Treatment Tone Spacing and Acute Effects of Acoustic Coordinated Reset Stimulation in Tinnitus Patients.

Acoustic coordinated reset (aCR) therapy for tinnitus aims to desynchronize neuronal populations in the auditory cortex that exhibit pathologically increased coincident firing. The original therapeutic paradigm involves fixed spacing of four low-intensity tones centered around the frequency of a tone matching the tinnitus pitch, f T , but it is unknown whether these tones are optimally spaced for induction of desynchronization. Computational and animal studies suggest that stimulus amplitude, and relatedly, spatial stimulation profiles, of coordinated reset pulses can have a major impact on the degree of desynchronization achievable. In this study, we transform the tone spacing of aCR into a scale that takes into account the frequency selectivity of the auditory system at each therapeutic tone's center frequency via a measure called the gap index. Higher gap indices are indicative of more loosely spaced aCR tones. The gap index was found to be a significant predictor of symptomatic improvement, with larger gap indices, i.e., more loosely spaced aCR tones, resulting in reduction of tinnitus loudness and annoyance scores in the acute stimulation setting. A notable limitation of this study is the intimate relationship of hearing impairment with the gap index. Particularly, the shape of the audiogram in the vicinity of the tinnitus frequency can have a major impact on tone spacing. However, based on our findings we suggest hypotheses-based experimental protocols that may help to disentangle the impact of hearing loss and tone spacing on clinical outcome, to assess the electrophysiologic correlates of clinical improvement, and to elucidate the effects following chronic rather than acute stimulation.

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.

Freehand direct arthrography of the shoulder using near real-time guidance in an open 1.0-T MRI scanner.

OBJECTIVE: To assess the technical success and duration of magnetic resonance imaging (MRI)-guided freehand direct shoulder arthrography (FDSA) with near real-time imaging implemented in a routine shoulder MRI examination on an open 1.0-T MRI scanner, and to assess the learning curve of residents new to this technique. METHODS: An experienced MRI interventionalist (the expert) performed 125 MRI-guided FDSA procedures, and 75 patients were treated by one of three residents without previous experience in MRI-guided FDSA. Technical success rate and duration of MRI-guided FDSA of the expert and the residents were compared. The residents' learning curves were assessed. The occurrence of extra-articular deposition and leakage of contrast media from the puncture site and the subsequent impairment of image interpretation were retrospectively analyzed. RESULTS: Overall technical success was 97.5 %. The expert needed overall fewer puncture needle readjustments and was faster at puncture needle positioning (p < 0.01). The learning curve of the residents, however, was steep. They leveled with the performance of the expert after ≈ 15 interventions. With a minimal amount of training all steps of MRI-guided FDSA can be performed in ≤10 min. CONCLUSION: Magnetic resonance-guided FDSA in an open 1.0-T MRI scanner can be performed with high technical success in a reasonably short amount of time. Only a short learning curve is necessary to achieve expert level.

Abnormal cross-frequency coupling in the tinnitus network.

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.

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.

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.

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.

Psychometric evaluation of visual analog scale for the assessment of chronic tinnitus.

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

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.

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.

Counteracting tinnitus by acoustic coordinated reset neuromodulation.

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

Data-driven approach to the estimation of connectivity and time delays in the coupling of interacting neuronal subsystems.

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

The causal relationship between subcortical local field potential oscillations and Parkinsonian resting tremor.

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