White matter tract microstructure of the mPFC-amygdala predicts interindividual differences in placebo response related to treatment in migraine patients

Abstract

To investigate whether interindividual variability of white matter (WM) tract microstructure of the medial prefrontal cortex (mPFC)-amygdala circuit could predict 8-week placebo treatment outcomes in patients with migraine without aura (MO) using diffusion tensor imaging (DTI) with a tractography atlas-based analysis algorithm and a linear support vector machine algorithm. This study received institutional review board approval, and all subjects gave informed consent. One hundred and twenty-four MO had an 8-week sham acupuncture treatment. Patients were subdivided into recovering (MOr, >50% improvement in migraine attack frequency after treatment) and persisting (MOp, <50% reduction in number of migraine days). Neuroimaging was collected via magnetic resonance imaging (MRI) in all subjects. Patients were imaged during the interictal phase of migraine (at least 72 hr after, and not within 24 hr of a migraine) before the treatment. WM microstructures were quantified along the selected fiber pathway and were used to evaluate the discrimination performance for classifying MOr and MOp. The combined features of diffusion measures from vertices along the pathways of the mPFC-amygdala accurately discriminated MOr from MOp migraineurs with an accuracy of 84.0% (p < .005, permutation test). The most discriminative WM features that contributed to the classification were located in the external capsule and ACC/mPFC. Our findings suggested that the variability of placebo treatment outcomes in migraineurs could be predicted from priori diffusion measures along the fiber pathways of the mPFC-amygdala, which may demonstrate a potential of WM neuroimaging features as imaging markers for identifying placebo responders in migraine patients.

Keywords: migraine; placebo; prediction; white matter tract microstructure.

Figure 1

Flow chart of patient inclusion and experimental procedure

Figure 2

Between‐group differences of diffusion properties along the fiber bundle of the mPFC‐amygdala. As compared with controls, patients with migraine exhibited abnormal white matter microstructure with increased fractional anisotropy, decreased mean diffusivity, decreased axial diffusivity, and decreased radial diffusivity. FA = fractional anisotropy; MD = mean diffusivity; RD = radial diffusivity; AD = axial diffusivity [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

The corresponding features to the classification were finally visualized in fiber bundles of a three‐dimensional brain. In our results, areas located at the external capsule (cluster 1) and anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) (cluster 2 and 3) significantly contributed to the classification performance to discriminate between MOr and MOp (MOr: migraine without aura, recovering; MOp: migraine without aura, persisting) [Color figure can be viewed at http://wileyonlinelibrary.com]