# Cortical Mechanisms of Headache: Beyond CSD

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $378,438

## Abstract

Project Summary
A large body of indirect evidence now strongly supports the idea that the nociceptive sensory pathway that
innervates the intracranial meninges (the trigeminovascular system) is involved in the generation of some
types of clinically occurring headaches, including migraine. The basic properties of this sensory pathway have
been studied in detail in animal studies, but it is not yet well understood how this pathway becomes activated
during a clinically occurring headache attack. One leading line of research has provided evidence in support of
the CSD (cortical spreading depression) theory of migraine, including the recent findings of trigeminovascular
neuron activation following CSD induction in animals. However, the study of CSD in migraine patients is
necessarily somewhat anecdotal because CSD cannot be detected by routine methods in humans, and so it is
not known how often it occurs, or what causes it to arise spontaneously. As a new avenue to further explore
the mechanisms that can trigger headache and the potential role of cortical pathophysiology, we now propose
to examine mechanisms of trigeminovascular neuron activation in an animal model of a common type of
cortical pathophysiology that is well described and intensively studied in humans: cortical seizure. Based on
the clinical observation that seizures are commonly followed by headache with features similar to migraine, we
hypothesize that seizure can produce activation of the trigeminovascular system. We therefore propose to test
this hypothesis, and to use seizure as a model to further investigate the mechanisms by which cortical
processes can influence the trigeminovascular system, in the following Aims: (1) Employing single-unit
recording to monitor changes in activity of first-order dura-sensitive neurons in the trigeminal ganglion, we will
test the hypothesis that chemically-induced seizures can induce activation and/or sensitization of dural
nociceptors. Seizure-induced effects will also be examined in trigeminal ganglion neurons that do not innervate
the dura. (2) Using single-unit recording, changes in activity of second-order dural-responsive neurons in the
superficial and deep laminae of the upper cervical and medullary dorsal horn will be examined following
seizures in anesthetized rats. As in Aim 1, neurons that lack a dural response will also be studied. Data
analysis will determine the latency, duration, and magnitude of changes in activity induced by seizure, and
compare the seizure effects in dura-sensitive vs. dura-insensitive neurons. Experiments will test the hypothesis
that neuronal activation will be produced by focal seizure in occipital but not parietal cortical sites, paralleling
the regionally selective pattern found for the occurrence of postictal headache. In order to determine whether
the seizure-induced discharge originates in terminals within the dural receptive field, lidocaine will be applied to
the dura either prior to seizure induction or...

## Key facts

- **NIH application ID:** 9898471
- **Project number:** 5R01NS094198-05
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Rami Burstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $378,438
- **Award type:** 5
- **Project period:** 2016-07-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898471

## Citation

> US National Institutes of Health, RePORTER application 9898471, Cortical Mechanisms of Headache: Beyond CSD (5R01NS094198-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9898471. Licensed CC0.

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