Study On Efficacy,Safety And Related Brain Functional Mechanisms Of Bright Light Therapy In The Patients With Unipolar And Bipolar Depression

Background With the accelerated rhythm of life and the increased pressure of work and study,the incidence of mood disorders has increased year by year,including uipolar depression,bipolar bipolar,etc.At present,there is a lack of effective methods to treat the depressive episode of unipolar and bipolar depression,and the condition often persists.The effect of light therapy on emotion has been confirmed,and it is also considered to have a certain impact on cognitive function.Yet the optimal timing of intervention of light therapy for patients with unipolar and bipolar depression is still controversial.In addition,patients with unipolar and bipolar depression have significant cognitive impairment,which is the core symptom of the diseases.Animal experiments have confirmed the benefits of light therapy on cognitive impairment,but few scholars pay attention to the improvement of cognitive impairment in patients with unipolar and bipolar depression by light therapy.Habenular nucleus(Hb),suprachiasmatic nucleus(SCN),and amygdala are important neural nuclei related to light regulating emotion and cognition.However,in the previous research on the mechanism of light regulating emotion and cognition through some non-invasive means,most scholars focused on the cerebral cortex,and less attention has been paid to the connection between subcortical structures(such as Hb,SCN and amygdala)and cortical structures.Based on previous animal and clinical trials,we hypothesized: bright light therapy in the morning or at midday may improve the depressive symptoms and cognitive impairment of patients with unipolar and bipolar depression,which may be related to the light regulation of brain function.This study will test this hypothesis from the following three parts:Part One Efficacy and Safety of Bright Light Therapy for the Patients with Unipolar and Bipolar DepressionObjective A large number of studies have shown that bright light therapy could significantly improve the depressive symptoms of patients with unipolar and bipolar depression.Yet the optimal timing of intervention of bright light therapy for patients with unipolar and bipolar depression is still controversial,which may be due to the heterogeneity of the studies.Therefore,this study will be minimizing the confounding factors,by stratified random double-blind method.The aim of the study is to determine the optimal timing of intervention,efficacy and safety(including rate of mood polarity switch).Methods The study enrolled patients with unipolar and bipolar depression.Patients were randomly assigned to morning bright light therapy group(MOBLT,light intensity(LI)= 10000 lux,n = 25),midday bright light therapy group(MIBLT,LI = 10000 lux,n =24)and placebo group(LI < 100 lux,n = 28).The timing of intervention of the three groups was the time after waking up ~ 9:30 a.m.,12:00 p.m.~ 2:30 p.m.and 12:00 p.m.~2:30 p.m.,respectively.The duration of each intervention gradually increased from 15 minutes to 45 minutes for 6 weeks.At baseline,at the end of the 3rd week and after the intervention,the clinical variables were evaluated by the 24 items Hamilton Depression Scale(HDRS-24),Hamilton Anxiety Scale(HAMA),Young Mania Rating Scale,Clinical Global Impressions Scale,and the Sheehan Disability Scale and Pittsburgh Sleep Quality Index.The adverse events were recorded using our self-made adverse effect scale,and their relationships with bright light therapy were analyzed.Results At baseline,three groups had moderate depression and no symptoms of hypomania or mania.After intervention,compared with the placebo group,the MOBLT group experienced lower HDRS-24 score(12.5 [SD = 7.5] vs.18.3 [SD = 11.6],mean difference(MD)=-3.75)and HAMA score(10.2 [SD = 8.0] vs.15.2 [SD = 8.8],MD =-2.71),higher remission rate(23.8% vs.19.0%,odds ratio(OR)= 60.26).Compared with the MIBLT group,the MOBLT group experienced lower HDRS-24 score(12.5 [SD = 7.5]vs.16.5 [SD = 8.2],MD =-2.25).There were no significant differences in the scores of clinical scales between the MIBLT group and the placebo group.About 4.0% of patients xperienced mood polarity switch,and there was not a significant difference for the ratio of mood polarity switch among the three groups(χ 2 = 0.013,P = 0.993).In addition,the adverse effects that may be related to bright light therapy were dazzle,dry eyes and burning feeling of facial skin.These adverse effects were mild and transient,which may not affect the treatment compliance of patients.Conclusions This study shows the efficacy of morning bright light therapy for patients with uipolar and bipolar depression.In addition,bright light therapy has high safety and compliance,and adverse effects are mild and transient.Part Two Cognitive Effects of Bright Light Therapy for Patients with Unipolar and Bipolar DepressionObjective Studies have confirmed that bright light therapy can improve working memory of the depressed mice,but there is still a lack of relevant clinical research.This study will explore the efficacy of bright light therapy for cognitive impairment in patients with unipolar and bipolar depression.Methods The study enrolled patients with unipolar and bipolar depression.Patients were randomly assigned to morning bright light therapy group(MOBLT,light intensity(LI)= 10000 lux,n = 19),midday bright light therapy group(MIBLT,LI = 10000 lux,n =15)and placebo group(LI < 100 lux,n = 19).The timing of intervention of the three groups was the time after waking up ~ 9:30 a.m.,12:00 p.m.~ 2:30 p.m.and 12:00 p.m.~2:30 p.m.,respectively.The duration of each intervention gradually increased from 15 minutes to 45 minutes for 6 weeks.At baseline and after the intervention,the subjective cognitive function was assessed by the Perceived Deficits Questionnaire,and the objective cognitive fields such as information processing speed,vigilance and attention,working memory,verbal learning,visual learning,and reasoning and problem solving and emotion management ability were assessed by the MATRICS Consensus Cognitive Battery.Based on the norm of Chinese healthy population,we calculated the standard T-scores of 7objective cognitive fields after adjusting gender,age and years of education with official software.Results After intervention,compared with the placebo group,the MOBLT group experienced higher T scores of vigilance and attention(50.8 [SD = 7.1] vs.45.2 [SD =10.6],mean difference(MD)= 4.78)and emotion management ability(55.4 [SD = 8.9] vs.47.4 [SD = 12.6],MD = 10.24);there were no significant differences in other objective cognitive fields between the two groups.Compared with the placebo group,the MIBLT group experienced higher T scores of vigilance and attention(50.4 [SD = 6.2] vs.45.2 [SD= 10.6],MD = 5.39)and working memory(52.1 [SD = 11.7] vs.44.0 [SD = 9.0],MD =8.39);there were no significant differences in other objective cognitive fields between the two groups.There were no differences in any objective cognitive fields between the MOBLT group and the MIBLT group.There was no a significant difference in the subjective cognitive function among the three groups.Conclusions This study shows the efficacy for morning and midday bright light therapy in improving vigilance and attention,working memory and emotion management ability in patients with unipolar and bipolar depression.Part Three Brain Functional Mechanism of Bright Light Therapy in Improving Depressive Symptoms and Cognitive Impairment in Patients with Unipolar and Bipolar DepressionObjective Previous studies with magnetic resonance imaging(MRI)have found some changes in the structure and function of human cortical regions related to the mechanism of light regulating emotion and cognitive function,but less attention has been paid to the connection between subcortical structures and cortical structures.This study will take the Habenular nucleus(Hb),suprachiasmatic nucleus(SCN)and amygdala as seed points to explore the brain function mechanism of bright light therapy in improving depressive symptoms and cognitive impairment using resting state functional MRI(rs-f MRI).Methods The study enrolled patients with unipolar and bipolar depression.Patients were randomly assigned to morning bright light therapy group(MOBLT,light intensity(LI)= 10000 lux,n = 18),midday bright light therapy group(MIBLT,LI = 10000 lux,n =14)and placebo group(LI < 100 lux,n = 15).The timing of intervention of the three groups was the time after waking up ~ 9:30 a.m.,12:00 p.m.~ 2:30 p.m.and 12:00 p.m.~2:30 p.m.,respectively.The duration of each intervention gradually increased from 15 minutes to 45 minutes for 6 weeks.At baseline and after the intervention,rs-f MRI was used to measure the functional connectivity(FC)between the three nuclei(Hb,SCN and amygdala)and the other brain regions.The relationships between the changes of degree of depression,anxiety and cognitive functions and the changes of FCs between the three nuclei and the other brain regions before and after bright light therapy were computed.Results(1)Changes of the FCs before and after bright light therapy After intervention,the FCs between the right Hb and the Frontal-Inf-Orb-R and Frontal-Inf-Oper-R;the right amygdala and the brainstem,Insular-R&L,Olfactory-R,Supper-Motor-Area-R,Thalamus-L,Rolandic-Oper-R&L and lnferior-Frontal-Gyrus-R&L;the left amygdala and the Hippocampus-L and Caudate-R were lower in the MOBLT group than those in the placebo group.The FCs between the bilateral Hb and the Frontal-Mid-L;the right Hb and the Cerebelum-crus2-R&L;the left Hb and the Inferior-Frontal-Gyrus-R;the bilateral SCN and the Temporal-Inf-R;the right amygdala and the Frontal-Inf-Orb-R,Heschl-R,Rolandic-Oper-R,Insula-L,Frontal-Mid and Inf-Orb-L,Cingulum-Mid-L and Thalamus-L;the left amygdala and the Frontal-Mid-Orb-R were lower in the MIBLT group than those in the placebo group.(2)Correlations between the changes of the FCs and the antidepressant efficacy The change of the FC between the left Hb and Frontal-Inf-Oper-L was related to the change of degree of depression,and the change of the right Hb and the Rolandic-Oper-L was related to the change of degree of anxiety before and after bright light therapy.(3)Correlations between the changes of the FCs and the efficacy in improving cognitive impairment The changes of the FCs between the left Hb and the Fusiform-L,the right Hb and the Putamen-L,and the right SCN and the Frontal-Sup-Medial-L were negatively related to the change of working memory T-score before and after bright light therapy.Conclusions(1)Bright light may affect the functional activity of some important brain regions closely related to the emotion and cognition by the mediation of Hb,SCN and amygdala.(2)Antidepressant efficacy of bright light therapy may be mediated by Hb and then affects the functional activity of lnferior Frontal Gyrus-L and Rolandic-Oper-L.(3)Efficacy of bright light therapy for cognitive impairment may be mediated by Hb and SCN and then affect the functional activity of Fusiform-L,Putamen-L and Frontal-Sup-Medial-L.