Imaging the brain and vascular reactions to headache treatments: a systematic review

Abstract

Background: Neuroimaging studies have made an important contribution to our understanding of headache pathophysiology. This systematic review aims to provide a comprehensive overview and critical appraisal of mechanisms of actions of headache treatments and potential biomarkers of treatment response disclosed by imaging studies.

Main body: We performed a systematic literature search on PubMed and Embase databases for imaging studies investigating central and vascular effects of pharmacological and non-pharmacological treatments used to abort and prevent headache attacks. Sixty-three studies were included in the final qualitative analysis. Of these, 54 investigated migraine patients, 4 cluster headache patients and 5 patients with medication overuse headache. Most studies used functional magnetic resonance imaging (MRI) (n = 33) or molecular imaging (n = 14). Eleven studies employed structural MRI and a few used arterial spin labeling (n = 3), magnetic resonance spectroscopy (n = 3) or magnetic resonance angiography (n = 2). Different imaging modalities were combined in eight studies. Despite of the variety of imaging approaches and results, some findings were consistent. This systematic review suggests that triptans may cross the blood-brain barrier to some extent, though perhaps not sufficiently to alter the intracranial cerebral blood flow. Acupuncture in migraine, neuromodulation in migraine and cluster headache patients, and medication withdrawal in patients with medication overuse headache could promote headache improvement by reverting headache-affected pain processing brain areas. Yet, there is currently no clear evidence for where each treatment acts, and no firm imaging predictors of efficacy. This is mainly due to a scarcity of studies and heterogeneous treatment schemes, study designs, subjects, and imaging techniques. In addition, most studies used small sample sizes and inadequate statistical approaches, which precludes generalizable conclusions.

Conclusion: Several aspects of headache treatments remain to be elucidated using imaging approaches, such as how pharmacological preventive therapies work, whether treatment-related brain changes may influence therapy effectiveness, and imaging biomarkers of clinical response. In the future, well-designed studies with homogeneous study populations, adequate sample sizes and statistical approaches are needed.

Keywords: Biomarkers; Headache; Migraine; Neuroimaging; Secondary headaches.

Fig. 1

Flow chart of study selection

Fig. 2

Imaging modalities employed by the included studies: 1) SPECT and PET are molecular imaging techniques that rely on the detection and quantification of rays released indirectly by radiolabelled molecules (tracers) injected into the body, thus providing information on the metabolism, perfusion and function of brain tissues [7]; 2A-B) Functional MRI (fMRI) techniques are based on the blood oxygenation level dependent mechanism. When a brain area is activated, the neuronal metabolism and regional cerebral blood flow (CBF) increase. The blood flow change is greater than the oxygen consumption, resulting in an increased ratio between the oxygenated and deoxygenated hemoglobin, which increase the MRI signal  [8]. fMRI approaches included task-related fMRI, which provide important information about the degree of activation and functional connectivity of brain regions that are involved in performing a specific task, and resting state (RS) fMRI that provide insight into the patterns of activity of brain networks or single brain areas during a rest condition [9]; 2C) Arterial Spin Labeling is a perfusion MRI technique that employs the arterial water to measure regional CBF changes associated with variations in regional neural activity [10]; 2D) Magnetic resonance spectroscopy is a non-invasive method that allows to identify and quantify metabolites present within a volume of interest based on the magnetic properties of their nuclei, mainly hydrogen and phosphorous. The main metabolites of interest are: N-acetylaspartate (NAA), a marker of neuronal integrity, choline (Cho), a marker of cellular membrane turnover, creatine (Cr), a marker of energy stores and the glutamate-glutamine and gamma-aminobutyric acid (Glx and GABA) neurotransmitters [11]; 2E) Magnetic resonance angiography is an approach that based on the magnetic properties of blood and surrounding tissues highlight the vasculature from the background without the use of contrast [12]; 2F-G) High resolution T1-weighted MRI with voxel-based (VBM) and surface-based morphometric (SBM)approaches provide information regarding the regional grey matter volume and cortical thickness; [13, 14] 2H) T2-weighted images without contrast can provide information regarding the presence of white matter hyperintensities. 2I) T2* and T1-weighted MRI with ultrasmall superparamagnetic iron oxide (USPIO), a cellular MR contrast agent, allows to investigate the macrophage-mediated inflammation [15]. Created by R.M. with BioRender.com

Fig. 3

A schematic illustration of the main central areas targeted by treatments described in the included studies. Created by R.C.H. and I.C. with BioRender.com