Christian Hauptmann

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.

Control of Neuronal Synchrony by Nonlinear Delayed Feedback

We present nonlinear delayed feedback stimulation as a technique for effective desynchronization. This method is intriguingly robust with respect to system and stimulation parameter variations. We demonstrate its broad applicability by applying it to different generic oscillator networks as well as to a population of bursting neurons. Nonlinear delayed feedback specifically counteracts abnormal interactions and, thus, restores the natural frequencies of the individual oscillatory units. Nevertheless, nonlinear delayed feedback enables to strongly detune the macroscopic frequency of the collective oscillation. We propose nonlinear delayed feedback stimulation for the therapy of neurological diseases characterized by abnormal synchrony.

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 Parkinsons 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. ANN NEUROL 2012;72:816–820

Effectively desynchronizing deep brain stimulation based on a coordinated delayed feedback stimulation via several sites: a computational study

In detailed simulations we present a coordinated delayed feedback stimulation as a particularly robust and mild technique for desynchronization. We feed back the measured and band-pass filtered local filed potential via several or multiple sites with different delays, respectively. This yields a resounding desynchronization in a naturally demand-controlled way. Our novel approach is superior to previously developed techniques: It is robust against variations of system parameters, e.g., the mean firing rate. It does not require time-consuming calibration. It also prevents intermittent resynchronization typically caused by all methods employing repetitive administration of shocks. We suggest our novel technique to be used for deep brain stimulation in patients suffering from neurological diseases with pathological synchronization, such as Parkinsonian tremor, essential tremor or epilepsy.

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

The discovery of abnormal synchronization of neuronal activity in the basal ganglia in Parkinsons 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.

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 Parkinsons 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.

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.

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.

The generation of Parkinsonian tremor as revealed by directional coupling analysis

To reveal the dynamic mechanism underlying Parkinsonian resting tremor, we applied a phase dynamics modelling technique to local field potentials and accelerometer signals recorded in three Parkinsonian patients with implanted depth electrodes. We detect a bidirectional coupling between the subcortical oscillation and the tremor. The tremor → brain driving is a linear effect with a small delay corresponding to the neural transmission time. In contrast, the brain → tremor driving is a nonlinear effect with a long delay in the order of 1–2 mean tremor periods. Our results are well reproduced for an ensemble of 41 tremor epochs in three Parkinsonian patients and confirmed by surrogate data tests and model simulations. The uncovered mechanism of tremor generation suggests to specifically counteract tremor by desynchronizing the subcortical oscillatory neural activity.

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

BackgroundDevelopment 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.Methods757 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.ResultsThe 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.ConclusionDistribution 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.