Cluster headache pathophysiology: What we have learned from advanced neuroimaging

Abstract

Background: Although remarkable progress has been achieved in understanding cluster headache (CH) pathophysiology, there are still several gaps about the mechanisms through which independent subcortical and cortical brain structures interact with each other. These gaps could be partially elucidated by structural and functional advanced neuroimaging investigations.

Objective: Although we are aware that substantial achievements have come from preclinical, neurophysiological, and biochemical experiments, the present narrative review aims to summarize the most significant findings from structural, microstructural, and functional neuroimaging investigations, as well as the consequent progresses in understanding CH pathophysiological mechanisms, to achieve a comprehensive and unifying model.

Results: Advanced neuroimaging techniques have contributed to overcoming the peripheral hypothesis that CH is of cavernous sinus pathology, in transitioning from the pure vascular hypothesis to a more comprehensive trigeminovascular model, and, above all, in clarifying the role of the hypothalamus and its connections in the genesis of CH.

Conclusion: Altogether, neuroimaging findings strongly suggest that, beyond the theoretical model of the "pain matrix," the model of the "neurolimbic pain network" that is accepted in migraine research could also be extended to CH. Indeed, although the hypothalamus' role is undeniable, the genesis of CH attacks is complex and seems to not be just the result of a single "generator." Cortical-hypothalamic-brainstem functional interconnections that can switch between out-of-bout and in-bout periods, igniting the trigeminovascular system (probably by means of top-down mechanisms) and the consensual trigeminal autonomic reflexes, may represent the "neuronal background" of CH.

Keywords: advanced neuroimaging; cluster headache; functional connectivity; gray matter; hypothalamus; structural.

FIGURE 1

Representation of FC changes demonstrated in patients with episodic CH during versus outside of attacks. ACC, anterior cingulate cortex; CH, cluster headache; FC, functional connectivity; PCC, posterior cingulate cortex [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Representation of GM changes demonstrated in patients with episodic or chronic CH compared with healthy controls. ACC, anterior cingulate cortex; CH, cluster headache; GM, gray matter; PCC, posterior cingulate cortex [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

Representation of GM changes in patients with CH during in‐bout period compared with out‐of‐bout period. ACC, anterior cingulate cortex; CH, cluster headache; GM, gray matter [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Representation of FC changes demonstrated in patients with CH compared with healthy controls. ACC, anterior cingulate cortex; CH, cluster headache; FC, functional connectivity [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 5

Representation of FC changes demonstrated in patients with episodic CH during the in‐bout compared with out‐of‐bout periods. FC, functional connectivity; CH, cluster headache [Color figure can be viewed at wileyonlinelibrary.com]