| BackgroundParkinson’s disease(PD)is one of the most common neurodegenerative diseases in humans.In addition to motor symptoms,some patients develop non-motor symptoms(NMS),such as somnipathy,cognitive impairment,affective disorders and autonomic dysfunction.With in-depth research in PD,NMS,especially cognitive impairment,have been receiving more and more attention.In newly diagnosed PD,up to 18%of patients suffered from cognitive impairment.Cognitive impairment is one of the most important risk factors for developing dementia,which diminish quality of life.The default mode network(DMN)consists of a group of brain regions with increased activity in resting state,but decreased activity when performing tasks.As a key resting-state network,the DMN has a strong correlation with cognitive processes.The malfunctioning in PD patients remains ill-defined,especially concerning the role of dopamine in modulatingthe DMN and its activation.Although some studies suggested that the dopaminergic drugs might have a specific and dose-dependent influence on both the DMN integrity and task-related activations in PD patients,these neuroimaging experiments were conducted on the comparison of the integrity of DMN between PD patients and healthy controls which may not directly and objectively reflect the changes of the FC of DMN in PD induced by dopaminergic modulation.And the results of available studies to evaluate the effect of dopaminergic challenge to DMN integrity in PD patients were conflicting,some results showed a positive effect,while other results show that it has a negative impact on the integrity of DMN.Therefore,studies on PD patients between ON-and OFF-medication conditions may be critical to elucidate the underlying mechanism of dopaminergic modulation of the DMN in PD.Eigenvector centrality mapping(ECM),a special type of graph theory-based methods,can detect each brain region serving as a hub,which has greater connectivity with other parts of the brain.It can effectively explore the global organization of the whole-brain network without a priori definitions of subnetworks and brain regions.However,the human brain network is an organic,complex,large-scale neural network,previous studies that explored cognitively relevant mechanisms in PD focused mainly on the alteration of a certain network,such as DMN.Therefore,the current study aimed to investigate resting state fMRI correlates of cognition in early PD patients with large sample from a large-scale network perspective,it may help to promote the understanding of the mechanism of PD cognitive impairment.MethodsStudy 1:According to the PD patients before or after taking levodopa(i.e."OFF"or "ON"),we divided all the 24 patients into two PD subgroups.The patients in the"OFF" state were included in the PD-drug-off group,and the patients in the "ON" state were in the PD-drug-on group,and 36 right hand normal subjects were enrolled in the HC group.Functional connectivity(FC)was examined by a seed-based correlation approach.We selected 18 following areas as seeds with 10 radius circular mask centered on the MNI coordinates:anterior,dorsal,and ventral medial prefrontal cortex(a/d/vmPFC),superior frontal gyrus(SFG),inferior frontal gyrus(IFG),posterior inferior parietal lobule(pIPL),precuneus,posterior cingulate cortex(PCC),temporal parietal junction(TPJ),anterior temporal lobe(ATL),superior temporal sulcus(STS),and hippocampal formation(HF).Correlation functional analyses were performed by computing the temporal correlation between each seed mentioned above and the rest of the brain in a voxel-wise manner.For improving the data normality,the correlation coefficients(i.e.FC)in each voxel were then transformed to z-value images using the Fisher r-to-z transformation and then an entire brain z-value map was created for each subject.Independent T-test was conducted to compare the functional connectivity between PD subgroups and Healthy controls.Paired T-test was performed to observe the drug-induced alterations of functional connectivity between PD-drug-off and PD-drug-on groups.Study 2:According to the Hoehn and Yahr staging,a total of 84 early PD patients were included in this study.Pre-processed resting-state fMRI data were further performed with fast Eigenvector centrality mapping(fECM)tool.ECM is a whole-brain network analytical measure by weighting every node based on their degree(both the number and the quality)of connections with the whole brain.Linear correlation analysis was performed between the eigenvector centrality(EC)and tests score in cognitive domains,including Montreal cognitive assessment,Hopkins Verbal Learning Test-Revised(HVLT-R),Benton Judgment of Line Orientation(BJLO),Letter Number Sequencing(LNS),Semantic Fluency(SF)and Symbol Digit Modalities Test(SDMT).The threshold was set at single voxel P<0.005 and cluster P<0.05,using GFR for multiple comparison corrections.Age and gender were used as irrelevant variables.ResultsStudy 1:Compared with the HCs,patients in PD-drug-off group showed significantly decreased FC in DMN with a set of regions in the brain cortex.It included some core nodes of DMN,such as the mPFC,precuneus,pIPL and TPJ.The mPFC(including anterior and dorsal parts)has significantly decreased FC with cerebellum,inferior and superior temporal,middle occipital and fusiform.The precuneus has evidently decreased FC with cerebellum,middle frontal gyrus,inferior frontal opercular and triangular parts,inferior and superior parietal gyrus,putamen,supra marginal and angular.Equally,the left pIPL has decreased FC with bilateral cingulum,middle occipital and precuneus,also we found that the left TPJ has exhibited distinctly decreased FC with bilateral cerebellum,calcarine,inferior parietal,inferior temporal,middle cingulum and precuneus.After dopaminergic medication,the significant differences of FC from DMN nodes including mPFC,SFG,IFG,pIPL,STS,precuneus and TPJ observed before medication,compared with HCs,were improve in PD patients at on state.More interestingly,relative to PD-drug-off group,the PD-drug-on group displayed increased connectivity pattern in DMN.The right IFG,left TPJ and bilateral STS showed significantly enhanced FC with the cerebellum(including cerebellar lobules IV,V,VI,VIII and Crus 1),and the left pIPL has significantly enhanced FC with bilateral anterior cingulate.Study 2:The test score of SF was positively correlated with EC in right inferior occipital gyrus.The test score of LNS was positively correlated with EC in left lingual gyrus,fusiform gyrus and cerebellum(lobule VI),but negatively correlated with EC in the right inferior parietal lobule and angular gyrus.The test score of immediate memory in HVLT was positively correlated with EC in bilateral superior frontal gyrus(SFG),medial SFG and middle frontal gyrus(MFG).However,there were no significant correlation of the scores of delayed memory in HVLT,MOCA and SDMT with EC.ConclusionsIn recent study,we initially revealed that the disturbance of DMN connectivity had already existed in PD patients without cognitive deficits,and levodopa replacement therapy imparted a normalizing or intensification effect on the DMN function integration.Moreover,to the best of our knowledge,this is the first study using ECM to analyze the whole-brain functional connectivity alterations relating to cognitive function in early PD.We found a significant correlation between the EC and the tests score in cognitive domains,which may provide important clues for further studies in the mechanisms of cognitive dysfunction in PD patients. |
