Evidence for chronic headaches induced by pathological changes of myodural bridge complex

Abstract

Clinical studies have shown that there may be a certain relationship between pathological changes of the myodural bridge complex (MDBC) and chronic headaches of unknown cause. But there is still a lack of experimental evidence to explain the possible mechanism. This study aims to further confirm this relationship between MDBC and chronic headaches and explore its potential occurrence mechanism in rats. Bleomycin (BLM) or phosphate-buffered saline (PBS) was injected into the myodural bridge fibers of rats to establish the hyperplastic model of MDBC. After 4 weeks, the occurrence of headaches in rats was evaluated through behavioral scores. The immunohistochemistry staining method was applied to observe the expression levels of headache-related neurotransmitters in the brain. Masson trichrome staining results showed that the number of collagen fibers of MDBC was increased in the BLM group compared to those of the other two groups. It revealed hyperplastic changes of MDBC. The behavioral scores of the BLM group were significantly higher than those of the PBS group and the blank control group. Meanwhile, expression levels of CGRP and 5-HT in the headache-related nuclei of the brain were increased in the BLM group. The current study further confirms the view that there is a relationship between pathological changes of MDBC and chronic headaches of unknown cause. This study may provide anatomical and physiological explanations for the pathogenesis of some chronic headaches of unknown cause.

Keywords: Bleomycin; Chronic headache; Myodural bridge; Myodural bridge complex; Referred pain.

Figure 1

BLM-induced hyperplasia of the MDBC after a single local injection. Images display the MDBC in sagittal sections obtained from the posterior atlanto-occipital region, with Masson staining in the BLM, PBS, and CTL groups. The scale bar indicated in image (A) is the same as in images (B) and (C). The posterior atlanto-occipital membrane (☆), MDBC fibers (black and yellow ▲), and RCDmi appeared denser in the BLM group. In addition, the MDB fibers in the BLM group had a wider connection with the SDM, (➡). The black and yellow arrows refer to fibers of the MDBC indirectly and directly connected to the SDM respectively. Image D shows the comparison of the collagen volume fraction with Masson staining. OCCI, occipital bone; C1, atlas; RCDmi, rectus capitis dorsal minor muscle.

Figure 2

The expression levels of CGRP were significantly increased in the MDBC hyperplasia rats in the BLM, compared with the PBS and CTL groups, as shown by immunohistochemical staining. The scale bar is for all figures. VPM, ventral posteromedial nucleus of the thalamus; AMY: amygdala; PBN: parabrachial nucleus; STN: spinal trigeminal nucleus. The immunoreactive cells were stained yellow–brown, as indicated by the black arrow.

Figure 3

The expression levels of 5-HT were significantly increased in the MDBC hyperplasia rats in the BLM, compared with the PBS and CTL groups, as shown by immunohistochemical staining. The scale bar is for all figures. ACC, anterior cingulate cortex; AMY, amygdala; DRN, dorsal raphe nucleus. The immunoreactive cells were stained in yellow–brown, as indicated by the black arrow.

Figure 4

A schematic illustration of a possible underlying mechanism of chronic headaches induced by hyperplastic changes of the MDBC. (f) and (g) are the schematic diagrams of the posterior atlanto-occipital interspace of MDBC hyperplastic rats and normal rats, respectively. When the MDBC (MDB fibers: ● and RCDmi) and the posterior atlanto-occipital membrane (☆) have hyperplastic changes, the flow pattern of CSF ( →) within the cranio-cervical junction can be changed accordingly. The abnormal CSF circulation may activate (dotted line) the conduction of neural pathways in the brain. The nociceptive activity from the spinal dura may then converge on the second-order neuron of the trigeminal nerve and be passed along to the cerebral cortex. (a–e) are the coronal sections of the rat brain where the positive expression nuclei are located. CSF: cerebrospinal fluid; OCCI: occipital bone; C1: atlas; RCDmi: rectus capitis dorsal minor muscle; SC: spinal cord.