A Systems Neuroscience Approach to Migraine

Brennan, KC; Pietrobon, Daniela

doi:10.1016/j.neuron.2018.01.029

Cited by 152 publications

(182 citation statements)

References 150 publications

(229 reference statements)

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“…Migraine with aura is a sensory disorder characterized by SD, and all known models of migraine with aura show an increased susceptibility to SD (Brennan and Pietrobon, 2018). Within the FHM2 model, the impaired rate of glutamate uptake by cortical astrocytes can largely account for the susceptibility to experimental SD in vitro (Capuani et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Migraine with aura is a common neurological disorder, consisting of severe head pain and sensory amplifications, preceded by an aura, which most commonly is a spreading sensory hallucination (flashing visual percepts, numbness and tingling) but can also take more severe forms (Brennan and Pietrobon, 2018). The aura is useful for investigative purposes because it is known to be caused by a spreading depolarization of brain tissue (SD; also known as cortical spreading depression) that can be induced and measured experimentally.…”

Section: Introductionmentioning

confidence: 99%

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Non-canonical glutamate signaling in a genetic model of migraine with aura

Parker

Suryavanshi

Melone

et al. 2020

Preprint

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Non-canonical glutamate signaling in a genetic model of migraine with aura

Parker

Suryavanshi

Melone

et al. 2020

Preprint

Self Cite

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“…TNc neurons receive peripheral nociceptive information through C-and Ad-fibers that terminate extensively in laminae I and II (Hamba and Onimaru 1998;Pradier et al 2018). They also receive synaptic innervation from local interneurons (Pradier et al 2018) and from long distance projections of top-down pain-regulating afferents (e.g., from the RVM, cortex, hypothalamus) (Noseda et al 2010;Abdallah et al 2013;Robert et al 2013;Brennan and Pietrobon 2018;Wang et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Properties of neurons in the superficial laminae of trigeminal nucleus caudalis

et al. 2019

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The trigeminal nucleus caudalis ( TN c) receives extensive afferent innervation from peripheral sensory neurons of the trigeminal ganglion (TG), and is the first central relay in the circuitry underpinning orofacial pain. Despite the initial characterization of the neurons in the superficial laminae, many questions remain. Here we report on electrophysiological properties of 535 superficial lamina I/ II TN c neurons. Based on their firing pattern, we assigned these cells to five main groups, including (1) tonic, (2) phasic, (3) delayed, (4) H‐current, and (5) tonic‐phasic neurons, groups that exhibit distinct intrinsic properties and share some similarity with groups identified in the spinal dorsal horn. Driving predominantly nociceptive TG primary afferents using optogenetic stimulation in TRPV 1/ChR2 animals, we found that tonic and H‐current cells are most likely to receive pure monosynaptic input, whereas delayed neurons are more likely to exhibit inputs that appear polysynaptic. Finally, for the first time in TN c neurons, we used unsupervised clustering analysis methods and found that the kinetics of the action potentials and other intrinsic properties of these groups differ significantly from one another. Unsupervised spectral clustering based solely on a single voltage response to rheobase current was sufficient to group cells with shared properties independent of action potential discharge pattern, indicating that this approach can be effectively applied to identify functional neuronal subclasses. Together, our data illustrate that cells in the TN c with distinct patterns of TRPV 1/ChR2 afferent innervation are physiologically diverse, but can be understood as a few major groups of cells having shared functional properties.

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“…Yet the disease remains poorly understood at the cellular and circuit level. Although migraine is typically associated with headache, multiple lines of evidence suggest it is a more widespread disorder of multisensory excitability and sensory gain of function 4 . Migraine attacks involve amplifications of multiple sensory inputs including light, sound, smell, touch, and interoception (photophobia, phonophobia, osmophobia, allodynia, and nausea, respectively) 5,6 .…”

Section: Introductionmentioning

confidence: 99%

Increased presynaptic excitability in a migraine with aura mutation

Suryavanshi

Sawant-Pokam

Brennan

2019

Preprint

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6 Migraine is a very common and disabling neurological disorder that remains poorly understood at 7 the cellular and circuit level. Transgenic mice harboring a mutation in casein kinase 1 delta 8 (CK1dT44A) represent the first animal model of non-hemiplegic migraine. These mice have 9decreased sensory thresholds to mechanical and thermal pain after treatment with the migraine 10 trigger nitroglycerin; and an increased susceptibility to cortical spreading depression (CSD), which 11 models the migraine aura. In this study, we investigated cellular and synaptic mechanisms within 12 sensory cortical circuits that might underlie the migraine relevant phenotypes of CK1dT44A mice, 13using in vitro and in vivo whole cell electrophysiology. Surprisingly we found that at resting state, 14CK1dT44A neurons exhibited hyperpolarized membrane potentials, due to increased tonic 15inhibition. Despite this reduction in baseline excitability, CK1dT44A neurons fired action potentials 16 more frequently in response to current injection. And despite similar synaptic and dendritic 17 characteristics to wild type neurons, excitatory but not inhibitory CK1dT44A synapses failed to adapt 18to high frequency short-stimulus trains, resulting in elevated steady state excitatory currents. The 19increased steady state currents were attributable to an increased replenishment rate of the readily 20 releasable pool, providing a presynaptic mechanism for the CK1dT44A phenotype. Finally, during 21in vivo experiments, CK1dT44A animals showed increased duration and membrane potential 22 variance at 'cortical up states', showing that the intrinsic and synaptic changes we observed have 23 excitatory consequences at the local network level. In conclusion excitatory sensory cortical 24 neurons and networks in CK1dT44A animals appear to exhibit decreased adaptation and increased 25 gain that may inform the migraine phenotype. 26 27

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A Systems Neuroscience Approach to Migraine

Abstract: Migraine is an extremely common but poorly understood nervous system disorder. We conceptualize migraine as a disorder of sensory network gain and plasticity, and we propose that this framing makes it amenable to the tools of current systems neuroscience.

Cited by 152 publications

References 150 publications

Non-canonical glutamate signaling in a genetic model of migraine with aura

Non-canonical glutamate signaling in a genetic model of migraine with aura

Properties of neurons in the superficial laminae of trigeminal nucleus caudalis

Increased presynaptic excitability in a migraine with aura mutation

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