Cortical and Subcortical Alterations in Medication Overuse Headache

Abstract

Medication-overuse headache is an increasing problem in headache clinics and therapy includes drug withdrawal. Although it has been shown that the orbitofrontal cortex is hypo-metabolic and exhibits less gray matter in these patients the functional role of this finding is still unclear as virtually no functional imaging studies exploring withdrawal of medication have been published. We compared structural and functional magnetic resonance images of 18 patients before and after drug withdrawal with age and gender matched controls using a well-established trigeminal, nociceptive fMRI paradigm. We reproduced structural changes in the orbitofrontal cortex of the patients which highly correlated with the clinical outcome of medication withdrawal. The neuronal activity before drug withdrawal in pain related regions (operculum, insula, spinal trigeminal nucleus) was reduced compared to after drug withdrawal and the orbitofrontal cortex showed a reduced functional connectivity to the nociceptive input region (spinal trigeminal nucleus) and the cerebellum which regained after withdrawal. These data suggest the seminal role of the orbitofrontal cortex as a mediator between bottom-up and top-down stream in headache processing.

Brain Structural and Functional Imaging Findings in Medication-Overuse Headache

“…Consistent with functional data, results of structural imaging reveal abnormalities within major regions of the mesocortical-limbic circuit in patients with MOH, including less orbitofrontal cortex volume and thickness (23,24,26). Results of several studies suggest that patients with better treatment response to medication withdrawal had more orbitofrontal volume at baseline, i.e., before withdrawal compared to patients who did not respond successfully to medication withdrawal (23,25).…”

Gray matter alteration in medication overuse headache: a coordinates-based activation likelihood estimation meta-analysis

“…Nevertheless, available studies found that MOH reported functional change in the pain network comparing to HCs. Multiple functional connectivity abnormalities was found in the trigeminal spinal tract nucleus, operculum, secondary somatosensory cortex (Mehnert et al, 2018 ). Hypermetabolism in insula was reported (Di et al, 2013 ).…”

“…Some of the altered brain regions, e.g. enlarged nucleus accumbens (May, 2009 ; Planchuelo-Gómez et al, 2020 ) and structural alteration in orbitofrontal gyrus (Mehnert et al, 2018 ; Planchuelo Gómez et al, 2021 ), are shared by both CM and MOH. To observe the sole neural impact associated with medication overuse, more studies comparing CM with MOH is needed.…”

“…Lai et al (Lai et al, 2016 ) reported that MOH patients, compared with healthy controls (HCs), displayed gray matter atrophy in the rectal gyrus, inferior frontal gyrus, middle frontal gyrus, and precuneus. While Mehnert et al (Mehnert et al, 2018 ) discovered that MOH related gray matter atrophy located in the medial orbital gyrus, hippocampus, inferior frontal gyrus, and precuneus. However, several researchers did not find gray matter changes in MOH relative to HCs (Beckmann et al, 2018 ; Chanraud et al, 2014 ).…”

High-Density Electroencephalography-Informed Multiband Functional Magnetic Resonance Imaging Reveals Rhythm-Specific Activations Within the Trigeminal Nociceptive Network

“…The stimulus design is well-established and has been published multiple times elsewhere ( Stankewitz et al, 2010 ; Schulte et al, 2016 ; Mehnert et al, 2017 , 2018 , 2019 ; Mehnert and May, 2019 ). In short, the volunteers received four different stimuli (ammonia, rose scent, or air into the left nostril, and a repetitive visual stimulation at 8 Hz) with an interstimulus interval of 46 ± 9 s, where the ammonia elicits a short-lasting, stinging, or stabbing painful sensations ( Hummel and Kobal, 1992 ; Stankewitz et al, 2010 ).…”