Peter Tass

A model of desynchronizing deep brain stimulation with a demand-controlled coordinated reset of neural subpopulations

Abstract.The coordinated reset of neural subpopulations is introduced as an effectively desynchronizing stimulation technique. For this, short sequences of high-frequency pulse trains are administered at different sites in a coordinated way. Desynchronization is easily maintained by performing a coordinated reset with demand-controlled timing or by periodically administering resetting high-frequency pulse trains of demand-controlled length. Unlike previously developed methods, this novel approach is robust against variations of model parameters and does not require time-consuming calibration. The novel technique is suggested to be used for demand-controlled deep brain stimulation in patients suffering from Parkinsons disease or essential tremor. It might even be applicable to diseases with intermittently emerging synchronized neural oscillations like epilepsy.

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

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.

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.

Cumulative and after-effects of short and weak coordinated reset stimulation: a modeling study

We show that the dynamical multistability of a network of bursting subthalamic neurons, caused by synaptic plasticity has a strong impact on the stimulus-response properties when exposed to weak and short desynchronizing stimuli. Intriguingly, such stimuli can reliably shift the network from a stable state with pathological synchrony and connectivity to a stable desynchronized state with down-regulated connectivity. However, unlike in the case of stronger coordinated reset stimulation, after termination of weaker stimulation the network may undergo a transient rebound of synchrony. When the coordinated reset stimulation is even weaker and/or shorter, so that a single stimulation epoch is not effective, the network dynamics and connectivity can still be reshaped in a cumulative manner by repetitive stimulation delivery.

Desynchronizing anti-resonance effect of m: n ON–OFF coordinated reset stimulation

This computational study is devoted to the optimal parameter calibration for coordinated reset (CR) stimulation, a stimulation technique suggested for an effective desynchronization of pathological neuronal synchronization. We present a detailed study of the parameter space of the CR stimulation method and show that CR stimulation can induce cluster states, desynchronization and oscillation death. The stimulation-induced cluster states (at CR offset) cause the longest desynchronizing post-stimulus transients, which constitute an essential part of the CR stimulation effect. We discover a desynchronization-related anti-resonance response of the stimulated oscillators induced by a periodic ON-OFF CR stimulation protocol with m cycles ON stimulation followed by n cycles OFF stimulation. The undesired collective oscillations are effectively desynchronized if the stimulation is administered at resonant frequencies of the controlled ensemble, which is in complete contrast to the typical effect of the usual periodic forcing.

Computational modeling of paroxysmal depolarization shifts in neurons induced by the glutamate release from astrocytes

Recent experimental studies have shown that astrocytes respond to external stimuli with a transient increase of the intracellular calcium concentration or can exhibit self-sustained spontaneous activity. Both evoked and spontaneous astrocytic calcium oscillations are accompanied by exocytosis of glutamate caged in astrocytes leading to paroxysmal depolarization shifts (PDS) in neighboring neurons. Here, we present a simple mathematical model of the interaction between astrocytes and neurons that is able to numerically reproduce the experimental results concerning the initiation of the PDS. The timing of glutamate release from the astrocyte is studied by means of a combined modeling of a vesicle cycle and the dynamics of SNARE-proteins. The neuronal slow inward currents (SICs), induced by the astrocytic glutamate and leading to PDS, are modeled via the activation of presynaptic glutamate receptors. The dependence of the bidirectional communication between neurons and astrocytes on the concentration of glutamate transporters is analyzed, as well. Our numerical results are in line with experimental findings showing that astrocyte can induce synchronous PDSs in neighboring neurons, resulting in a transient synchronous spiking activity.

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.