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Central vs. Peripheral Mechanisms of Headache: Cortex, Thalamus, Dorsal Horn

Award Number: R01NS133226
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/05/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Central vs. Peripheral Mechanisms of Headache: Cortex, Thalamus, Dorsal Horn - The mechanisms of migraine are poorly understood, but a large body of indirect evidence has implicated the nociceptive sensory innervation of the cranial meninges as playing a critical role in the generation of the headache. A key finding, in single-unit recording studies, was the prolonged activation of the 1st- and 2nd -order neurons of this meningeal sensory pathway following the induction of cortical spreading depression (CSD), the cortical phenomenon that underlies the migraine aura. However, there is a fundamental gap in understanding the neural basis for the perceptual effects of CSD, and the putative role of the meningeal sensory pathway in these effects: as yet there has been no study of CSD’s effects on the 3rd-order meningeal sensory neurons in the thalamus, the structure that serves as the gateway to sensory cortex. This is particularly critical because the thalamus stands apart from the trigeminal ganglion and the dorsal horn (containing the 1st- and 2nd-order neurons) in 1) its extremely strong reciprocal connectivity with the cortex, and 2) in containing populations of neurons bilateral receptive fields (in addition to those in the ventrobasal complex with unilateral receptive fields), whose activity would be critical in clarifying the long-standing problem of the laterality of the migraine headache and its relation to the laterality of the aura (see Significance). In addition, this information is relevant to the ongoing question in headache research of to what degree migraine is a result of processes in the central vs peripheral nervous system. Arguments for a central mechanism for the generation of the headache have focused on the possibility that CSD might activate the central neurons of the meningeal sensory pathway through central mechanisms that are independent of peripheral activation. Such a finding, of activation of a central nociceptive pathway through a central mechanism, has long been hypothesized but has not yet been demonstrated to occur, in any pain pathway. We explore these questions in the following two aims: Aim 1: Characterize the effect of CSD on the activity on thalamic neurons that receive peripheral sensory input from the cranial meninges, using single-unit recording in anesthetized male and female rats. Aim 2. Test the hypothesis that the activation of 2nd- and 3rd-order neurons in the meningeal sensory pathway by CSD can occur independent of peripheral input. These experiments will investigate the peripheral vs central contribution to the CSD-induced responses. These studies will have impact on our basic understanding of headache in relation to the key questions, fundamental to current migraine research, of the sensory perceptual effects of CSD and the contribution of peripheral vs. central mechanisms to the migraine headache. More broadly, the finding of activation of nociceptive neurons by a central process that is independent of peripheral input would be a novel finding in the study of pain mechanisms.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $419,283 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/30/2026	NON-COMPETING CONTINUATION	$419,283
														Subtotal = $419,283

Issue Date FY: 2025 ( Subtotal = $377,354 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/28/2025	NON-COMPETING CONTINUATION	$377,354
														Subtotal = $377,354

Issue Date FY: 2024 ( Subtotal = $419,283 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/4/2024	NEW	$419,283
														Subtotal = $419,283

Grand Total All Awards = $1,215,920

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Central vs. Peripheral Mechanisms of Headache: Cortex, Thalamus, Dorsal Horn

Award Number: R01NS133226

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/05/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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