Abstract
A number of studies showed that deep brain stimulation (DBS) can modulate the activity in the epileptic brain and that a decrease of seizures can be achieved in “responding” patients. In most of these studies, the choice of stimulation parameters is critical to obtain desired clinical effects. In particular, the stimulation frequency is a key parameter that is difficult to tune. A reason is that our knowledge about the frequency-dependant mechanisms according to which DBS indirectly impacts the dynamics of pathological neuronal systems located in the neocortex is still limited. We address this issue using both computational modeling and intracerebral EEG (iEEG) data. We developed a macroscopic (neural mass) model of the thalamocortical network. In line with already-existing models, it includes interconnected neocortical pyramidal cells and interneurons, thalamocortical cells and reticular neurons. The novelty was to introduce, in the thalamic compartment, the biophysical effects of direct stimulation. Regarding clinical data, we used a quite unique data set recorded in a patient (drug-resistant epilepsy) with a focal cortical dysplasia (FCD). In this patient, DBS strongly reduced the sustained epileptic activity of the FCD for low-frequency (LFS, < 2 Hz) and high-frequency stimulation (HFS, > 70 Hz) while intermediate-frequency stimulation (IFS, around 50 Hz) had no effect. Signal processing, clustering, and optimization techniques allowed us to identify the necessary conditions for reproducing, in the model, the observed frequency-dependent stimulation effects. Key elements which explain the suppression of epileptic activity in the FCD include: (a) feed-forward inhibition and synaptic short-term depression of thalamocortical connections at LFS, and (b) inhibition of the thalamic output at HFS. Conversely, modeling results indicate that IFS favors thalamic oscillations and entrains epileptic dynamics.
Highlights
Deep brain stimulation (DBS) for Parkinson’s disease (PD) and other movement and psychiatric disorders—including dystonia, tremor, and depression—is clinically used today as a conventional therapeutic procedure for the alleviation of symptoms (Sillay and Starr, 2009)
Since the early 90s, neurologists attempted to apply deep brain stimulation (DBS) to other neurological disorders, typically to intractable epilepsies in order to suppress—or at least dramatically reduce— the occurrence of seizures [see recent review in Boon et al (2009)]. These studies followed early scientific evidence showing potentially beneficial effects of DBS on epileptic neural dynamics in animal models (Reimer et al, 1967; Hablitz, 1976) as well as in patients
SIMULATION OF local field potentials recorded in the FCD (LFPsFCD) UNDER NO STIMULATION CONDITION As a first step, we verified the ability of the model to generate signals that resemble those recorded from the focal cortical dysplasia (FCD) in the considered patient (LFPsFCD)
Summary
Deep brain stimulation (DBS) for Parkinson’s disease (PD) and other movement and psychiatric disorders—including dystonia, tremor, and depression—is clinically used today as a conventional therapeutic procedure for the alleviation of symptoms (Sillay and Starr, 2009). Since the early 90s, neurologists attempted to apply DBS to other neurological disorders, typically to intractable epilepsies in order to suppress—or at least dramatically reduce— the occurrence of seizures [see recent review in Boon et al (2009)] These studies followed early scientific evidence showing potentially beneficial effects of DBS on epileptic neural dynamics in animal models (Reimer et al, 1967; Hablitz, 1976) as well as in patients (Cooper et al, 1973; Davis et al, 1982; Wright and Abbreviations: CMN, Centromedian Nucleus; DBS, Deep Brain Stimulation; EPSP, Excitatory Postsynaptic Potentials; FCD, Focal Cortical Dysplasia; FFI, FeedForward Inhibition; GPi, Globus Pallidus; HFS, High Frequency Stimulation; iEEG, Intracerebral EEG (depth electrodes); IFS, Intermediate Frequency Stimulation; IPSP, Inhibitory Postsynaptic Potentials; LFP, Local Field Potential; LFPsFCD, Local Field Potentials recorded in the FCD; LFS, Low Frequency Stimulation; NS, No Stimulation; PMC, Premotor cortex; RtN, Reticular thalamic Nucleus, STD, Short-Term Depression; STN, Subthalamic Nucleus. Many fundamental questions are frequently raised: where and when to stimulate, at which frequency, at which current intensity, and with which current waveform?
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