BackgroundThe 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.MethodsIn 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.ResultsCoordinated 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.ConclusionsThese 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. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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In computational models it has been shown that appropriate stimulation protocols may reshape the connectivity pattern of neural or oscillator networks with synaptic plasticity in a way that the network learns or unlearns strong synchronization. The underlying mechanism is that a network is shifted from one attractor to another, so that long-lasting stimulation effects are caused which persist after the cessation of stimulation. Here we study long-lasting effects of multisite electrical stimulation in a rat hippocampal slice rendered epileptic by magnesium withdrawal. We show that desynchronizing coordinated reset stimulation causes a long-lasting desynchronization between hippocampal neuronal populations together with a widespread decrease in the amplitude of the epileptiform activity. In contrast, periodic stimulation induces a long-lasting increase in both synchronization and amplitude. Synchronization is a classical self-organization phenomenon ͓1͔. Abnormally strong neuronal synchronization is, e.g., found in epilepsy ͓2͔. Experiments have been devoted to suppress epileptiform activity by continuous or adaptive pulsatile or smooth electrical stimulation ͓3͔. Reinitiation of epileptiform activity follows stimulus removal immediately or after a few minutes ͑e.g., 4 min͒ ͓3͔. In contrast, our modelbased approach does not aim at a suppression of epileptiform activity during stimulation, but at a long-lasting change in the network's dynamics due to a stimulation-induced reshaping of the network connectivity.Network topology strongly impacts on network dynamics ͓4͔. Unlike in many physical systems, in biological neural networks the ͑coupling͒ strength of a synapse ͑conveying signals from a presynaptic to a postsynaptic neuron͒, is not constant, but depends on the neuronal timing ͓5͔: if a presynaptic spike advances the postsynaptic spike, the synaptic weight increases, whereas in the opposite case the synaptic weight decreases. This mechanism, the spike timingdependent plasticity ͑STDP͒, is fundamental to learning and memory in nervous systems ͓5͔. Dynamical and connectivity changes are tightly connected in neuronal populations ͓6͔. Neural and phase oscillator networks with STDP are multistable ͓7͔: the attractors differ in their fast neuronal dynamics and their slow synaptic dynamics ͑connectivity pattern͒. Stable states with stronger synchronization and stronger average synaptic weight coexist with stable desynchronized states with a weaker average synaptic weight ͓7͔.As shown numerically, the tight relationship between network dynamics and connectivity enables to reshape the connectivity by controlling the dynamics. Stimulation techniques may shift a network from one attractor to another, so that the stimulation effect outlasts stimulus offset: the network learns or unlearns synchrony ͓7,8͔. Periodic stimulation increases the amount of synchrony along with the rate of coincidences and the mean synaptic weight. The network is shifted from a desynchronized state with weak coupling to a synchronized state with str...

Topologies of invariant manifolds and optimal trajectories are investigated in stochastic continuous systems and maps. A topological method is introduced that simplifies the solution of boundary value problems: The activation energy is calculated as a function of a set of parameters characterizing the initial conditions of the escape path. The method is applied explicitly to compute the optimal escape path and the activation energy for a variety of dynamical systems and maps.

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 12 weeks 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 12 weeks 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.