Eva Henje Blom

Emotion-Dependent Functional Connectivity of the Default Mode Network in Adolescent Depression

BACKGROUND Functional magnetic resonance imaging research suggests that major depressive disorder (MDD) in both adults and adolescents is marked by aberrant connectivity of the default mode network (DMN) during resting state. However, emotional dysregulation is also a key feature of MDD. No studies to date have examined emotion-related DMN pathology in adolescent depression. Comprehensively understanding the dynamics of DMN connectivity across brain states in individuals with depression with short disease histories could provide insight into the etiology of MDD. METHODS We collected functional magnetic resonance imaging data during an emotion identification task and during resting state from 26 medication-free adolescents (13-17 years old) with MDD and 37 well-matched healthy control subjects. We examined between-group differences in blood oxygenation level-dependent task responses and emotion-dependent and resting-state functional connectivity of the two primary nodes of the DMN: medial prefrontal cortex and posterior cingulate cortex (PCC). Additionally, we examined between-group differences in DMN functional connectivity and its relationship to depression severity and onset. RESULTS Relative to healthy control subjects, unmedicated adolescents with MDD demonstrated reduced medial prefrontal cortex and PCC emotion-related deactivation and greater medial prefrontal cortex and PCC emotion-dependent functional connectivity with precuneus, cingulate gyrus, and striatum/subcallosal cingulate gyrus. The PCC-subcallosal cingulate connectivity remained inflexibly elevated in the subjects with MDD versus healthy control subjects during resting state. Stronger PCC emotion-dependent functional connectivity was associated with greater depression severity and an earlier age of depression onset. CONCLUSIONS Adolescent depression is associated with inflexibly elevated DMN connections. Given more recent evidence of DMN maturation throughout adolescence, our findings suggest that early-onset depression adversely affects normal development of functional brain networks.

Low Sense of Coherence (SOC) is a mirror of general anxiety and persistent depressive symptoms in adolescent girls - a cross-sectional study of a clinical and a non-clinical cohort

BackgroundThe Sense of Coherence (SOC) scale is assumed to measure a distinct salutogenic construct separated from measures of anxiety and depression. Our aim was to challenge this concept.MethodsThe SOC-scale, Becks Depression Inventory (BDI), Becks Anxiety Inventory (BAI) , the emotional subscale of the Strengths and Difficulties Questionnaire (SDQ-em) and self-assessed health-related and physiological parameters were collected from a sample of non-clinical adolescent females (n = 66, mean age 16.5 years with a range of 15.9-17.7 years) and from female psychiatric patients (n = 73), mean age 16.8 years with a range of 14.5-18.4 years), with diagnoses of major depressive disorders (MDD) and anxiety disorders.ResultsThe SOC scores showed high inverse correlations to BDI, BAI and SDQ-em. In the non-clinical sample the correlation coefficient was -0.86 to -0.73 and in the clinical samples -0.74 to -0.53 (p < 0.001). Multiple regression models showed that BDI was the strongest predictor of SOC in the non-clinical (beta coefficient -0.47) and clinical sample (beta coefficient -0.52). The total degree of explanation of self assessed anxiety and depression on the SOC variance estimated by multiple R2 = 0.74, adjusted R2 = 0.73 in the non-clinical sample and multiple R2 = 0.66, adjusted R2 = 0.65 in the clinical sample.Multivariate analyses failed to isolate SOC as a separate construct and the SOC-scale, BDI, BAI and SDQ-em showed similar patterns of correlations to self-reported and physiological health parameters in both samples. The SOC-scale was the most stable measure over six months.ConclusionsThe SOC-scale did not appear to be a measure of a distinct salutogenic construct, but an inverse measure of persistent depressive symptoms and generalized social anxiety similar to the diagnostic criteria for major depressive disorder (MDD), dysthymic disorder, generalized anxiety disorder (GAD) or generalized social anxiety disorder (SAD) according to DSM-IV. These symptoms were better captured with SOC than by the specialized scales for anxiety and depression. Self-assessment scales that adequately identify MDD, dysthymic disorder, GAD and SAD need to be implemented. Comorbidity of these disorders is common in adolescent females and corresponds to a more severe symptomatology and impaired global function.

Pro-inflammatory cytokines are elevated in adolescent females with emotional disorders not treated with SSRIs

BACKGROUND Adults with major depressive disorder (MDD) show elevated levels of IL-6 and TNF-alpha. Studies of adolescents with MDD or anxiety disorders (AD) are few and present conflicting results. METHODS We studied plasma cytokines in a clinical sample of adolescent females with MDD and/or clinical AD (n=60, mean age 16.8 years), compared to healthy controls (n=44; mean age 16.5 years). RESULTS The clinical sample showed significantly higher values of IL-2 (Z=-4.09, p>0.0001), IL1-beta (Z=-2.40, p<0.05) and IL-10 (Z=-2.38, p<0.05) as compared to controls. The subgroup of the clinical sample not treated with SSRIs had a significant difference of IL-6 (Z=-2.26, p<0.05) in addition to the difference of IL-2 and IL1-beta, but showed no difference of IL-10 as compared to the controls. SSRI treatment was related to IL-6, explaining 26% of the variance in the clinical sample after controlling for BMI and symptom severity. In the clinical sample, levels of IL-6 and IFN-gamma were positively correlated with self-assessed symptoms of anxiety and/or depression (corr.coeff 0.35 resp 0.40 at p<0.05). LIMITATIONS The cross-sectional design does not allow for conclusions on causality. The sample sizes were relatively small and a large drop-out in the clinical sample may have influenced the representativity. DISCUSSION The study suggests that pro-inflammatory cytokines are part of the pathophysiology of emotional disorders in adolescent females and that SSRIs have anti-inflammatory properties. The findings prompt further studies on the specific mechanisms involved and may contribute to the development of more effective treatment and prevention.

Altered insular activation and increased insular functional connectivity during sad and happy face processing in adolescent major depressive disorder

BACKGROUND Major depressive disorder (MDD) is a leading cause of disability worldwide and occurs commonly first during adolescence. The insular cortex (IC) plays an important role in integrating emotion processing with interoception and has been implicated recently in the pathophysiology of adult and adolescent MDD. However, no studies have yet specifically examined the IC in adolescent MDD during processing of faces in the sad-happy continuum. Thus, the aim of the present study is to investigate the IC during sad and happy face processing in adolescents with MDD compared to healthy controls (HCL). METHODS Thirty-one adolescents (22 female) with MDD and 36 (23 female) HCL underwent a well-validated emotional processing fMRI paradigm that included sad and happy face stimuli. RESULTS The MDD group showed significantly less differential activation of the anterior/middle insular cortex (AMIC) in response to sad versus happy faces compared to the HCL group. AMIC also showed greater functional connectivity with right fusiform gyrus, left middle frontal gyrus, and right amygdala/parahippocampal gyrus in the MDD compared to HCL group. Moreover, differential activation to sad and happy faces in AMIC correlated negatively with depression severity within the MDD group. LIMITATIONS Small age-range and cross-sectional nature precluded assessment of development of the AMIC in adolescent depression. CONCLUSIONS Given the role of the IC in integrating bodily stimuli with conscious cognitive and emotional processes, our findings of aberrant AMIC function in adolescent MDD provide a neuroscientific rationale for targeting the AMIC in the development of new treatment modalities.

Neurophysiological and neurocognitive mechanisms underlying the effects of yoga-based practices: towards a comprehensive theoretical framework

During recent decades numerous yoga-based practices (YBP) have emerged in the West, with their aims ranging from fitness gains to therapeutic benefits and spiritual development. Yoga is also beginning to spark growing interest within the scientific community, and yoga-based interventions have been associated with measureable changes in physiological parameters, perceived emotional states, and cognitive functioning. YBP typically involve a combination of postures or movement sequences, conscious regulation of the breath, and various techniques to improve attentional focus. However, so far little if any research has attempted to deconstruct the role of these different component parts in order to better understand their respective contribution to the effects of YBP. A clear operational definition of yoga-based therapeutic interventions for scientific purposes, as well as a comprehensive theoretical framework from which testable hypotheses can be formulated, is therefore needed. Here we propose such a framework, and outline the bottom-up neurophysiological and top-down neurocognitive mechanisms hypothesized to be at play in YBP.

The differentiation between depressive and anxious adolescent females and controls by behavioural self-rating scales

BACKGROUND This study aimed to validate the ability of frequently used self-assessment scales in Swedish child and adolescent psychiatric practice to differentiate between adolescent girls with manifest anxiety disorders and depression from those with less severe symptoms. METHODS The receiver-operating characteristic (ROC) curve was calculated for Becks Depression Inventory (BDI), Becks Anxiety Inventory (BAI), Hospital Anxiety and Depression Scale (HAD), the emotional subscale (SDQ-em), the impact score and the total difficulties score of the Strengths and Difficulties Questionnaire and Sense of Coherence (SOC) in a sample of 73 adolescent, female patients, diagnosed with one or several anxiety disorders and/or depression. ROC was also calculated for 66 age-matched controls. RESULTS SOC and the SDQ-em showed the best ability to differentiate cases of anxiety disorders and/ or depression from non-cases. SOC and SDQ-em had an equivalent ability to differentiate depression from non-cases compared to the specialised scales for depression, BDI and HAD-dep. SOC and SDQ-em were significantly better in differentiating cases of anxiety from non-cases than the specialised scales BAI and HAD-anx. Selection bias and several forms to fill in can have influenced the result. CONCLUSIONS SOC and SDQ-em seemed to be valid tools for identifying girls with anxiety disorders and depression. This is of clinical importance since self-reported symptoms of anxiety and depression show a major increase in adolescent girls and methods to identify those in need of treatment are needed.

Screening for depressed mood in an adolescent psychiatric context by brief self-assessment scales - testing psychometric validity of WHO-5 and BDI-6 indices by latent trait analyses

BackgroundMajor depressive disorder is prevalent in the adolescent psychiatric clinical setting and often comorbid with other primary psychiatric diagnoses such as ADHD or social anxiety disorder. Systematic manual-based diagnostic procedures are recommended to identify such comorbidity but they are time-consuming and often not fully implemented in clinical practice. Screening for depressive symptoms in the child psychiatric context using brief, user-friendly and easily managed self-assessment scales may be of clinical value and utility. The aim of the study is to test the psychometric validity of two such scales, which may be used in a two-step screening procedure, the WHO-Five Well-being Index (WHO-5) and the six-item version of Beck’s Depression Inventory (BDI-6).Method66 adolescent psychiatric patients with a clinical diagnosis of major depressive disorder (MDD), 60 girls and 6 boys, aged 14–18 years, mean age 16.8 years, completed the WHO-5 scale as well as the BDI-6. Statistical validity was tested by Mokken and Rasch analyses.ResultsThe correlation between WHO-5 and BDI-6 was −0.49 (p=0.0001). Mokken analyses showed a coefficient of homogeneity for the WHO-5 of 0.52 and for the BDI-6 of 0.46. Rasch analysis also accepted unidimensionality when testing males versus females (p > 0.05).ConclusionsThe WHO-5 is psychometrically valid in an adolescent psychiatric context including both genders to assess the wellness dimension and applicable as a first step in screening for MDD. The BDI-6 may be recommended as a second step in the screening procedure, since it is statistically valid and has the ability to unidimensionally capture the severity of depressed mood.

Resting-state functional connectivity of the amygdala and longitudinal changes in depression severity in adolescent depression

BACKGROUND The incidence of major depressive disorder (MDD) rises during adolescence, yet the neural mechanisms of MDD during this key developmental period are unclear. Altered amygdala resting-state functional connectivity (RSFC) has been associated with both adolescent and adult MDD, as well as symptom improvement in response to treatment in adults. However, no study to date has examined whether amygdala RSFC is associated with changes in depressive symptom severity in adolescents. METHOD We examined group differences in amygdala RSFC between medication-naïve depressed adolescents (N=48) and well-matched healthy controls (N=53) cross-sectionally. We then longitudinally examined whether baseline amygdala RSFC was associated with change in depression symptoms three months later in a subset of the MDD group (N=24). RESULTS Compared to healthy controls, depressed adolescents showed reduced amygdala-based RSFC with the dorsolateral prefrontal cortex (DLPFC)and the ventromedial prefrontal cortex (VMPFC). Within the depressed group, more positive baseline RSFC between the amygdala and insulae was associated with greater reduction in depression symptoms three months later. LIMITATIONS Only a subset of depressed participants was assessed at follow-up and treatment type and delivery were not standardized. CONCLUSIONS Adolescent depression may be characterized by dysfunction of frontolimbic circuits (amygdala-DLPFC, amygdala-VMPFC) underpinning emotional regulation, whereas those circuits (amygdala-insula) subserving affective integration may index changes in depression symptom severity and may therefore potentially serve as a candidate biomarker for treatment response. Furthermore, these results suggest that the biomarkers of MDD presence are distinct from those associated with change in depression symptoms over time.

Large-Scale Hypoconnectivity Between Resting-State Functional Networks in Unmedicated Adolescent Major Depressive Disorder

Major depressive disorder (MDD) often emerges during adolescence, a critical period of brain development. Recent resting-state fMRI studies of adults suggest that MDD is associated with abnormalities within and between resting-state networks (RSNs). Here we tested whether adolescent MDD is characterized by abnormalities in interactions among RSNs. Participants were 55 unmedicated adolescents diagnosed with MDD and 56 matched healthy controls. Functional connectivity was mapped using resting-state fMRI. We used the network-based statistic (NBS) to compare large-scale connectivity between groups and also compared the groups on graph metrics. We further assessed whether group differences identified using nodes defined from functionally defined RSNs were also evident when using anatomically defined nodes. In addition, we examined relations between network abnormalities and depression severity and duration. Finally, we compared intranetwork connectivity between groups and assessed the replication of previously reported MDD-related abnormalities in connectivity. The NBS indicated that, compared with controls, depressed adolescents exhibited reduced connectivity (p<0.024, corrected) between a specific set of RSNs, including components of the attention, central executive, salience, and default mode networks. The NBS did not identify group differences in network connectivity when using anatomically defined nodes. Longer duration of depression was significantly correlated with reduced connectivity in this set of network interactions (p=0.020, corrected), specifically with reduced connectivity between components of the dorsal attention network. The dorsal attention network was also characterized by reduced intranetwork connectivity in the MDD group. Finally, we replicated previously reported abnormal connectivity in individuals with MDD. In summary, adolescents with MDD show hypoconnectivity between large-scale brain networks compared with healthy controls. Given that connectivity among these networks typically increases during adolescent neurodevelopment, these results suggest that adolescent depression is associated with abnormalities in neural systems that are still developing during this critical period.

The development of an RDoC-based treatment program for adolescent depression: "Training for Awareness, Resilience, and Action" (TARA).

Major depressive disorder (MDD) is one of the current leading causes of disability worldwide. Adolescence is a vulnerable period for the onset of depression, with MDD affecting 8–20% of all youth. Traditional treatment methods have not been sufficiently effective to slow the increasing prevalence of adolescent depression. We therefore propose a new model for the treatment of adolescent depression – Training for Awareness, Resilience, and Action (TARA) – that is based on current understanding of developmental and depression neurobiology. The TARA model is aligned with the Research Domain Criteria (RDoC) of the National Institute of Mental Health. In this article, we first address the relevance of RDoC to adolescent depression. Second, we identify the major RDoC domains of function involved in adolescent depression and organize them in a way that gives priority to domains thought to be driving the psychopathology. Third, we select therapeutic training strategies for TARA based on current scientific evidence of efficacy for the prioritized domains of function in a manner that maximizes time, resources, and feasibility. The TARA model takes into consideration the developmental limitation in top-down cognitive control in adolescence and promotes bottom-up strategies such as vagal afference to decrease limbic hyperactivation and its secondary effects. The program has been informed by mindfulness-based therapy and yoga, as well as modern psychotherapeutic techniques. The treatment program is semi-manualized, progressive, and applied in a module-based approach designed for a group setting that is to be conducted one session per week for 12 weeks. We hope that this work may form the basis for a novel and more effective treatment strategy for adolescent depression, as well as broaden the discussion on how to address this challenge.