Biology subjects

Paschen, E.

Publications and source records attributed to Paschen, E..

6 recordsLinked to original sources

bioRxiv2025

Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice

BackgroundMesial temporal lobe epilepsy (MTLE) is a prevalent form of focal epilepsy characterized by seizures originating from the hippocampus and adjacent regions. Neurostimulation presents an alternative for surgery-ineligible patients with intractable seizures. However, conventional approaches have limited efficacy and require refinement for better seizure control. While hippocampal low-frequency stimulation (LFS) has shown promising seizure reduction in animal studies and small clinical cohorts, its mechanisms, sex-specific outcomes, and long-term effects remain unknown. ObjectivesWe aimed to identify the long-term antiepileptic and cognitive outcomes and potential underlying mechanisms of hippocampal LFS in chronically epileptic male and female mice. MethodsWe used the intrahippocampal kainate mouse model replicating the features of MTLE: spontaneous seizures, hippocampal sclerosis, and memory deficits. We applied 1 Hz electrical LFS in the sclerotic hippocampus 6 hours a day, four times a week for 5 weeks and examined its effects on epileptiform activity, spatial memory, and kainate-induced pathological features at cellular and synaptic levels. ResultsLong-term hippocampal LFS consistently diminished focal seizures in epileptic male and female mice, with seizure reduction extending beyond the stimulation period. Additionally, LFS relieved spatial memory deficits and reversed pathological long-term potentiation-like changes at perforant path-dentate granule cell synapses. LFS had no significant effect on generalized convulsive seizures, anxiety-like behaviour, neurogenesis, hippocampal sclerosis, excitatory synapse marker expression, or presynaptic vesicles in perforant path fibers. ConclusionThese findings provide clinically relevant insights into the seizure type-specific effects of hippocampal LFS, which, alongside synaptic and behavioural improvements, could contribute to enhanced seizure control and quality of life in MTLE patients.

neuroscience↗

bioRxiv2024

Low frequency stimulation for seizure suppression: identification of optimal targets in the entorhinal-hippocampal circuit

BackgroundMesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is a common form of drug-resistant focal epilepsy in adults. Treatment for pharmacoresistant patients remains a challenge, with deep brain stimulation (DBS) showing promise for alleviating intractable seizures. This study explores the efficacy of low-frequency stimulation (LFS) on specific neuronal targets within the entorhinal-hippocampal circuit in a mouse model of MTLE. Objective/HypothesisOur previous research demonstrated that LFS of the medial perforant path (MPP) fibers in the sclerotic hippocampus reduced seizures in epileptic mice. Here, we aimed to identify the critical neuronal population responsible for this antiepileptic effect by optogenetically stimulating presynaptic and postsynaptic compartments of the MPP-dentate granule cell (DGC) synapse at 1 Hz. We hypothesize that specific targets for LFS can differentially influence seizure activity depending on the cellular identity and location within or outside the seizure focus. MethodsWe utilized the intrahippocampal kainate (ihKA) mouse model of MTLE and targeted specific neural populations using Channelrhodopsin2 (ChR2) and stereotactic optic fiber implantation. We recorded intracranial neuronal activity from freely moving chronically epileptic mice with and without optogenetic LFS up to three hours. ResultsWe found that LFS of MPP fibers in the sclerotic hippocampus effectively suppressed epileptiform activity while stimulating principal cells in the MEC had no impact. Targeting DGCs in the sclerotic septal or non-sclerotic temporal hippocampus with LFS did not reduce seizure numbers but shortened the epileptiform bursts. ConclusionPresynaptic stimulation of the MPP-DGC synapse within the sclerotic hippocampus is critical for seizure suppression via LFS.

neuroscience↗

bioRxiv2023

Probing hippocampal stimulation in experimental temporal lobe epilepsy with functional MRI

BackgroundElectrical neurostimulation is a potentially effective therapy in epilepsy but the optimal approach is not yet clear. The parameter space is wide and the effects of different stimulations are not immediately obvious. Functional MRI (fMRI) can reveal which brain areas are affected by stimulation and help understand the induced effects. However, simultaneous deep brain stimulation (DBS)-fMRI examinations in patients are rare and the possibility to investigate multiple stimulation protocols is limited. Preclinical stimulation-fMRI studies can provide predictive value and help identify optimal neurostimulation parameters. ObjectiveTo systematically investigate the brain-wide responses to hippocampal electrical stimulations in a mouse model of mesial temporal lobe epilepsy (mTLE) using fMRI. MethodsWe applied electrical stimulation in the intrahippocampal kainate mouse model of mTLE and assessed the effect of different stimulation amplitudes (80-230 {micro}A) and frequencies (1-100 Hz). In addition, the effect of prolonged 1 Hz stimulation was explored. Saline-injected mice served as controls. ResultsVarying the stimulation amplitudes had little effect on the resulting activation patterns. Low frequency stimulation led to a local response at the stimulation site only, whereas high frequency resulted in a spread of activation from the hippocampal formation into cortical and frontal areas. Prolonged low frequency stimulation reduced excitability. ConclusionsWhile the amplitude parameter offers little opportunity to vary the outcome, the frequency represented the key parameter and determined whether the induced activation remained local or spread across the brain. This is in line with the few DBS-fMRI results obtained in epilepsy patients demonstrating the translational value of fMRI.

neuroscience↗

bioRxiv2023

On-demand low-frequency stimulation for seizure control: efficacy and behavioral implications

Mesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsy in adults, is often refractory to medication and associated with hippocampal sclerosis. Deep brain stimulation represents an alternative treatment option for drug-resistant patients who are ineligible for resective brain surgery. In clinical practice, closed-loop stimulation at high frequencies is applied to interrupt ongoing seizures, yet with a high incidence of false detections, the drawback of delayed seizure-suppressive intervention and limited success in sclerotic tissue. More recently, hippocampal low-frequency stimulation (LFS) has been shown to reduce excitability in clinical settings and prevent seizures in experimental MTLE when applied continuously. However, as the hippocampus is important for navigation and memory, it would be beneficial to stimulate it only on-demand to reduce its exposure to LFS pulses, and to investigate LFS-related effects on cognition. Using the intrahippocampal kainate mouse model, which recapitulates the key features of MTLE, we developed an on-demand LFS setup and investigated its effects on spontaneous seizure activity and hippocampal function. Specifically, our online detection algorithm monitored epileptiform activity in hippocampal local field potential recordings and identified short epileptiform bursts preceding focal seizure clusters, triggering hippocampal LFS to stabilize the network state. In addition, we investigated the acute influence of LFS on behavioral performance, including anxiety-like behavior in the light-dark box test, spatial and non-spatial memory in the object location memory and novel object recognition test, as well as spatial navigation and long-term memory in the Barnes maze. Compared to open-loop stimulation protocols, on-demand LFS was more efficient in preventing focal seizure clusters, as the strong anti-epileptic effect was achieved with a reduced stimulation load. In behavioral tests, chronically epileptic mice were as mobile as healthy controls but showed increased anxiety, an altered spatial learning strategy and impaired memory performance. Most importantly, our experiments ruled out deleterious effects of hippocampal LFS on cognition and even showed alleviation of deficits in long-term memory recall. Taken together, our findings may provide a promising alternative to current therapies, overcoming some of their major limitations, and inspire further investigation of LFS for seizure control in MTLE.

neuroscience↗

bioRxiv2021

In vivo characterization and application of a novel potassium channel-based optogenetic silencer in the healthy and epileptic mouse hippocampus

The performance of available optogenetic inhibitors remains insufficient due to low light sensitivity, short-lasting photocurrents, and unintended changes in ion distributions. To overcome these limitations, a novel potassium channel-based optogenetic silencer was developed and successfully applied in various in vitro and acute in vivo settings (Bernal Sierra et al., 2018). This tool, a two-component construct called PACK, comprises a photoactivated adenylyl cyclase (bPAC) and a cAMP-dependent potassium channel (SthK). Here, we examined the long-term inhibitory action and side effects of the PACK construct in healthy and epileptic adult male mice. We targeted hippocampal CA1 pyramidal cells using a viral vector and enabled illumination of these neurons via an implanted optic fiber. Local field potential (LFP) recordings from the CA1 of freely moving mice revealed significantly reduced neuronal activity during 50-minute intermittent illumination, especially in the beta and gamma frequency ranges. Adversely, PACK expression in healthy mice induced chronic astrogliosis, dispersion of pyramidal cells, and generalized seizures. These side effects were independent of the light application and were also present in mice expressing bPAC without the potassium channel. Additionally, light-activation of bPAC alone increased neuronal activity, presumably via enhanced cAMP signaling. In chronically epileptic mice, the dark activity of bPAC/PACK in CA1 prevented the spread of spontaneous epileptiform activity from the seizure focus to the contralateral bPAC/PACK-expressing hippocampus. Taken together, the PACK tool is a potent optogenetic inhibitor but requires refinement of its light-sensitive domain to avoid unexpected physiological changes. Significance statementOptogenetics allows precise manipulation of neuronal activity via genetically encoded light-sensitive proteins. Unfortunately, available optogenetic inhibitors are not suitable for prolonged use. The newly developed two-component potassium channel-based optogenetic inhibitor, PACK, has been identified as a potent silencer of neurons in various acute experiments. Here, we characterized the PACK construct in freely behaving healthy and epileptic mice. We targeted the PACK silencer specifically to CA1 pyramidal neurons, where illumination with short light pulses at low frequencies reliably reduced neuronal activity. In chronically epileptic mice, PACK prevented the spread of epileptiform activity from the seizure focus to the contralateral PACK-expressing hippocampus. The major disadvantage of the PACK silencer is its light-sensitive domain, the bPAC adenylyl cyclase, which may induce side effects.

neuroscience↗

bioRxiv2020

Optogenetic low-frequency stimulation of dentate granule cells prevents seizure generation in experimental epilepsy

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy in adults and is typically associated with hippocampal sclerosis and drug-resistant seizures. As an alternative to curative epilepsy surgery, brain stimulation evolves as a promising approach for seizure-interference. However, particularly in MTLE with severe hippocampal sclerosis, current stimulation protocols are often not effective. Here, we show that optogenetic low-frequency stimulation (oLFS) of entorhinal afferents exhibits unprecedented anti-ictogenic effects in chronically epileptic mice. Photostimulation at 1 Hz resulted in an almost complete suppression of focal seizures, independent of the degree of hippocampal sclerosis. Furthermore, by performing oLFS for 30 min before a pro-convulsive stimulus, seizure generalization was successfully prevented. Finally, acute slice experiments revealed a decreased excitability upon oLFS, which may partially explain the observed anti-epileptic effects. Taken together, our results suggest that oLFS of entorhinal afferents constitutes a promising approach for seizure control in MTLE.

physiology↗