Effects Of Computerized Cognitive Training On Improvement Of Cognitive Performance In AMCI And Its Neuroimaging Mechanism

Objective: Alzheimer’s Disease(AD)is a chronic degenerative disease of the central nervous system with insidious onset,which seriously affects the quality of life of patients and brings a heavy burden to society and family.At present,there are no effective means to prevent and treat AD.Therefore,it is particularly important to intervene effectively to delay or prevent the development of amnestic mild cognitive impairment(aMCI),a high-risk group of AD.In a variety of intervention methods,cognitive training has been widely used in the study of cognitive improvement in the elderly population,because of its standardization,systematization,operability,few side effects,and other advantages.However,"one-to-one" artificial cognitive training,with low efficiency and high labor cost,is difficult to be popularized in clinical practice in the face of the huge population of cognitive impairment in China.Computerized Cognitive Training(CCT)is used in research on the intervention of various cognitive disorders for its simplicity and high therapeutic efficiency.CCT is a new cognitive training system that presents cognitive training tasks in the form of computer programs.Cognitive improvement can be achieved by completing computer game tasks that target different cognitive domains.Although studies have proved that CCT can improve the cognitive function of the aMCI population,evidence-based medical evidence is insufficient and the neurobiological mechanism of improving cognitive function is unclear.Some researchers believe that its effectiveness is related to the placebo effect.Therefore,a scientific and rigorous experimental design is urgently needed to study the effect of CCT on improving the cognitive function of an aMCI population,and to explore its possible neurobiological mechanism by using neuroimaging methods,to provide objective and reliable scientific evidence for the effectiveness of CCT,and to promote CCT playing an important role in delaying or preventing aMCI become AD,and in-home care and clinical diagnosis and treatment in the application.Therefore,aMCI and healthy control(HC)populations will be collected in this study,and the two groups will be divided into the intervention group and the control group for the first time,and the intervention factorial design study of the four groups will be conducted.After excluding the two confounding factors of normal aging and pathological decline,the true effect of CCT on the cognitive function of aMCI population was determined.Moreover,resting-state functional magnetic resonance imaging(rs-f MRI)technology and DTI technology were combined for the first time to study the effects of CCT on brain function and structure in the aMCI population.Thus,the role of CCT on cognitive function and neuroimaging mechanism of CCT in the elderly population with aMCI may be discussed more comprehensively.Methods:1 Subject:Fifty aMCI elderly participants and 50 HC participants matched with age and gender were recruited.Inclusion criteria for aMCI were elders aged 60-79 years;participants who were able to understand instructions and communicate with the experimenter;participants who could meet Peterson’s aMCI diagnostic criteria;No other mental disorders;The Geriatric Depression Scale(GDS)score <15.Inclusion criteria for HC were elders aged 60-79 years;participants who were able to understand instructions and communicate with the experimenter normally;participants with normal cognitive function;GDS < 15 points.Participants were excluded if the participants had mental and neurological disorders,history of brain injury or coma,received general anesthesia in past 6 months,failed cognitive tests,contraindications to magnetic resonance scan,used medications that affected cognitive function;other unstable physical disorders that might affect cognitive function or training.2 Experimental Scheme2.1 Grouping of subjectsAMCI and HC groups were divided into training and control groups,which matched with age,sex and years of education.At baseline: aMCI training group(group 1)and aMCI control group(group 2);At follow-up: aMCI training group(group 3);aMCI control group(group 4).At baseline: HC training group(group A),HC control group(group B);At follow-up: HC training group(group C);HC control group(group D).2.2 Experimental ProcedureNeuropsychological assessment and MRI scan were performed in the four groups at baseline.Then CCT was performed in the two training groups(group 1 and group A),and the two control groups(group 2 and group B)maintained their original lifestyle.Neuropsychological assessment and MRI scan were performed again 12 weeks later.2.3 Neuropsychological AssessmentThe neuropsychological assessment was performed using the Mini-mental State Examination(MMSE),the Montreal Cognitive Assessment Scale(Mo CA),the Auditory Vocabulary Learning Scale(AVLT),the Word Fluency Test(VFT),the Digital Breadth Test(DST),the Drawing Clock Test(CDT),the Attachment Test(TMT),Daily Living Scale(ADL)and Geriatric Depression Scale(GDS).2.4 The intervention of CCTThe Heisman training system was used.The comprehensive cognitive training program was adopted.Participants were trained three times a week,each time 35 minutes for 12 weeks,a total of 36 training sessions,a total of 21 hours.2.5 MRI scansThe MRI scans were performed within 1 week after cognitive assessment.Rs-f MRI and diffusion tensor imaging(DTI)scans were performed with Toshiba MRT-3010 superconducting 3.0T MRI scanner.3.Data processing and statistical analysis3.1 General demographic data and neuropsychological assessment data processing and statistical analysisSPSS 24.0 software was used to analyze and compare general demographic data and cognitive function score at baseline between the aMCI group and HC group by T-test,analysis of variance,Chi-square test,and other methods.Repeated measures ANOVA was performed for groups(training group and control group)and time(baseline and follow-up)within the aMCI group(groups 1 to 4).Diagnosis(aMCI group and HC group)and intervention(training and control group)were used as independent variables to analyze the difference of cognitive scores between the aMCI group and HC group(group 3-1,group4-2,group C-A,group D-B)before and after training.3.2 Image data preprocessing and statistical analysisRs-f MRI data were preprocessed by DPARSFA software based on the MATLAB platform,and functional connectivity(FC)data of the whole brain with left and right hippocampus as seed points respectively were obtained.DTI data were preprocessed by PANDA software to obtain the FA graph of each subject.The DPABI software was used to conduct an independent sample T-test for rs-f MRI data and DTI data with age,sex,and years of education as covariables at baseline(aMCI group and HC group)and at follow-up(group 3 and D).The mixed effects of intervention(training-control)* time(baseline-follow-up)within the aMCI group(groups 1 to 4)were analyzed,and FC and FA values were extracted from the brain regions with significant changes.After the elevation,SPSS was used for the inter-group post-hoc t-test.Results:1.Cognitive assessment results1.1 At baseline,cognitive function outcomes in the aMCI group: Compared with the HC group,the total Mo CA scores,AVLT delayed memory factor scores,and word fluency test scores were significantly lower in the aMCI group(T =3.701,P<0.001;T = 14.461,P < 0.001;T =2.207,P=0.03);There was no significant difference in other cognitive scores.1.2 Repeat measure ANOVA results of cognitive score in aMCI group(groups 1 to 4):(1)Main effect of intervention: There was a statistically significant difference in DST reverse dorsal score between the training group and the control group(F=0.492,P=0.006),and the score of the training group was higher than that of the control group.(2)Interaction between intervention and time: there was a statistically significant difference in Mo CA score between the training group and the control group(F=11.256,P=0.002),and the intervention made the training group score higher;(3)Time the main effect: In terms of delayed AVLT recall factor scores,there was a statistically significant difference between the baseline group and the follow-up group(F=55.799,P< 0.001),and the follow-up group scored higher than the baseline group.(4)There were no main effects or interaction results in other cognitive domains.1.3 Analysis of variance by factorial design of changes in cognitive function assessment before and after intervention in aMCI group and HC group(group 3-1,Group 4-2,Group C-A,group D-B):(1)Main effect of intervention: In terms of changes in Mo CA scores,the difference between the training group and the control group was statistically significant(F=6.318,P=0.015).The changes in the training group were higher than those in the control group,supporting the result of 1.2.(2)Effect of interaction between intervention and time: in terms of changes in CDT scores,there was a statistically significant difference in the effects of the intervention on the aMCI group and HC group(F=7.056,P=0.010),and the changes in THE aMCI training group were higher due to intervention.Results 1.2 showed no such cognitive domain results.(3)Main effect of diagnosis: In terms of changes in AVLT delayed memory factor,the difference between the aMCI group and HC group was statistically significant(F=6.266,P=0.015),and the changes in the aMCI group were higher than HC group,supporting the result of 1.2.(4)There were no main effects or effect of interaction results in other cognitive domains.2.MRI results2.1 Comparison results of brain images between aMCI group and HC group at baseline.(1)Results of right hippocampal FC with whole brain: Compared with HC group,FC of right hippocampus and bilateral medial superior frontal gyrus and left dorsolateral superior frontal gyrus were significantly decreased in the aMCI group(P<0.005,GRF corrected);(2)Results of left hippocampal FC with whole brain: Compared with HC group,FC of the left hippocampus,bilateral medial superior frontal gyrus,bilateral anterior cingulate,bilateral orbital frontal gyrus,and left gyrus rectus were significantly decreased in the aMCI group(P<0.005,GRF corrected).(3)DTI results: Compared with HC group,FA value in aMCI group had no significant change.2.2 Comparison of brain imaging results between aMCI training group(group 3)and HC control group(group D)during follow-up.Compared with HC group,the aMCI group showed no significant change in FA values of DTI analysis and in right and left hippocampal FC with whole brain.2.3 aMCI group(groups 1 to 4)brain imaging mixed effect model results.(1)Results of the mixed effect model between hippocampus and whole brain FC: The right hippocampus: there was a significant effect of interaction between intervention and time with FC in bilateral medial orbitofrontal gyrus,bilateral gyrus rectus,bilateral precuneus,left superior occipital gyrus(GRF corrected P < 0.05,voxel P < 0.005).Intra-group post-hoc t-test results showed that,compared with baseline,FC values between the right hippocampus and bilateral medial orbital middle frontal gyrus and bilateral gyrus rectus did not change significantly after intervention in the aMCI group,while FC values between the right hippocampus and bilateral medial orbital middle frontal gyrus and bilateral gyrus rectus significantly increased in the control group at follow-up(t=-2.447,P=0.019).In the aMCI group,FC values between the right hippocampus and bilateral precuneus and left superior occipital gyrus decreased significantly after the intervention compared to baseline(t=2.785,P=0.008),while in the control group,FC values in the right hippocampus and bilateral precuneus and left superior occipital gyrus did not change significantly at follow-up.(2)Left hippocampus: there was no significant interaction between intervention and time with FC in the whole brain.(3)DTI analysis of MCI group showed no significant effect of interaction.Conclusion:1.Conclusion of cognitive assessment(1)The overall cognitive function,memory of the aMCI group were significantly decreased.(2)The CCT can improve the overall cognitive function of aMCI population and HC elderly.(3)After excluding the effect of normal aging and pathological decline on cognitive function,the CCT significantly improved visual spatial ability and learning effect of short-term memory in aMCI group.2.MRI conclusions(1)There were significantly decreased FC between the hippocampus and frontal lobe,including bilateral medial obital superior frontal gyrus,left dorsolateral superior frontal gyrus,bilateral anterior cingulate gyrus,bilateral orbitofrontal gyrus and left gyrus rectus.After 12 weeks of the CCT,the FC between the hippocampus and the whole brain of aMCI was close to the normal level of the elderly.(2)The CCT altered the FC between right hippocampus and the anterior brain region,including(bilateral medial orbital middle frontal gyrus and bilateral gyrus rectus,)and posterior brain regions(bilateral cuneus and left superior occipital gyrus)in the aMCI group,which may be the neuroimaging mechanism of the CCT’s effect on cognitive improvement.(3)There were no effect of the CCT on the FC between the left hippocampus and the whole brain in aMCI patients,suggesting that there are lateralization on the effect of the CCT on the brain of aMCI patients.(4)The CCT might had no effect on the integrity of white matter in aMCI patients.