Abstract Background There is accumulating evidence of alterations in neural circuitry underlying the processing of social-affective information in adolescent Major Depressive Disorder (MDD). However ...the extent to which such alterations are present in youth at risk for mood disorders remains unclear. Method Whole-brain blood oxygenation level-dependent task responses and functional connectivity using generalized psychophysiological interaction (gPPI) analyses to mild and intense happy face stimuli was examined in 29 adolescents with MDD (MDD; M age, 16.0, S.D. 1.2 years), 38 healthy adolescents at risk of a mood disorder, by virtue of having a parent diagnosed with either Bipolar Disorder (BD) or MDD (Mood-risk; M age 13.4, S.D. 2.5 years) and 43 healthy control adolescents, having parents with no psychiatric disorder (HC; M age 14.6, S.D. 2.2 years). Results Relative to HC adolescents, Mood-risk adolescents showed elevated right dorsolateral prefrontal cortex (DLPFC) activation to 100% intensity happy (vs. neutral) faces and concomitant lowered ventral putamen activity to 50% intensity happy (vs. neutral) faces. gPPI analyses revealed that MDD adolescents showed significantly lower right DLPFC functional connectivity with the ventrolateral PFC (VLPFC) compared to HC to all happy faces. Limitations The current study is limited by the smaller number of healthy offspring at risk for MDD compared to BD. Conclusions Because Mood-risk adolescents were healthy at the time of the scan, elevated DLPFC and lowered ventral striatal activity in Mood-risk adolescents may be associated with risk or resiliency. In contrast, altered DLPFC–VLPFC functional connectivity in MDD adolescents may be associated with depressed mood state. Such alterations may affect social-affective development and progression to a mood disorder in Mood-risk adolescents. Future longitudinal follow-up studies are needed to directly answer this research question.
Major depressive disorder (MDD) affects approximately 15 million Americans. Approximately 2 million of these are classified as being refractory to treatment (TR‐MDD). Because of the lack of available ...therapies for TR‐MDD, and the high risk of suicide, there is interest in identifying new treatment modalities and diagnostic methods. Understanding of the impact of genomic copy number variation in the etiology of a variety of neuropsychiatric phenotypes is increasing. Low copy repeat elements at 15q13.3 facilitate non‐allelic homologous recombination, resulting in recurrent copy number variants (CNVs). Numerous reports have described association between microdeletions in this region and a variety of neuropsychiatric phenotypes, with CHRNA7 implicated as a candidate gene. However, the pathogenicity of 15q13.3 duplications is less clear. As part of an ongoing study, in which we have identified a number of metabolomic anomalies in spinal fluid from TR‐MDD patients, we also evaluated genomic copy number variation in patients (n = 125) and controls (n = 26) via array‐based copy number genomic hybridization (CGH); the case frequency was compared with frequencies reported in a prior study as well as a larger population‐sized cohort. We identified five TR‐MDD patients with microduplications involving CHRNA7. CHRNA7 duplications are the most common CNVs identified by clinical CGH in this cohort. Therefore, this study provides insight into the potential involvement of CHRNA7 duplications in the etiology of TR‐MDD and informs those involved with care of affected individuals.
This study shows that chromosome 15q13.3 microduplications are associated with treatment refractory major depressive disorder.
Previous studies have explored the role of stressful life events in the development of mood disorders. We examined the frequency and nature of stressful life events as measured by the Stressful Life ...Events Schedule (SLES) among 3 groups of adolescent offspring of probands with bipolar (BD), with non-BD psychiatric disorders, and healthy controls. Furthermore, we examined the relationship between stressful life events and the presence of DSM-IV Axis I disorders in these offspring. Stressful life events were characterized as dependent, independent, or uncertain (neither dependent nor independent) and positive, negative, or neutral (neither positive nor negative).
Offspring of probands with BD aged 13-18 years (n = 269), demographically matched offspring of probands with non-BD Axis I disorders (n = 88), and offspring of healthy controls (n = 81) from the Pittsburgh Bipolar Offspring Study were assessed from 2002 to 2007 with standardized instruments at intake. Probands completed the SLES for their offspring for life events within the prior year. Life events were evaluated with regard to current Axis I diagnoses in offspring after adjusting for confounds.
After adjusting for demographic and clinical between-group differences (in probands and offspring), offspring of probands with BD had greater independent (χ² = 11.96, P < .04) and neutral (χ² = 17.99, P < .003) life events compared with offspring of healthy controls and greater number of more severe stressful life events than offspring of healthy controls, but not offspring of probands with non-BD. Offspring of BD probands with comorbid substance use disorder reported more independent stressful life events compared to those without comorbid substance use disorder (P = .024). Greater frequency and severity of stressful life events were associated with current Axis I disorder in offspring of both probands with BD and probands with other Axis I disorders regardless of dependency or valence. Greater frequency and severity of stressful life events were associated with greater current Axis I disorder in all offspring.
Offspring of probands with BD have greater exposure to independent and neutral life events than offspring of healthy controls. Greater frequency and severity of stressful life events were associated with Axis I disorder in offspring of both BD and non-BD affected probands.
Cognitive control deficits are commonly seen in Depression of Bipolar Disorder (BDd) and Unipolar Major Depressive Disorder (UDd). Because failure to differentiate BDd from UDd has significant ...clinical consequences we aimed to identify differential patterns of neural activity in BDd versus UDd underlying response inhibition and motor control in adolescents.
Functional MRI was used to compare 12 BDd adolescents (mean age= 15.5±1.2) with age- and sex-matched ten UDd and ten healthy control (HC) adolescents during the performance of well-validated Go/NoGo task. NoGo response inhibition versus Go motor control blocks was used in whole-brain analysis and results were corrected for multiple comparisons.
There were no significant behavioral or neuroimaging findings between adolescents with BDd and UDd. However, both groups relative to HC showed significantly higher left superior temporal and left caudate activity during the NoGo condition. Moreover, left anterior cingulate (ACC) activity relative to HC was significantly higher only in BDd - not UDd - adolescents during the NoGo condition, and left caudate activity was higher only in UDd - not BDd - adolescents during the Go condition. In addition, several neural regions including dorsolateral prefrontal (DLPFC) were positively correlated with increased reaction time in UDd - not BDd - adolescents.
Despite some similarities, neural correlates of depression are different in BDd and UDd relative to HC, and greater recruitment of ACC resources during response inhibition can help distinguish BDd.
Depressive mood in adolescents with bipolar disorder (BDd) is associated with significant morbidity and mortality, but we have limited information about neural correlates of depression and treatment ...response in BDd. Ten adolescents with BDd (8 females, mean age = 15.6 ± 0.9) completed two (fearful and happy) face gender labeling fMRI experiments at baseline and after 6-weeks of open treatment. Whole-brain analysis was used at baseline to compare their neural activity with those of 10 age and sex-matched healthy controls (HC). For comparisons of the neural activity at baseline and after treatment of youth with BDd, region of interest analysis for dorsal/ventral prefrontal, anterior cingulate, and amygdala activity, and significant regions identified by wholebrain analysis between BDd and HC were analyzed. There was significant improvement in depression scores (mean percentage change on the Child Depression Rating Scale-Revised 57 % ± 28). Neural activity after treatment was decreased in left occipital cortex in the intense fearful experiment, but increased in left insula, left cerebellum, and right ventrolateral prefrontal cortex in the intense happy experiment. Greater improvement in depression was associated with baseline higher activity in ventral ACC to mild happy faces. Study sample size was relatively small for subgroup analysis and consisted of mainly female adolescents that were predominantly on psychotropic medications during scanning. Our results of reduced negative emotion processing versus increased positive emotion processing after treatment of depression (improvement of cognitive bias to negative and away from positive) are consistent with the improvement of depression according to Beck’s cognitive theory.
•Unique relationships may exist between cytokines and depression in adolescents.•Higher baseline TNFα levels are associated with greater subsequent depression.•Higher baseline TNFα levels are linked ...with greater baseline anhedonia.•Higher baseline TNFα levels are linked with greater subsequent anhedonia.
Depression has been associated with low-grade elevation of plasma cytokines (e.g. interleukin-6, IL-6; tumor necrosis factor alpha, TNFα) in both cross-sectional and longitudinal studies in adults. Preclinical and clinical studies also suggest that IL-6 and TNFα elevation are associated with anhedonia. However, few studies have examined longitudinal relationships between cytokines and depression/anhedonia in clinically depressed samples, particularly adolescents.
Thirty-six adolescents with a depressive disorder receiving standard-of-care community treatment were assessed at a baseline and a follow-up timepoint. Self-report and clinical measures of depression and anhedonia, along with plasma IL-6 and TNFα levels, were obtained at both timepoints. Baseline cytokine measures were examined in association with baseline and follow-up clinical measures. On an exploratory basis, change in clinical measures over time was examined in relation to change in cytokine levels over time.
Higher baseline TNFα levels predicted higher follow-up depression severity after approximately four months (controlling for baseline depression). Higher baseline TNFα levels also associated positively with baseline anhedonia and predicted higher anhedonia at follow-up (controlling for baseline anhedonia). No association was found between change in clinical measures and change in cytokine levels over time.
Among adolescents receiving standard-of-care community treatment for depression, higher levels of TNFα predicted greater depressive symptoms at 4-month follow-up, suggesting this cytokine may be used to help identify patients in need of more intensive treatment. Elevated TNFα levels were also associated with concurrent and future anhedonia symptoms, suggesting a specific mechanism in which TNFα affects depression trajectories. Future studies should examine the relationships between cytokine levels and depression/anhedonia symptoms at multiple timepoints in larger cohorts of depressed adolescents.
Our goal was to undertake a genome‐wide epigenomic liquid biopsy of cerebrospinal fluid (CSF) for the comprehensive analysis of cell‐free DNA (cfDNA) methylation signatures in the human central ...nervous system (CNS). Solution‐phase hybridization and massively parallel sequencing of bisulfite converted human DNA was employed to compare methylation signatures of cfDNA obtained from CSF with plasma. Recovery of cfDNA from CSF was relatively low (68–840 pg/mL) compared to plasma (2720–8390 pg/mL) and cfDNA fragments from CSF were approximately 20 bp shorter than their plasma‐derived counterparts. Distributions of CpG methylation signatures were significantly altered between CSF and plasma, both globally and at the level of functional elements including exons, introns, CpG islands, and shores. Sliding window analysis was used to identify differentially methylated regions. We found numerous gene/locus‐specific differences in CpG methylation between cfDNA from CSF and plasma. These loci were more frequently hypomethylated in CSF compared to plasma. Differentially methylated CpGs in CSF were identified in genes related to branching of neurites and neuronal development. Using the GTEx RNA expression database, we found clear association between tissue‐specific gene expression in the CNS and cfDNA methylation patterns in CSF. Ingenuity pathway analysis of differentially methylated regions identified an enrichment of functional pathways related to neurobiology. In conclusion, we present a genome‐wide analysis of DNA methylation in human CSF. Our methods and the resulting data demonstrate the potential of epigenomic liquid biopsy of the human CNS for molecular phenotyping of brain‐derived DNA methylation signatures.
We present a comprehensive genome‐wide analysis of DNA methylation in human cerebrospinal fluid. We demonstrate the potential of epigenomic liquid biopsy of the human central nervous system (CNS) for molecular phenotyping of brain DNA methylation signatures. We anticipate that these approaches will be utilized for the molecular profiling of CNS phenotypes in both research and clinical settings and suggest that a new era of epigenomic liquid biopsy may be imminent.
•Participants with current suicidal ideation show reduced volume than healthy controls in the left rostral middle frontal gyrus.•Participants with current suicidal ideation show reduced thickness ...than healthy controls in the left and right precentral gyrus.•Findings may contribute to emotional dysregulation and poor decision making, which are risk factors for suicidal behavior.
The extent to which observed differences in emotion processing and regulation neural circuitry in young adults with current suicidal ideation are paralleled by structural differences is unknown. We measured brain cortical thickness and gray and white matter volumes in 78 young adults aged 18–35: 35 with current suicidal ideation (SI) and 43 healthy controls (HC). The SI group, compared to HC, showed reduction in cortical thickness in the bilateral precentral gyri and diminished cortical volume in the left middle frontal gyrus. These regions are implicated in executive function, stress regulation, and emotion processing. We propose that these structural differences among the SI group could be contributing to suicidal thought patterns.
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