Low-frequency Stimulation at the Subiculum is Anti-convulsant and Anti-drug-resistant in a Mouse Model of Lamotrigine-resistant Temporal Lobe Epilepsy.
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ABSTRACT:
SUBMITTER: Ruan Y
PROVIDER: S-EPMC7271341 | biostudies-literature | 2020 Jun
REPOSITORIES: biostudies-literature
Publications
Low-frequency Stimulation at the Subiculum is Anti-convulsant and Anti-drug-resistant in a Mouse Model of Lamotrigine-resistant Temporal Lobe Epilepsy.
Ruan Yeping Y Xu Cenglin C Lan Jile J Nao Jiazhen J Zhang Shuo S Fan Fei F Wang Yi Y Chen Zhong Z
Neuroscience bulletin 20200310 6
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Project description:Background and objectivesWe assessed correlations between the resting state functional connectivity (RSFC) of different thalamic nuclei and seizure frequency in patients with drug-resistant medial temporal lobe epilepsy (mTLE).MethodsSeventeen patients with mTLE and 17 sex-/age-/handedness-matched controls participated. A seed-based correlation method for the resting-state FMRI data was implemented to get RSFC maps of 70 thalamic nuclei seed masks. Group statistics for individual RSFC for subjects and seed masks were performed to obtain within-group characteristics and between-group differences with age covariates. A linear regression was applied to test whether seizure frequency correlated with thalamic nuclear RSFC with the whole brain in mTLE patients.ResultsRSFC of thalamic nuclei showed spatially distinguishable connectivity patterns that reflected principal inputs and outputs that were derived from priori anatomical knowledge. We found group differences between normal control and mTLE groups in RSFC for nuclei seeds located in various subdivisions of thalamus. The RSFCs in some of those nuclei were strongly correlated with seizure frequency.ConclusionsMediodorsal thalamic nuclei may play important roles in seizure activity or in the regulation of neuronal activity in the limbic system. The RSFC of motor- and sensory-relay nuclei may help elucidate sensory-motor deficits associated with chronic seizure activity. RSFC of the pulvinar nuclei of the thalamus could also be a key reflection of symptom-related functional deficits in mTLE.
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Project description:Mesial temporal lobe epilepsy (MTLE) is the most common form of focal, pharmacoresistant epilepsy in adults and is often associated with hippocampal sclerosis. Here, we established the efficacy of optogenetic and electrical low-frequency stimulation (LFS) in interfering with seizure generation in a mouse model of MTLE. Specifically, we applied LFS in the sclerotic hippocampus to study the effects on spontaneous subclinical and evoked generalized seizures. We found that stimulation at 1 Hz for 1 hr resulted in an almost complete suppression of spontaneous seizures in both hippocampi. This seizure-suppressive action during daily stimulation remained stable over several weeks. Furthermore, LFS for 30 min before a pro-convulsive stimulus successfully prevented seizure generalization. Finally, acute slice experiments revealed a reduced efficacy of perforant path transmission onto granule cells upon LFS. Taken together, our results suggest that hippocampal LFS constitutes a promising approach for seizure control in MTLE.
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Project description:This study was performed to test the hypothesis that systemic leukocyte gene expression has prognostic value differentiating low from high seizure frequency refractory temporal lobe epilepsy (TLE). A consecutive series of sixteen patients with refractory temporal lobe epilepsy was studied. Based on a median baseline seizure frequency of 2.0 seizures per month, low versus high seizure frequency was defined as < 2 seizures/month and > 2 seizures/month, respectively.
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Project description:The mRNA levels of NKCC1, an inwardly directed Na(+), K(+)-2Cl(-) cotransporter that facilitates the accumulation of intracellular Cl(-), and of KCC2, an outwardly directed K(+)-Cl(-) cotransporter that extrudes Cl(-), were studied in surgically resected brain specimens from drug-resistant temporal lobe (TL) epilepsy (TLE) patients. Quantitative RT-PCR analyses of the mRNAs extracted from the human TLE-associated brain regions revealed an up-regulation of NKCC1 mRNA and a down-regulation of KCC2 mRNA in the hippocampal subiculum, compared with the hippocampus proper or the TL neocortex, suggesting an abnormal transcription of Cl(-) transporters in the TLE subiculum. In parallel experiments, cell membranes isolated from the same TLE-associated brain regions were injected into Xenopus oocytes that rapidly incorporated human GABA(A) receptors into their surface membrane. The GABA currents elicited in oocytes injected with membranes from the subiculum had a more depolarized reversal potential (E(GABA)) compared with the hippocampus proper or the neocortex. The NKCC1 blocker bumetanide or a temperature decrease of 10 degrees C shifted the GABA-current E(GABA) more negative in oocytes injected with membranes from TLE hippocampal subiculum, matching the E(GABA) of TL neocortex-injected oocytes. We conclude that the anomalous expression of both Cl(-) transporters, NKCC1 and KCC2 [corrected] in TLE hippocampal subiculum probably causes altered Cl(-) transport in the "epileptic" neurons, as revealed in the microtransplanted Xenopus oocytes, and renders GABA aberrantly "exciting," a feature that may contribute to the precipitation of epileptic seizures.
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Project description:Responsive neural stimulation (RNS) is considered a promising neural modulation therapy for refractory epilepsy. Combined stimulation on different targets may hold great promise for improving the efficacy of seizure control since neural activity changed dynamically within associated brain targets in the epileptic network. Three major issues need to be further explored to achieve better efficacy of combined stimulation: (1) which nodes within the epileptogenic network should be chosen as stimulation targets? (2) What stimulus frequency should be delivered to different targets? and (3) Could the efficacy of RNS for seizure control be optimized by combined different stimulation targets together? In our current study, Granger causality (GC) method was applied to analyze epileptogenic networks for finding key targets of RNS. Single target stimulation (100 μA amplitude, 300 μs pulse width, 5s duration, biphasic, charge-balanced) with high frequency (130 Hz, HFS) or low frequency (5 Hz, LFS) was firstly delivered by our lab designed RNS systems to CA3, CA1, subiculum (SUB) of hippocampi, and anterior nucleus of thalamus (ANT). The efficacy of combined stimulation with different groups of frequencies was finally assessed to find out better combined key targets with optimal stimulus frequency. Our results showed that stimulation individually delivered to SUB and CA1 could shorten the average duration of seizures. Different stimulation frequencies impacted the efficacy of seizure control, as HFS delivered to CA1 and LFS delivered to SUB, respectively, were more effective for shortening the average duration of electrographic seizure in Sprague-Dawley rats (n = 3). Moreover, the synchronous stimulation of HFS in CA1 combined with LFS in SUB reduced the duration of discharge significantly in rats (n = 6). The combination of responsive stimulation at different targets may be an inspiration to optimize stimulation therapy for epilepsy.
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Project description:High frequency anterior nucleus of the thalamus deep brain stimulation (ANT DBS) is an established therapy for treatment resistant focal epilepsies. Although high frequency-ANT DBS is well tolerated, patients are rarely seizure free and the efficacy of other DBS parameters and their impact on comorbidities of epilepsy such as depression and memory dysfunction remain unclear. The purpose of this study was to assess the impact of low vs high frequency ANT DBS on verbal memory and self-reported anxiety and depression symptoms. Five patients with treatment resistant temporal lobe epilepsy were implanted with an investigational brain stimulation and sensing device capable of ANT DBS and ambulatory intracranial electroencephalographic (iEEG) monitoring, enabling long-term detection of electrographic seizures. While patients received therapeutic high frequency (100 and 145 Hz continuous and cycling) and low frequency (2 and 7 Hz continuous) stimulation, they completed weekly free recall verbal memory tasks and thrice weekly self-reports of anxiety and depression symptom severity. Mixed effects models were then used to evaluate associations between memory scores, anxiety and depression self-reports, seizure counts, and stimulation frequency. Memory score was significantly associated with stimulation frequency, with higher free recall verbal memory scores during low frequency ANT DBS. Self-reported anxiety and depression symptom severity was not significantly associated with stimulation frequency. These findings suggest the choice of ANT DBS stimulation parameter may impact patients' cognitive function, independently of its impact on seizure rates.
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Project description:Electrical neurostimulation is currently used to manage epilepsy, but the most effective approach for minimizing seizure occurrence is uncertain. While functional MRI (fMRI) can reveal which brain areas are affected by stimulation, simultaneous deep brain stimulation (DBS)-fMRI examinations in patients are rare and the possibility to investigate multiple stimulation protocols is limited. In this study, we utilized the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy (mTLE) to systematically examine the brain-wide responses to electrical stimulation using fMRI. We compared fMRI responses of saline-injected controls and epileptic mice during stimulation in the septal hippocampus (HC) at 10 Hz and demonstrated the effects of different stimulation amplitudes (80-230 μA) and frequencies (1-100 Hz) in epileptic mice. Motivated by recent studies exploring 1 Hz stimulation to prevent epileptic seizures, we furthermore investigated the effect of prolonged 1 Hz stimulation with fMRI. Compared to sham controls, epileptic mice showed less propagation to the contralateral HC, but significantly stronger responses in the ipsilateral HC and a wider spread to the entorhinal cortex and septal region. Varying the stimulation amplitude had little effect on the resulting activation patterns, whereas the stimulation frequency represented the key parameter and determined whether the induced activation remained local or spread from the hippocampal formation into cortical areas. Prolonged stimulation of epileptic mice at 1 Hz caused a slight reduction in local excitability. In this way, our study contributes to a better understanding of these stimulation paradigms.
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