The Neural Mechanism Of The Association Between Vitamin D,Inflammation And Depression

Background As the world’s largest cause of disability,major depressive disorder(MDD)has devastating effects on virtually all areas of a patient’s personal life and is a major contributor to the overall burden of disease.The main clinical features of depression are persistent low mood,anhedonia,cognitive bias(e.g.,negative thoughts and feelings of worthlessness and guilt),fatigue,changes in appetite and weight,sleep disturbance,psychomotor retardation and agitation,suicidal thoughts and attempts,and cognitive impairment.However,the pathogenesis of depression is quite complex,and its pathophysiological mechanism is still unclear.Vitamin D is engaged in various neural processes,and it has been suggested to play a prominent role in the pathogenesis of depression and its treatment.However,the neural mechanism of the relationship between vitamin D and depression is highly complex,and the current research is limited to the level of epidemiology and behavior,and there is no use of multimodal magnetic resonance imaging(MRI)technology to explore its neuropathological mechanism.Moreover,amassing evidence supports inflammation as one pathophysiologic mechanism contributing to depression.This is proposed to occur through downstream effects of inflammatory cytokines on neuroplasticity,neurogenesis and neurotransmitter function,although these effects exact genetic and neural mechanisms remain poorly understood.Interestingly,an important role of vitamin D is to reduce inflammation by reducing the expression of inflammatory cytokines.ObjectiveBy collecting multimodal MRI and clinical data(including clinical symptoms,cognitive function and hematological indicators)from the MDD patients and healthy controls,this study aims to explore the neuropathological mechanism of the relationship between vitamin D,peripheral inflammation and depression through a variety of analysis methods.(1)To explore the relationship between vitamin D level,brain structure and function abnormalities and clinical manifestations in patients with MDD.(2)To investigate the relationship between vitamin D and inflammation in patients with MDD,and then explore the neural mechanism and genetic basis of the relationship between peripheral inflammation and depression.Methods(1)Part 1: Multimodal magnetic resonance imaging data were acquisited from 122 patients with MDD and 119 controls.Gray matter volume(GMV),fractional amplitude of low-frequency fluctuations(f ALFF),large-scale functional network connectivity,fractional anisotropy(FA),axial diffusivity(AD),radial diffusivity(RD),and mean diffusivity(MD)were calculated to assess brain structure and function,respectively.Serum concentration of vitamin D(SCVD)and cognition(i.e.prospective memory and sustained attention)were also measured.(2)Part 2: Multimodal magnetic resonance imaging data were collected from 120 patients with MDD and 118 controls.GMV,f ALFF,large-scale functional network connectivity,FA,AD,RD,and MD were calculated to assess brain structure and function,respectively.SCVD,serum C-reactive protein(CRP)level and clinical manifestations were also measured.The Allen Human Brain Atlas,neurotransmitter maps and Neurosynth databases were leveraged to uncover potential genetic and neural mechanisms of CRP-related f ALFF alterations in MDD patients.Results(1)Part 1: We found a significant group-by-gender interaction effect on SCVD whereby MDD patients showed a reduction in SCVD relative to controls in females but not males.Moreover,there were cognitive dysfunction,and f ALFF alterations in widespread brain regions as well as abnormal large-scale functional network connectivity in female MDD patients.Further analyses showed that there were significant associations of SCVD with cognition,MDD-related f ALFF alterations in widespread brain regions as well as MDD-related functional network connectivity changes in females.Concurrently,MDD-related functional network connectivity changes were correlated with depression and anxiety symptoms in female patients.Remarkably,MDD-and SCVD-related f ALFF and functional network connectivity changes mediated the relation between SCVD and cognition in females.In males,no significant correlations were found between SCVD and cognition,between SCVD and f ALFF and functional network connectivity,and between cognition and f ALFF and functional network connectivity,indicating female specificity of our results.(2)Part 2: There is no significant correlation between SCVD and CRP,but significant positive correlation was found between CRP and f ALFF of right precentral gyrus,and negative correlations between CRP and f ALFF of bilateral anterior cingulate cortex and middle cingulate cortex,as well as AD of multiple white matter regions in patients with MDD.However,such relationships between CRP and brain imaging measuring observed in patients with MDD were absent in healthy controls.Further,we showed that the CRP-related f ALFF alterations were spatial correlations with the expression profiles of gene modules associated with various biological functions,particularly inflammation-related signaling pathways.Concurrently,these brain function alterations were spatially correlated with serotonergic,gamma aminobutyric acid and glutamate neurotransmitter systems,as well as multiple behavioral terms including cognition,sleep,emotion and stress.More importantly,f ALFF of anterior cingulate cortex and AD of left superior corona radiate were correlated with sleep and/or cognition,and further analysis showed that these brain alterations mediated the associations between CRP and sleep and/or cognition.Conclusions(1)Our study revealed an association between low vitamin D,brain dysfunction,and cognitive impairment in female patients with MDD.It could help elucidate the neural mechanisms by which low vitamin D contributes to cognitive impairment in MDD in a gender-dependent manner.More generally,these findings might have clinical implications for assignment of female patients with MDD and cognitive dysfunction to adjuvant vitamin D supplementation therapy,which may ultimately advance a precision approach to personalized antidepressant choice.(2)Our findings not only provide direct evidence for the associations between CRP and widespread brain functional and microstructural alterations in patients with MDD,but support the inflammatory hypothesis of depression from the perspective of genes and neurotransmitters.Moreover,the current research also reveals the neural mechanism of the relationship between inflammation and depression and its core symptoms.Therefore,our findings help to identify neural and genetic correlates underlying the association between inflammation and depression,and these correlates may be related to complex polygenetic and polypathway mechanisms.Taken together,we combined multimodal MRI technology and various analysis methods to profound study the potential neural mechanism of the associations between serum vitamin D level and CRP and depression and its core symptoms.Although we did not find a direct relationship between vitamin D and CRP in MDD patients,the current findings preliminarily determine the theoretical basis for the relationship between vitamin D and inflammation and the neuropathological mechanism of depression,which is of great significance for the prevention and clinical treatment of depression.