Mesocorticolimbic system abnormalities in chronic cluster headache patients: A neural signature?

Abstract

Background Converging evidence suggests that anatomical and functional mesocorticolimbic abnormalities support the chronicization of pain disorders. Methods We mapped structural and functional alterations of the mesocorticolimbic system in a sample of chronic cluster headache patients (n = 28) in comparison to age and sex-matched healthy individuals (n = 28) employing structural MRI and resting-state functional MRI. Results Univariate logistic regression models showed that several of the examined structures/areas (i.e., the bilateral nucleus accumbens, ventral diencephalon, hippocampus, and frontal pole, and the right amygdala) differentiated chronic cluster headache patients from healthy individuals (p < 0.05, uncorrected). Specifically, all the significant structures/areas had increased volumes in chronic cluster headache patients compared to healthy individuals. The examination of the groups suffering from left and right-sided cranial attacks showed a lateralization effect: ipsilateral to the pain ventral diencephalic regions and contralateral to the pain nucleus accumbens discriminated chronic cluster headache patients from healthy individuals. The resting-state functional MRI data analyses showed that chronic cluster headache patients compared to CTRL individuals present robust reduced functional connectivity in the right frontal pole-right amygdala pathway (p < 0.05, FDR-corrected) Conclusion Our results showed that chronic cluster headache patients present anatomical and functional maladaptation of the mesocorticolimbic system, with functional data indicating a possible prefrontal areas' failure to modulate the mesolimbic structures. These results were opposite to what we hypothesized based on the previous literature on chronic pain conditions. Future studies should assess whether the observed mesocorticolimbic abnormalities are due to the neuroprotective effects of the assumed medications, or to the frequent comorbidity of CH with neuropsychiatric disorders or if they are a genuine neural signature of CH and/or chronic cluster headache condition.

Association of Clinical and Neuroanatomic Factors With Response to Ventral Tegmental Area DBS in Chronic Cluster Headache

“…Increased volumes of these brain regions and associated connectivity abnormalities have been shown in a previous study of CCH. 36 Interestingly, the opposite finding of smaller amygdala volume has been shown to be a predictor of persistence in other chronic pain syndromes. 37 This could be further investigated in future studies using connectivity measures, quantitative analysis of amygdala volume, and/or cortical thickness measures of the relevant frontal brain regions.…”

Pathophysiology of cluster headache: From the trigeminovascular system to the cerebral networks

“…According to structural MRI research, chronic CH patients had larger volumes of the bilateral nucleus accumbens, ventral diencephalon, hippocampus, frontal pole, and right amygdala than healthy people (11).…”

“…This inevitably reshapes the role of the hypothalamus as the sole site of primary dysfunction underlying cluster headache. Some suggestions come from a re-evaluation of neuroimaging studies of patients implanted with deep brain stimulators for the treatment of refractory forms and from more recent functional connectivity studies (10,11).…”

“…According to structural MRI research, chronic CH patients had larger volumes of the bilateral nucleus accumbens, ventral diencephalon, hippocampus, frontal pole, and right amygdala than healthy people (11). When compared to controls, the resting-state functional MRI data analysis on the same patients revealed significantly reduced functional connectivity in the right frontal pole-right amygdala pathway, suggesting that the prefrontal areas may have failed to modulate the mesolimbic structures (11).…”

“…According to structural MRI research, chronic CH patients had larger volumes of the bilateral nucleus accumbens, ventral diencephalon, hippocampus, frontal pole, and right amygdala than healthy people (11). When compared to controls, the resting-state functional MRI data analysis on the same patients revealed significantly reduced functional connectivity in the right frontal pole-right amygdala pathway, suggesting that the prefrontal areas may have failed to modulate the mesolimbic structures (11). As mentioned above, one patient with drug-resistant chronic CH was successfully returned to episodic behaviour with the use of the transdermal dopamine agonist rotigotine (55,110).…”