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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 DBS on the frequency of spontaneous recurrent seizures in chronic epileptic rats.(A) Four months after pilocarpine-induced (Pilo) status epilepticus (SE), animals were videotaped for two weeks, followed by the implantation of anterior thalamic nucleus (AN) electrodes or sham surgery. On the first postoperative week, the frequency of behavioral seizures was recorded to study the effects of surgery and electrode insertion. On the second postoperative week, animals were given DBS (horizontal bar). (B) Animals treated with 100 µA had a 52% reduction in seizure rate as compared to sham-treated controls (p = 0.1) and 61% less seizures than at baseline (p = 0.05). In contrast, rats given DBS at 500 µA had 5.1 times more seizures than controls (p<0.01) and a 2.8 fold increase in seizure rate as compared to preoperative values (p = 0.03). (C) Schematic representation of coronal brain sections depicting the region in which the tips of the electrodes were identified. For clarity, we did not plot the tip of each of the 58 electrodes implanted in animals receiving stimulation but rather indicate the boundaries of the regions in which they were identified (circles). Values in B are presented as mean and SE. Numbers in parenthesis represent animals per group. In C, numbers on the right denote distance from the bregma. AD- anterodorsal nucleus of the thalamus; AV- anteroventral nucleus of the thalamus; AM- anteromedial nucleus of the thalamus. * statistically significant compared to preoperative values. § statistically significant compared to controls. Figure C was modified and reprinted from Paxinos and Watson, Copyright (1998) with permission from Elsevier.
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pone-0097618-g001: Effects of DBS on the frequency of spontaneous recurrent seizures in chronic epileptic rats.(A) Four months after pilocarpine-induced (Pilo) status epilepticus (SE), animals were videotaped for two weeks, followed by the implantation of anterior thalamic nucleus (AN) electrodes or sham surgery. On the first postoperative week, the frequency of behavioral seizures was recorded to study the effects of surgery and electrode insertion. On the second postoperative week, animals were given DBS (horizontal bar). (B) Animals treated with 100 µA had a 52% reduction in seizure rate as compared to sham-treated controls (p = 0.1) and 61% less seizures than at baseline (p = 0.05). In contrast, rats given DBS at 500 µA had 5.1 times more seizures than controls (p<0.01) and a 2.8 fold increase in seizure rate as compared to preoperative values (p = 0.03). (C) Schematic representation of coronal brain sections depicting the region in which the tips of the electrodes were identified. For clarity, we did not plot the tip of each of the 58 electrodes implanted in animals receiving stimulation but rather indicate the boundaries of the regions in which they were identified (circles). Values in B are presented as mean and SE. Numbers in parenthesis represent animals per group. In C, numbers on the right denote distance from the bregma. AD- anterodorsal nucleus of the thalamus; AV- anteroventral nucleus of the thalamus; AM- anteromedial nucleus of the thalamus. * statistically significant compared to preoperative values. § statistically significant compared to controls. Figure C was modified and reprinted from Paxinos and Watson, Copyright (1998) with permission from Elsevier.

Mentions: Adult male Wistar rats (250–300 g) were injected with pilocarpine (Pilo; 320 mg/Kg i.p.). Four months after Pilo-induced SE, chronic epileptic rats were videotaped for 6 h/day, 5 days/week for 2 weeks to register their baseline frequency of behavioral seizures (Figure 1A). Animals were then paired according to seizure rate and assigned to receive either DBS or sham-surgery (holes drilled to the skull without the insertion of electrodes). Under ketamine/xylazine anesthesia (100/7.5 mg/kg i.p.), animals in the DBS group had insulated stainless steel electrodes (cathodes; 250 µm diameter; 0.5 mm exposed length) bilaterally implanted in the AN (anteroposterior −1.5, lateral±1.5, depth 5.2) [24]. A screw implanted over the right somatosensory cortex was used as the anode. On the first postoperative week, the effects of electrode insertion in the frequency of seizures were studied. On the second postoperative week, DBS was administered for 5 days (6 h/day) using a portable stimulator (St Jude Medical, Plano, TX) at 130 Hz, 90 µsec, and either 500 µA or 100 µA (Figure 1A). These settings were chosen as they were either effective against pilocarpine-induced seizures in our previous study (500 µA) [14] or estimated to generate a charge density (current x pulse width/area of exposed electrode) similar to that used in the clinic (100 µA) [5], [23], [25]. Stimulation frequency and pulse width were in the range of those used in clinical practice [5], [7], [9], [10].


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 DBS on the frequency of spontaneous recurrent seizures in chronic epileptic rats.(A) Four months after pilocarpine-induced (Pilo) status epilepticus (SE), animals were videotaped for two weeks, followed by the implantation of anterior thalamic nucleus (AN) electrodes or sham surgery. On the first postoperative week, the frequency of behavioral seizures was recorded to study the effects of surgery and electrode insertion. On the second postoperative week, animals were given DBS (horizontal bar). (B) Animals treated with 100 µA had a 52% reduction in seizure rate as compared to sham-treated controls (p = 0.1) and 61% less seizures than at baseline (p = 0.05). In contrast, rats given DBS at 500 µA had 5.1 times more seizures than controls (p<0.01) and a 2.8 fold increase in seizure rate as compared to preoperative values (p = 0.03). (C) Schematic representation of coronal brain sections depicting the region in which the tips of the electrodes were identified. For clarity, we did not plot the tip of each of the 58 electrodes implanted in animals receiving stimulation but rather indicate the boundaries of the regions in which they were identified (circles). Values in B are presented as mean and SE. Numbers in parenthesis represent animals per group. In C, numbers on the right denote distance from the bregma. AD- anterodorsal nucleus of the thalamus; AV- anteroventral nucleus of the thalamus; AM- anteromedial nucleus of the thalamus. * statistically significant compared to preoperative values. § statistically significant compared to controls. Figure C was modified and reprinted from Paxinos and Watson, Copyright (1998) with permission from Elsevier.
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pone-0097618-g001: Effects of DBS on the frequency of spontaneous recurrent seizures in chronic epileptic rats.(A) Four months after pilocarpine-induced (Pilo) status epilepticus (SE), animals were videotaped for two weeks, followed by the implantation of anterior thalamic nucleus (AN) electrodes or sham surgery. On the first postoperative week, the frequency of behavioral seizures was recorded to study the effects of surgery and electrode insertion. On the second postoperative week, animals were given DBS (horizontal bar). (B) Animals treated with 100 µA had a 52% reduction in seizure rate as compared to sham-treated controls (p = 0.1) and 61% less seizures than at baseline (p = 0.05). In contrast, rats given DBS at 500 µA had 5.1 times more seizures than controls (p<0.01) and a 2.8 fold increase in seizure rate as compared to preoperative values (p = 0.03). (C) Schematic representation of coronal brain sections depicting the region in which the tips of the electrodes were identified. For clarity, we did not plot the tip of each of the 58 electrodes implanted in animals receiving stimulation but rather indicate the boundaries of the regions in which they were identified (circles). Values in B are presented as mean and SE. Numbers in parenthesis represent animals per group. In C, numbers on the right denote distance from the bregma. AD- anterodorsal nucleus of the thalamus; AV- anteroventral nucleus of the thalamus; AM- anteromedial nucleus of the thalamus. * statistically significant compared to preoperative values. § statistically significant compared to controls. Figure C was modified and reprinted from Paxinos and Watson, Copyright (1998) with permission from Elsevier.
Mentions: Adult male Wistar rats (250–300 g) were injected with pilocarpine (Pilo; 320 mg/Kg i.p.). Four months after Pilo-induced SE, chronic epileptic rats were videotaped for 6 h/day, 5 days/week for 2 weeks to register their baseline frequency of behavioral seizures (Figure 1A). Animals were then paired according to seizure rate and assigned to receive either DBS or sham-surgery (holes drilled to the skull without the insertion of electrodes). Under ketamine/xylazine anesthesia (100/7.5 mg/kg i.p.), animals in the DBS group had insulated stainless steel electrodes (cathodes; 250 µm diameter; 0.5 mm exposed length) bilaterally implanted in the AN (anteroposterior −1.5, lateral±1.5, depth 5.2) [24]. A screw implanted over the right somatosensory cortex was used as the anode. On the first postoperative week, the effects of electrode insertion in the frequency of seizures were studied. On the second postoperative week, DBS was administered for 5 days (6 h/day) using a portable stimulator (St Jude Medical, Plano, TX) at 130 Hz, 90 µsec, and either 500 µA or 100 µA (Figure 1A). These settings were chosen as they were either effective against pilocarpine-induced seizures in our previous study (500 µA) [14] or estimated to generate a charge density (current x pulse width/area of exposed electrode) similar to that used in the clinic (100 µA) [5], [23], [25]. Stimulation frequency and pulse width were in the range of those used in clinical practice [5], [7], [9], [10].

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