Amygdala Low-Frequency Stimulation Reduces Pathological Phase-Amplitude Coupling in the Pilocarpine Model of Epilepsy (original) (raw)
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Brain Stimulation, 2015
Background: In many temporal lobe epilepsy (TLE) patients both hippocampi are seizure onset zones. These patients are unsuitable candidates for epilepsy surgery but may be amenable to hippocampal deep brain stimulation (DBS). The optimal DBS parameters for these patients are unknown. Recent observations suggest that even in patients with a unilateral focus switching from unilateral hippocampal DBS to bilateral hippocampal DBS could improve seizure control. Objective: Compare the effect of unilateral with bilateral hippocampal DBS on seizures in a rat model for TLE. Methods: In the post status epilepticus (SE) kainic acid rat model for TLE continuous EEG monitoring was performed for 50 days during which rats were subjected to 10 days of unilateral and 10 days of bilateral Poisson-distributed high frequency hippocampal DBS in a cross-over trial. During bilateral DBS, each hippocampus was stimulated with a separate stimulator and its own generated Poisson distribution with a mean and variance of 1/130 s. Results: Electrographic seizure rate was 23% lower during bilateral compared to unilateral hippocampal DBS (P < 0.05). No effect of unilateral nor bilateral hippocampal DBS was observed on seizure duration. When bilateral hippocampal DBS was applied, lower stimulation intensities were required to evoke after discharges (P < 0.05), reflecting a higher potency of bilateral hippocampal DBS compared to unilateral hippocampal DBS to affect hippocampal networks. Conclusions: Superior outcome in seizure control with bilateral compared to unilateral hippocampal DBS indicates that targeting larger regions of the hippocampal formation with more than one stimulation electrode may be more successful in suppressing seizures in TLE.
Effects of Anterior Thalamic Nucleus Deep Brain Stimulation in Chronic Epileptic Rats
PLoS ONE, 2014
Deep brain stimulation (DBS) has been investigated for the treatment of epilepsy. In rodents, an increase in the latency for the development of seizures and status epilepticus (SE) has been reported in different animal models but the consequences of delivering stimulation to chronic epileptic animals have not been extensively addressed. We study the effects of anterior thalamic nucleus (AN) stimulation at different current intensities in rats rendered epileptic following pilocarpine (Pilo) administration. Four months after Pilo-induced SE, chronic epileptic rats were bilaterally implanted with AN electrodes or had sham-surgery. Stimulation was delivered for 6 h/day, 5 days/week at 130 Hz, 90 msec. and either 100 mA or 500 mA. The frequency of spontaneous recurrent seizures in animals receiving stimulation was compared to that recorded in the preoperative period and in rats given sham treatment. To investigate the effects of DBS on hippocampal excitability, brain slices from animals receiving AN DBS or sham surgery were studied with electrophysiology. We found that rats treated with AN DBS at 100 mA had a 52% non-significant reduction in the frequency of seizures as compared to sham-treated controls and 61% less seizures than at baseline. Animals given DBS at 500 mA had 5.1 times more seizures than controls and a 2.8 fold increase in seizure rate as compared to preoperative values. In non-stimulated controls, the average frequency of seizures before and after surgery remained unaltered. In vitro recordings have shown that slices from animals previously given DBS at 100 mA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude compared to non-stimulated controls. In contrast, a higher spike amplitude was recorded in slices from animals given AN DBS at 500 mA.
Electrical stimulation for the treatment of epilepsy
Despite the advent of new pharmacological treatments and the high success rate of many surgical treatments for epilepsy, a substantial number of patients either do not become seizure-free or they experience major adverse events (or both). Neurostimulation-based treatments have gained considerable interest in the last decade. Vagus nerve stimulation (VNS) is an alternative treatment for patients with medically refractory epilepsy, who are unsuitable candidates for conventional epilepsy surgery, or who have had such surgery without optimal outcome. Although responder identification studies are lacking, long-term VNS studies show response rates between 40% and 50% and long-term seizure freedom in 5% to 10% of patients. Surgical complications and perioperative morbidity are low. Research into the mechanism of action of VNS has revealed a crucial role for the thalamus and cortical areas that are important in the epileptogenic pro-cess. Acute deep brain stimulation (DBS) in various thalamic nuclei and medial temporal lobe structures has recently been shown to be efficacious in small pilot studies. There is little evidence-based information on rational targets and stimulation parameters. Amygdalohippocampal DBS has yielded a significant decrease of seizure counts and interictal EEG abnormalities during long-term follow-up. Data from pilot studies suggest that chronic DBS for epilepsy may be a feasible, effective, and safe procedure. Further trials with larger patient populations and with controlled, randomized, and closed-loop designs should now be initiated. Further progress in understanding the mechanism of action of DBS for epilepsy is a necessary step to making this therapy more efficacious and established.
Turkish Neurosurgery, 2010
Experimental and clinical studies have revealed that hippocampal DBS can control epileptic activity, but the mechanism of action is obscure and optimal stimulation parameters are not clearly defined. The aim was to evaluate the effects of high frequency hippocampal stimulation on cortical epileptic activity in penicillin-induced epilepsy model. mAterIAl and methOds: Twenty-five Sprague-Dawley rats were implanted DBS electrodes. In group-1 (n=10) hippocampal DBS was off and in the group-2 (n=10) hippocampal DBS was on (185 Hz, 0.5V, 1V, 2V, and 5V for 60 sec) following penicillin G injection intracortically. In the control group hippocampal DBS was on following 8µl saline injection intracortically. EEG recordings were obtained before and 15 minutes following penicillin-G injection, and at 10th minutes following each stimulus for analysis in terms of frequency, amplitude, and power spectrum.
Epilepsia, 2015
Objective: Deep-brain electrical stimulation (DBS) is a treatment modality being explored for many neurologic diseases and is a potentially potent means of disrupting the aberrant rhythms that arise during the epileptic seizures that afflict >1% of the population. However, current DBS protocols typically employed are formulated a priori and do not reflect the electrophysiologic dynamics within the brain as seizures arise, which may underlie their limited efficacy. This study investigates how the efficacy of DBS could be improved using endogenous dynamics to inform stimulation protocols. Methods: Multisite brain dynamics within the circuit of Papez were calculated in a chronic rat limbic epilepsy model induced via lithium chloride/pilocarpine intraperitoneal injections. Stimulation/recording electrodes were placed in the CA3 region of the left and right hippocampi and the anteromedial nucleus of the left thalamus. Deconvolution of local field potentials using empirical mode decomposition (EMD) and phase synchrony analysis revealed multisite coherence as seizures approached natural termination that could not be detected with Fourier analysis. Multisite stimulation used charge-neutral biphasic square waves at frequencies observed during natural termination. Results: Synchronization of electrical activity across sites occurred as both spontaneous and evoked seizures naturally terminated. Furthermore, the location and frequency of the synchrony varied between subjects but was stable in time within each animal. DBS protocols were significantly more effective at rapidly stopping seizures when the frequency and location of multisite stimulation reflected the endogenous synchrony dynamics observed in each subject as seizures naturally terminated. Significance: These results strongly support the approach of tailoring DBS protocols to individual endogenous rhythms that may represent how brains naturally resolve epileptic seizures. This approach may significantly improve the overall efficacy of this potentially important therapy.
Epilepsy Research, 2008
Electrical stimulation of the anterior nucleus of the thalamus appears to be effective against seizures in animals and humans. As the optimal stimulation settings remain elusive, we studied the effects of different stimulation parameters against pilocarpine induced seizures and status epilepticus (SE).Adult rats had electrodes implanted bilaterally into the AN. Five days later, different groups of animals were stimulated with 1000 μA, 500 μA, or 200 μA and frequencies of either 20 Hz or 130 Hz. Pilocarpine (350 mg/kg i.p.) was injected 5 min after stimulation onset and seizures were monitored. Sham-treated controls had electrodes implanted but did not receive stimulation until they developed SE. After SE, these animals had the electrodes turned on to assess whether AN stimulation could arrest ongoing ictal activity.Compared to sham-treated controls (n = 8), stimulation at 500 μA (n = 13) significantly increased the latency for seizures and SE by 1.9–2.2-fold. In contrast, stimulation at 1000 μA (n = 8) produced a non-significant decrease in the latencies to these events. No major effect was observed with stimulation at 200 μA (n = 11). Similar results were obtained for each current intensity, regardless of the stimulation frequency used (20 Hz and 130 Hz). In sham-treated controls that had the electrodes turned on after SE, stimulation was not able to arrest ongoing ictal activity.The anticonvulsant effects of AN stimulation against pilocarpine-induced seizures were mainly determined by the current and not the frequency of stimulation. AN stimulation initiated after SE onset was ineffective.
Depolarization Block of Neurons During Maintenance of Electrographic Seizures
Journal of Neurophysiology, 2003
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Cells, 2021
Temporal lobe epilepsy (TLE) is characterized by changes in interneuron numbers in the hippocampus. Deep brain stimulation (DBS) is an emerging tool to treat TLE seizures, although its mechanisms are not fully deciphered. We aimed to depict the effect of amygdala DBS on the density of the most common interneuron types in the CA1 hippocampal subfield in the lithium-pilocarpine model of epilepsy. Status epilepticus was induced in male Wistar rats. Eight weeks later, a stimulation electrode was implanted to the left basolateral amygdala of both pilocarpine-treated (Pilo, n = 14) and age-matched control rats (n = 12). Ten Pilo and 4 control animals received for 10 days 4 daily packages of 50 s 4 Hz regular stimulation trains. At the end of the stimulation period, interneurons were identified by immunolabeling for parvalbumin (PV), neuropeptide Y (NPY), and neuronal nitric oxide synthase (nNOS). Cell density was determined in the CA1 subfield of the hippocampus using confocal microscopy....