KR-102962617-B1 - Imaging of individual hippocampal seizures and long-term effects of recurrent seizures

Abstract

Ventral hippocampal firing has been shown to induce functional reorganization of the ventral hippocampal excitatory circuit. Most notably, connectivity to the medial prefrontal cortex is observed, accompanied by increased activation volume on fMRI and increased activation amplitude in electrophysiology. There is evidence of increased anxiety following firing. A method for concurrent LFP-fMRI to visualize single seizures is provided. Imaging of the visuospatial dynamics of individual seizures can characterize the propagation patterns of focal and secondary-generalized seizures, which provide targeted interventions.

Inventors

• 이진형
• 초이, 맨킨
• 더피, 벤 에이.

Assignees

• 더 보드 어브 트러스티스 어브 더 리랜드 스탠포드 주니어 유니버시티

Dates

Publication Date

20260508

Application Date

20201207

Priority Date

20191206

Claims (20)

1. In a method for generating a model for the analysis of events related to brain seizures, The method includes the step of receiving electrophysiological data and magnetic resonance imaging (MRI) data simultaneously collected from a kindled animal brain, and Herein, the electrophysiological data, MRI data, or both include data of at least one neural event indicating functional and neural circuit changes, and Herein, the above-mentioned at least one neural event is characterized by responding to a stimulus in the brain; The method includes the step of analyzing the electrophysiological data and the MRI data to determine corresponding changes in the electrophysiological data and MRI data representing neurological events, Here, analyzing the above electrophysiological data includes calculating the value obtained by dividing the band power during stimulation by the band power before stimulation, and Analyzing the above MRI data here is, A step of segmenting the MRI data of the animal brain into multiple individual regions; A step of quantifying the activation volume of the plurality of individual regions; and The method includes the step of selecting a subset of the plurality of individual regions having the largest activation volume; A method comprising the step of generating a map of a network associated with at least one neural event based on the above MRI data, electrophysiological data, or a combination thereof.
2. In paragraph 1, the step of analyzing MRI data to determine the propagation of a neural event is additionally included, The above analysis step is, A step of low-pass filtering the above MRI data; Step of registering the above MRI data to the atlas of the brain; A step of segmenting the MRI data into a plurality of individual regions based on the above registration; and A method comprising the step of calculating an average time process for a plurality of voxels within one of the plurality of individual regions.
3. In paragraph 2, the step of calculating the average time process includes the step of determining the time when the signal reaches four standard deviations from the baseline.
4. In claim 1, the above stimulus was an electrical stimulus, and the model is targeted to a region of interest.
5. In paragraph 4, the method wherein the region of interest is the hippocampus.
6. The method of claim 1, wherein the at least one neural event indicating functional and neural circuit changes comprises one or more of focal to bilateral tonic-clonic (FBTC) seizures, changes in the excitable ventral hippocampal (VH) network, changes triggered by a sub-threhold stimulus, and induction of a migrating seizure core.
7. In paragraph 6, a method in which the stimulus provided for a neural event indicating a functional and neural circuit change was an electrical stimulus.
8. In claim 7, the method in which the electrical stimulation was delivered by optogenetics.
9. In paragraph 2, the method wherein the low-pass filtering is performed at 0.1 Hz.
10. A method according to claim 1, further comprising the step of generating connectivity data by calculating a conditional probability that one of a plurality of regions of an animal brain will be activated during a neural event.
11. In paragraph 8, a method in which the stimulus providing the neurological event is below the threshold that triggers a seizure.
12. In claim 11, the method wherein the stimulation is 5 Hz to 15 Hz.
13. In paragraph 11, the method in which the above stimulus was applied to evaluate an underlying functional circuit change.
14. In paragraph 8, a method in which the above stimulus is sufficient to trigger a seizure.
15. In paragraph 14, the method wherein the stimulus is 35 Hz to 45 Hz.
16. In paragraph 14, the method in which the above stimulus was applied to evaluate seizure circuit dynamics.
17. A method according to claim 1, further comprising the step of identifying a mobile seizure core.
18. A method according to claim 17, further comprising the step of localizing a seizure inset zone based on an identified mobile seizure core.
19. A method according to claim 18, wherein SOZ is imaged by single-photon emission computed tomography (SPECT).
20. In paragraph 1, the step of generating a network map is Calculate the rate at which voxels are activated during part of the induction period, but A step of determining a maximum percentage bold change for the above voxel; and A method comprising the step of binarizing an image containing the above voxels.

Description

Imaging of individual hippocampal seizures and long-term effects of recurrent seizures Cross-reference regarding related applications This application claims priority to U.S. Provisional Application No. 62/945,012 filed December 6, 2019, the entire text of which is incorporated herein by reference for all purposes. When seizure activity encroaches upon critical circuits associated with consciousness or cardiopulmonary control, the risk of accidents or death increases, respectively. While the mechanisms by which these seizures develop and propagate are not well understood, there is evidence involving both cortical and subcortical circuits. Standard methods for recording seizures, such as electrophysiology and optical imaging, limit spatial coverage and cannot capture the development of whole-brain activity associated with a specific event. For example, focal to bilateral tonic-clonic (FBTC) seizures, previously known as secondary generalized seizures, are difficult to treat and have a significant impact on patients' quality of life and safety. Although fMRI provides information across the brain and has been used to visualize both focal and generalized seizures in humans and animals, its use to visualize FBTC seizures is challenging due to associated motor activity that results in motion artifacts. The relationship behind seizures, kindling, and sub-threshold activity has long been difficult to understand. This is important for the diagnosis and treatment of epilepsy. The methodology provided herein can be used to diagnose epilepsy and make treatment decisions. This is a novel method capable of defining, for the first time, the specific relationship between seizures, kindling, and sub-threshold activity. A method and a model for the analysis of seizure-related events in the brain, e.g., events modeling epileptic seizures, are provided, including evaluating the effects of changes in functional and electrical neural circuits. The method and the model may include one or more of, e.g., analysis of a single seizure, triggering by subthreshold stimulation, analysis of focal to bilateral tonic-clonic (FBTC) seizures, analysis of an excitable ventral hippocampal (VH) network, analysis of a migrating seizure core, etc. In some embodiments, methods and models for identifying and localizing a migratory seizure core in an individual are provided. In some embodiments, methods and models for designing therapeutic agents for treating epileptic seizures, including, but not limited to, FBTC seizures, are provided. In some embodiments, identification of the migratory seizure core is used in identifying the seizure onset zone. The analytical methods may include, but are not limited to, electrophysiological determinations, e.g., local field potential (LFP), and functional magnetic resonance imaging (fMRI). The models may, but are not limited to, optogenetic models and the use of optogenetic stimulation for ignition and seizure induction. Other stimulation methods, e.g., electrical, magnetic, pharmacological stimulation, etc., are also used. For example, a stimulation method that can be applied to induce a single seizure in the hippocampal region is preferred. The stimulation method includes subthreshold activity. The data provided herein demonstrate the use of ignition and seizure induction models that can be analyzed by simultaneous electrophysiology and functional MRI. To image a single seizure by simultaneous LFP-fMRI in animal models, the animal may be sedated and treated with a fast-acting neuromuscular blocker to eliminate movement during the imaging of the seizure; exemplary agents for this purpose include, but are not limited to, dexmedetomidine sedatives and vecuronium. Imaging of individual seizures allows for the detailed analysis of events associated with the seizure. For example, the core of slow-moving activity in the hippocampus has been shown to provide novel mechanisms for seizure propagation and generalization. The model comprises the brain of an ignition animal, e.g., a living animal, which may be a mammal, e.g., a rodent such as a rat or mouse, or a non-human primate. In some embodiments, an optogenetic ignition model for seizures is provided, wherein electrographic seizures are induced in an animal model by cell-type specific optogenetic stimulation, and such animals subsequently provide reliable induction of FBTC seizures over an extended period, wherein the extended period may be up to 2 weeks, up to 3 weeks, up to 4 weeks, up to 2 months, up to 3 months, or exceed. The photo-activated polypeptide for stimulation may be, for example, a channelrhodopsin containing CHR2 without limitation. The photo-activated polypeptide may be operably coupled to a promoter expressed in excitatory hippocampal neurons. The stimulation paradigm includes a series of short, weak stimuli below the seizure-inducing threshold, for example, of approximately 10 Hz, to evaluate underlying functional circuit changes. Long, intense sti