Brain Mechanisms And Plasticity Of Individuals With Subthreshold Depression

Depression is one of the most common mental and emotional disability in the population. It is mainly characterized by the presence of depressed mood and the loss of interest or pleasure in daily activities. World Health Organization states that depression is the second leading cause of death and disability worldwide. The subthreshold depression (SubD), which is defined as subjects who scored above a cutoff score in a self-report depressive measure but do not fulfill the criteria for major depression disorder (MDD), is thought to be more prevalent than MDD in population. SubD has been found to have a considerable impact on the quality of life and psychosocial functions of individuals. SubD is regarded as the prodromal phase of MDD and increases the risk of developing MDD and other adverse outcomes. Given the SubD was regarded as the transition from non-depressed of the continuum to another position MDD, it is important to improve our understanding on this transition. Because it will give more evidence on the intervention and prevention of depression in population.With the development of brain science and neuroimaging techniques recent years, functional magnetic resonance imaging (fMRI) and structural magnetic resonance imaging (sMRI) give a better way to explore the brain functions and structural morphometry of individuals with SubD. For example, resting state fMRI can be used to explore the spontaneous brain activity of individuals with SubD and sMRI can be used to explore the abnormal structural morphometry. Moreover, negative cognitive biases were regarded as not only markers of depression but also vulnerability factors for depression, however, limited researches explored the negative cognitive bias of SubD, not mention the neural mechanisms of attentional bias for negative information among individuals with SubD. In addition, recent experimental works has found that attentional bias modification (ABM) training can be used to improve the severity of depression and anxiety. However, no study have been conduct to explore the effects of ABM on reducing depression among individuals with SubD. In addition, whether the ABM training procedure will induce brain plasticity corresponding to the depression reducetion still unknown. Therefore, the current study explored the altered spontaneous brain activity and brain structure among individuals with SubD using resting state fMRI and sMRI in study 2 and study 3. In study 4, we examined the neural mechanism of attentional bias for negative stimuli among individuals with SubD. Finally, the effects of ABM training on reducing depression among individuals with SubD were explored before and after four weeks training in study 5 and study 6. In addition, resting state fMRI were used to explore the changes of spontaneous brain activity and brain involvement when negative stimuli processing. Through three researches, we want to give a full understand on the altered spontaneous brain activity and brain structure, neural mechanisms of negative attentional bias and ABM training effects on reducing depression and inducing brain plasticity among individuals with SubD.Study one explored the altered spontaneous brain activity and brain structures of individuals with SubD using resting state fMRI and sMRI. In experiment 1, two-stage screening procedure, Beck depression inventory (BDI) and Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) were used to screen individuals with SubD and Non-depressed controls (NCs). And the difference between SubD and NCs on Reven intelligence, trait anxiety, neuroticism, self-esteem, negative life events, and rumination were explored. The results found that individuals with SubD showed greater trait anxiety, neuroticism, and rumination and lower self-esteem than NCs. No difference was found on Reven intelligence between two groups. All these results were not affacts by sex. Experiment 2, we explored gray matter volume (GMV) and white matter volume (WMV) alterations associated with SubD using sMRI and voxel-based morphometry. VBM results indicated that individuals with SubD had significantly less GMV in the right dorsal medial prefrontal cortex (dmPFC), right inferior parietal lobule than NCs. Increased GMV in amygdala and parahippocampus, and increased GMV/WMV in the posterior cingulate cortex and precuneus were also observed among individuals with SubD. Furthermore, GMV alterations in the right dmPFC significantly and positively correlated with BDI scores among individuals with SubD. Experiment 3, resting state fMRI were used to explore altered spontaneous brain activity associated with SubD. We mainly explored the difference on amplitude of low frequency fluctuations (ALFF) between individuals with SubD and NCs. The results indicate that SubDs showed greater ALFF activity in the right anterior insular (AI), right middle frontal gyrus (MFG), right superior temporal gyrus (STG), and right fusiform gyrus (FFG) and less activity in the lingual gyrus than NC. The altered brain structures and spontaneous brain activity on the regions concerning emotion monitoring, attentional control and emotional regulation may help to explain why individuals with SubD expressed negative cognitive bias, high emotion sensitivity and low emotional regulation ability.Study two examined the neural basis of attentional bias for negative stimuli among individuals with SubD using dot probe task and fMRI. Behavioral results showed that individuals with SubD expressed attentional bias for negative stimuli relative to neutral stimuli. fMRI results found that activations in the lateral prefrontal cortex (PFC) and AI of individuals with SubD were reduced in negative condition relative to neutral condition compared with the NCs. Psycho-Physiological Interactions (PPI) results showed that the strength of functional connectivity between amygdala and lateral PFC of individuals with SubD were reduced in negative condition relative to neutral condition compared with the NCs. The present study suggests that attentional bias for negative stimuli may related to the dysfunction of amygdala-PFC connectivity.Study three investigated the effects of ABM on depression reduction, corresponding spontaneous brain activity (both regional activity and functional connectivity patterns) changes and neural response to negative stimuli changes using ABM, resting state fMRI and task fMRI among individuals with SubD. ABM changed the measure of attentional bias in the expected direction-- increased attention toward positive stimuli and decreased attention toward negative stimuli--although the difference between the ABM and active controls (AC) groups was not significant. More importantly, ABM, relative to the AC group, significantly reduced symptoms of depression and anxiety on BDI and state anxiety inventory. Experiment 5 resting state fMRI found that ABM task significantly reduced ALFF activity in the right RAI, RMFG, and bilateral inferior frontal gyrus (RIFG and LIFG); Functional connectivity strength between RAI and the RIFG/AI, and right supramarginal gyrus (RSMG) were significant decreased in. ABM group; Moreover, depressive symptoms improvements following ABM significantly correlated with the connectivity strength reductions between RAI and RIFG/AI, and RSMG. Experiment 6 task fMRI found that activation in the bilateral IFC of individuals with SubD among ABM group were increased in negative condition relative to neutral condition after training, however, the activation in the bilateral IFC of individuals with SubD among AC group were reduced in negative condition relative to neutral condition after training. In addition, activation of bilateral IFG in response to negative stimuli relative to neutral stimuli were greater among individuals with SubD among ABM group than among AC group after training.In addition, depressive symptoms improvements following ABM significantly and positively correlated with activation increase in the right IFG in response to negative stimuli relative to neutral stimuli. The present study suggest that ABM is an effective way to prevent depression. ABM has the potential to reshape the abnormal patterns of spontaneous brain activity in relevant neural circuits associated with depression and improve the function of relevant regions associated with negative attentional bias processing.In conclusion, the current study found that individuals with SubD showed decreased GMV in the dmPFC and increased GMV in the amygdala than NCs, deficits in the recruitment of these regions in depression may contribute to specific biases in attention, memory and dysfunction of emotional regulation that characterizes depressed individuals. Individuals with SubD showed greater ALFF in the right AI and right MFG than NCs, this may affects the involvement of these regions in the processing of negative stimuli. Individuals with SubD showed attentional bias for negative stimuli and fMRI results found the reduced activations in the lateral PFC and AI and functional connectivity between amygdala and lateral PFC among individuals with SubD in response to negative stimuli relative to neutral stimuli. The dysfunction of amygdala-PFC circuit may contribute to negative attentional bias of individuals with SubD. Finally, ABM training has the effect on reducing depression, reshaping abnormal spontaneous brain activity and increasing the involvement of lateral PFC in the processing of negative stimuli of individuals with SubD.