Pathophysiological Research Of Pain In Migraine And Cluster Headache

Objective1.To observe the effect of cortical spreading depression(CSD) on firing rate of trigeminal nucleus caudalis(TNC) neurons in rats so as to determine the correlation between CSD and central trigeminovascular neurons.2.To investigate the effect of CSD on CGRP and SP levels in serum and trigeminal ganglia in rats so as to determine the correlation between CSD and peripheral trigeminovascular neurons.3.To examine the changes of brain activity and functional correlations during spontaneous cluster headache attack as compared with during remission in the cluster period of patients with cluster headache by using resting-state functional magnetic resonance imaging(fMRI).Methods1.The rats were divided into four goups,including control group,ipsilateral TNC group,contralateral TNC group,and flunarizine group.The CSD waves were evoked by application of potassium chloride on brain surface with filter paper.For control group,saline,instead of potassium chloride,was used for stimulation on brain surface with filter paper.For flunarizine group, funarizine hydrochloride was intravenously administered to rats five minutes prior to application of potassium chloride.CSD waves and extracellular single-unit recordings in the site of TNC were simultaneously recorded by glass microelectrodes.The data of CSD and firing rates of TNC neurons were collected by PowerLab system and analysed by Chart5.0 for Windows software.2.The rats were randomly divided into three goups,including control group, CSD group,and flunarizine group.The levels of CGRP and SP in plasma and trigeminal ganglia were measured by radioimmunity assay.The neurons with positive CGRP and SP immunoreactivity in trigeminal ganglia were identified by immunohistochemistry technique.3.Twenty male patients with episodic cluster headache were divided into two groups including right-sided headache group and left-sided headache group. Two resting-fMRI scans were successfully acquired respectively during the acute spontaneous attack and again during headache remission.The changes of brain activity and functional correlations between the whole brain and region of interest(ROI) were respectively analysed by the regional homogeneity(ReHo) method and functional connectivity method.Results1.There was no CSD wave in control group.The firing rates in the site of ipsilateral TNC neuron during CSD were higher as compared with during post-CSD,and the later were higher as compared with during pre-CSD(P＜0.05).There were no significant differences for the firing rates in the site of contralateral TNC neurons among during pre-CSD,CSD,and post-CSD (P＞0.05).For flunarizine group,the firing rates in the site of ipsilateral TNC neurons during pre-CSD were higher as compared with during CSD(P＜0.05).2.1) There were statistical differences on palasma levels of CGRP and SP among the three groups(P＜0.05).The levels of CGRP and SP in CSD group were higher than control group(P＜0.05).No significant differences on the levels of CGRP and SP in ipsilateral trigeminal ganglia were found among the three groups(P＞0.05).2) The number of neurons with positive CGRP and SP immunoreactivity was statistically different in right-sided trigeminal ganglia among the three groups (P＜0.05).The number in fight-sided trigeminal ganglia in CSD group was higher as compared with control group(P＜0.05).The number in right-sided trigeminal ganglia was statistically higher than that in left-sided trigeminal ganglion in CSD group(P＜0.05).3.1) Altered ReHo in ipsilateral pons and other brain regions response to pain such as basal nuclei,thalamus,cingulated gyms and prefrontal cortex was detected during the acute spontaneous attack as compared with during headache remission(P＜0.05,corrected by Monte Carlo simulation). 2) Positive functional connectivity was detected between ipsilateral pons and other brain regions related to pain within pain state and within non-pain state (P＜0.05,corrected by false discovery rate,FDR).Increased functional correlation between ipsilateral pons and other pain-related brain regions such as ipsilateral prefrontal cortex and contralateral subcallosal gyrus was detected during the acute spontaneous attack as compared with during headache remission(P＜0.05,corrected by Monte Carlo simulation).Conclusion1.The firing rates in the site of ipsilateral TNC neurons are increased by CSD, and decreased after intravenous administration of flunarizine hydrochloride.It is inferred that CSD may activate central trigeminovascular neuron through certain mechanism,and flunarizine hydrochloride may prevent migraine by inhibiting the process.2.CSD increases the serum level of CGRP and SP and the number of CGRP and SP positive immunoreactivity neurons in ipsilateral trigemnal ganglia.It is implicated that CSD may activate peripheral trigeminovascular reflex.3.Our findings suggest that increased brain activity in ipsilateral pons involved in trigeminal vascular reflex may be related to the pathogenesis of pain in cluster headache.Other brain regions known to be response to pain,such as cingulated gyrus and prefrontal cortex might be also involved in CH attack processing.