Sustained efficacy of closed loop electrical stimulation for long-term treatment of absence epilepsy in rats

Abstract

Closed-loop brain stimulation is a promising alternative to treat drug-resistant epilepsies. In contrast to optogenetic interventions, transcranial electrical stimulation (TES) does not require cellular modification of neurons to be effective, and it is less invasive compared to deep brain stimulation. Furthermore, on-demand TES of targeted brain regions allows the potential for normal function of these networks during interictal periods, a possibility that is eliminated by resective surgical treatment approaches. To further explore the translation of closed-loop TES for treatment of epilepsy, we show here for the first time that unsupervised closed-loop TES in rats can consistently interrupt seizures for 6 weeks and has the potential to control seizure activity up to 4 months (longest periods examined). On-demand TES significantly reduced the time spent in seizure and the individual seizure duration, although significantly higher seizure rate was observed during the treatment. The 6 week long stimulation had no residual adverse effects on the electrophysiologic characteristics of the brain after the termination of the treatment and did not induce glial remodelling in the brain. Our findings demonstrate the safety and effectiveness of minimally invasive, potentially lifelong TES treatment of epilepsy either alone or as a complement to drug treatments.

Spike-and-Wave Discharges Are Not Pathological Sleep Spindles, Network-Level Aspects of Age-Dependent Absence Seizure Development in Rats

“…The animals for longitudinal observations (n ϭ 5, three months old), animals for pharmacological experiments (n ϭ 3, five to seven months) and animals for transcranial electrical stimulation experiments (n ϭ 6, five to seven months) were implanted with intracortical recording electrode triplets (interwire spacing, 0.4 mm), which targeted the frontal and parietal cortical areas of both hemispheres and unilaterally the CA1 subfield of the hippocampus, as already reported elsewhere in details (Kozák and Berényi, 2017). For transcranial stimulation experiments, additional stimulation electrodes were implanted over the temporal bone bilaterally (Kozák and Berényi, 2017;Kozák et al, 2018). Unit recordings and intracortical stimulation experiments were performed in rats divided into two age groups: juvenile (2.5-4 months, n ϭ 5) and mature (five to seven months, n ϭ 4) animals.…”

“…All recording sessions took place in the same room in 12/12 h light/dark cycles. After recovery from the surgery (minimum 3 d), the maturing rats were connected to the recording system and were observed for three months continuously in their home cage, as reported elsewhere already (Kozák and Berényi, 2017). The neuronal signals were preamplified, amplified (total gain 400ϫ), multiplexed on head and stored after digitalization at 20-kHz sampling rate per channel (KJE-1001, Amplipex).…”

“…To investigate the effect of closed-loop transcranial electrical disruption of seizure activity on sleep patterns, animals implanted with transcranial stimulation and intracortical recording electrodes were connected to a custom programmed unsupervised seizure detection and intervention system (RX-8, Tucker-Davis Technologies), reported elsewhere in details (Kozák and Berényi, 2017). Each detected seizure triggered a charge neutral, triphasic single-pulse (100 ms) stimulation (STG4008; Multi Channel Systems) through the bitemporal stimulation electrodes.…”

An Electrocorticography Device with an Integrated Microfluidic Ion Pump for Simultaneous Neural Recording and Electrophoretic Drug Delivery In Vivo

“…In this work, we combine the design principles from state‐of‐the‐art ECoG devices and electrophoretic drug delivery devices to present a cortical device that can simultaneously deliver drugs and record local neural activity. This represents a significant advancement in cortical devices for neural interfacing as the ability to monitor neural activity in real time can greatly enhance the efficacy of drug treatment regimens . The device design is presented in Figure 1 with arrows and text marking the primary components including the electrode pads for connecting to an external recording system, the source and target pads for connecting to the source and target electrodes of the µFIP as well as the fluidic inlet/outlet for loading/exchanging the drug solution (see the Experimental Section for fabrication details).…”

A Closed-Loop Brain Stimulation Control System Design Based on Brain-Machine Interface for Epilepsy

“…us, the research of absence epilepsy is significant and far-reaching. e most common treatment for epilepsy now remains in drug-assisted or surgical resection [16]. In some investigations, it has been shown that long-term service of epilepsy drugs may lead to liver decline or even damage due to epilepsy is a long-term chronic disease [17,18].…”