MicroRNA132 associated multimodal neuroimaging patterns in unmedicated major depressive disorder.
ABSTRACT: There is compelling evidence that epigenetic factors contribute to the manifestation of depression, in which microRNA132 (miR-132) is suggested to play a pivotal role in the pathogenesis and neuronal mechanisms underlying the symptoms of depression. Additionally, several depression-associated genes [MECP2, ARHGAP32 (p250GAP), CREB, and period genes] were experimentally validated as miR-132 targets. However, most studies regarding miR-132 in major depressive disorder are based on post-mortem, animal models or genetic comparisons. This work will be the first attempt to investigate how miR-132 dysregulation may impact covariation of multimodal brain imaging data in 81 unmedicated major depressive patients and 123 demographically-matched healthy controls, as well as in a medication-naïve subset of major depressive patients. MiR-132 values in blood (patients > controls) was used as a prior reference to guide fusion of three MRI features: fractional amplitude of low frequency fluctuations, grey matter volume, and fractional anisotropy. The multimodal components correlated with miR-132 also show significant group difference in loadings. Results indicate that (i) higher miR-132 levels in major depressive disorder are associated with both lower fractional amplitude of low frequency fluctuations and lower grey matter volume in fronto-limbic network; and (ii) the identified brain regions linked with increased miR-132 levels were also associated with poorer cognitive performance in attention and executive function. Using a data-driven, supervised-learning method, we determined that miR-132 dysregulation in major depressive disorder is associated with multi-facets of brain function and structure in fronto-limbic network (the key network for emotional regulation and memory), which deepens our understanding of how miR-132 dysregulation in major depressive disorders contribute to the loss of specific brain areas and is linked to relevant cognitive impairments.
Project description:BACKGROUND:The biological mechanism of depression in multiple sclerosis (MS) is not well understood. Based on work in major depressive disorder, fronto-limbic disconnection might be important. OBJECTIVE:To investigate structural and functional fronto-limbic changes in depressed MS (DMS) and non-depressed MS (nDMS) patients. METHODS:In this retrospective study, 22 moderate-to-severe DMS patients (disease duration 8.2?±?7.7?years), 21 nDMS patients (disease duration 15.3?±?8.3?years), and 12 healthy controls underwent neuropsychological testing and magnetic resonance imaging (MRI; 1.5?T). Brain volumes (white matter (WM), gray matter, amygdala, hippocampus, thalamus), lesion load, fractional anisotropy (FA) of fronto-limbic tracts, and resting-state functional connectivity (FC) between limbic and frontal areas were measured and compared between groups. Regression analysis was performed to relate MRI measures to the severity of depression. RESULTS:Compared to nDMS patients, DMS patients (shorter disease duration) had lower WM volume ( p?<?0.01), decreased FA of the uncinate fasciculus ( p?<?0.05), and lower FC between the amygdala and frontal regions ( p?<?0.05). Disease duration, FA of the uncinate fasciculus, and FC of the amygdala could explain 48% of variance in the severity of depression. No differences in cognition were found. CONCLUSION:DMS patients showed more pronounced (MS) damage, that is, structural and functional changes in temporo-frontal regions, compared to nDMS patients, suggestive of fronto-limbic disconnection.
Project description:Depression is among the most common neuropsychiatric disorders. It remains unclear whether brain abnormalities associated with depression reflect the pathological state of the disease or neurobiological traits predisposing individuals to depression. Parental history of depression is a risk factor that more than triples the risk of depression. We compared white matter (WM) microstructure cross-sectionally in 40 children ages 8-14 with versus without parental history of depression (At-Risk vs. Control). There were significant differences in age-related changes of fractional anisotropy (FA) between the groups, localized in the anterior fronto-limbic WM pathways, including the anterior cingulum and the genu of the corpus callosum. Control children exhibited typical increasing FA with age, whereas At-Risk children exhibited atypical decreasing FA with age in these fronto-limbic regions. Furthermore, dorsal cingulate FA significantly correlated with depressive symptoms for At-Risk children. The results suggest maturational WM microstructure differences in mood-regulatory neurocircuitry that may contribute to neurodevelopmental risk for depression. The study provides new insights into neurodevelopmental susceptibility to depression and related disabilities that may promote early preventive intervention approaches.
Project description:Despite the significant prevalence of adolescent depression, little is known about the neuroanatomical basis of this disorder. Functional dysregulation in frontolimbic circuitry has been suggested as a key neural correlate of adult and adolescent depression impeding emotional regulation. However, less is known about whether this dysregulation is overlaid on impaired white matter microstructure. Guided by neuroimaging findings, we test the a priori hypotheses that adolescent depression is associated with alterations in white matter microstructure in the uncinate fasciculus (UF) and cingulum bundles.Diffusion tensor magnetic resonance imaging (DTI) data were obtained on 52 unmedicated adolescents with major depressive disorder (MDD) and 42 matched controls. We calculated fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) for bilateral UF and cingulum. We also completed a voxelwise comparison of participants with depression and control participants using tract-based spatial statistics (TBSS).Adolescents with depression had significantly lower FA and higher RD in bilateral UF; no significant differences were observed in cingulum. TBSS results additionally revealed lower FA values in the white matter associated with the limbic-cortical-striatal-thalamic circuit, corpus callosum, and anterior and superior corona radiata.Unmedicated adolescent depression is associated with reduced fractional anisotropy in emotion regulatory networks, which may underlie the functional differences in frontolimbic circuitry characterizing depressive disorder. Given the relatively recent onset of depression in our sample, our findings in the context of the current literature provide preliminary evidence that reduced fractional anisotropy in the UF could be a predisposing risk factor for depression.
Project description:Major depressive disorder (MDD) has been associated with abnormalities in cortical thickness and autonomic function. Adolescence is a time notable for brain development and MDD onset. In healthy adolescents, greater resting state vagal activity (RVA) is associated with lower cortical thickness. The relationship between brain structural thickness and RVA in adolescents with MDD has not previously been studied. This secondary analysis drew on a sample of 37 non-depressed controls and 53 adolescents with MDD. Resting state heart rate and two indices of RVA (HF-HRV and RMSSD) were recorded during a neuroimaging session. Cortical thickness within fronto-limbic regions of interest was measured using Freesurfer analysis of T1-weighted high-resolution structural images. Self-reports of depression severity showed a significant interaction with cortical thickness of the right insula in predicting RMSSD [t?=?2.22, P=0.030, ??=?5.44; model fit of the interaction term as indicated by the 'Bayes Factor' (BF): 7.58] and HF-HRV (t?=?2.09, P=0.041, ??=?4.72; BF: 7.94). Clinician ratings of depression severity showed further interactions. Findings underscore the important relationships between RVA and cortical development, suggesting two possible explanations: (i) in adolescent MDD, greater fronto-limbic thickness is compensatory for deficits in autonomic regulation or (ii) increased autonomic arousal results in delayed fronto-limbic maturation. Longitudinal research is necessary to further clarify the nature of the relationship between autonomic functioning and cortical development.
Project description:Neuroanatomical abnormalities in patients with major depression disorder (MDD) have been attracted great research attention. However, the structural alterations associated with subthreshold depression (StD) remain unclear and, therefore, require further investigation. In this study, 42 young women with StD, and 30 matched non-depressed controls (NCs) were identified based on two-time Beck Depression Inventory scores. Whole-brain voxel-based morphometry (VBM) and region of interest method were used to investigate altered gray matter volume (GMV) and white matter volume (WMV) among a non-clinical sample of young women with StD. VBM results indicated that young women with StD showed significantly decreased GMV in the right inferior parietal lobule than NCs; increased GMV in the amygdala, posterior cingulate cortex, and precuneus; and increased WMV in the posterior cingulate cortex and precuneus. Together, structural alterations in specific brain regions, which are known to be involved in the fronto-limbic circuits implicated in depression may precede the occurrence of depressive episodes and influence the development of MDD.
Project description:Recent research shows that blunted cardiovascular and cortisol reactions to acute psychological stress are associated with adverse behavioural and health outcomes: depression, obesity, bulimia, and addictions. These outcomes may reflect suboptimal functioning of the brain's fronto-limbic systems that are needed to regulate motivated behaviour in the face of challenge. In support of this, brain imaging data demonstrate fronto-limbic hypoactivation during acute stress exposure. Those demonstrating blunted reactions also show impairments of motivation, including lower cognitive ability, more rapid cognitive decline, and poorer performance on motivation-dependent tests of lung function. Persons exhibiting blunted stress reactivity display well established temperament characteristics, including neuroticism and impulsivity, characteristic of various behavioural disorders. Notably, the outcomes related to blunted stress reactivity are similar to those that define Reward Deficiency Syndrome. Accordingly, some individuals may be characterised by a broad failure in cardiovascular and cortisol responding to both stress and reward, reflecting fronto-limbic dysregulation. Finally, we proffer a model of blunted stress reactivity, its antecedents and sequelae, and identify future research priorities.
Project description:Four of the most consistently replicated variants associated with mood disorder occur in genes important for synaptic function: ANK3 (rs10994336), BDNF (rs6265), CACNA1C (rs1006737), and DGKH (rs1170191).The present study examined associations between these candidates, mood disorder diagnoses, cognition, and fronto-limbic regions implicated in affect regulation.Participants included 128 individuals with bipolar disorder (33% male, Mean age = 38.5), 48 with major depressive disorder (29% male, Mean age = 40.4), and 149 healthy controls (35% male, Mean age = 36.5). Genotypes were determined by 5'-fluorogenic exonuclease assays (TaqMan®). Fronto-limbic volumes were obtained from high resolution brain images using Freesurfer. Chi-square analyses, bivariate correlations, and mediational models examined relationships between genetic variants, mood diagnoses, cognitive measures, and brain volumes.Carriers of the minor BDNF and ANK3 alleles showed nonsignificant trends toward protective association in controls relative to mood disorder patients (P = 0.047). CACNA1C minor allele carriers had larger bilateral caudate, insula, globus pallidus, frontal pole, and nucleus accumbens volumes (smallest r = 0.13, P = 0.043), and increased IQ (r = 0.18, P < 0.001). CACNA1C associations with brain volumes and IQ were independent; larger fronto-limbic volumes did not mediate increased IQ. Other candidate variants were not significantly associated with diagnoses, cognition, or fronto-limbic volumes.CACNA1C may be associated with biological systems altered in mood disorder. Increases in fronto-limbic volumes and cognitive ability associated with CACNA1C minor allele genotypes are congruent with findings in healthy samples and may be a marker for increased risk for neuropsychiatric phenotypes. Even larger multimodal studies are needed to quantify the magnitude and specificity of genetic-imaging-cognition-symptom relationships.
Project description:OBJECTIVE:The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism is suggested to be associated with the pathophysiology of anxiety disorders, including panic disorder (PD). Although the fronto-limbic white matter (WM) microstructures have been investigated, the corpus callosum (CC) has not yet been studied regarding its relationship with BDNF Val66Met polymorphism in PD. METHODS:Ninety-five PD patients were enrolled. The Neuroticism, the Anxiety Sensitivity Inventory-Revised, Panic Disorder Severity Scale, and Beck Depression Inventory-II (BDI-II) were administered. Voxel-wise statistical analysis of diffusion tensor imaging data was performed within the CC regions using Tract-Based Spatial Statistics. RESULTS:The GG genotype in BDNF Val66Met polymorphism has significantly higher fractional anisotropy (FA) values of the body and splenium of the CC, neuroticism and depressive symptom scale scores than the non-GG genotype in PD. The FA values of the body of the CC in the two groups were significantly different independent of age, sex, neuroticism, and BDI-II. CONCLUSION:Our findings demonstrate that the BDNF Val66Met polymorphism is associated with WM connectivity of the body and splenium of the CC, and may be related to neuroticism and depressive symptoms in PD. Additionally, the CC connectivity according to BDNF polymorphism may play a role in the pathophysiology of PD.
Project description:Attentional bias toward negative stimuli has been observed in major depression disorders (MDDs). Imaging studies suggest the engagement of fronto-limbic regions like amygdala, anterior cingulate cortex (ACC), and lateral prefrontal cortex, is related to negatively biased attention. However, neural correlates of attentional bias for negative stimuli in individuals with subthreshold depression (SubD), that is individuals who have clinically relevant depressive symptoms but do not fulfill the criteria for MDD, remain unclear. Here, we used functional neuroimaging and the dot-probe task to elucidate the neural substrates of negatively biased attention among individuals with SubD. Behavioral results found that individuals with SubD allocated more attention toward negative stimuli relative to neutral stimuli, which were not observed among non-depressed controls (NCs). Imaging results found greater amygdala and rostral ACC activity in attentional bias toward negative stimuli among participants with SubD compared to NCs; Additionally, participants with SubD showed reduced engagement of bilateral inferior frontal gyrus compared with NCs in the attentional processing of negative stimuli. Together, these results suggest that alteration of fronto-limbic systems relative to controls, known to be related to negative detection and attentional control, is associated with negatively biased attention in individuals with SubD.
Project description:Fronto-limbic regions of the brain including the sub-genual (sgPFC) and medial prefrontal (mPFC) cortices are central to processing emotionally salient and hedonic stimuli (Mayberg, 2009) and implicated in depression. The relevance of cortico-limbic models of emotion and reward processing in children with genetic risk for psychiatric disorders has not been assessed.Here we studied adolescents at risk for schizophrenia (HRS) and controls (HC) using an event-related fMRI continuous affective appraisal task. HRS were divided into sub-groups based on the presence or absence of negative symptoms (Miller et al., 2003), HRS_NS+ and HRS_NS- respectively. Brain responses to positive, negative and neutral emotional stimuli were estimated.Consistent with observations in the depressive phenotype, for positively valenced stimuli, HRS_NS+ (relative to HC and HRS_NS-) were characterized by hypo-responsivity of the sgPFC and the mPFC, but hyper-responsivity of the mid-brain. sgPFC and mPFC signals were coupled across groups.Such studies can benefit from larger sample sizes, though our observed effect sizes were in the moderate to large range.Children and adolescents at risk for psychiatric illness and who evince reliably present negative symptoms show brain responses to socially rewarding stimuli similar to those observed in depression. Studies in at-risk children and adolescents may be important in understanding how early manifestations of depression-like characteristics impact brain function.