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  • 1.
    Blom, Eva Henje
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, Division of Child and Adolescent Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco (UCSF), San Francisco, CA, USA.
    Tymofiyeva, Olga
    Chesney, Margaret A.
    Ho, Tiffany C.
    Moran, Patricia
    Connolly, Colm G.
    Duncan, Larissa G.
    Baldini, Lisa
    Weng, Helen Y.
    Acree, Michael
    Goldman, Veronica
    Hecht, Frederick M.
    Yang, Tony T.
    Feasibility and Preliminary Efficacy of a Novel RDoC-Based Treatment Program for Adolescent Depression: "Training for Awareness Resilience and Action" (TARA)-A Pilot Study2017In: Frontiers in Psychiatry, ISSN 1664-0640, E-ISSN 1664-0640, Vol. 7, article id 208Article in journal (Refereed)
    Abstract [en]

    Background: The novel group treatment program Training for Awareness, Resilience, and Action (TARA) was developed to target specific mechanisms based on neuroscience findings in adolescent depression and framed within the National Institute of Mental Health Research Domain Criteria. TARA contains training of autonomic and emotional self-regulation, interoceptive awareness, relational skills, and value-based committed action.

    Methods: We performed a single-arm trial to test the feasibility and preliminary efficacy of TARA in reducing depression and anxiety levels and assessed whether the specific targeted domains of function reflected the hypothesized symptom change. Twenty-six adolescents (14–18 years old, 7 males and 19 females) participated in the 12-week group program. Assessment was performed before (T0), immediately after (T1), and 3 months after the end of TARA (T2).

    Results: Significant improvement was seen in depression symptoms (Reynolds Adolescent Depression Scale Second Edition) between T0–T1 (t-value = −3.56, p = 0.002, CI = −6.64, −1.77) and T0–T2 (t-value = −4.17, p < 0.001, CI = −11.20, −3.75) and anxiety symptoms (Multidimensional Anxiety Scale for Children) between T0–T1 (t-value = −2.26, p = 0.033, CI = −4.61, −0.21) and T0–T2 (t-value = −3.06, p = 0.006, 95% confidence interval = −9.02, −1.73). Significant improvements in psychological flexibility, sleep, and mindfulness skills were also found between T0 and T2.

    Limitations: The sample size was small without a control condition. The pilot design did not allow for testing the hypothesized brain changes and effect of TARA on relevant systemic biomarkers.

    Conclusion: TARA is feasible in a sample of clinically depressed and/or anxious adolescents and preliminary efficacy was demonstrated by reduced depression and anxiety symptoms. The specific symptom and behavioral outcomes corresponded well with the hypothesized mechanisms of change.

  • 2.
    Blomqvist, Ida
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Henje Blom, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Hägglöf, Bruno
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Hammarström, Anne
    Increase of internalized mental health symptoms among adolescents during the last three decades2019In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360XArticle in journal (Refereed)
    Abstract [en]

    Background: Previous studies suggest an overall increase of adolescent mental health symptoms globally since the 1980s until today, especially an increase of internalizing symptoms in girls. Due to methodological limitations of these studies, further studies are warranted to obtain a more solid knowledgebase.

    Methods: This study was cross-sectional and compared two separate but geographically identical groups of adolescents in a middle-sized industrial municipality in Northern Sweden at two time-points [(i) 1981, n = 1083, (505 girls, 577 boys), response rate 99.7%; (ii) 2014, n = 682, (338 girls, 344 boys), response rate 98.3%]. All students in their last year of compulsory school were included. The same self-report questionnaire, consisting of four sub-scales (functional somatic-, anxiety-, depressive symptoms and conduct problems), was used at both occasions. Data were analyzed with descriptive statistics, two-way ANOVA and general linear model.

    Results: Symptoms of anxiety and depression and functional somatic symptoms, increased among both boys and girls from 1981 until 2014 (P < 0.001 for all subscales), and the increase of these symptoms was higher in girls. Conduct problems were significantly higher in boys in 1981 and decreased over time so that in 2014 there was no longer a significant difference between boys and girls regarding conduct problems (P = 0.286).

    Conclusion: In this population-based study spanning over 30 years, both girls and boys showed increasing internalizing problems, while conduct problems decreased. To halt this trend, we need a deeper understanding of the impact of the major societal changes that have occurred during the last three decades.

  • 3. Connolly, Colm G.
    et al.
    Ho, Tiffany C.
    Henje Blom, Eva
    Department of Psychiatry, Division of Child and Adolescent Psychiatry, and Weill Institute for Neurosciences, University of California, San Francisco, 401 Parnassus Avenue, San Francisco, CA, USA; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    LeWinn, Kaja Z.
    Sacchet, Matthew D.
    Tymofiyeva, Olga
    Simmons, Alan N.
    Yang, Tony T.
    Resting-state functional connectivity of the amygdala and longitudinal changes in depression severity in adolescent depression2017In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 207, p. 86-94Article in journal (Refereed)
    Abstract [en]

    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.

  • 4.
    Henje Blom, Eva
    et al.
    Karolinska Institutet.
    Bech, Per
    Högberg, Göran
    Larsson, Jan Olov
    Serlachius, Eva
    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.2012In: Health and Quality of Life Outcomes, ISSN 1477-7525, E-ISSN 1477-7525, Vol. 10, article id 149Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Major 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).

    METHOD: 66 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.

    RESULTS: The 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).

    CONCLUSIONS: The 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.

  • 5.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Connolly, Colm G
    Ho, Tiffany C
    LeWinn, Kaja Z
    Mobayed, Nisreen
    Han, Laura
    Paulus, Martin P
    Wu, Jing
    Simmons, Alan N
    Yang, Tony T
    Altered insular activation and increased insular functional connectivity during sad and happy face processing in adolescent major depressive disorder.2015In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 178, p. 215-23, article id S0165-0327(15)00141-XArticle in journal (Refereed)
    Abstract [en]

    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.

  • 6.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Duncan, Larissa G
    Ho, Tiffany C
    Connolly, Colm G
    LeWinn, Kaja Z
    Chesney, Margaret
    Hecht, Frederick M
    Yang, Tony T
    The development of an RDoC-based treatment program for adolescent depression: "Training for Awareness, Resilience, and Action" (TARA).2014In: Frontiers in human neuroscience, Vol. 8, article id 630Article in journal (Refereed)
    Abstract [en]

    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.

  • 7.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Forsman, Mats
    Yang, Tony T
    Serlachius, Eva
    Larsson, Jan-Olov
    Latent Classes of Symptoms related to Clinically Depressed Mood in Adolescents.2014In: Scandinavian journal of child and adolescent psychiatry and psychology, Vol. 2, no 1, p. 19-28Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The diagnosis of major depressive disorder (MDD), according to the Diagnostic and Statistical Manual of Mental Disorders, is based only on adult symptomatology of depression and not adapted for age and gender. This may contribute to the low diagnostic specificity and validity of adolescent MDD. In this study, we investigated whether latent classes based on symptoms associated with depressed mood could be identified in a sample of adolescents seeking psychiatric care, regardless of traditionally defined diagnostic categories.

    METHODS: Self-reports of the Strengths and Difficulties Questionnaire and the Development and Well-Being Assessment were collected consecutively from all new patients between the ages of 13 and 17 years at two psychiatric outpatient clinics in Stockholm, Sweden. Those who reported depressed mood at intake yielded a sample of 21 boys and 156 girls. Latent class analyses were performed for all screening items and for the depression-specific items of the Development and Well-Being Assessment.

    RESULTS: The symptoms that were reported in association with depressed mood differentiated the adolescents into two classes. One class had moderate emotional severity scores on the Strengths and Difficulties Questionnaire and mainly symptoms that were congruent with the Diagnostic and Statistical Manual of Mental Disorders criteria for MDD. The other class had higher emotional severity scores and similar symptoms to those reported in the first class. However, in addition, this group demonstrated more diverse symptomatology, including vegetative symptoms, suicidal ideation, anxiety, conduct problems, body dysmorphic symptoms, and deliberate vomiting. The classes predicted functional impairment in that the members of the second class showed more functional impairment.

    LIMITATIONS: The relatively small sample size limited the generalizability of the results of this study, and the amount of items included in the analysis was restricted by the rules of latent class analysis. No conclusions about gender differences between the classes could be could be drawn as a result of the low number of boys included in the study.

    CONCLUSIONS: Two distinct classes were identified among adolescents with depressed mood. The class with highest emotional symptom severity score and the most functional impairment had a more diverse symptomatology that included symptoms that were not congruent with the traditional diagnostic criteria of MDD. However, this additional symptomatology is clinically important to consider. As a result, the clinical usefulness of the Diagnostic and Statistical Manual of Mental Disorders during the diagnostic process of adolescent depression is questioned.

  • 8.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Han, L K M
    Connolly, C G
    Ho, T C
    Lin, J
    LeWinn, K Z
    Simmons, A N
    Sacchet, M D
    Mobayed, N
    Luna, M E
    Paulus, M
    Epel, E S
    Blackburn, E H
    Wolkowitz, O M
    Yang, T T
    Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.2015In: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 5, article id e676Article in journal (Refereed)
    Abstract [en]

    Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.

  • 9.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Ho, Tiffany C.
    Connolly, Colm G.
    LeWinn, Kaja Z.
    Sacchet, Matthew D.
    Tymofiyeva, Olga
    Weng, Helen Y.
    Yang, Tony T.
    The neuroscience and context of adolescent depression2016In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 105, no 4, p. 358-365Article, review/survey (Refereed)
    Abstract [en]

    Adolescent depression is a growing public health concern with an increased risk of negative health outcomes, including suicide. The use of antidepressants and psychotherapy has not halted its increasing prevalence, and there is a critical need for effective prevention and treatment. We reviewed the neuroscience of adolescent depression, with a focus on the neurocircuitry of sustained threat and summarised contextual factors that have an impact on brain development and the pathophysiology of depression. We also reviewed novel treatment models.

    Conclusion: Attention to the relevant neurocircuitry and contextual factors implicated in adolescent depression is necessary to advance prevention and treatment development.

  • 10.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Larsson, Jan-Olov
    Serlachius, Eva
    Ingvar, Martin
    The differentiation between depressive and anxious adolescent females and controls by behavioural self-rating scales2010In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 122, no 3, p. 232-240Article in journal (Refereed)
    Abstract [en]

    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 Beck's Depression Inventory (BDI), Beck's 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.

  • 11.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Lekander, Mats
    Ingvar, Martin
    Åsberg, Marie
    Mobarrez, Fariborz
    Serlachius, Eva
    Pro-inflammatory cytokines are elevated in adolescent females with emotional disorders not treated with SSRIs.2012In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 136, no 3, p. 716-23Article in journal (Refereed)
    Abstract [en]

    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.

  • 12.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Olsson, E M
    Serlachius, E
    Ericson, M
    Ingvar, M
    Heart rate variability (HRV) in adolescent females with anxiety disorders and major depressive disorder.2010In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 99, no 4, p. 604-11Article in journal (Refereed)
    Abstract [en]

    AIM: The aim of this study was to investigate heart rate variability (HRV) in a clinical sample of female adolescents with anxiety disorders (AD) and/or major depressive disorder (MDD) compared with healthy controls and to assess the effect of selective serotonin reuptake inhibitors (SSRI) on HRV.

    METHODS: Heart rate variability was measured in adolescent female psychiatric patients with AD and/or MDD (n = 69), mean age 16.8 years (range: 14.5-18.4), from 13 out-patient clinics and in healthy controls (n = 65), mean age 16.5 years (range: 15.9-17.7). HRV was registered in the sitting position during 4 min with no interventions.

    RESULTS: Logarithmically transformed high frequency HRV (HF), low frequency HRV (LF) and standard deviation of inter beat intervals (SDNN) were lower in the clinical sample compared with the controls (Cohen's d for HF = 0.57, LF = 0.55, SDNN = 0.60). This was not explained by body mass index, blood pressure or physical activity. Medication with SSRI explained 15.5% of the total variance of HF, 3.0% of LF and 6.5% of SDNN.

    CONCLUSIONS: Adolescent female psychiatric patients with AD and/or MDD show reduced HRV compared with healthy controls. Medication with SSRI explained a part of this difference.

  • 13.
    Henje Blom, Eva
    et al.
    Department of Clinical Neuroscience, Osher Center for Integrative Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
    Olsson, Erik M G
    Serlachius, Eva
    Ericson, Mats
    Ingvar, Martin
    Heart rate variability is related to self-reported physical activity in a healthy adolescent population2009In: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 106, no 6, p. 877-883Article in journal (Refereed)
    Abstract [en]

    This study investigated whether there is a relationship between heart rate variability (HRV) versus lifestyle and risk factors for cardiovascular disease in a population of healthy adolescents. HRV is as an index of tonic autonomic activity and in adults HRV is related to lifestyle and risk factors for cardiovascular disease, but it is not known if this is the case in adolescents. HRV was registered for 4 min in sitting position in 99 healthy adolescents (age range 15 years 11 months-17 years 7 months) and repeated after 6 months. On both occasions there were significant correlations (P < 0.05) between physical activity and HRV, with respective r values: high frequency (HF) 0.26, 0.30; low frequency power (LF) 0.35, 0.29 and the standard deviation of inter-beat intervals (SDNN) 0.28, 0.37. There was no significant interaction between first and second measurements. In contrast, there were no correlations to sleeping patterns, eating habits and smoking. Risk factors for cardiovascular disease [body mass index (BMI = weight (kg)/length in m(2)), systolic blood pressure and p-glucose] did not show any repeatable significant correlations to HRV. Multiple regression models showed that physical activity was a predictor for HF, LF and SDNN in both measurements. In conclusion HF, LF and SDNN were reproducible after 6 months and were related to physical activity on both occasions.

  • 14.
    Henje Blom, Eva
    et al.
    Karolinska Institutet.
    Serlachius, Eva
    Chesney, Margaret A
    Olsson, Erik M G
    Adolescent girls with emotional disorders have a lower end-tidal CO2 and increased respiratory rate compared with healthy controls.2014In: Psychophysiology, ISSN 1540-5958, Vol. 51, no 5, p. 412-8Article in journal (Refereed)
    Abstract [en]

    Hyperventilation has been linked to emotional distress in adults. This study investigates end-tidal carbon dioxide (ETCO2 ), respiratory rate (RR), and heart rate variability (HRV) in adolescent girls with emotional disorders and healthy controls. ETCO2 , RR, HRV, and ratings of emotional symptom severity were collected in adolescent female psychiatric patients with emotional disorders (n = 63) and healthy controls (n = 62). ETCO2 and RR differed significantly between patients and controls. ETCO2, HR, and HRV were significant independent predictors of group status, that is, clinical or healthy, while RR was not. ETCO2 and RR were significantly related to emotional symptom severity and to HRV in the total group. ETCO2 and RR were not affected by use of selective serotonin reuptake inhibitors. It is concluded that emotional dysregulation is related to hyperventilation in adolescent girls. Respiratory-based treatments may be relevant to investigate in future research.

  • 15.
    Henje Blom, Eva
    et al.
    Karolinska Institutet, University of California San Francsisco.
    Serlachius, Eva
    Larsson, Jan-Olov
    Theorell, Töres
    Ingvar, Martin
    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.2010In: Health and Quality of Life Outcomes, ISSN 1477-7525, E-ISSN 1477-7525, Vol. 8, article id 58Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The 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.

    METHODS: The SOC-scale, Beck's Depression Inventory (BDI), Beck's 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.

    RESULTS: The 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.

    CONCLUSIONS: The 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.

  • 16. Ho, Tiffany C
    et al.
    Connolly, Colm G
    Henje Blom, Eva
    Karolinska Institutet, University of California San Francsisco.
    LeWinn, Kaja Z
    Strigo, Irina A
    Paulus, Martin P
    Frank, Guido
    Max, Jeffrey E
    Wu, Jing
    Chan, Melanie
    Tapert, Susan F
    Simmons, Alan N
    Yang, Tony T
    Emotion-Dependent Functional Connectivity of the Default Mode Network in Adolescent Depression.2015In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 78, no 9, p. 635-46, article id S0006-3223(14)00697-0Article in journal (Refereed)
    Abstract [en]

    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.

  • 17. Ho, Tiffany C
    et al.
    Yang, Guang
    Wu, Jing
    Cassey, Pete
    Brown, Scott D
    Hoang, Napoleon
    Chan, Melanie
    Connolly, Colm G
    Henje Blom, Eva
    Karolinska Institutet, University of California San Francsisco.
    Duncan, Larissa G
    Chesney, Margaret A
    Paulus, Martin P
    Max, Jeffrey E
    Patel, Ronak
    Simmons, Alan N
    Yang, Tony T
    Functional connectivity of negative emotional processing in adolescent depression.2014In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 155, p. 65-74, article id S0165-0327(13)00767-2Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The subgenual anterior cingulate cortex (sgACC) and its connected circuitry have been heavily implicated in emotional functioning in adolescent-onset major depressive disorder (MDD). While several recent studies have examined sgACC functional connectivity (FC) in depressed youth at rest, no studies to date have investigated sgACC FC in adolescent depression during negative emotional processing.

    METHODS: Nineteen medication-naïve adolescents with MDD and 19 matched healthy controls (HCL) performed an implicit fear facial affect recognition task during functional magnetic resonance imaging (fMRI). We defined seeds in bilateral sgACC and assessed FC using the psychophysiological interaction method. We also applied cognitive behavioral modeling to estimate group differences in perceptual sensitivity in this task. Finally, we correlated connectivity strength with clinical data and perceptual sensitivity.

    RESULTS: Depressed adolescents showed increased sgACC-amygdala FC and decreased sgACC-fusiform gyrus, sgACC-precuneus, sgACC-insula, and sgACC-middle frontal gyrus FC compared to HCL (p<0.05, corrected). Among the MDD, sgACC-precuneus FC negatively correlated with depression severity (p<0.05, corrected). Lastly, MDD adolescents exhibited poorer perceptual sensitivity in the task than HCL, and individual differences in perceptual sensitivity significantly correlated with sgACC FC and depression scores (p<0.05, corrected).

    LIMITATIONS: Subjects were clinically homogenous, possibly limiting generalizability of the findings.

    CONCLUSIONS: Adolescent depression is associated with biased processing of negative stimuli that may be driven by sgACC dysregulation and may possibly lead to an imbalance among intrinsic functional brain networks. This work also establishes the use of combining neuroimaging and cognitive behavioral modeling methods to investigate cognitive and neural differences between psychiatric and healthy populations.

  • 18. Ho, Tiffany C.
    et al.
    Zhang, Shunan
    Sacchet, Matthew D.
    Weng, Helen
    Connolly, Colm G.
    Henje Blom, Eva
    Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA; Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Han, Laura K. M.
    Mobayed, Nisreen O.
    Yang, Tony T.
    Fusiform gyrus dysfunction is associated with perceptual processing efficiency to emotional faces in adolescent depression: a model-based approach2016In: Frontiers in Psychology, ISSN 1664-1078, E-ISSN 1664-1078, Vol. 7, article id 40Article in journal (Refereed)
    Abstract [en]

    While the extant literature has focused on major depressive disorder (MDD) as being characterized by abnormalities in processing affective stimuli (e.g., facial expressions), little is known regarding which specific aspects of cognition influence the evaluation of affective stimuli, and what are the underlying neural correlates. To investigate these issues, we assessed 26 adolescents diagnosed with MDD and 37 well-matched healthy controls (HCL) who completed an emotion identification task of dynamically morphing faces during functional magnetic resonance imaging (fMRI). We analyzed the behavioral data using a sequential sampling model of response time (RT) commonly used to elucidate aspects of cognition in binary perceptual decision making tasks: the Linear Ballistic Accumulator (LBA) model. Using a hierarchical Bayesian estimation method, we obtained group-level and individual-level estimates of LBA parameters on the facial emotion identification task. While the MDD and HCL groups did not differ in mean RT, accuracy, or group-level estimates of perceptual processing efficiency (i.e., drift rate parameter of the LBA), the MDD group showed significantly reduced responses in left fusiform gyrus compared to the HCL group during the facial emotion identification task. Furthermore, within the MDD group, fMRI signal in the left fusiform gyrus during affective face processing was significantly associated with greater individual-level estimates of perceptual processing efficiency. Our results therefore suggest that affective processing biases in adolescents with MDD are characterized by greater perceptual processing efficiency of affective visual information in sensory brain regions responsible for the early processing of visual information. The theoretical, methodological, and clinical implications of our results are discussed.

  • 19. LeWinn, Kaja Z.
    et al.
    Strigo, Irina A.
    Connolly, Colm G.
    Ho, Tiffany C.
    Tymofiyeva, Olga
    Sacchet, Matthew D.
    Weng, Helen Y.
    Henje Blom, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Simmons, Alan N.
    Yang, Tony T.
    An exploratory examination of reappraisal success in depressed adolescents: Preliminary evidence of functional differences in cognitive control brain regions2018In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 240, p. 155-164Article in journal (Refereed)
    Abstract [en]

    Background: Most neuroimaging studies of adolescent depression employ tasks not designed to engage brain regions necessary for the cognitive control of emotion, which is central to many behavioral therapies for depression. Depressed adults demonstrate less effective activation of these regions and greater amygdala activation during cognitive reappraisal; we examined whether depressed adolescents show similar patterns of brain activation.

    Methods: We collected functional magnetic resonance imaging (fMRI) data during cognitive reappraisal in 41 adolescents with major depressive disorder (MDD) and 34 matched controls (ages 13-17). We examined group differences in (1) activations associated with reappraisal and reappraisal success (i.e., negative affect reduction during reappraisal) using whole brain and amygdala region-of-interest analyses, and (2) functional connectivity of regions from the group-by-reappraisal success interaction.

    Results: We found no significant group differences in whole brain or amygdala analyses during reappraisal. In the group-by-reappraisal success interaction, activations in the left dorsomedial prefrontal cortex (dmPFC) and left dorsolateral PFC (dlPFC) were associated with reappraisal success in healthy controls but not depressed adolescents. Depressed adolescents demonstrated reduced connectivity between the left dmPFC and the anterior insula/inferior frontal gyri bilaterally (AI/IFG) and between left dlPFC and left AI/IFG.

    Limitations: Our results should be considered exploratory given our less conservative statistical threshold in the group-by-reappraisal interaction.

    Conclusions: We find preliminary evidence that depressed adolescents engage cognitive control regions less efficiently than healthy controls, suggesting delayed maturation of regulatory prefrontal cortex regions; more research is needed to determine whether cognitive therapies improve functioning of these regions in depressed youth.

  • 20. Sacchet, Matthew D.
    et al.
    Ho, Tiffany C.
    Connolly, Colm G.
    Tymofiyeva, Olga
    Lewinn, Kaja Z.
    Han, Laura K.M.
    Henje Blom, Eva
    Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden; Department of Psychiatry, Division of Child and Adolescent Psychiatry, University of California San Francisco, San Francisco, CA, USA.
    Tapert, Susan F.
    Max, Jeffrey E.
    Frank, Guido K.W.
    Paulus, Martin P.
    Simmons, Alan N.
    Gotlib, Ian H.
    Yang, Tony T.
    Large-scale hypoconnectivity between resting-state functional networks in unmedicated adolescent major depressive disorder2016In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, no 12, p. 2951-2960Article in journal (Refereed)
    Abstract [en]

    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.

  • 21. Schmalzl, Laura
    et al.
    Powers, Chivon
    Henje Blom, Eva
    Karolinska Institutet, University of California San Francsisco.
    Neurophysiological and neurocognitive mechanisms underlying the effects of yoga-based practices: towards a comprehensive theoretical framework.2015In: Frontiers in human neuroscience, Vol. 9, article id 235Article in journal (Refereed)
    Abstract [en]

    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.

  • 22. Tymofiyeva, Olga
    et al.
    Connolly, Colm G.
    Ho, Tiffany C.
    Sacchet, Matthew D.
    Henje Blom, Eva
    Department of Psychiatry, University of California San Francisco, United States; Department of Clinical Neuroscience, Karolinska Institute, Sweden.
    LeWinn, Kaja Z.
    Xu, Duan
    Yang, Tony T.
    DTI-based connectome analysis of adolescents with major depressive disorder reveals hypoconnectivity of the right caudate2017In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 207, p. 18-25Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Adolescence is a vulnerable period for the onset of major depressive disorder (MDD). While some studies have shown white matter alterations in adolescent MDD, there is still a gap in understanding how the brain is affected at a network level.

    METHODS: We compared diffusion tensor imaging (DTI)-based brain networks in a cohort of 57 adolescents with MDD and 41 well-matched healthy controls who completed self-reports of depression symptoms and stressful life events. Using atlas-based brain regions as network nodes and tractography streamline count or mean fractional anisotropy (FA) as edge weights, we examined weighted local and global network properties and performed Network-Based Statistic (NBS) analysis.

    RESULTS: While there were no significant group differences in the global network properties, the FA-weighted node strength of the right caudate was significantly lower in depressed adolescents and correlated positively with age across both groups. The NBS analysis revealed a cluster of lower FA-based connectivity in depressed subjects centered on the right caudate, including connections to frontal gyri, insula, and anterior cingulate. Within this cluster, the most robust difference between groups was the connection between the right caudate and middle frontal gyrus. This connection showed a significant diagnosis by stress interaction and a negative correlation with total stress in depressed adolescents.

    LIMITATIONS: Use of DTI-based tractography, one atlas-based parcellation, and FA values to characterize brain networks represent this study's limitations.

    CONCLUSIONS: Our results allowed us to suggest caudate-centric models of dysfunctional processes underlying adolescent depression, which might guide future studies and help better understand and treat this disorder.

  • 23. Tymofiyeva, Olga
    et al.
    Henje Blom, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry. Department of Psychiatry and Weill Institute for Neurosciences, University of California San Francisco, United States.
    Ho, Tiffany C.
    Connolly, Colm G.
    Lindqvist, Daniel
    Wolkowitz, Owen M.
    Lin, Jue
    LeWinn, Kaja Z.
    Sacchet, Matthew D.
    Han, Laura K. M.
    Yuan, Justin P.
    Bhandari, Sarina P.
    Xu, Duan
    Yang, Tony T.
    High levels of mitochondrial DNA are associated with adolescent brain structural hypoconnectivity and increased anxiety but not depression2018In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 232, p. 283-290Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Adolescent anxiety and depression are highly prevalent psychiatric disorders that are associated with altered molecular and neurocircuit profiles. Recently, increased mitochondrial DNA copy number (mtDNA-cn) has been found to be associated with several psychopathologies in adults, especially anxiety and depression. The associations between mtDNA-cn and anxiety and depression have not, however, been investigated in adolescents. Moreover, to date there have been no studies examining associations between mtDNA-cn and brain network alterations in mood disorders in any age group.

    METHODS: The first aim of this study was to compare salivary mtDNA-cn between 49 depressed and/or anxious adolescents and 35 well-matched healthy controls. The second aim of this study was to identify neural correlates of mtDNA-cn derived from diffusion tensor imaging (DTI) and tractography, in the full sample of adolescents.

    RESULTS: There were no diagnosis-specific alterations in mtDNA-cn. However, there was a positive correlation between mtDNA-cn and levels of anxiety, but not depression, in the full sample of adolescents. A subnetwork of connections largely corresponding to the left fronto-occipital fasciculus had significantly lower fractional anisotropy (FA) values in adolescents with higher than median mtDNA-cn.

    LIMITATIONS: Undifferentiated analysis of free and intracellular mtDNA and use of DTI-based tractography represent this study's limitations.

    CONCLUSIONS: The results of this study help elucidate the relationships between clinical symptoms, molecular changes, and neurocircuitry alterations in adolescents with and without anxiety and depression, and they suggest that increased mtDNA-cn is associated both with increased anxiety symptoms and with decreased fronto-occipital structural connectivity in this population.

  • 24. Yuan, Justin P.
    et al.
    Henje Blom, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry. Department of Psychiatry and the Langley Porter Psychiatric Institute Weill Institute for Neurosciences University of California, San Francisco.
    Flynn, Trevor
    Chen, Yiran
    Ho, Tiffany C.
    Connolly, Colm G.
    Dumont Walter, Rebecca A.
    Yang, Tony T.
    Xu, Duan
    Tymofiyeva, Olga
    Test-retest reliability of graph theoretic metrics in adolescent brains2019In: Brain Connectivity, ISSN 2158-0014, E-ISSN 2158-0022, Vol. 9, no 2, p. 144-154Article in journal (Refereed)
    Abstract [en]

    Graph theory analysis of structural brain networks derived from diffusion tensor imaging (DTI) has become a popular analytical method in neuroscience, enabling advanced investigations of neurological and psychiatric disorders. The purpose of this study was to investigate: 1) the effects of edge weighting schemes, and 2) the effects of varying interscan periods on graph metrics' test-retest reliability within the adolescent brain. We compared a binary (B) network definition with three weighting schemes: fractional anisotropy (FA), streamline count (SC), and streamline count with density and length correction (SDL). Two commonly used global and two local graph metrics were examined. The analysis was conducted with two groups of adolescent volunteers who received DTI scans either 12 weeks apart (16.62±1.10yrs) or within the same scanning session (30 minutes apart) (16.65±1.14yrs). The intraclass correlation coefficient (ICC) was used to assess test-retest reliability and the coefficient of variation (CV) was used to assess precision. On average, each edge scheme produced reliable results at both time intervals. Weighted measures outperformed binary measures, with SDL-weights producing the most reliable metrics. All edge schemes except FA displayed high CV values, leaving FA as the only edge scheme that consistently showed high precision while also producing reliable results. Overall findings suggest that FA-weights are more suited for DTI connectome studies in adolescents.

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