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.

Keywords: analgesic-overuse headache; functional connectivity; gray matter volume; nociception; orbitofrontal cortex; ventromedial prefrontal cortex.

Figure 1

Gray matter volume decrease in Medial Orbital Gyrus (MOG) and Inferior Frontal Gyrus (IFG) in the patient group compared to the healthy controls before and after medication withdrawal. The threshold for visualization is set to p < 0.001 uncorrected with a minimal cluster extent of 20 voxel.

Figure 2

Correlation of gray matter volume in Medial Orbital Gyrus before drug withdrawal and clinical outcome of headache reduction. Absolute reduction of headache days in blue and relative reduction of headache days in red.

Figure 3

(A) Increased neuronal activity following trigeminal nociceptive input after drug withdrawal in spinal trigeminal nucleus (STN), insula (INS), and operculum (OP) at a visualization threshold of p < 0.001 uncorrected. (B) Increase of functional connectivity by means of a psychophysiological interaction (PPI) analysis from OFC/MOG to spinal trigeminal nucleus (STN) and the cerebellum during drug withdrawal in the patient group. Shown at a visualization threshold of p < 0.001, uncorrected. Coordinates are given according to the MNI system.

Figure 4

The hypothesized down regulated network in MOH. The connectivity from orbitofrontal cortex (OFC) to spinal trigeminal nucleus (STN), Operculum (OC), and somatosensory cortex (SII) is reduced (red crosses) in MOH but recovers after withdrawal.