The Neural Mechanism Of Bipolar Disorder And Effect Of Transcranial Direct Current Stimulation On Alleviating Depression

BackgroundBipolar disorder(BP)is a severe,recurrent,and chronic disorder characterized by a fluctuating mood state ranging from extreme elation or mania to severe depression.Due to the poor understanding of the pathophysiological mechanism of BP,BP are often delayed diagnosed and incorrectly treated,that lead to poor prognosis,additional comorbidity and greater health-care costs.The fronto-limbic circuit abnormalities lead to labile mood and impaired emotion regulation in BP.By comparing between different state of BP would show common pathological mechanism of BP,as well as state-specific abnormal neural activity.Mood stabilisers and antipsychotics are the mainstream management of bipolar mania and depression.Lithium reduces the risk of manic relapses compared with placebo.Given few treatments are proven efficacy,the treatment of bipolar depression is a major challenge,particularly the controversy on the therapeutic effects of antidepressant drugs.TDCS(Transcranial direct current stimulation)is a safe,noninvasive method that regulates cortical activity and excitability.Some studies have shown that stimulation on the left dorsolateral prefrontal cortex(dl PFC)can effectively alleviate depression,but the neural mechanism is poorly understood.Then we applied neuroimaging tools to investigate the neural mechanism of tDCS on improving depression.Indexes based on the resting state functional Magnetic Resonance Imaging(rs-f MRI)could represent the brain local activity,functional connectivity and brain network.ObjectiveThis study used rs-f MRI technology to study the neural mechanisms of different states of bipolar disorder,and further studied the effect and the neural mechanism of tDCS on alleviating depression.(1)The right inferior frontal gyrus(r IFG)is a key cortical node in the circuits of emotion and cognitive control,and it has been frequently associated with bipolar disorder(BP);however,a reliable pattern of aberrant r IFG activation and connectivity in bipolar disorder has yet to be established.(2)Characterizing the brain networks properties across mood states of Bipolar disorder(BP)can provide insight into the mechanisms of bipolar disorder.In this study,we analyzed the topological organization of the whole-brain intrinsic functional networks to identify the convergent and divergent patterns of disrupted topological organization of the functional connectome in the BPM and BPD..(3)Recent findings suggest that left dl PFC transcranial direct current stimulation(tDCS)with the anode placed over the left dl PFC can alleviate depression.However,brain correlates of the depression alleviation are unclear.Here,we investigated the effect of tDCS on the resting-state functional connectivity(rs-FC)based on two seeds of the left dl PFC and left amygdala respectively.Methods(1)To further elucidate r IFG abnormalities in different states of bipolar disorder,we examined activation and functional connectivity(FC)in five subregions of r IFG in bipolar disorder.A total of 88 participants,including those with bipolar depression(BPD;n = 25)and bipolar mania(BPM;n = 37)along with healthy control(HC;n = 26),were examined by resting state functional magnetic resonance imaging(rs-f MRI)..(2)Graph theoretical methods were used to examine global,modular and nodal brain network topology in resting-state functional MRI data acquired from 95 participants,including those with bipolar depression(BPD;n = 30)and bipolar mania(BPM;n = 39)along with healthy control(HC)subjects(n = 26)(3)Here,we investigated the effect of tDCS on the resting-state functional connectivity(rs-FC)of the left dl PFC.Thirty-three patients with depression were pseudo randomly allocated to receive 14 sessions of active(2 m A,20 min)or sham tDCS.We compared the rs-FC of the left dl PFC and left amygdala between patients before and after they received active or sham tDCS..Results(1)Both BPD and BPM groups showed higher values of amplitude of low-frequency fluctuations(ALFF)than healthy control in four of the five r IFG subregions except cluster 2(posterior-ventral r IFG).Using five subregions of r IFG as seeds,the decreased FC in bipolar disorder was mainly between posterior-ventral r IFG(cluster 2)and multiple brain regions including the postcentral gyrus,the precentral gyrus,paracentral lobule,lingual Gyrus,fusiform and cerebellum posterior lobe.(2)(1)at the global level,BP patients showed a significantly increased global efficiency(GE)and synchronization and a decreased path length(L);(2)at the nodal level,BP patients showed impaired nodal parameters predominantly within regions of the VLPFC and limbic network;(3)at the module level,BP patients had increased FCs(edges)between Module III(the front-parietal system)and Module V(limbic/paralimbic systems);(4)at the nodal level,the BPD and BPM groups showed state-specific differences in the left superior frontal gyrus,orbital part,right putamen,right parahippocampal gyrus and left fusiform gyrus.(3)Relative to sham tDCS,active tDCS significantly reduced depression symptom.Active tDCS significantly reduced the rs-FC based on the left amygdala rs-FC with left fusiform gyrus?left middle frontal gyrus? right superior frontal gyrus and middle frontal gyrus,orbital part,and significantly increased the rs-FC based on the left dl PFC rs-FC with occipital lobe including the right cuneus and the calcarine/Middle Occipital Gyrus.Reduction in rs-FC between the left amygdala and left fusiform gyrus?left middle frontal gyrus was correlated with the reduced scores of HAMD.The improvement of depression severity was correlated with the the increase in rs-FC of the left dl PFC rs-FC with occipital lobe and reduction in rs-FC between the left amygdala and left fusiform gyrus?left middle frontal gyrus.Conclusion(1)These results indicated that local activity and FC were altered within specific subregions of the r IFG in BP.These findings may provide the distinct functional connectivity of r IFG subregions in BP and suggest that the cluster2(posterior-ventral r IFG)circuitry plays a crucial role in BP.Also,such abnormalities might help define a more precise intervention targets.(2)our study revealed convergent and divergent abnormality in the topological organization in the whole brain and frontoparietal-limbic circuit in BPD and BPM.These deficits may reflect the pathophysiological processes in BP.In addition,state-specific regional nodal alteration of BP could potentially provide biomarkers of conversion across different mood states.(3)These findings suggest that the reduction of depression symptom induced by tDCS is associated with a modulation of the rs-FC within an emotion-related brainnetwork.