Functional Brain Network Study Of Essential Tremor With Anxiety Or Depression:A Brain Connectome-based Study

Background and Purpose:Anxiety and depression are the most common neuropsychiatric symptoms of Essential tremor(ET),which can seriously affect the quality of life of patients.However,the exact incidence and pathophysiology of anxiety and depression in ET are still unclear,which were not fully recognized.Therefore,more than 60% of ET patients with anxiety and depression have not been treated in time.Recently,with the development of neuroimaging techniques,the pathogenesis of anxiety and depression has been further discussed,but few were on ET studies.And mostly,they only focused on the structural or functional abnormalities of specific brain regions,without the brain network analysis at the whole-brain level.This study is the first to study the clinical characteristics of ET with pure anxiety,ET with pure depression and ET with anxiety and depression,and to combine the resting-state functional magnetic resonance imaging(rs-f MRI)with the graph theory approaches to investigate the functional brain network topological metrics in drug-na(?)ve ET with anxiety or/and depression.We aim to explore the whole-brain network of ET patients with anxiety or depression from the whole-brain level and to provide evidence for the early recognition and diagnosis.Materials and Methods:Chapter one: The ET patients who visited the Department of Neurology of our hospital from October 2018 to January 2021 were collected and enrolled sequentially.They were interviewed face to face by two specialized neurologists in an isolated and quiet room.We collected and assessed the demographic data and clinical characteristics of all subjects,including the locations and types of tremor,disease severity,and non-motor symptoms such as mood and cognition.According to the scores of Hamilton Anxiety Scales(HAMA)and Hamilton Depression Scale(HAMD),the patients were divided into ET with pure anxiety(PA-ET),ET with pure depression(PDep-ET),ET with anxiety and depression(Dep+A-ET),and ET without anxiety or depression(NDep+NA-ET).SPSS 21.0 was used for statistical analysis,and group differences in clinical characteristics were analyzed by using an independent-samples t-test or X2 test,as appropriate.Logistic regression analysis was used to investigate the anxiety or depression-related risk factors in ET.Spearman correlation analysis was used to analyze the correlations between the severity of tremor and anxiety or depression in ET patients.P < 0.05 was statistically significant.Chapter two : Resting-state f MRI data were obtained on a 3.0 T MR imaging system from drug-na(?)ve 33 ET with depression(Dep-ET),45 ET without depression(NDep-ET),36 ET with anxiety(A-ET),42 ET without anxiety(NA-ET),and 79 healthy controls(HC).The rs-f MRI data were conducted by GRETNA software running on Matlab,and then the brain was segmented into 116 nodes by using an anatomical automatic labeling(AAL)template.Pearson correlation coefficient was used to establish a 116 × 116 undirected weighted global brain functional network for each subject.The graph theory method was used to calculate the topological metrics of the brain functional network in each group,and a non-parametric permutation test was used to analyze the differences of the topological metrics of the functional brain network between groups.The network-based statistics(NBS)method was used to analyze the functional connectivity in the patient groups.Partial correlation analysis was used to assess the relationships between the topological metrics and clinical features in each patient group.Chapter three: To exclude the interference caused by the overlap of anxiety and depression,we further collected the rs-f MRI data from 10 PA-ET,30 Dep+A-ET,and 46 NDep+NA-ET.The topological metrics of the three groups of functional brain networks were analyzed by using the graph theory approaches(The specific method refers to Chapter two).Results:Chapter one:(1)A total of 444 ET patients who met the criteria were included in this study,including 23 PDep-ET(5.18%),67 PA-ET(15.09%),112 Dep+A-ET(25.23%),and 242 NDep+NA-ET(54.50%).(2)Compared with the NDep+NA-ET group,ET patients with anxiety and/or depression had the following clinical characteristics: only in Dep+A-ET patients were more common of women(P3 = 0.017),were older(P3 = 0.003),mean years of education were shorter(P3 = 0.007),and more patients with head tremor(P3 = 0.007).Both PDep-ET and Dep+A-ET patients were older at of onset(P1 = 0.010,P3= 0.007),more patients started with head(P1 = 0.047,P3 = 0.044).Both PA-ET group and Dep+A-ET group patients were more likely to have resting tremor(P2 = 0.030,P3 = 0.010).(3)Compared with the NDep+NA-ET group,tremor of PDep-ET,PA-ET and Dep+A-ET patients were more severe: only the Dep+A-ET group had a higher tremor level(P3 < 0.001);both the PDep-ET group and Dep+A-ET group had a higher total score of Fahn-Tolosa-Marin Tremor Rating Scale(TRS)(P1 = 0.034,P3 < 0.001);In PA-ET group,only TRS-C(the effect of tremor on patients’ life)was higher(P2 = 0.008);In Dep+A-ET group,TRS-A(tremor type and level score),TRS-B(tremor score of writing,water pouring,Archimedean spiral and straight line)and TRS-C were all increased(P3 < 0.001);the disease progression rate was all faster in PDep-ET,PA-ET,and Dep+A-ET groups(P1 = 0.001,P2 = 0.026,P3 < 0.001).(4)The impact of anxiety and depression on life: compared with the NDep+NA-ET group,the quality of life(the Quality of life in Essential Tremor questionnaire,QUEST)was more affected in PDep-ET,PA-ET and Dep+A-ET groups(P1 = 0.006,P2 = 0.005,P3 < 0.001).However,activities of daily living(ADL)were more affected only in the PA-ET group(P2 = 0.044).(5)Cognitive function: compared with the NDep+NA-ET group,the Dep+A-ET group had lower scores on Mini-Mental State Examination(MMSE)(P3 = 0.002)and Montreal Cognitive Assessment(Mo CA)(P3 < 0.001),the most commonly affected domains were visual-spatial executive(P3 < 0.001),attention(P3= 0.003),language(P3 = 0.015),abstract(P3 = 0.018)and memory(P3 < 0.001).PDep-ET group showed only decreased attention(P1 = 0.014).PA-ET group showed lower Mo CA score(P2 = 0.009)and the mainly affected domains were visual-spatial executive ability(P2 = 0.017)and memory(P2 = 0.004).(6)Correlation analysis displayed that HAMD and HAMA scores were positively correlated with tremor severity(r = 0.287,P < 0.001;r = 0.225,P < 0.001).Chapter two:(1)Compared with NDep-ET group,the Dep-ET group had longer disease duration(P = 0.036),more likely to have resting tremor(P = 0.032),had higher TRS score(P = 0.006),higher HAMD score(P < 0.001)and higher HAMA score(P < 0.001).Compared with the NA-ET group,A-ET group patients were older(P = 0.047),had longer disease duration(P = 0.046),higher TRS score(P = 0.002),higher HAMD score(P < 0.001)and higher HAMA score(P < 0.001).(2)The brain functional networks of all the subjects exhibited small-world topology,which met the criteria of both γ >> 1 and λ ≈ 1.There were significant differences between all patient groups and the HC group.Compared with the HC group,Dep-ET group,NDep-ET group,A-ET group,and NA-ET group all showed decreased global efficiency(Eglobal),local efficiency(Elocal),and clustering coefficient(Cp),and increased characteristic path length(Lp)(P < 0.05),and showed a shift towards “weaker small-worldization” with decreased segregation and decreased integration.However,no significant differences in global metrics were found between Dep-ET and NDep-ET group,and between A-ET and NA-ET group(P > 0.05).(3)Compared with the HC group,both Dep-ET and NDep-ET groups showed reduced nodal efficiency in the right inferior frontal gyrus,opercular part,right supplementary motor area(SMA),left superior orbitofrontal gyrus,bilateral rectus,right inferior parietal gyrus,right supramarginal gyrus,left precuneus and cerebulum_crus Ⅰ_R;NDep-ET group specifically showed decreased nodal efficiency in the bilateral precentral gyrus,left superior frontal gyrus,bilateral rolandic operculum,bilateral posterior cingulate gyrus,right postcentral gyrus,and left supramarginal gyrus.Compared with the NDep-ET group,the Dep-ET group showed increased nodal efficiency in the right posterior cingulate gyrus.(4)Compared with the HC group,both the A-ET group and NA-ET group showed decreased nodal efficiency in the right inferior frontal gyrus,opercular part,right SMA,left superior orbitofrontal gyrus,bilateral rectus,right inferior parietal gyrus,right supramarginal gyrus and left precuneus;the NA-ET group specifically showed decreased nodal efficiency in the bilateral precentral gyrus,left superior frontal gyrus,bilateral rolandic operculum,bilateral posterior cingulate gyrus,right postcentral gyrus,and right fusiform gyrus.Compared with the NA-ET group,the A-ET group showed increased node efficiency in the right posterior cingulate gyrus.(5)The abnormalities of functional network connectivity in Dep-ET,NDep-ET,A-ET,NA-ET subgroups were mainly concentrated in the motor cortex,prefrontal-limbic network and default mode network(DMN);and the abnormalities of network connectivity in the Dep-ET group and A-ET group were less than those in the NDep-ET group and NA-ET group,respectively.(6)The nodal efficiency of left and right precentral gyrus in NDep-ET patients was significantly positively correlated with age of onset(left: r = 0.38,P = 0.011;right: r = 0.442,P = 0.003),but negatively correlated with disease duration(left: r =-0.393,P = 0.011;right: r =-0.430,P = 0.005).The nodal efficiency of the right SMA in A-ET patients was significantly positively correlated with the age of onset(r = 0.363,P = 0.035),but negatively correlated with the disease duration(r =-0.363,P = 0.035).Chapter three:(1)Compared with the NDep+NA-ET group,only the Dep+A-ET group had a longer disease duration(P3 = 0.019),was more likely to have resting tremor(P3 = 0.026),had a lower MMSE score(P3 = 0.044);both PA-ET group and Dep+A-ET group had higher HAMD and HAMA scores(P < 0.05).Compared with the PA-ET group,the Dep+A-ET group had higher HAMD and HAMA scores(P < 0.05).(2)There were no significant differences in network efficiency parameters and small-world parameters among the PA-ET group,Dep+A-ET group and NDep+NA-ET group(P > 0.05).(3)Compared with the NDep+NA-ET group,only the Dep+A-ET group showed increased nodal degree in the left superior frontal gyrus and right posterior cingulate gyrus(P = 0.001,P = 0.001);Compared with the PA-ET group,Dep+A-ET group showed increased nodal degree in the right posterior cingulate gyrus(P = 0.046).(4)The nodal degree of right posterior cingulate gyrus in PA-ET patients was significantly positively correlated with the HAMA score(r = 0.708,P = 0.049).Conclusion:1.This study firstly investigated the ET with anxiety or depression separately and found that the incidence of PDep-ET was 5.18%,PA-ET was 15.09%,and Dep+A-ET was 25.23%,and only Dep+A-ET patients were more common in women,were older,and more commonly involved in the head.2.This study firstly found that the clinical characteristics of PDep-ET patients and PA-ET patients were different,and the symptoms were milder than Dep+A-ET patients.Moreover,PDep-ET patients,PA-ET patients and Dep+A-ET patients all had different degree of aggravation of tremor and were correlated with anxiety and depression,and all had different degree of cognitive decline.3.This study firstly used the graph theory approaches to investigate the functional brain network of drug-na(?)ve ET with anxiety or depression at the whole-brain level,and found that no matter whether ET with or without anxiety or depression,those network topological properties were prone to “weaker small-worldization”.However,anxiety or depression alone was not enough to cause significant changes in the global properties of ET patients.4.Dep-ET,NDep-ET,A-ET and NA-ET groups all showed the impaired functional connectomes in the motor cortex,prefrontal-limbic network and DMN.However,compared with NDep-ET and NA-ET,Dep-ET and A-ET patients had some compensatory changes in the prefrontal-limbic network and DMN,respectively.5.Only Dep+A-ET patients had significant compensatory changes in the prefrontal-limbic network and the DMN,but the compensatory changes in ET with pure anxiety or with pure depression were not obvious.