Sensorimotor rhythm neurofeedback as adjunct therapy for Parkinson's disease

Philippens, Ingrid H.C.H.M.; Wubben, Jacqueline; Vanwersch, R.A.P.; Estevao, Dave L.; Tass, Peter A.

doi:10.1002/acn3.434

Cited by 22 publications

(29 citation statements)

References 23 publications

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“…Also, quantities assessing the interaction of brain oscillation, e.g., phase amplitude coupling (PAC) might be used as biomarker to represent the amount of symptoms (Beudel and Brown, 2016 ). Also, activity in the beta band might be relevant for compensatory purposes, as recently shown in a parkinsonian monkey study with sensorimotor rhythm neurofeedback (Philippens et al, 2017 ).…”

Section: Discussionmentioning

confidence: 83%

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization

Manos

Zeitler²,

Tass

2018

Front. Physiol.

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In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long-term desynchronization at comparably short stimulation duration and low integral stimulation duration. Currently, clinical proof of concept is available for deep brain CR stimulation for Parkinson's therapy and acoustic CR stimulation for tinnitus therapy. Promising first in human data is available for vibrotactile CR stimulation for Parkinson's treatment. For the clinical development of these treatments it is mandatory to perform dose-finding studies to reveal optimal stimulation parameters and dosage regimens. Our findings can straightforwardly be tested in human dose-finding studies.

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Section: Discussionmentioning

confidence: 83%

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization

Manos

Zeitler²,

Tass

2018

Front. Physiol.

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“…However, for instance in Parkinson’s disease it is still a matter of debate whether there is a measurable quantity that reasonably represents the extent of symptoms, in a biomarker-like manner [ 126 , 127 ]. In fact, a number of studies provided results that are in contradiction of the biomarker notion [ 127 – 133 ]. Accordingly, so far, it is not possible to provide ranges of the amount of synchrony–reflected by R av —that correspond to physiological as opposed to abnormal, Parkinsonian states.…”

Section: Discussionmentioning

confidence: 99%

How stimulation frequency and intensity impact on the long-lasting effects of coordinated reset stimulation

Manos

Zeitler²,

Tass

2018

PLoS Comput Biol

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Several brain diseases are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was computationally designed to specifically counteract abnormal neuronal synchronization processes by desynchronization. In the presence of spike-timing-dependent plasticity (STDP) this may lead to a decrease of synaptic excitatory weights and ultimately to an anti-kindling, i.e. unlearning of abnormal synaptic connectivity and abnormal neuronal synchrony. The long-lasting desynchronizing impact of CR stimulation has been verified in pre-clinical and clinical proof of concept studies. However, as yet it is unclear how to optimally choose the CR stimulation frequency, i.e. the repetition rate at which the CR stimuli are delivered. This work presents the first computational study on the dependence of the acute and long-term outcome on the CR stimulation frequency in neuronal networks with STDP. For this purpose, CR stimulation was applied with Rapidly Varying Sequences (RVS) as well as with Slowly Varying Sequences (SVS) in a wide range of stimulation frequencies and intensities. Our findings demonstrate that acute desynchronization, achieved during stimulation, does not necessarily lead to long-term desynchronization after cessation of stimulation. By comparing the long-term effects of the two different CR protocols, the RVS CR stimulation turned out to be more robust against variations of the stimulation frequency. However, SVS CR stimulation can obtain stronger anti-kindling effects. We revealed specific parameter ranges that are favorable for long-term desynchronization. For instance, RVS CR stimulation at weak intensities and with stimulation frequencies in the range of the neuronal firing rates turned out to be effective and robust, in particular, if no closed loop adaptation of stimulation parameters is (technically) available. From a clinical standpoint, this may be relevant in the context of both invasive as well as non-invasive CR stimulation.

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“…Also, beta band oscillations need not be entirely pathological. Rather activity in the beta frequency range might be key for compensatory purposes, as demonstrated in an MPTP monkey study with sensorimotor rhythm neurofeedback (Philippens et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, MLDF requires a reliably measurable clean biomarker signal sufficiently representing the amount of abnormal synchronization. Despite first positive results (Little et al, 2013 ; Rosa et al, 2015 ), several findings indicate that beta-band STN LFP does not provide a reliable biomarker (Özkurt et al, 2011 ; Quinn et al, 2015 ; Johnson et al, 2016 ; Kühn and Volkmann, 2017 ; Philippens et al, 2017 ), see above. In addition, MLDF requires a challenging registration-stimulation setup: An LFP signal, representative for the entire neuronal target population, has to be measured at one site, while stimuli have to be delivered to different sites of the target population.…”

Section: Discussionmentioning

confidence: 99%

Multisite Delayed Feedback for Electrical Brain Stimulation

Popovych¹,

Tass²

2018

Front. Physiol.

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Demand-controlled deep brain stimulation (DBS) appears to be a promising approach for the treatment of Parkinson's disease (PD) as revealed by computational, pre-clinical and clinical studies. Stimulation delivery is adapted to brain activity, for example, to the amount of neuronal activity considered to be abnormal. Such a closed-loop stimulation setup might help to reduce the amount of stimulation current, thereby maintaining therapeutic efficacy. In the context of the development of stimulation techniques that aim to restore desynchronized neuronal activity on a long-term basis, specific closed-loop stimulation protocols were designed computationally. These feedback techniques, e.g., pulsatile linear delayed feedback (LDF) or pulsatile nonlinear delayed feedback (NDF), were computationally developed to counteract abnormal neuronal synchronization characteristic for PD and other neurological disorders. By design, these techniques are intrinsically demand-controlled methods, where the amplitude of the stimulation signal is reduced when the desired desynchronized regime is reached. We here introduce a novel demand-controlled stimulation method, pulsatile multisite linear delayed feedback (MLDF), by employing MLDF to modulate the pulse amplitude of high-frequency (HF) DBS, in this way aiming at a specific, MLDF-related desynchronizing impact, while maintaining safety requirements with the charge-balanced HF DBS. Previously, MLDF was computationally developed for the control of spatio-temporal synchronized patterns and cluster states in neuronal populations. Here, in a physiologically motivated model network comprising neurons from subthalamic nucleus (STN) and external globus pallidus (GPe), we compare pulsatile MLDF to pulsatile LDF for the case where the smooth feedback signals are used to modulate the amplitude of charge-balanced HF DBS and suggest a modification of pulsatile MLDF which enables a pronounced desynchronizing impact. Our results may contribute to further clinical development of closed-loop DBS techniques.

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Sensorimotor rhythm neurofeedback as adjunct therapy for Parkinson's disease

Cited by 22 publications

References 23 publications

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization

How stimulation frequency and intensity impact on the long-lasting effects of coordinated reset stimulation

Multisite Delayed Feedback for Electrical Brain Stimulation

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