Research On Autonomic Nerve Damage And Related TCM Syndromes In Parkinson's Disease

Background:Autonomic dysfunction that occurs before Parkinson’s disease(PD)motor symptoms account for 70%-89%of non-motor symptoms is an important factor that seriously affects patients quality of life.However,previous studies rarely involved the characteristics of PD autonomic nervous system damage and its relationship with TCM syndromes.Objective:Based on high-resolution ultrasonography,resting functional magnetic resonance imaging and polysomnography,this research aims to investigate the characteristics of autonomic nervous system damage in Parkinson’s disease from both structural and functional aspects,and hope to provide a basis for early diagnosis and traditional Chinese medicine(TCM)treatment of Parkinson’s disease.Methods:In the first study,131 patients with Parkinson’s disease(PD)and 132 healthy controls(HC)subjects were included.Through high-resolution ultrasonography,this study explored changes in cervical vagus cross-sectional area in PD patients compared to healthy control subjects,and explored the correlation between the changes in the cross-sectional area of the cervical vagus nerve and the clinical symptoms of PD and TCM syndromes.Study 2 included 57 patients with Parkinson’s disease and 60 healthy control subjects.Based on polysomnography,the study exploded the changes in heart rate variability in the PD group during the complete sleep cycle compared with healthy control subjects,and explored the degree of change of heart rate variability during the transition of sleep stage.In addition,the correlation between the change of heart rate variability in PD and cervical vagus cross-sectional area and TCM syndromes was studied.Study 3 included 31 patients with Parkinson’s disease and 30 healthy control subjects.Based on resting functional magnetic resonance imaging,this study took the forebrain structure of the central autonomic network which include hypothalamus and amygdala and insular lobe as the "seed",and investigated the differences of central autonomic network functional connections between PD patients and healthy individuals,and explored the correlation between autonomic nervous system functional impairment in PD and changes of central autonomic network functional connections;and studied the correlation between changes of central autonomic network functional connections of PD patients and the changes in the cross-sectional area of the cervical vagus nerve,the change of heart rate variability in PD and TCM syndromes.Results:1.Variation of cross-sectional area of cervical vagus nerve.(1)The cross-sectional area(CSA)of left cervical vagus nerve in PD group(0.58±0.17mm2)was significantly lower than that in HC group(1.00± 0.09mm2)(P<0.001).The CSA of right cervical vagus nerve in PD group(0.65±0.21mm2)was significantly lower than that in HC group(1.16 ± 0.11mm2)(P<0.001).The left CSA in PD patients with HY grade 1-2.5 group(0.61±10.15mm2)was significantly higher than that in the grade 3-5 group(0.52 ±0.18mm2)(P<0.001).(2)Using the CSA values of the left and right cervical vagus nerve as indicators to identify PD,and draw the receiver operating characteristic curve(ROC).The area under the ROC curve of the left CSA value was 0.975.When the cutoff value is 0.856 mm2,the sensitivity was 96.21%,and the specificity was 94.66%.The area under the ROC curve of the CSA value on the right was 0.971.When the cutoff value is 1.028 mm2,the sensitivity was 95.45%and the specificity was 96.18%.(3)In PD patients,correlation analysis results showed that the left vagus nerve CSA was negatively correlated with HY grade(r=-0.407,P<0.001)and UPDRS score(r=-0.183,P=0.037)and Gastrointestinal factor score of SCOPA-AUT scale(r=-0.224,P=0.010),and the right vagus nerve CSA was negatively correlated with Gastrointestinal factor score of SCOPA-AUT scale(r=-0.205,P=0.019)and temperature regulation factor score of SCOPA-AUT scale(r=-0.193,P=0.027).In PD patients,when comes to TCM syndromes,Qi deficiency score was negatively correlated with the left vagus nerve CSA(r=-0.302,P<0.001)and right vagus nerve CSA(r=-0.220,P=0.012).In PD patients,in terms of clinical indicators,the results of stepwise regression analysis showed that H-Y grade and UPDRS score were the main factors affecting the left vagus nerve CSA(P<0.05),and the Gastrointestinal factor score of SCOPA-AUT scale was the main factor affecting the right vagus nerve CSA(P<0.05).Qi deficiency and kidney deficiency were the main TCM syndromes that affect the left vagus CSA(P<0.05),and Qi deficiency was the main TCM syndromes that affect the right vagus nerve CSA(P=0.038)2.Changes of heart rate variability during the sleep cycle(1)the values of Mean RR,SDNN,RMSSD,pNN50,LF,HF,LF nu,LF/HF and PNS Index in PD group were significantly lower than that in HC group,and the SNS Index(2.26±1.45)in PD group was significantly higher than that in HC group(1.28±1.09)(P<0.001).(2)The HRV within the W period,N2 period,and REM period of sleep cycle in the two groups were analyzed with repeated measures analysis of variance and the results showed that there were significant group*stage interactions regarding Mean RR(F=8.739,P<0.001),SDNN(F=3.108,P=0.047),RMSSD(F=3.971,P=0.024)and Log HF(F=4.231,P=0.019).Mean RR,SDNN,Log HF and RMSSD values of PD group and HC group all increased frorm W stage to N2 stage,and decreased from N2 stage to REM stage.However,the degree of change of heart rate variability in PD group was less than that in HC group during the transition of sleep stage.(3)In PD patients,correlation analysis results showed that liver wind score was negatively correlated with the value of Mean RR(r=-0.301,P=0.023),SDNN(r=-0.333,P=0.011),pN-N50(r=-0.271,P=0.041),LF(r=-0.331,P=0.012)and PNS Index(r=-0.286,P=0.031).Qi deficiency score was negatively correlated with the value of LF nu(r=-0.345,P=0.009),HF nu(r=-0.345,P=0.009)and LF/HF(r=-0.303,P=0.022).In terms of clinical indicators,UPDRS scale scores were negatively correlated with the values of SDNN(r=-0.356,P=0.007),LF(r=-0.429,P=0.001)and HF(r=-0.343,P=0.009).H-Y grade was negatively correlated with the values SDNN(r=-0.320,P=0.015),LF(r=-0.391,P=0.003)and HF(r=-0.292,P=0.027).In addition,the left cervical vagus nerve CSA was positively correlated with the values of LF nu(r=0.318,P=0.016),LF/HF(r=0.318,P=0.016),and negatively correlated with the values of HF nu(r=-0.318,P=0.016).3.Changes in central autonomous network function connections.(1)Compared with the HC group,the left hypothalamus was weakly connected with the left medulla,insula,thalamus,cerebellum posterior lobe and right hippocampus in PD patients;the right hypothalamus was weakly connected with the left medulla and the right frontal lobe,the thalamus,the precuneus,and the cerebellum posterior lobe;the left amygdala was weakly connected with the left frontal lobe,the middle frontal gyrus,the cingulate gyrus,and the right insula and the cerebellum posterior lobe.The right amygdala was weakly connected with the right insular and cingulate gyrus;the right insular was weakly connected with the the left precuneus and right frontal lobe.In addition,the functional connection between the left hypothalamus and the right midbrain,as well as the functional connection between left amygdala and the left midbrain is enhanced(2)The correlation analysis show that in the weakly connective regions of PD patients,the functional connectivity between the left amygdala and the left frontal lobe(r=-0.384,P=0.036)was negatively correlated with the UPDRS score;The functional connection between the left hypothalamus and the left medulla(r=-0.515,P=0.004)was negatively correlated with the NMS score;the functional connection between the left hypothalamus and the left thalamus(r=-0.371,P=0.044)was negatively correlated with H-Y grade.(3)Correlation analysis with heart rate variability found that in regions with reduced functional connectivity in PD patients,the functional connectivity between the left amygdala and the right insular was positively correlated with LF/HF(r=0.365,P=0.044).The functional connectivity between the right insular and the right frontal lobe was positively correlated with LF(r=0.422,P=0.020).(4)Correlation analysis with the cervical vagus nerve CSA found that in regions with reduced functional connectivity in PD patients,the functional connection between the left amygdala and the left frontal lobe in PD patients was positively correlated with the left cervical vagus nerve CSA(r=0.419,P=0.024).In regions with enhanced functional connectivity in PD patients,the functional connectivity between the left amygdala and the left midbrain was negatively correlated with the right cervical vagus nerve CSA(r=-0.488,P=0.007).(5)Correlation analysis between regions with reduced functional connectivity in PD patients and TCM syndromes showed that the functional connectivity between the left hypothalamus and the right hippocampus was negatively correlated with the spleen deficiency score(r=-0.380,P=0.038)and Yin deficiency score(r=-0.410,P=0.024).The functional connectivity between the left hypothalamus and the left middle temporal gyrus(r=-0.377,P=0.040)was negatively correlated with liver wind score.From right hypothalamus to left parietal lobe(r=-0.379,P=0.039)was negatively correlated with Qi deficiency score.Correlation analysis between regions with enhanced functional connectivity in PD patients and the TCM syndromes showed that the functional connectivity between the left hypothalamus and the right midbrain(r=0.374,P=0.042)was positively correlated with Yang deficiency score.Conclusion:The cervical vagus nerve of PD patients is atrophic compared with healthy people,which may lead to the damage of visceral sensory afferent pathways,thus causing abnormal changes in the functional connection between the forebrain and brainstem structures involved in the output of sympathetic and parasympathetic nerves in the central autonomic network.Damaged synergy may lead to regulatory dysfunction of heart rate variability,followed by weakened PD heart rate variability.In addition,the degree of damage to the above loop is positively correlated with the severity of PD disease.Qi deficiency is the key syndrome that through the damages of autonomic nervous system loop in Parkinson’s disease.