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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

Experimental setup and design. (A) Rat tDCS-EEG setup. In Experiments 1 and 2, with the rat restrained on a platform, disk (active), and sponge (reference) electrodes were secured to the rat’s scalp and torso, respectively. Constant cathodal DC (1 or 0.1 mA) or sham (0 mA) current was delivered via wires connecting a DC stimulator to the electrodes. One-channel EEG was recorded using SWE. The recording SWE was positioned on the scalp over the parietal region and the reference over the dorsal snout at midline. (B) Rat ppTMS-EMG-tDCS setup. In Experiment 3, a figure-of-eight TMS coil was fixed to a micromanipulator arm and positioned over the left hemisphere. Motor evoked potentials were recorded using monopolar stainless steel needle electrodes placed into the brachioradialis of the contralateral right forelimb and between the digits of the footpad. A ground electrode was inserted in the tail. Also tDCS electrodes were secured to the scalp and torso as described previously. (C) Experimental design. In Experiments 1 and 2, the rats were closely observed after baseline EEG acquisition and the injection of PTZ alone (Experiment 1) or together with LZP (Experiment 2), for occurrence of first myoclonic jerk. One minute after the myoclonus, 20 min tDCS treatment was started: sham, cathodal 1 mA or cathodal 0.1 mA in Experiment 1, and sham or cathodal 1 mA in Experiment 2. The rats were then monitored clinically and by EEG for 10 min before and 15 after administration of a second dose of PTZ (20 mg/kg, i.p.). The entire session lasted for about 60 min and was video-monitored. In Experiment 3, sham or cathodal 1 mA tDCS was administered for 20 min immediately after injection of saline or PTZ. MEP ppTMS inhibition was continuously recorded at baseline, during sham or cathodal tDCS and 25 min after the tDCS treatment. tDCS, transcranial direct current stimulation; EEG, electroencephalography; SWE, subdermal wire electrodes; ppTMS, paired-pulse transcranial magnetic stimulation; PTZ, pentylenetetrazol; LZP, lorazepam; MEP, motor evoked potential.
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fig01: Experimental setup and design. (A) Rat tDCS-EEG setup. In Experiments 1 and 2, with the rat restrained on a platform, disk (active), and sponge (reference) electrodes were secured to the rat’s scalp and torso, respectively. Constant cathodal DC (1 or 0.1 mA) or sham (0 mA) current was delivered via wires connecting a DC stimulator to the electrodes. One-channel EEG was recorded using SWE. The recording SWE was positioned on the scalp over the parietal region and the reference over the dorsal snout at midline. (B) Rat ppTMS-EMG-tDCS setup. In Experiment 3, a figure-of-eight TMS coil was fixed to a micromanipulator arm and positioned over the left hemisphere. Motor evoked potentials were recorded using monopolar stainless steel needle electrodes placed into the brachioradialis of the contralateral right forelimb and between the digits of the footpad. A ground electrode was inserted in the tail. Also tDCS electrodes were secured to the scalp and torso as described previously. (C) Experimental design. In Experiments 1 and 2, the rats were closely observed after baseline EEG acquisition and the injection of PTZ alone (Experiment 1) or together with LZP (Experiment 2), for occurrence of first myoclonic jerk. One minute after the myoclonus, 20 min tDCS treatment was started: sham, cathodal 1 mA or cathodal 0.1 mA in Experiment 1, and sham or cathodal 1 mA in Experiment 2. The rats were then monitored clinically and by EEG for 10 min before and 15 after administration of a second dose of PTZ (20 mg/kg, i.p.). The entire session lasted for about 60 min and was video-monitored. In Experiment 3, sham or cathodal 1 mA tDCS was administered for 20 min immediately after injection of saline or PTZ. MEP ppTMS inhibition was continuously recorded at baseline, during sham or cathodal tDCS and 25 min after the tDCS treatment. tDCS, transcranial direct current stimulation; EEG, electroencephalography; SWE, subdermal wire electrodes; ppTMS, paired-pulse transcranial magnetic stimulation; PTZ, pentylenetetrazol; LZP, lorazepam; MEP, motor evoked potential.

Mentions: We used a constant current DC-stimulator (Model no: ALX-1.0/0/.1; Soterix Medical, New York, NY) capable of outputting either 0.1 or 1 mA current. The tDCS montage consisted of an active electrode in form of a electroencephalography (EEG) disc electrode (10 mm gold, Grass Technologies, West Warwick, RI) placed on the dorsal scalp and a reference electrode in the form of saline-soaked (3% NaCl) sponge (3 × 3 cm) pressed underneath the ventral torso. Prior to placement of the active tDCS electrode, after shaving, the rat’s scalp was gently rubbed using NuPrep™ Skin Prep Gel (Cardinal Health, Dublin, OH) to lower skin impedance. The active electrode was filled with conductive EEG paste (Ten20; D.O. Weaver and Co., Aurora, CO) to ensure maximal electrical conductance between the scalp and the electrode, and was secured to the dorsal scalp at midline using adhesive collodion. During cathodal tDCS, the active electrode on the scalp served as the cathode and the sponge as anode. No current was delivered during sham tDCS. The rats experienced only minimal discomfort during electrode placement. Animals were mechanically restrained on a platform with two broad Velcro straps positioned over the torso behind the forelimbs and in front of the hindlimbs (Fig.1A), as per laboratory protocol.17,18 Once the straps were secured, the animal was confined to the platform but retained full range of motion of the head, limbs, and tail. An advantage of this mechanical restraint is that it enables a continuous view of the animal’s head and extremities allowing for clinical seizures to be observed, and that it allows easy access to the rat’s head for EEG and tDCS electrodes.


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)

Experimental setup and design. (A) Rat tDCS-EEG setup. In Experiments 1 and 2, with the rat restrained on a platform, disk (active), and sponge (reference) electrodes were secured to the rat’s scalp and torso, respectively. Constant cathodal DC (1 or 0.1 mA) or sham (0 mA) current was delivered via wires connecting a DC stimulator to the electrodes. One-channel EEG was recorded using SWE. The recording SWE was positioned on the scalp over the parietal region and the reference over the dorsal snout at midline. (B) Rat ppTMS-EMG-tDCS setup. In Experiment 3, a figure-of-eight TMS coil was fixed to a micromanipulator arm and positioned over the left hemisphere. Motor evoked potentials were recorded using monopolar stainless steel needle electrodes placed into the brachioradialis of the contralateral right forelimb and between the digits of the footpad. A ground electrode was inserted in the tail. Also tDCS electrodes were secured to the scalp and torso as described previously. (C) Experimental design. In Experiments 1 and 2, the rats were closely observed after baseline EEG acquisition and the injection of PTZ alone (Experiment 1) or together with LZP (Experiment 2), for occurrence of first myoclonic jerk. One minute after the myoclonus, 20 min tDCS treatment was started: sham, cathodal 1 mA or cathodal 0.1 mA in Experiment 1, and sham or cathodal 1 mA in Experiment 2. The rats were then monitored clinically and by EEG for 10 min before and 15 after administration of a second dose of PTZ (20 mg/kg, i.p.). The entire session lasted for about 60 min and was video-monitored. In Experiment 3, sham or cathodal 1 mA tDCS was administered for 20 min immediately after injection of saline or PTZ. MEP ppTMS inhibition was continuously recorded at baseline, during sham or cathodal tDCS and 25 min after the tDCS treatment. tDCS, transcranial direct current stimulation; EEG, electroencephalography; SWE, subdermal wire electrodes; ppTMS, paired-pulse transcranial magnetic stimulation; PTZ, pentylenetetrazol; LZP, lorazepam; MEP, motor evoked potential.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554445&req=5

fig01: Experimental setup and design. (A) Rat tDCS-EEG setup. In Experiments 1 and 2, with the rat restrained on a platform, disk (active), and sponge (reference) electrodes were secured to the rat’s scalp and torso, respectively. Constant cathodal DC (1 or 0.1 mA) or sham (0 mA) current was delivered via wires connecting a DC stimulator to the electrodes. One-channel EEG was recorded using SWE. The recording SWE was positioned on the scalp over the parietal region and the reference over the dorsal snout at midline. (B) Rat ppTMS-EMG-tDCS setup. In Experiment 3, a figure-of-eight TMS coil was fixed to a micromanipulator arm and positioned over the left hemisphere. Motor evoked potentials were recorded using monopolar stainless steel needle electrodes placed into the brachioradialis of the contralateral right forelimb and between the digits of the footpad. A ground electrode was inserted in the tail. Also tDCS electrodes were secured to the scalp and torso as described previously. (C) Experimental design. In Experiments 1 and 2, the rats were closely observed after baseline EEG acquisition and the injection of PTZ alone (Experiment 1) or together with LZP (Experiment 2), for occurrence of first myoclonic jerk. One minute after the myoclonus, 20 min tDCS treatment was started: sham, cathodal 1 mA or cathodal 0.1 mA in Experiment 1, and sham or cathodal 1 mA in Experiment 2. The rats were then monitored clinically and by EEG for 10 min before and 15 after administration of a second dose of PTZ (20 mg/kg, i.p.). The entire session lasted for about 60 min and was video-monitored. In Experiment 3, sham or cathodal 1 mA tDCS was administered for 20 min immediately after injection of saline or PTZ. MEP ppTMS inhibition was continuously recorded at baseline, during sham or cathodal tDCS and 25 min after the tDCS treatment. tDCS, transcranial direct current stimulation; EEG, electroencephalography; SWE, subdermal wire electrodes; ppTMS, paired-pulse transcranial magnetic stimulation; PTZ, pentylenetetrazol; LZP, lorazepam; MEP, motor evoked potential.
Mentions: We used a constant current DC-stimulator (Model no: ALX-1.0/0/.1; Soterix Medical, New York, NY) capable of outputting either 0.1 or 1 mA current. The tDCS montage consisted of an active electrode in form of a electroencephalography (EEG) disc electrode (10 mm gold, Grass Technologies, West Warwick, RI) placed on the dorsal scalp and a reference electrode in the form of saline-soaked (3% NaCl) sponge (3 × 3 cm) pressed underneath the ventral torso. Prior to placement of the active tDCS electrode, after shaving, the rat’s scalp was gently rubbed using NuPrep™ Skin Prep Gel (Cardinal Health, Dublin, OH) to lower skin impedance. The active electrode was filled with conductive EEG paste (Ten20; D.O. Weaver and Co., Aurora, CO) to ensure maximal electrical conductance between the scalp and the electrode, and was secured to the dorsal scalp at midline using adhesive collodion. During cathodal tDCS, the active electrode on the scalp served as the cathode and the sponge as anode. No current was delivered during sham tDCS. The rats experienced only minimal discomfort during electrode placement. Animals were mechanically restrained on a platform with two broad Velcro straps positioned over the torso behind the forelimbs and in front of the hindlimbs (Fig.1A), as per laboratory protocol.17,18 Once the straps were secured, the animal was confined to the platform but retained full range of motion of the head, limbs, and tail. An advantage of this mechanical restraint is that it enables a continuous view of the animal’s head and extremities allowing for clinical seizures to be observed, and that it allows easy access to the rat’s head for EEG and tDCS electrodes.

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