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Effects of anterior thalamic nucleus deep brain stimulation in chronic epileptic rats.

Covolan L, de Almeida AC, Amorim B, Cavarsan C, Miranda MF, Aarão MC, Madureira AP, Rodrigues AM, Nobrega JN, Mello LE, Hamani C - PLoS ONE (2014)

Bottom Line: We found that rats treated with AN DBS at 100 µA 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 µA had 5.1 times more seizures than controls and a 2.8 fold increase in seizure rate as compared to preoperative values.In vitro recordings have shown that slices from animals previously given DBS at 100 µA 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.

View Article: PubMed Central - PubMed

Affiliation: Disciplina de Neurofisiologia, Universidade Federal de São Paulo, São Paulo, Brazil.

ABSTRACT
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 µsec. and either 100 µA or 500 µA. 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 µA 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 µA 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 µA 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 µA.

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Effects of anterior thalamic nucleus (AN) stimulation in vitro.(A) Dentate gyrus extracellular activity in slices from chronic epileptic rats previously given sham surgery (n = 7), AN DBS at 100 µA (n = 9) or 500 µA (n = 5). When slices from different groups were perfused with a zero calcium high potassium solution, DC shifts intermingled with spiking discharges were promptly recorded. (B) Overall, slices from animals previously given DBS at 100 µA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude as compared to those from animals previously given no stimulation or DBS at 500 µA. In contrast, a higher spike amplitude was detected in slices from rats that had AN stimulation at 500 µA. * Statistically significant (p≤0.05) as compared to controls. # Statistically significant (p≤0.05) as compared to animals in the other DBS group.
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pone-0097618-g002: Effects of anterior thalamic nucleus (AN) stimulation in vitro.(A) Dentate gyrus extracellular activity in slices from chronic epileptic rats previously given sham surgery (n = 7), AN DBS at 100 µA (n = 9) or 500 µA (n = 5). When slices from different groups were perfused with a zero calcium high potassium solution, DC shifts intermingled with spiking discharges were promptly recorded. (B) Overall, slices from animals previously given DBS at 100 µA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude as compared to those from animals previously given no stimulation or DBS at 500 µA. In contrast, a higher spike amplitude was detected in slices from rats that had AN stimulation at 500 µA. * Statistically significant (p≤0.05) as compared to controls. # Statistically significant (p≤0.05) as compared to animals in the other DBS group.

Mentions: Our initial hypothesis to explain the antiepileptic effects of AN DBS was that of a stimulation-induced decrease in hippocampal excitability. This was based on two fold. First, the AN is an important relay of the limbic circuitry having both direct and indirect connections with the hippocampus [27], [28]. Second, AN high frequency stimulation in rodents reduces neuronal firing rate in the hippocampal dentate gyrus [25]. To test this hypothesis, we recorded DG extracellular activity in slices from epileptic rats that did or did not receive 5 days of treatment with AN DBS. Epileptiform events have not been registered at baseline in either group. When slices were exposed to a zero calcium high potassium solution, however, DC shifts intermingled with spike discharges were clearly discriminated (Figure 2A).


Effects of anterior thalamic nucleus deep brain stimulation in chronic epileptic rats.

Covolan L, de Almeida AC, Amorim B, Cavarsan C, Miranda MF, Aarão MC, Madureira AP, Rodrigues AM, Nobrega JN, Mello LE, Hamani C - PLoS ONE (2014)

Effects of anterior thalamic nucleus (AN) stimulation in vitro.(A) Dentate gyrus extracellular activity in slices from chronic epileptic rats previously given sham surgery (n = 7), AN DBS at 100 µA (n = 9) or 500 µA (n = 5). When slices from different groups were perfused with a zero calcium high potassium solution, DC shifts intermingled with spiking discharges were promptly recorded. (B) Overall, slices from animals previously given DBS at 100 µA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude as compared to those from animals previously given no stimulation or DBS at 500 µA. In contrast, a higher spike amplitude was detected in slices from rats that had AN stimulation at 500 µA. * Statistically significant (p≤0.05) as compared to controls. # Statistically significant (p≤0.05) as compared to animals in the other DBS group.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4043725&req=5

pone-0097618-g002: Effects of anterior thalamic nucleus (AN) stimulation in vitro.(A) Dentate gyrus extracellular activity in slices from chronic epileptic rats previously given sham surgery (n = 7), AN DBS at 100 µA (n = 9) or 500 µA (n = 5). When slices from different groups were perfused with a zero calcium high potassium solution, DC shifts intermingled with spiking discharges were promptly recorded. (B) Overall, slices from animals previously given DBS at 100 µA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude as compared to those from animals previously given no stimulation or DBS at 500 µA. In contrast, a higher spike amplitude was detected in slices from rats that had AN stimulation at 500 µA. * Statistically significant (p≤0.05) as compared to controls. # Statistically significant (p≤0.05) as compared to animals in the other DBS group.
Mentions: Our initial hypothesis to explain the antiepileptic effects of AN DBS was that of a stimulation-induced decrease in hippocampal excitability. This was based on two fold. First, the AN is an important relay of the limbic circuitry having both direct and indirect connections with the hippocampus [27], [28]. Second, AN high frequency stimulation in rodents reduces neuronal firing rate in the hippocampal dentate gyrus [25]. To test this hypothesis, we recorded DG extracellular activity in slices from epileptic rats that did or did not receive 5 days of treatment with AN DBS. Epileptiform events have not been registered at baseline in either group. When slices were exposed to a zero calcium high potassium solution, however, DC shifts intermingled with spike discharges were clearly discriminated (Figure 2A).

Bottom Line: We found that rats treated with AN DBS at 100 µA 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 µA had 5.1 times more seizures than controls and a 2.8 fold increase in seizure rate as compared to preoperative values.In vitro recordings have shown that slices from animals previously given DBS at 100 µA 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.

View Article: PubMed Central - PubMed

Affiliation: Disciplina de Neurofisiologia, Universidade Federal de São Paulo, São Paulo, Brazil.

ABSTRACT
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 µsec. and either 100 µA or 500 µA. 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 µA 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 µA 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 µA 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 µA.

Show MeSH
Related in: MedlinePlus