# Secondarily generalized tonic clonic seizure; a functional anatomy

> **NIH NIH R37** · UNIVERSITY OF VIRGINIA · 2021 · $554,363

## Abstract

We propose to map focal motor to bilateral tonic-clonic seizures (FMBSs), which are the most
dangerous epileptic seizures. These seizures increase the risk of sudden unexpected death in epilepsy
(SUDEP) and lead to fractures and dislocations due to violent falls. SUDEP is the most common cause of
death in patients with epilepsy. We propose that the canonical circuit published in Kandel's Principles of Neural
Science (2013), which posits that focal seizures engage diencephalic thalamocortical circuits, which leads to
secondarily generalized tonic-clonic seizures is too simplistic. It is not consistent with known neuroanatomy of
the motor cortex, and modulation of seizures by subcortical structures. We propose that FMBSs originating in
the frontal cortex spread through the striatum to the globus pallidus, substantia nigra and thalamus via the
indirect pathway, in addition to spreading directly to the thalamus .. We test this hypothesis in three aims. Aim
1: to map FMBS spread at the mesoscale and compare it to anatomical connections of the seizure focus in
TRAP mice using tissue clearing and 3D imaging combined with tract tracing and electrophysiological
techniques). Aim 2 to map FMBS spread at the microscopic scale through the cortex and direct and indirect
basal ganglia circuits in TRAP mice using immunohistochemistry. In aim 3, we will study dopamine type 2
receptor modulation of seizures at the mesoscale and microcircuit levels using a combination of techniques.
We incorporated tools and techniques developed by the BRAIN initiative in our laboratory to move
seizure circuit mapping research forward. We have used TRAP mice, the CLARITY technique, high resolution,
high-throughput imaging, and 3D reconstruction of images to visualize activated neuronal pathways. We have
constructed a highly collaborative team with expertise in anatomy, electrophysiology and computer science of
imaging, which allows us to generate and analyze large volumes of data and build on each other's creativity.
We have acquired sufficient equipment to perform these studies. These studies will generate new targets for
the modulation of seizures by deep brain stimulation. Currently, this method is used for anterior thalamic
stimulation and responsive neurostimulation, but in the future, multiple subcortical structures could sites for
neuromodulation. Receptors and ion channels known to modulate basal ganglia circuits may emerge as novel
targets for anticonvulsant development. If our studies confirm seizure passage through the striatum, then ii
would be important to understand the underlying cellular mechanisms.

## Key facts

- **NIH application ID:** 10317485
- **Project number:** 1R37NS119012-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Jaideep Kapur
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $554,363
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317485

## Citation

> US National Institutes of Health, RePORTER application 10317485, Secondarily generalized tonic clonic seizure; a functional anatomy (1R37NS119012-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10317485. Licensed CC0.

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