Frequency-specific Alteration Of Functional Connectivity Density In Primary Dysmenorrhea And The Modulation Effect Of Acupuncture

Objective1.To investigate the brain function alteration in patients with primary dysmenorrhea(PDM)in different frequency filter-bands(Slow5(0.01-0.027Hz),Slow4(0.027-0.073Hz),Slow3(0.073-0.198Hz)and full low frequency(0.01-0.08Hz))of resting-state functional magnetic resonance imaging(rs-f MRI)data by using functional connectivity density(FCD)approach.2.To explore the different brain central functional response features to acupuncture and non-acupuncture treatment of patients with PDM.To investigate the potential central response mechanism of acupuncture treatment of PDM.Methods1.Forty-seven patients with PDM and 36 healthy controls underwent resting-state functional magnetic resonance imaging scanning and clinical evaluation.Visual analogue scale(VAS)was used for assessing severity of pain.Cox Menstruation Symptom Scale(CMSS)was used for assessing the severity of dysmenorrhea(CMSS-t)and the time of duration of dysmenorrhea symptom(CMSS-t).Anxiety self-rating(SAS)and depression self-rating scale(SDS)were used to assess anxiety and depression symptom,respectively.Brain function global FCD(g FCD),local FCD(l FCD)and long-range FCD(lr FCD)were calculated based on the data-driven method.The difference in FCD between the healthy control group and the PDM group in different frequency bands was compared by two sample T-tests.The correlation analyses were used to explore the relationships between abnormal FCD brain and clinical features(VAS pain score,CMSS-t,CMSS-s,anxiety and depressive symptoms)in different frequency bands of primary dysmenorrhea.The mediation analysis was used to investigate the mediating role of abnormalities of FCD in the relationship between disease duration and clinical symptoms.2.Thirty-four patients with PDM were divided into acupuncture and non-acupuncture group for three menstrual cycles,and the acupuncture was located at Sanyinjiao(SP6)and non-acupuncture at non-acupoint.First,we compared the alteration of clinical features in each groups.Then,we conducted the correlation between the baseline clinical features and the changes of clinical characteristics after treatment in real acupuncture group,to explore whether the baseline characteristics have a significant effect on the treatment response.Second,to explore the central response characteristics of acupuncture and nonacupuncture treatment of primary dysmenorrhea,the treatment effects on different frequency bands of global FCD in each group were conducted by using voxel-wise Paired t-tests,and using repeated measurement of analysis of variance(RMANOVA)to compare the group difference of two group after treatment on brain function in different frequency bands.Finally,we extract the g FCD value in the effected brain area after acupuncture treatment,and investigate the relationship between the alteration of g FCD and clinical symptoms.Results1.The brain functional abnormalities in patients with primary dysmenorrhea compared with healthy controls.(1)Compared with the healthy control group,in the full low frequency band,the reduced FCD brain regions were found in the medial primary somatosensory cortex / primary motor cortex(m S1/M1)and the dorsolateral prefrontal cortex(DLPFC),and the enhanced brain region was located in the medial temporal frontal lobe(m OFC);In the Slow5 band,the reduced FCD of brain region was located in DLPFC,and the increased FCD of brain region includes m OFC,medial prefrontal cortex(m PFC),second somatosensory area(S2),and hippocampus;in the slow4 band,the decreased FCD of brain area was located anterior of the inferior frontal gyrus(a IFG)and m S1/M1,the increased FCD of brain regions were located in the m OFC,hippocampus,and parahippocampal;in the Slow3 band,the reduced FCD of brain regions was found in angular gyrus.(2)The l FCD of the right hippocampus in the low-frequency band was negatively correlated with the VAS score,and the l FCD of right hippocampal in the slow4 band was negatively correlated with the VAS score in the PDM group,and the g FCD of the left second somatosensory area(S2)in the Slow5 band was positively correlated with the VAS score.The l FCD of the left m OFC in the full low-frequency band was positively correlated with the CMSS-t score of PDM patients,and the g FCD and l FCD of the left m OFC in the Slow4 band were positively correlated with the CMSS-t score,and the g FCD and l FCD of the right DLPFC of the Slow5 band were negatively correlated with the CMSS-t total score of PDM patients.The l FCD of left S2 of the Slow5 band was significantly positively correlated with the CMSS-s score in PDM group.The g FCD and l FCD of left S2 of the Slow5 band were positively correlated with SAS and SDS score,while the g FCD and l FCD of the right DLPFC in Slow5 band were negatively correlated with SAS and SDS score in PDM group.(3)The results of the mediation analysis showed that the local FCD on the left S2 in Slow 5 band could mediate the relationship between the duration of disease and the CMSS-s score in PDM group.2.The central response mechanism of acupuncture and non-acupuncture for primary dysmenorrhea(1)The pain VAS score,SAS,SDS,CMSS-t score and CMSS-s score were significantly decreased in patients with PDM after the acupuncture treatment.In the nonacupuncture group,CMSS-t score was decreased after treatment,no significant alteration was found in the pain VAS score,SAS and CMSS-degree scores.Compared with the nonacupuncture group,the acupuncture group showed higher alterations in term of pain VAS score and the CMSS-s score.(2)After acupuncture treatment,in the full low frequency band,the decreased g FCD was found in hippocampal;In the Slow5 band,the g FCD of hippocampus and middle cingulate(MCC)was decreased,and the g FCD of anterior cingulate,DLPFC and a IFG was increased.In the Slow4 band,the g FCD of S2 was increased;In the Slow3 band,the g FCD of the precuneus was decreased,while the g FCD of the insula was increased.After the non-acupuncture,the alterations were found in angular gyrus and the IFG in full low frequency band,the hippocampus in Slow5 band and the m PFC in Slow3 band.(3)For the increased g FCD brain region after acupuncture: no significant group difference in full low frequency band,compared with non-acupuncture,in the Slow5 band,acupuncture treatment show higher increasing g FCD in the left DLPFC;In the Slow4 band,the acupuncture treatment group show higher increasing g FCD in left middle cingulate gyrus(MCC).For the decreased g FCD brain region after acupuncture: in the full low frequency band,the acupuncture treatment show higher decreasing g FCD than that of the non-acupuncture treatment in left caudate and nucleus accumbens,right hippocampus and parahippocampal;In the Slow5 band,there was no significant group difference;In the Slow4 band,the acupuncture treatment show higher decreasing g FCD than that of the non-acupuncture treatment in left caudate and nucleus accumbens,and right a IFG;In the Slow3 band,the acupuncture treatment show higher decreasing g FCD than that of the non-acupuncture treatment in left hippocampus and right supplementary motor area(SMA).(4)In the acupuncture group,the g FCD change in DLPFC in the Slow5 band was negatively correlated with the change of VAS,and the change of g FCD in S2 in Slow4 band was positively correlated with the change of VAS;the change of g FCD of posterior insula in Slow3 band was negatively correlated with the change of CMSS-t;the change of g FCD in the anterior insula in Slow3 band was positively correlated with the change of anxiety score,while the change of g FCD in the anterior cingulate cortex(ACC)in Slow5 was negatively correlated with the change of anxiety score.Conclusions1.The brain function connectivity density was abnormal in PDM patients,including sensorimotor network(SMA),central executive network(CEN),default mode network(DMN)and memory network,in addition,the brain function changes was frequency band dependent.2.The dysfunctional FCD was associated with clinical features in PDM patients.The changed FCD in S2 could mediate the duration associated disease severity in PDM patients.3.The Sanyinjiao acupuncture treatment was more effective than non-acupoint acupuncture treatment for PDM.The Sanyinjiao acupuncture could not only improve the symptoms of pain and,but also improve the anxiety and depression symptom in PDM.4.There was a frequency-dependent brain central response to Sanyinjiao acupuncture treatment of PDM.For different frequency bands,the brain region of the central response was different.The main regulation mechanism in the brain of Sanyinjiao acupuncture might increase the FCD in CEN and decrease the FCD in hippocampus.5.The brain central response to Sanyinjiao acupuncture treatment was associated with the clinical improvement in PDM patients.