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Acute seizure suppression by transcranial direct current stimulation in rats.

Dhamne SC, Ekstein D, Zhuo Z, Gersner R, Zurakowski D, Loddenkemper T, Pascual-Leone A, Jensen FE, Rotenberg A - Ann Clin Transl Neurol (2015)

Bottom Line: Clinical and electroencephalography (EEG) epileptic activity were compared between all groups.Cathodal 1 mA tDCS (1) reduced EEG spike bursts, and suppressed clinical seizures after the second PTZ challenge, (2) in combination with LZP was more effective in seizure suppression and improved the clinical seizure outcomes compared to either tDCS or LZP alone, and (3) prevented the loss of ppTMS motor cortex inhibition that accompanied PTZ injection.These results suggest that cathodal 1 mA tDCS alone and in combination with LZP can suppress seizures by augmenting GABAergic cortical inhibition.

View Article: PubMed Central - PubMed

Affiliation: Neuromodulation Program, Division of Epilepsy and Clinical Neurophysiology, and the F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School Boston, Massachusetts, USA.

ABSTRACT

Objective: Cathodal transcranial direct current stimulation (tDCS) is a focal neuromodulation technique that suppresses cortical excitability by low-amplitude constant electrical current, and may have an antiepileptic effect. Yet, tDCS has not been tested in status epilepticus (SE). Furthermore, a combined tDCS and pharmacotherapy antiseizure approach is unexplored. We therefore examined in the rat pentylenetetrazol (PTZ) SE model whether cathodal tDCS (1) suppresses seizures, (2) augments lorazepam (LZP) efficacy, and (3) enhances GABAergic cortical inhibition.

Methods: Experiment 1 aimed to identify an effective cathodal tDCS intensity. Rats received intraperitoneal PTZ followed by tDCS (sham, cathodal 1 mA, or cathodal 0.1 mA; for 20 min), and then a second PTZ challenge. In Experiment 2, two additional animal groups received a subtherapeutic LZP dose after PTZ, and then verum or sham tDCS. Clinical and electroencephalography (EEG) epileptic activity were compared between all groups. In Experiment 3, we measured GABA-mediated paired-pulse inhibition of the motor evoked potential by paired-pulse transcranial magnetic stimulation (ppTMS) in rats that received PTZ or saline, and either verum or sham tDCS.

Results: Cathodal 1 mA tDCS (1) reduced EEG spike bursts, and suppressed clinical seizures after the second PTZ challenge, (2) in combination with LZP was more effective in seizure suppression and improved the clinical seizure outcomes compared to either tDCS or LZP alone, and (3) prevented the loss of ppTMS motor cortex inhibition that accompanied PTZ injection.

Interpretation: These results suggest that cathodal 1 mA tDCS alone and in combination with LZP can suppress seizures by augmenting GABAergic cortical inhibition.

No MeSH data available.


Related in: MedlinePlus

Clinical and EEG outcomes of Lorazepam + tDCS treatment. (A) GTCS incidence and latency after first PTZ injection. Kaplan–Meier survival curve is used to display percentage incidence of GTCS (y-axis) and its latency (x-axis), after first PTZ injection in all treatment conditions. All three groups, Sham, LZP + Sham and LZP + tDCS were significantly different from each other with respect to seizure incidence rate and its latency. Note the distinct separation in the group treated with both LZP and 1 mA cathodal tDCS (LZP + tDCS) to have a very low seizure incidence rate and longer latencies. (B) GTCS duration after first PTZ injection. The two groups treated with LZP had significantly shorter seizures after first PTZ injection relative to no treatment sham group. But LZP in combination with 1 mA cathodal tDCS was more effective than LZP alone in reducing the seizure durations. *P < 0.05, ***P < 0.0001. (C) Spike burst count after first PTZ injection. Graph depicts the number of digitally counted burst discharges per 10 min of recording in the three groups of rats after stimulation. Treatment with LZP + tDCS aborted EEG seizures relative to the LZP + sham or sham groups. Boxes indicate median and first and third quartile. Tukey’s error bars are indicated by top and bottom whiskers. An outlier value is indicated, beyond the Tukey’s error range by the solid circle. ***P < 0.001. EEG, electroencephalography; tDCS, transcranial direct current stimulation; GTCS, generalized tonic-clonic seizures; PTZ, pentylenetetrazol; LZP, lorazepam.
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fig03: Clinical and EEG outcomes of Lorazepam + tDCS treatment. (A) GTCS incidence and latency after first PTZ injection. Kaplan–Meier survival curve is used to display percentage incidence of GTCS (y-axis) and its latency (x-axis), after first PTZ injection in all treatment conditions. All three groups, Sham, LZP + Sham and LZP + tDCS were significantly different from each other with respect to seizure incidence rate and its latency. Note the distinct separation in the group treated with both LZP and 1 mA cathodal tDCS (LZP + tDCS) to have a very low seizure incidence rate and longer latencies. (B) GTCS duration after first PTZ injection. The two groups treated with LZP had significantly shorter seizures after first PTZ injection relative to no treatment sham group. But LZP in combination with 1 mA cathodal tDCS was more effective than LZP alone in reducing the seizure durations. *P < 0.05, ***P < 0.0001. (C) Spike burst count after first PTZ injection. Graph depicts the number of digitally counted burst discharges per 10 min of recording in the three groups of rats after stimulation. Treatment with LZP + tDCS aborted EEG seizures relative to the LZP + sham or sham groups. Boxes indicate median and first and third quartile. Tukey’s error bars are indicated by top and bottom whiskers. An outlier value is indicated, beyond the Tukey’s error range by the solid circle. ***P < 0.001. EEG, electroencephalography; tDCS, transcranial direct current stimulation; GTCS, generalized tonic-clonic seizures; PTZ, pentylenetetrazol; LZP, lorazepam.

Mentions: Similar to the first experiment, the latency to the first clinical myoclonic jerk was not significantly different between the LZP + sham and LZP + tDCS treatment groups. The first PTZ injection induced a GTCS in 67% of rats treated with LZP alone and only 13% in the group treated with LZP + tDCS. Kaplan–Meier analysis (Fig.3A) shows the percent of animals with a GTCS after first PTZ injection revealing significant differences among all three conditions (sham tDCS from Experiment I, LZP + sham, LZP + tDCS) by Log-rank (Mantel–Cox) test (χ2 = 13; P = 0.0015). As expected, individual comparisons using Mantel–Cox test also demonstrated significant differences in the median GTCS incidence and latencies between groups. Comparison of median GTCS durations using Kruskal–Wallis reveals a significant group effect (P < 0.0001). The median duration of 43 sec (IQR, 24.5–140 sec) was significantly longer in sham-stimulated rats relative to 20 sec (IQR, 0–22.75 sec) of LZP + sham (P < 0.05) and 0 sec (IQR, 0–12.25 sec) of LZP + tDCS treatment (P < 0.001) as calculated by post hoc Dunn’s tests (Fig.3B). There were two deaths in the LZP + sham group and none in the LZP + tDCS. Thus the LZP + tDCS combination, in contrast to tDCS in isolation or LZP + sham treatment acutely aborted seizures induced by PTZ.


Acute seizure suppression by transcranial direct current stimulation in rats.

Dhamne SC, Ekstein D, Zhuo Z, Gersner R, Zurakowski D, Loddenkemper T, Pascual-Leone A, Jensen FE, Rotenberg A - Ann Clin Transl Neurol (2015)

Clinical and EEG outcomes of Lorazepam + tDCS treatment. (A) GTCS incidence and latency after first PTZ injection. Kaplan–Meier survival curve is used to display percentage incidence of GTCS (y-axis) and its latency (x-axis), after first PTZ injection in all treatment conditions. All three groups, Sham, LZP + Sham and LZP + tDCS were significantly different from each other with respect to seizure incidence rate and its latency. Note the distinct separation in the group treated with both LZP and 1 mA cathodal tDCS (LZP + tDCS) to have a very low seizure incidence rate and longer latencies. (B) GTCS duration after first PTZ injection. The two groups treated with LZP had significantly shorter seizures after first PTZ injection relative to no treatment sham group. But LZP in combination with 1 mA cathodal tDCS was more effective than LZP alone in reducing the seizure durations. *P < 0.05, ***P < 0.0001. (C) Spike burst count after first PTZ injection. Graph depicts the number of digitally counted burst discharges per 10 min of recording in the three groups of rats after stimulation. Treatment with LZP + tDCS aborted EEG seizures relative to the LZP + sham or sham groups. Boxes indicate median and first and third quartile. Tukey’s error bars are indicated by top and bottom whiskers. An outlier value is indicated, beyond the Tukey’s error range by the solid circle. ***P < 0.001. EEG, electroencephalography; tDCS, transcranial direct current stimulation; GTCS, generalized tonic-clonic seizures; PTZ, pentylenetetrazol; LZP, lorazepam.
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fig03: Clinical and EEG outcomes of Lorazepam + tDCS treatment. (A) GTCS incidence and latency after first PTZ injection. Kaplan–Meier survival curve is used to display percentage incidence of GTCS (y-axis) and its latency (x-axis), after first PTZ injection in all treatment conditions. All three groups, Sham, LZP + Sham and LZP + tDCS were significantly different from each other with respect to seizure incidence rate and its latency. Note the distinct separation in the group treated with both LZP and 1 mA cathodal tDCS (LZP + tDCS) to have a very low seizure incidence rate and longer latencies. (B) GTCS duration after first PTZ injection. The two groups treated with LZP had significantly shorter seizures after first PTZ injection relative to no treatment sham group. But LZP in combination with 1 mA cathodal tDCS was more effective than LZP alone in reducing the seizure durations. *P < 0.05, ***P < 0.0001. (C) Spike burst count after first PTZ injection. Graph depicts the number of digitally counted burst discharges per 10 min of recording in the three groups of rats after stimulation. Treatment with LZP + tDCS aborted EEG seizures relative to the LZP + sham or sham groups. Boxes indicate median and first and third quartile. Tukey’s error bars are indicated by top and bottom whiskers. An outlier value is indicated, beyond the Tukey’s error range by the solid circle. ***P < 0.001. EEG, electroencephalography; tDCS, transcranial direct current stimulation; GTCS, generalized tonic-clonic seizures; PTZ, pentylenetetrazol; LZP, lorazepam.
Mentions: Similar to the first experiment, the latency to the first clinical myoclonic jerk was not significantly different between the LZP + sham and LZP + tDCS treatment groups. The first PTZ injection induced a GTCS in 67% of rats treated with LZP alone and only 13% in the group treated with LZP + tDCS. Kaplan–Meier analysis (Fig.3A) shows the percent of animals with a GTCS after first PTZ injection revealing significant differences among all three conditions (sham tDCS from Experiment I, LZP + sham, LZP + tDCS) by Log-rank (Mantel–Cox) test (χ2 = 13; P = 0.0015). As expected, individual comparisons using Mantel–Cox test also demonstrated significant differences in the median GTCS incidence and latencies between groups. Comparison of median GTCS durations using Kruskal–Wallis reveals a significant group effect (P < 0.0001). The median duration of 43 sec (IQR, 24.5–140 sec) was significantly longer in sham-stimulated rats relative to 20 sec (IQR, 0–22.75 sec) of LZP + sham (P < 0.05) and 0 sec (IQR, 0–12.25 sec) of LZP + tDCS treatment (P < 0.001) as calculated by post hoc Dunn’s tests (Fig.3B). There were two deaths in the LZP + sham group and none in the LZP + tDCS. Thus the LZP + tDCS combination, in contrast to tDCS in isolation or LZP + sham treatment acutely aborted seizures induced by PTZ.

Bottom Line: Clinical and electroencephalography (EEG) epileptic activity were compared between all groups.Cathodal 1 mA tDCS (1) reduced EEG spike bursts, and suppressed clinical seizures after the second PTZ challenge, (2) in combination with LZP was more effective in seizure suppression and improved the clinical seizure outcomes compared to either tDCS or LZP alone, and (3) prevented the loss of ppTMS motor cortex inhibition that accompanied PTZ injection.These results suggest that cathodal 1 mA tDCS alone and in combination with LZP can suppress seizures by augmenting GABAergic cortical inhibition.

View Article: PubMed Central - PubMed

Affiliation: Neuromodulation Program, Division of Epilepsy and Clinical Neurophysiology, and the F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School Boston, Massachusetts, USA.

ABSTRACT

Objective: Cathodal transcranial direct current stimulation (tDCS) is a focal neuromodulation technique that suppresses cortical excitability by low-amplitude constant electrical current, and may have an antiepileptic effect. Yet, tDCS has not been tested in status epilepticus (SE). Furthermore, a combined tDCS and pharmacotherapy antiseizure approach is unexplored. We therefore examined in the rat pentylenetetrazol (PTZ) SE model whether cathodal tDCS (1) suppresses seizures, (2) augments lorazepam (LZP) efficacy, and (3) enhances GABAergic cortical inhibition.

Methods: Experiment 1 aimed to identify an effective cathodal tDCS intensity. Rats received intraperitoneal PTZ followed by tDCS (sham, cathodal 1 mA, or cathodal 0.1 mA; for 20 min), and then a second PTZ challenge. In Experiment 2, two additional animal groups received a subtherapeutic LZP dose after PTZ, and then verum or sham tDCS. Clinical and electroencephalography (EEG) epileptic activity were compared between all groups. In Experiment 3, we measured GABA-mediated paired-pulse inhibition of the motor evoked potential by paired-pulse transcranial magnetic stimulation (ppTMS) in rats that received PTZ or saline, and either verum or sham tDCS.

Results: Cathodal 1 mA tDCS (1) reduced EEG spike bursts, and suppressed clinical seizures after the second PTZ challenge, (2) in combination with LZP was more effective in seizure suppression and improved the clinical seizure outcomes compared to either tDCS or LZP alone, and (3) prevented the loss of ppTMS motor cortex inhibition that accompanied PTZ injection.

Interpretation: These results suggest that cathodal 1 mA tDCS alone and in combination with LZP can suppress seizures by augmenting GABAergic cortical inhibition.

No MeSH data available.


Related in: MedlinePlus