Reduced insula habituation associated with amplification of trigeminal brainstem input in migraine

Abstract

Background: Impaired sensory processing in migraine can reflect diminished habituation, increased activation, or even increased gain or amplification of activity from the primary synapse in the brainstem to higher cortical/subcortical brain regions. Methods: We scanned 16 episodic migraine (interictal) and 16 healthy controls (cross-sectional study), and evaluated brain response to innocuous air-puff stimulation over the right forehead in the ophthalmic nerve (V 1 ) trigeminal territory. We further evaluated habituation, and cortical/subcortical amplification relative to spinal trigeminal nucleus (Sp5) activation. Results: Migraine subjects showed greater amplification from Sp5 to the posterior insula and hypothalamus. In addition, while controls showed habituation to repetitive sensory stimulation in all activated cortical regions (e.g. the bilateral posterior insula and secondary somatosensory cortices), for migraine subjects, habituation was not found in the posterior insula. Moreover, in migraine, the habituation slope was correlated with the amplification ratio in the posterior insula and secondary somatosensory cortex, i.e. greater amplification was associated with reduced habituation in these regions. Conclusions: These findings suggest that in episodic migraine, amplified information processing from spinal trigeminal relay nuclei is linked to an impaired habituation response. This phenomenon was localized in the posterior insula, highlighting the important role of this structure in mechanisms supporting altered sensory processing in episodic migraine.

Resting state connectivity between default mode network and insula encodes acute migraine headache

“…Previous neuroimaging studies during migraine attacks have repeatedly provided evidence of activation in bilateral insula, which was considered as a non-specific response to pain (2,4,9,10,38). Between attacks, migraineurs also had abnormal insular cortex connectivity (39,40) and habituation in response to repeated sensory stimuli (41,42). In the present study, we show that migraine patients during an attack have greater bilateral insula connectivity with MPFC and right IPL areas of the DMN than healthy volunteers, in the absence of a specific task.…”

Modulation of brainstem activity and connectivity by respiratory-gated auricular vagal afferent nerve stimulation in migraine patients

“…These comparisons were performed using a two-way ANOVA followed by post-hoc testing (STATA 14, Stata Corporation, College Station, TX). Our previous study [40] found altered trigeminal air-puff processing in MIG, and the current study investigated how eRAVANS affects brainstem response to such trigeminal input.…”

“…This index has some advantages over other measurements such as the number of days after or preceding an attack, because it takes into account the variability of attack frequency between patients, normalizing the time since last attack by the total duration of the interictal period. This measurement has been previously shown by our group to correlate with fMRI activation in brainstem trigeminal nuclei in response to ophthalmic nerve somatosensory input [40], and our current analysis explored whether the interictal phase index is also sensitive to brainstem processing of RAVANS stimulation.…”

“…Despite this impact, the pathophysiology of migraine remains to be elucidated [13]. Hypersensitization of the brainstem trigeminal sensory complex may underlie the primary brain dysfunction in migraine [1; 10; 58; 71], leading to brainstem-mediated upregulation of cortical excitability [14; 40]. Therapeutic options have targeted brainstem neuromodulatory centers, including serotonergic (raphe nuclei) and noradrenergic (locus coeruleus) nuclei [19; 63], via dihydroergotamine, triptans, and other 5HT1B/1D agonists [21; 41; 62].…”

“…With such caveats in mind, imaging studies have shown interictal abnormalities in migraneurs in subcortical and brainstem regions responsible for somatosensory processing [2; 30; 45; 49; 50]. For instance, our recent fMRI study found that Sp5 response to tactile stimuli in migraine was amplified in higher cortical regions and sensitive to interictal phase [40]. Neuromodulatory interventions, such as tVNS, can target specific brainstem nuclei and the trigeminal sensory pathway to ameliorate migraine pathophysiology and reduce headache frequency and severity.…”