Dr. Dan Levy is an Associate Professor of Anaesthesia at Harvard Medical School and a Principal Investigator of the basic Headache and Pain research lab in the Department of Anesthesia, Critical Care and Pain Medicine. Dr. Levy received his PhD in Neuroscience from the University of Calgary, AB in 1999 and joined the Department in 1999.

Dr. Levy’s research seeks to define the mechanisms underlying the onset of headaches - vital information that is required for the development of better evidence-based therapeutic approaches that can prevent their onset, in cases such as migraine. To address this fundamental question, studies in Dr. Levy’s lab focus on the intracranial meninges (the dura, arachnoid and pia mater layers that cover the brain) and its trigeminal sensory innervation--the peripheral neuronal population whose activation has been most directly implicated in the genesis of headaches. The responses of meningeal sensory afferents are examined using in-vivo extracellular single-unit electrophysiology in anesthetized animals, as well as state-of-the-art two-photon calcium imaging in awake, behaving animals.

To decipher the triggering mechanisms of headache, studies combine these neural recording approaches as well as behavioral studies in rodent models with pharmacological tools to investigate key cellular and molecular processes that modulate the ongoing activity and mechanosensitivity of meningeal afferents in responses to endogenous and exogenous conditions that can be linked to headache genesis. Studies in the Levy Lab already identified several endogenous mediators and intracellular signaling cascades (cAMP-PKA, NO-cGMP, pERK, COX1/2 and K(ATP) activation) that contribute to the enhancement or inhibition of meningeal afferent responses. Additional studies revealed the role of meningeal immune cells (i.e. mast cells) as key endogenous factors that can lead to the activation and increased mechanosensitivity of the meningeal sensory system and the headache pain pathway.

Recent studies are also dedicated to better understand the mechanisms underlying the onset and chronification mechanisms that contribute to the emergence of headache after traumatic brain injuries (concussion).

Dr. Levy’s studies are sponsored by the National Institutes of Health (NIH/NINDS) as well as private pharmaceutical companies. 

Selected publications:

[1] Bree D, Levy D. Development of CGRP-dependent pain and headache related behaviors in a rat model of concussion: Implications for mechanisms of post-traumatic headache. Cephalalgia 2018;38(2):246-258.

[2] Levy D, Burstein R, Kainz V, Jakubowski M, Strassman AM. Mast cell degranulation activates a pain pathway underlying migraine headache. Pain 2007;130(1-2):166-176.

[3] Levy D, Jakubowski M, Burstein R. Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists. Proc Natl Acad Sci U S A 2004;101(12):4274-4279.

[4] Levy D, Strassman AM. Distinct sensitizing effects of the cAMP-PKA second messenger cascade on rat dural mechanonociceptors. J Physiol (Lond) 2002;538(2):483-493.

[5] Zhang X, Kainz V, Zhao J, Strassman AM, Levy D. Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Ann Neurol 2013;73(6):741-750.

[6] Zhang X, Levy D, Noseda R, Kainz V, Jakubowski M, Burstein R. Activation of meningeal nociceptors by cortical spreading depression: implications for migraine with aura. J Neurosci 2010;30(26):8807-8814.

[7] Zhang XC, Kainz V, Burstein R, Levy D. Tumor necrosis factor-alpha induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain 2010;152(1):140-149.

[8] Zhang XC, Kainz V, Burstein R, Levy D. Tumor necrosis factor-alpha induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain 2011;152(1):140-149.

[9] Zhao J, Levy D. Cortical Spreading Depression Promotes Persistent Mechanical Sensitization of Intracranial Meningeal Afferents: Implications for the Intracranial Mechanosensitivity of Migraine. eNeuro 2016;3(6):ENEURO.0287-0216.2016.

[10] Zhao J, Levy D. Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset. J Neurosci 2018;38(22):5053-5066.