Dataset Information

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy.

ABSTRACT: Objective: To determine if closed-loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well-established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory.

Methods: Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin-expressing interneurons, were implanted with optical fibers and electrodes, and tested for response to closed-loop light intervention of seizures. Animals that responded to closed-loop optogenetic curtailment of seizures were tested in the object location memory test and then given closed-loop optogenetic intervention on all detected seizures for 2 weeks. Following this, they were tested with a second object location memory test, with different objects and contexts than used previously, to assess if seizure suppression can improve deficits in spatial memory.

Results: Animals that received closed-loop optogenetic intervention performed significantly better in the second object location memory test compared to the first test. Epileptic controls with no intervention showed stable frequency and duration of seizures, as well as stable spatial memory deficits, for several months after the precipitating insult.

Significance: Many currently available treatments for epilepsy target seizures but not the associated comorbidities, therefore there is a need to investigate new potential therapies that may be able to improve both seizure burden and associated comorbidities of epilepsy. In this study, we showed that optogenetic intervention may be able to both shorten seizure duration and improve cognitive outcomes of spatial memory.

SUBMITTER: Kim HK

PROVIDER: S-EPMC7708390 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy.

Kim Hannah K HK Gschwind Tilo T Nguyen Theresa M TM Bui Anh D AD Felong Sylwia S Ampig Kristen K Suh David D Ciernia Annie V AV Wood Marcelo A MA Soltesz Ivan I

Epilepsia 20200218 3

<h4>Objective</h4>To determine if closed-loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well-established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory.<h4>Methods</h4>Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin-expressing interneurons, were implanted with optical fibers and electrodes, ...[more]

PMID: 32072628

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Project description:BackgroundMedial temporal lobe epilepsy (MTLE) is associated with limbic atrophy involving the hippocampus, peri-hippocampal and extra-temporal structures. While MTLE is related to static structural limbic compromise, it is unknown whether the limbic system undergoes dynamic regional perfusion network alterations during seizures. In this study, we aimed to investigate state specific (i.e. ictal versus interictal) perfusional limbic networks in patients with MTLE.MethodsWe studied clinical information and single photon emission computed tomography (SPECT) images obtained with intravenous infusion of the radioactive tracer Technetium- Tc 99 m Hexamethylpropyleneamine Oxime (Tc-99 m HMPAO) during ictal and interictal state confirmed by video-electroencephalography (VEEG) in 20 patients with unilateral MTLE (12 left and 8 right MTLE). Pair-wise voxel-based analyses were used to define global changes in tracer between states. Regional tracer uptake was calculated and state specific adjacency matrices were constructed based on regional correlation of uptake across subjects. Graph theoretical measures were applied to investigate global and regional state specific network reconfigurations.ResultsA significant increase in tracer uptake was observed during the ictal state in the medial temporal region, cerebellum, thalamus, insula and putamen. From network analyses, we observed a relative decreased correlation between the epileptogenic temporal region and remaining cortex during the interictal state, followed by a surge of cross-correlated perfusion in epileptogenic temporal-limbic structures during a seizure, corresponding to local network integration.ConclusionsThese results suggest that MTLE is associated with a state specific perfusion and possibly functional organization consisting of a surge of limbic cross-correlated tracer uptake during a seizure, with a relative disconnection of the epileptogenic temporal lobe in the interictal period. This pattern of state specific shift in metabolic networks in MTLE may improve the understanding of epileptogenesis and neuropsychological impairments associated with MTLE.

Project description:Working memory is a critical building block for almost all cognitive tasks, and impairment can cause significant disruption to daily life routines. We investigated the functional connectivity (FC) of the visuo-spatial working memory network in temporal lobe epilepsy and its relationship to the underlying white matter tracts emanating from the hippocampus. Fifty-two patients with unilateral hippocampal sclerosis (HS) (30 left) and 30 healthy controls underwent working memory functional MRI (fMRI) and Diffusion Tensor Imaging (DTI). Six seed regions were identified for FC analysis; 4 within a task-positive network (left and right middle frontal gyri and superior parietal lobes), and 2 within a task-negative network (left and right hippocampi). FC maps were created by extracting the time-series of the fMRI signal in each region in each subject and were used as regressors of interest for additional GLM fMRI analyses. Structural connectivity (SC) corresponding to areas to which the left and right hippocampi were connected was determined using tractography, and a mean FA for each hippocampal SC map was calculated. Both left and right HS groups showed atypical FC between task-positive and task-negative networks compared to controls. This was characterised by co-activation of the task-positive superior parietal lobe ipsilateral to the typically task-negative sclerosed hippocampus. Correlational analysis revealed stronger FC between superior parietal lobe and ipsilateral hippocampus, was associated with worse performance in each patient group. The SC of the hippocampus was associated with the intra-hemispheric FC of the superior parietal lobe, in that greater SC was associated with weaker parieto-frontal FC. The findings suggest that the segregation of the task-positive and task-negative FC networks supporting working memory in TLE is disrupted, and is associated with abnormal structural connectivity of the sclerosed hippocampus. Co-activation of parieto-temporal regions was associated with poorer working memory and this may be associated with working memory dysfunction in TLE.

Dataset Information

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy.

Publications

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy.

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