Decrease of Gray Matter Volume in the Midbrain is Associated with Treatment Response in Medication-Overuse Headache: Possible Influence of Orbitofrontal Cortex

Abstract

Patients with chronic daily headache and overuse of analgesics, triptans, or other acute headache compounds, are considered to suffer from medication-overuse headache (MOH). This implies that medication overuse is the cause of headache chronification. It remains a key question why only two-thirds of patients with chronic migraine-like headache and overuse of pain medication improve after detoxification, whereas the remainder continue to have chronic headache. In the present longitudinal MRI study, we used voxel-based morphometry to investigate gray matter changes related to medication withdrawal in a group of humans with MOH. As a main result, we found that only patients with significant clinical improvement showed a significant decrease of previously increased gray matter in the midbrain including periaqueductal gray matter and nucleus cuneiformis, whereas patients without improvement did not. Patients without treatment response had less gray matter in the orbitofrontal cortex. Another striking result is the correlation of treatment response with the amount of orbitofrontal gray matter. Thus, we demonstrate adaptive gray matter changes within the pain modulatory system in patients with MOH who responded to detoxification, probably reflecting neuronal plasticity. Decreased gray matter in the orbitofrontal cortex at baseline may be predictive of poor response to treatment.

Diagnosis, pathophysiology and management of chronic migraine: a proposal of the Belgian Headache Society

“…It can be found during migraine attacks [40] as well as in CM patients in whom it persists despite occipital nerve stimulation [47]. The upper brain stem, probably the periaqueductal grey matter, is also the site where tissue density is increased in MOH [48]. Overuse of analgesics and/or migraine-specific acute medications is indeed by far the most frequent chronifying Table 2 Brain changes in episodic migraine, chronic migraine and medication overuse headache (recent findings with electrophysiological and neuroimaging methods)…”

“…central pain modulation [133,134] no % of posterior circulation infarcts [104] Medication overuse headache ! metabolism and tissue density orbitofrontal cortex [48,50] ! metabolism/activation of lateral pain system [50,135] %% cortical sensitivity depending on drug overused [49] precuneus connectivity: !…”

“…metabolism/activation of lateral pain system [50,135] %% cortical sensitivity depending on drug overused [49] precuneus connectivity: ! with DMN, % with hippocampus [51] % tissue density in PAG [48] Acta Neurol Belg…”

“…As in CM, some of these changes like the increase in tissue density of the PAG are reversible in patients who succeed in withdrawing from drugs and reverse to EM [48]. Considering the above findings and present knowledge in EM pathophysiology, a neurophysiological model of CM pathophysiology can be proposed (Fig.…”

“…In MOH, sensory cortices become markedly sensitized depending on the drugs overused [49], the orbitofrontal cortex is hypometabolic [50] and atrophic [48], and connectivity of the precuneus is decreased with the default mode network, but increased with the hippocampus [51].…”