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.

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.

Mechanism of suppression of sustained neuronal spiking under high-frequency stimulation.

Using Hodgkin-Huxley and isolated subthalamic nucleus (STN) model neurons as examples, we show that electrical high-frequency stimulation (HFS) suppresses sustained neuronal spiking. The mechanism of suppression is explained on the basis of averaged equations derived from the original neuron equations in the limit of high frequencies. We show that for frequencies considerably greater than the reciprocal of the neuron's characteristic time scale, the result of action of HFS is defined by the ratio between the amplitude and the frequency of the stimulating signal. The effect of suppression emerges due to a stabilization of the neuron's resting state or due to a stabilization of a low-amplitude subthreshold oscillation of its membrane potential. Intriguingly, although we neglect synaptic dynamics, neural circuity as well as contribution of glial cells, the results obtained with the isolated high-frequency stimulated STN model neuron resemble the clinically observed relations between stimulation amplitude and stimulation frequency required to suppress Parkinsonian tremor.

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.

Modified pulse shapes for effective neural stimulation.

The electrical stimulation of neuronal structures is used as a treatment for many neurological disorders, e.g., for the treatment of Parkinson's disease via deep brain stimulation (DBS). To reduce side effects, to avoid tissue or electrode damage, and to increase battery lifetimes, an effective but gentle electrical stimulation is of prime importance. We studied different modified pulse shapes for application in DBS with respect to their efficiency to initiate neuronal activity. Numerical simulations of two mathematical neuron models were performed to investigate the effectiveness of different modified pulse shapes. According to our results, the pulse shapes considered showed a considerably increased efficiency in terms of both activation and entrainment of neural activity. We found that the introduction of a gap with a specific and optimized duration in a biphasic pulse and the reversal of the standard pulse phase order yielded stimulation protocols that could increase the efficiency and therefore reduce the energy consumption of stimulation. The improvements were achieved by simple modifications of existing stimulation techniques. The modification of the pulse shapes resulted in an improvement of up to 50% for both the activation of resting neurons and the entrainment of bursting neurons.