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 12weeks 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 12weeks 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

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.Keywords: tinnitus pitch, oscillations, delta band activity, alpha rhythm, gamma band activity, coordinated reset neuromodulation, cross frequency couplin

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

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

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

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

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

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

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. 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. 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 aeaEuroe15 interventions. With a minimal amount of training all steps of MRI-guided FDSA can be performed in 10 min. 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

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 stimulationON 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 CRlike 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

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

Abstract 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  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.</p