trial in 63 patients, allocated to five treatment arms. For the statistical analysis of this design we would expect a direct comparison, such as an analysis of covariance (ANCOVA), with the visual analogue scale (VAS) and a tinnitus questionnaire (TQ) as outcomes of interest (Senn, 2006). The baseline values could serve as a covariate, especially since it seems necessary to adjust for baseline differences given the small sample size, apart from the large number of arms. However, throughout the more than 20 pages of the article, we did not find such an analysis. We did find pre-post comparisons within each treatment arm, which, on their own, do not allow a valid comparison between groups. Moreover, a concise definition of groups and treatments is missing. Such a definition

Rebuttal to reply by G. Rücker and G. Antes on Tass et al. “Counteracting tinnitus by acoustic coordinated reset neuromodulation”, Restorative Neurology and Neuroscience Vol. 30(2), 2012

We would like to thank Dr. Gerta Rucker and Prof. Gerd Antes for their interest in our article “Counteracting tinnitus by acoustic coordinated reset neuromodulation” and for their suggestions especially as the Cochrane collaboration has a long-standing track record for reviewing tinnitus therapies. Specifically, they found very limited evidence for efficacy of commonly used tinnitus therapies (www.thecochranelibrary.com) such as tinnitus retraining therapy (TRT, Phillips & McFarran 2010) and cognitive behavioral therapy (CBT, MartinezDevesa et al. 2010). Cochrane defines evidence as not limited to randomized controlled trials and metaanalyses but including the best available evidence at any one time encompassing all kinds of medical research, which can be also the result from basic

Recent technological advances in sound-based approaches to tinnitus treatment: A review of efficacy considered against putative physiological mechanisms

The past decade has seen an escalating enthusiasm to comprehend chronic tinnitus from the perspective of both scientific understanding and clinical management. At the same time, there is a significant interest and commercial investment in providing targeted and individualized approaches to care, which incorporate novel sound-based technologies, with standard audiological and psychological strategies. Commercially produced sound-based devices for the tinnitus market include Co-ordinated Reset Neuromodulation ® , Neuromonics © , Serenade ® , and Widex ® Zen. Additionally, experimental interventions such as those based on frequency-discrimination training are of current interest. Many of these interventions overtly claim to target the underlying neurological causes of tinnitus. Here, we briefly summarize current perspectives on the pathophysiology of tinnitus and evaluate claims made by the device supporters from a critical point of view. We provide an opinion on how future research in the field of individualized sound-based interventions might best provide a reliable evidence-base in this growing area of translational medicine.

Optimal number of stimulation contacts for coordinated reset neuromodulation

In this computational study we investigate coordinated reset (CR) neuromodulation designed for an effective control of synchronization by multi-site stimulation of neuronal target populations. This method was suggested to effectively counteract pathological neuronal synchrony characteristic for several neurological disorders. We study how many stimulation sites are required for optimal CR-induced desynchronization. We found that a moderate increase of the number of stimulation sites may significantly prolong the post-stimulation desynchronized transient after the stimulation is completely switched off. This can, in turn, reduce the amount of the administered stimulation current for the intermittent ON–OFF CR stimulation protocol, where time intervals with stimulation ON are recurrently followed by time intervals with stimulation OFF. In addition, we found that the optimal number of stimulation sites essentially depends on how strongly the administered current decays within the neuronal tissue with increasing distance from the stimulation site. In particular, for a broad spatial stimulation profile, i.e., for a weak spatial decay rate of the stimulation current, CR stimulation can optimally be delivered via a small number of stimulation sites. Our findings may contribute to an optimization of therapeutic applications of CR neuromodulation.

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.

Desynchronizing electrical and sensory coordinated reset neuromodulation

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.

Counteracting tinnitus by acoustic coordinated reset neuromodulation

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.

Changes of oscillatory activity in pitch processing network and related tinnitus relief induced by acoustic CR neuromodulation.

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.