In the present study, bilateral amygdala perfusion presented significant decreased cerebral perfusion, but the alteration was not correlated with the clinical variables. Then, there was no significant difference for the bilateral amygdala volume between two groups. In addition, the ROC analysis showed that 3D-PCASL had moderate diagnostic efficacy in discrimination.
Altered interictal perfusion of amygdala may reflect differences in neuronal activity or density, in other words accompanying with structural and functional changes. A voxel-based morphometry (VBM) analysis showed CM patients presented a significant volume reduction in the amygdala compared with EM10, differing from the increased volume with chronic low back pain18. Another study demonstrated that the amygdala volume changed structurally with headache frequency, and correlated with frequency in specific ranges19, while the headache frequency and disease duration equally had influence on CBF20. This could be the consequence of repetitive migraine attacks or chronic adaptive mechanisms, leading the volume and perfusion changes of amygdala, which implied a possible damage or degeneration of neurons. Thus, the current study suggested that the decreased perfusion might be another proof of structural damage and attributed to neuroplasticity induced by pain. Mesnwhlie, this study measured the volume of amygdala at the same time, finding there was no siginificant difference between two groups. Therefore, the perfusion change happened prior to the volume alternation, which could supply another clue to definite the possible relationship: whether decreased perfusion was the trigger or consequence of volume alteration, or a bidirectional relationship between them.
Hemodynamic changes could identify the pain perception process, and multiple brain regions both responded to pain and participated in pain control in the process21. The abnormal functional connectivity may be the direct manifestation of pain perception process in migraine from the viewpoint of blood oxygen level dependent (BOLD) effect in resting state. Some studies have proved that migraine is associated with changes in functional connectivity between different regions12–14, 22 as following: (1) a significantly decreased effective connectivity from the right amygdala to bilateral superior temporal gyrus, right inferior occipital lobe, while enhanced from left inferior frontal gyrus to left amygdale; (2) increased connectivity of amygdala in migraineurs was observed to the visceroceptive cortex. Therefore, it could be speculated that the altered functional connectivity (BOLD effect) might be associated with the perfusion change in amygdala in CM, which also indicated that it should be performed with the functional connectivity and 3D-PCASL study simultaneously to construct neurovascular coupling (NVC) model for amygdala in the future migraine research23.
Previous perfusion studies, using single photon emission computed tomography (SPECT) or PET, reported contradicting results about cerebral hemodynamics. Migraine patients presented a normal cerebral blood flow pattern during migraine attacks24, which was conflict with the interictal hypoperfusion of single or multiple brain regions in migraineurs 25 and interictal global hyperperfusion mainly locating in frontal regions in migraine without aura26. These inconsistent results might be partly associated with the unreliability of visual evaluation of data acquisition from SPECT CBF images27. Subsequently, dynamic susceptibility contrast-perfusion weighted imaging (DSC-PWI) study identified areas of hypoperfusion more than one vascular territory in patients with migraine with aura28. Besides these, the prior study using dynamic contrast material–enhanced (DCE) MRI with a voxel-wise whole brain comparison showed interictal migraineurs had discrete areas of cerebral hyperperfusion and hypoperfusion20. Another DCE-MRI research quantified blood-brain barrier (BBB) permeability in migraine, observing the mean fractional plasma volume in the left amygdala was lower in the migraine group29. This finding was consistent with the decreased perfusion of the current results to some degree although the relationship between BBB integrity and metabolic changes in migraine cannot be directly correlated29. The discrepancy in perfusion status may be associated with the spatial heterogeneity of CBF changes during migraine30. And the comparison between these complicated techniques remained unsubstantiated because of differences in post-processing.
Abnormal regional cerebral hyperperfusion was associated with migraine headache using ASL in hemiplegic migraine patient and EM31, while bilateral amygdala was coupled with hypoperfusion in CM in this study. The discrepancy in the cerebral perfusion status might signal the chronicization of migraine at hemodynamics level and further provide a novel view to the mechanisms of initiation, continuation, and termination of migraine.
Alterations in amygdala that modulated the pain in migraine suggested a possible neurobiological mechanism, which may explain the link between CM and psychiatric disturbances. This study found CM patients were more susceptible of anxiety in accordance with earlier finding32, while there was no any significant correlation between the CBF value of amygdala with clinical variables including HAMA assessing anxiety. However, earlier findings reported the associations between migraine and stress, anxiety and depression33–35. Therefore, CBF value would be an independent factor in CM, but the possibility relationship between pathophysiologic mechanism and perfusion alteration should be discussed further.
Figure 3 presented perfusion of bilateral amygdala with moderate discrimination for the diagnosis of CM with the AUC of 0.78 (95% CI 0.58–0.91) and 0.75 (95% CI 0.55–0.89) for the left and right amygdala, respectively. Note that the AUC describes the test’s ability to discriminate between subjects with and without the condition36. The current study could confirm that the decreased perfusion of amygdala is more common in CM than that in NC in the about 75% -78% of comparisons from the statistical viewpoint. Therefore, the CBF value could be a potential imaging biomarker for the diagnosis of CM with objective and comprehensive considerations.
The 3D-PCASL analysis in the current study was applied with more advanced acquisition and post-processing technique than traditional methods. Compared with SPECT and PET, 3D-PCASL does not expose the subjects to ionizing radiation and has the possibility for repeated measurements to increase the sensitivity. On the other hand, one study had proposed 3D-PCASL methodology may provide an alternative to PET that can be obtained during routine MRI in clinical practice and research37. Instead of DSC-MRI exogenous contrast agent, 3D-PCASL is based on the endogenous blood-based water in the arteries itself, therefore, has the superiority of avoiding the risk of drug allergy38. Meanwhile, 3D-PCASL can break through the limitations of traditional 2D-ASL, accelerate the acquisition time and produce quantitative images of perfusion37, 38. Therefore, 3D-PCASL technique could be considered as a simple and effective tool to evaluate the perfusion status of amygdala in migraine research.
Limitations of this study included as follows: (1) the sample size was relatively small, and the further ASL studies are required larger-population to reflect the neuromechanism of CM; (2) this study only presented the perfusion changes in the interictal stage, future studies should assess different (interictal and ictal) timepoints in the migraine cycle to evaluate the reproducibility of 3D-pASL; (3) our study relied on cross-sectional data rather than longitudinal data, therefore, the exact causal relationship between amygdala perfusion and migraine chronicization could not be determined.