The Role Of Inhibition Of Return In Depression And Cerebral Mechanism

Depression is one of the most commonly occurred mental disorders. The WHO has predicted that it will become the second leading cause of death and disability by 2020. A global survey showed that for human beings, depressive disorder was more dangerous than angina, arthritis, asthma and diabetes. These studies suggest that depressive disorder is an important public health problem, which needs further attention.Previous studies suggested that prefrontal cortex was the main target in antidepressant treatment. However, the mechanism remained unclear. It was found that patients who suffered from major depressive disorders(MDD) had abnormal functional activity at sub-cortex of prefrontal cortex, the orbitofrontal cortex(OFC). Moreover, it was recently confirmed that MDD had deficient inhibition of return(IOR) ability for negative materials. IOR is the key component of attentional control, and also the important function of OFC. Importantly, latest research suggested that antidepressant treatment might be functioned by improving IOR ability, OFC and 5-hydroxytryptamine(5-HT) system might be the possible biological foundation. However, the evidence was limited.Combined with behavioral study, functional magnetic resonance imaging(f MRI), transcranial magnetic stimulation(TMS), and attentional bias training(ATT), present study observed the relationship between IOR and cerebral neurotransmitter concentration(39 never-depressed controls(NC), 30 MDD, and 26 remitted patients(RMD)), cortex activation(33 NC, 30 MDD, and 27 RMD), also the difference of neurotransmitter concentration and depressive state before and after IOR training(14 patients in training group and control group, respectively), and the change of IOR and cerebral activation before and after TMS treatment which targeting at OFC(15 patients in treatment group and control group, respectively).Following outcomes and conclusions were obtained:1. In behavioral cue target task, all three groups showed cue validity for emotional faces, F(1, 123) = 32.355, p < 0.001. Among them, RMD group had higher cue validity for happy faces compared with other two groups, F(2, 246) = 4.701, p = 0.011, and also compared with sad faces, F(2, 86) = 11.142, p < 0.001. However, under f MRI condition, MDD showed IOR effect for all emotional faces while RMD patients indicated cue effect for all faces, F(2, 96) = 3.916, p = 0.023. Depressed patients had higher cue validity toward emotional faces after IOR training, F(1, 28) = 5.695, p = 0.024, and TMS treatment which targeting at OFC, F(1, 28) = 5.136, p = 0.031. The results suggested that IOR ability was closely correlated with depressive status, and might be modulated by cognitive burden.2. Neurotransmitter assessment indicated that MDD group had higher cerebral 5-HT concentration, F(2, 92) = 4.201, p = 0.018, and lower dopamine concentration compared with RMD group, F(2, 92) = 3.423, p = 0.037. They also showed lower acetylcholine concentration compared with NC group, F(2, 92) = 2.883, p = 0.061. The 5-HT concentration in training group decreased after IOR training, t(13) = 3.150, p = 0.008, while the dopamine concentration increased, t(13) =-2.783, p = 0.016. The results suggested that IOR ability of depressed patients was correlated with disturbances in several neurotransmitters including 5-HT and dopamine, depression could not be fully explained by variation in single neurotransmitter.3. f MRI results suggested that in resting state, the model of OFC activities was: RMD > MDD > NC(p < 0.01), and in cue target task: NC > MDD > RMD(p < 0.01). After TMS treatment which targeting at OFC, training group had higher resting state activity in medial OFC, t(13) = 5.40, k(cluster) = 31, p < 0.05, while in cue target task, the training group showed lower activation in bilateral OFC, t(13) ≤-2.90, k ≥ 16, p < 0.05. Functional connectivity results showed that compared with MDD group, RMD group had stronger functional connectivity between middle, superior OFC and ventral tegmental area(VTA), nucleus accumbens(NA), hippocampus, and amygdala, F(2, 87) ≥ 3.14, p < 0.05, while they had weaker functional connectivity between these cortexes and medial, inferior OFC, F(2, 87) ≥ 3.15, p < 0.05. The results suggested that OFC played an important role in IOR ability of depression, and different parts of OFC functioned differently.4. Correlation analysis indicated a negative correlation between 5-HT concentration and behavioral IOR scores for happy faces, r =-0.36, p < 0.05. For MDD and RMD group, correlations were mainly found between OFC and behavioral IOR scores, r ≤-0.38, p < 0.05. The results suggested that IOR ability was closely correlated with depressive status, 5-HT and OFC might be the possible cerebral foundation.5. IOR training confirmed that undergraduates showed no obvious benefit from dot probe task training, while depression reduction was confirmed after cue target task training(Beck depression inventory(BDI) : F(2, 282) = 4.156, p = 0.017; patient health questionnaire(PHQ) : F(2, 282) = 2.506, p = 0.083), although without obvious attentional bias modification. The results suggested that IOR training(cue target task) was effective in depression reduction in undergraduates, training strategy and gender of participants were influential.6. After IOR training, the concentration of 5-HT and dopamine in depressed patients changed, training group had significant lower depression scores compared with controls 1 year after the training, BDI(t(26) =-7.201, p < 0.01), PHQ(t(26) =-3.29, p = 0.003), Hamilton depression rating scale(HDRS)(t(26) =-2.642, p = 0.014). The results suggested that the IOR training was effective on depression reduction in medium and long term, cerebral neurotransmitter concentration might be the possible cerebral foundation, which might be important to prevent the recurrence of depression.7. After TMS treatment which targeting at OFC, treatment group didn’t differ with control group on depression scores. However, the two groups had different models in functional connectivity. The results suggested that the factor which critical to depression was not the activation in single cortex, but the functional connectivity between cortexes. Depressive disorders could be improved effectively by different functional connectivity models. This offered reliable evidence to modulate depression with treatment which targeting at cerebral cortexes.8. In f MRI cue target task, compared with RMD group, MDD group had higher activation difference for happy faces in bilateral OFC, left MPFC, right superior frontal gyrus, ACC, VTA, and hippocampus(t(53) ≥ 3.10, k ≥ 10, p < 0.01). RMD group showed higher activation difference for neutral faces in right OFC, amygdale, VTA, and bilateral hippocampus compared with NC group(t(57) ≥ 3.32,k ≥ 24,p < 0.01). This suggested that different cortexes(ACC, amygdala, hippocampus, NA, and VTA) took part in depression in different ways.9. Compared with RMD group, MDD group had higher gray matter density in right hippocampus, t(55) = 3.05, k = 69, p < 0.05, and lower gray matter density in left hippocampus, t(55) =-3.95, k = 10, p < 0.05. Moreover, the gray matter density in left hippocampus increased after TMS treatment, t(13) = 4.26, k = 32, p < 0.01. Furthermore, the activation differences for happy faces, sad faces, in RMD group, and in treatment group after TMS treatment were mainly in left hemisphere, while the activation differences for neutral faces and in MDD and NC groups were mainly in right hemisphere. This suggested that the role of left and right hemisphere in depression might be different, left hemisphere was correlated with depression remission, while right hemisphere was correlated with depressive mood.10. Current study tried to raise negative self schema- rumination- deficient attentional inhibition theory, which was confirmed partly by current study. Based on Beck’s theory, present model had three improvements: proposed the possible role of rumination between self schema and attentional bias, pointed out the substance of attentional bias in depression was attentional inhibition deficiency, and discriminated different types of attentional inhibition(inhibition of enter, attentional disengagement, and inhibition of return). Present model supplemented and improved Beck’s schema model.Current study observed the IOR phenomenon in depression and the relationship between IOR and neurotransmitter, cerebral activation, also the change of neurotransmitter concentration and depressive state before and after IOR training, and the difference of IOR and cerebral activation before and after TMS treatment which targeting at OFC. Current study intended to confirm the role and cerebral mechanism of IOR ability in depression, and the possibility of IOR training as new model of cognitive-behavioral therapy in depression. Present study would offer evidence to understand the occurrence, recurrence, remission of depression, and might be important to explore new model of cognitive-behavioral therapy in depression.