title: Brain Changes in Responders vs. Non-Responders in Chronic Migraine: Markers of Disease Reversal.
abstract: The aim of this study was to identify structural and functional brain changes that accompanied the transition from chronic (CM; ≥15 headache days/month) to episodic (EM; <15 headache days/month) migraine following prophylactic treatment with onabotulinumtoxinA (BoNT-A). Specifically, we examined whether CM patients responsive to prophylaxis (responders;n= 11), as evidenced by a reversal in disease status (defined by at least a 50% reduction in migraine frequency and <15 headache days/month), compared to CM patients whose migraine frequency remained unchanged (non-responders;n= 12), showed differences in cortical thickness using surface-based morphometry. We also investigated whether areas showing group differences in cortical thickness displayed altered resting-state functional connectivity (RS-FC) using seed-to-voxel analyses. Migraine characteristics measured across groups included disease duration, pain intensity and headache frequency. Patient reports of headache frequency over the 4 weeks prior to (pre-treatment) and following (post-treatment) prophylaxis were compared (post minus pre) and this measure served as the clinical endpoint that determined group assignment. All patients were scanned within 2 weeks of the post-treatment visit. Results revealed that responders showed significant cortical thickening in the right primary somatosensory cortex (SI) and anterior insula (aINS), and left superior temporal gyrus (STG) and pars opercularis (ParsOp) compared to non-responders. In addition, disease duration was negatively correlated with cortical thickness in fronto-parietal and temporo-occipital regions in responders but not non-responders, with the exception of the primary motor cortex (MI) that showed the opposite pattern; disease duration was positively associated with MI cortical thickness in responders versus non-responders. Our seed-based RS-FC analyses revealed anti-correlations between the SI seed and lateral occipital (LOC) and dorsomedial prefrontal cortices (DMPFC) in responders, whereas non-responders showed increased connectivity between the ParsOp seed and LOC. Overall, our findings revealed distinct morphometric and functional brain changes in CM patients that reverted to EM following prophylactic treatment compared to CM patients that showed no change in disease status. Elucidating the CNS changes involved in disease reversal may be critical to discovering interventions that prevent or slow the progression of CM. Such changes may aid in the evaluation of treatments as well as provide markers for disease "de-chronification".
authors.affiliation: Center for Pain and the Brain, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's HospitalBoston, MA, USA; Department of Anaesthesia, Harvard Medical SchoolBoston, MA, USA.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Hubbard
authors.affiliation: Center for Pain and the Brain, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's HospitalBoston, MA, USA; Department of Anaesthesia, Harvard Medical SchoolBoston, MA, USA.
authors.forename: Lino
authors.initials: L
authors.lastname: Becerra
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Smith
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: DeLange
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Smith
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Black
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN, USA.
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Welker
authors.affiliation: Department of Anaesthesia, Harvard Medical SchoolBoston, MA, USA; Department of Anaesthesia, Beth Israel Deaconess Medical CenterBoston, MA, USA.
authors.forename: Rami
authors.initials: R
authors.lastname: Burstein
authors.affiliation: Department of Neurology, Mayo Clinic Rochester, MN, USA.
authors.forename: Fred M
authors.initials: FM
authors.lastname: Cutrer
authors.affiliation: Center for Pain and the Brain, Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's HospitalBoston, MA, USA; Department of Anaesthesia, Harvard Medical SchoolBoston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Borsook
keywords: BOTOX®; fMRI; gray matter; headache; migraine transformation; network connectivity; pain; preventative therapy