Friday, May 16, 2025
5/16/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).