The Clinical Efficacy And Neural Mechanism Of Transcranial Direct Current Stimulation Combined With Cognitive Training In The Intervention Of Alzheimer's Disease

BackgroundAlzheimer's disease(AD)is a serious neurodegenerative disease characterized by progressive cognitive impairment.The high prevalence of the disease places a serious burden on families and society.Currently,patients with AD mainly rely on medication,which can delay the progression of the disease to some extent,but may be accompanied by adverse reactions.With the development of science and technology,transcranial Direct Current Stimulation(t DCS),as a non-invasive neuroregulatory brain stimulation technique,has the characteristics of safety,economy and good tolerance.In recent years,it has become an effective physiotherapy method and gradually been applied to the field of neurodegenerative diseases.In addition,cognitive training(CT),as a safe,low-cost and scalable intervention,is a common non-drug intervention in the treatment of AD,aiming to maintain the cognitive ability of the elderly.The neuronal stimulation of t DCS itself triggers the firing of subthreshold neurons,leading to changes in the threshold of neuronal depolarization.When t DCS is combined with cognitive training,which may enhance the synaptic transmission strength of activated neuronal pathways,thus enhancing the training effect.At present,there are few studies on t DCS combined with CCT strategy in AD,and a large number of studies are needed to explore its cognitive promoting effect and potential neural mechanism.Cognitive functions such as memory are supported by an extensive neural network that includes the Dorsolateral Prefrontal Cortex(DLPFC)and the medial prefrontal cortex,inferior frontal lobe,cingulate gyrus,inferior parietal lobe,and posterior parietal cortex.DLPFC is a key region of the executive control network(ECN),which is involved in the regulation of attention,decision making,working memory and cognitive Control,and is a key center of dorsal neural pathways that Control behavioral cognition.DLPFC,as an important node of ECN,was the most commonly used stimulus target for memory enhancement.Understanding its functional mechanism is of great significance for designing effective interventions for AD patients.Here,we mainly stimulated the left DLPFC with anodic HD-t DCS combined with CCT,focused on its potential cognitive promoting effect,and explored and verified its neural mechanism using neuroimaging technology.ObjectiveThis study first explored the effects of anodized HD-t DCS combined with CCT and anodized HD-t DCS alone or CCT on the cognitive functions of working memory and associative memory in healthy adults.The optimal intervention plan was then selected to further verify its therapeutic effect on clinical symptoms and cognitive function in AD patients.Magnetic resonance imaging was used to explore the neural mechanism of intervention.Study 1: The purpose of this study was to explore the effects of three intervention regimes-anodal HD-t DCS combined with CCT,anodal HD-t DCS alone or CCT alone on cognitive functions such as working memory and episodic memory.The results of this study will be used to select the most appropriate intervention to fully realize the clinical potential of these interventions.Study 2: To explore whether the intervention regimen of anodal HD-t DCS combined with CCT has a synergistic effect on AD patients,resulting in greater benefits than that of CCT or HD-t DCS alone,and has a better effect on delaying the cognitive decline and clinical symptoms of AD patients,so as to provide evidence for future clinical application.Study 3: Firstly,the characteristics of functional connectivity changes in the executive control network between AD patients and healthy people were explored to provide a basis for the selection of intervention targets.Subsequently,anodic HD-t DCS combined with CCT targeted stimulation of the left DLPFC within the executive control network in AD patients to further verify whether the DLPFC can improve memory function and clinical symptoms by regulating the activity of the brain network related to the frontal lobe.MethodsStudy 1: The enrolled healthy people were divided into four independent groups,which received four different intervention schemes of anodal HD-t DCS combined with CCT,anodal HD-t DCS stimulation and CCT stimulation,and sham stimulation respectively,for 2 consecutive weeks of intervention stimulation(current intensity:2m A,intervention time: 30 minutes).Associative memory,working memory and other observational indicators were used to evaluate the effects of pre-intervention baseline(T0),post-intervention(T1)and 4-week follow-up(T2),and to compare the promoting effects of the four intervention programs on memory function.To verify whether anodal HD-t DCS combined with CCT intervention program has better cognitive promotion effect than anodic HD-t DCS stimulation or CCT alone.Study 2: Patients with AD were randomly divided into three independent groups to receive anodal HD-t DCS combined with CCT,CCT alone,and HD-t DCS,respectively,for 2 consecutive weeks of intervention stimulation(current intensity: 2m A,each intervention lasted 30 minutes).Clinical symptoms and cognitive function were evaluated by clinical symptom assessment scale and neuropsychological assessment scale.The effects of the three intervention programs on cognitive function were compared to verify whether anodal HD-t DCS combined with CCT had better clinical rehabilitation and cognitive promotion effects than CCT or HD-t DCS alone.Study 3: This study is divided into two parts.In experiment 1,two groups of AD patients and normal controls were included.Based on seed points in bilateral ECN,resting state functional connectivity analysis was conducted in the network to explore abnormal brain areas in ECN and their correlation with cognitive function,providing evidence for intervention targets.Subsequently,in experiment 2,eligible AD patients were included for anodal HD-t DCS combined with CCT intervention,and their resting state functional connectivity in the network was analyzed to explore its neural mechanism.ResultsStudy 1: A total of 26 patients were enrolled in the anodal HD-t DCS combined CCT group,23 patients in the anodal HD-t DCS group,18 patients in the CCT group,and 16 patients in the sham stimulation group.The results showed that compared with the sham stimulus group,the cognitive changes in memory,executive attention and language function were improved between the three intervention programs(all P <0.05).Post-hoc analysis showed that the improvement of memory function in the anodal HD-t DCS group was more significant than that in the anodal HD-t DCS group and CCT group.In addition,we found significant differences in memory and general executive function in the anodal HD-t DCS combined with CCT group at 1-month follow-up(P <0.05).Study 2: A total of 52 patients with mild to moderate AD were enrolled,including21 patients in the anodal HD-t DCS combined with CCT group,18 patients in the CCT alone group,and 13 patients in the HD-t DCS group.Mixed design repeated measure ANOVA was used to analyze the clinical symptoms and cognitive function of AD patients before and after intervention.It was found that the three groups had significant interaction in mental behavioral symptoms,general cognitive behavioral ability and associative memory before and after intervention(all P < 0.05).Further analysis showed that the three intervention programs significantly improved the mental behavioral symptoms,daily living ability,general cognitive function of AD patients(P< 0.05).However,compared with CCT group and HD-t DCS group,anodal HD-t DCS combined with CCT treatment improved mental behavioral symptoms,general cognitive behavioral ability and associative memory more significantly in AD patients(all P < 0.05).Study 3: Cross-sectional results of Experiment 1 showed significant differences in resting state functional connectivity analysis among brain regions within the ECN of AD patients compared with normal elderly patients.Compared to normal elders,the functional connectivity of network between left DLPFC and left inferior parietal lobule(IPL),left MFG and left IPL,left middle frontal gyrus(MFG)and right IPL,left IPL and right IPL,right DLPFC and right MFG was significantly enhanced in AD patients(all P < 0.05),and correlated with cognitive function and clinical symptoms.Subsequently,in experiment 2,we found that after 2 weeks of anodal HD-t DCS combined with CCT intervention,the functional connectivity between the left DLPFC and the right DLPFC was significantly enhanced in AD patients(P < 0.05),and correlation analysis showed that the improvement of daily living ability was correlated with the change of left DLPFC and right DLPFC intensity in ECN(P < 0.05).ConclusionStudy 1: The results of this study showed that compared with HD-t DCS or CCT,the HD-t DCS combined with CCT stimulated the left DLPFC to promote the memory function of healthy people more significantly,and confirmed the sustained effect of HDt DCS combined with CCT intervention program.Study 2: It was proved that long-term anodal HD-t DCS combined with CCT therapy can promote clinical symptoms and cognitive function of AD patients,providing clinical evidence for HD-t DCS combined with CCT as an adjunctive nondrug intervention therapy to alleviate clinical symptoms and improve cognitive function of AD patients.Study 3: This study proved that cognitive dysfunction in AD patients was associated with abnormal functional connectivity between left DLPFC and local brain regions within ECN.At the same time,the changes of functional connectivity in ECN before and after anodal HD-t DCS combined with CCT intervention further verified the abnormal brain function of AD patients.