The addition of the new variable to dr. singh’s study could be thought of as which of the following?

• Bio
• Research & Scholarship
• Teaching
• Publications

Bio

Dr. Singh is Associate Professor of Psychiatry and Behavioral Sciences and her multidisciplinary research investigates the neurobiology underlying mood disorders and related psychiatric conditions. Her team uses a clinical translational approach to examine neural circuit dynamics in the human brain in order to ascertain neurobiological correlates of behavior. A major focus of the research is directed to risk factors of mood disorders including genetics as well as developmental exposure and adaptation to early life and family environmental stress. Her team also conducts human clinical trials in developing novel therapies for youth onset mood disorders.

The Stanford Pediatric Mood Disorders Research Program promotes healthy brain development across the lifespan through a deeper understanding of how youth adapt to mood symptoms and stress to have successful transitions into adulthood. The program's bold vision is to prevent chronic and progressive mood disorder and to improve the mental health of children, adolescents, young adults, and families through globally recognized research, education, and innovation. The program’s research is multidisciplinary, bringing together experts from the fields of psychiatry, psychology, neuroscience, computer science, biostatistics, genetics, regulatory, and industry to seek answers for complex questions related to brain-behavior-environment relations in developing youth with and at risk for mood disorders, and to accelerate discovery of novel therapeutic strategies.

Clinical Focus

• Psychiatry
• Child and Adolescent Psychiatry

Academic Appointments

Administrative Appointments

• Faculty Affiliate, Wu Tang Neurosciences Institute (2019 - Present)

• Member, Education Committee, Child Health Research Institute (2018 - Present)

• Member, Stanford Diabetes Research Center (2017 - Present)

Honors & Awards

• Virginia Q. Anthony Outstanding Woman Leader Award, American Academy of Child and Adolescent Psychiatry (2021)

• Best Paper in Depression/Suicide published in JAACAP, Klingenstein Third Generation Foundation and American Academy of Child and Adolescent Psychiatry (2019)

• Blanche F. Ittleson Award for Research in Child/Adolescent Psychiatry, American Psychiatric Association (APA) and APA Foundation (2019)

• Chairman's Award for Excellence in Research, Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences (2018)

• Samuel Gershon Award for Junior Investigators, International Society for Bipolar Disorders (2014)

• Honorable Mention for the Gerald R. Klerman Award for Outstanding Clinical Research Achievement, Brain and Behavior Research Foundation (2012)

• NCDEU New Investigator Award, American Society of Clinical Psychopharmacology (2011)

• Distinguished Young Alumni Award, Michigan State University (2010)

• Depression Fellow, Klingenstein Third Generation Foundation (2008-2010)

• Young Investigator Award, NARSAD (2008-2010)

• Pediatric Loan Repayment Program, National Institutes of Health (2007-2011)

• Dean's Fellowship for Post-doctoral Scholars, Stanford University School of Medicine (2007, 2008)

• Resident Research Award, American Psychiatric Association (2007)

• Adolescent Medicine Award, Cincinnati Children's Hospital Medical Center (2006-2007)

Boards, Advisory Committees, Professional Organizations

• Editorial Board, Journal of the American Academy of Child and Adolescent Psychiatry (2014 - Present)

• Council Member, Society for Biological Psychiatry (2019 - 2021)

• Co-Chair of the Research Committee, American Academy of Child and Adolescent Psychiatry (2017 - Present)

• Child & Adolescent Mood Disorders Task Group Member, National Network of Depression Centers (2013 - Present)

Professional Education

• Medical Education: Michigan State University College of Human Medicine Office of the Registrar (2002) MI

• Board Certification: American Board of Psychiatry and Neurology, Child and Adolescent Psychiatry (2010)

• Board Certification: American Board of Psychiatry and Neurology, Psychiatry (2009)

• Fellowship: Cincinnati Children's Hospital (2007) OH

• Residency: Cincinnati Children's Hospital (2007) OH

• Internship: Cincinnati Children's Hospital (2007) OH

• M.S., University of Michigan, Clinical Research & Statistics (2007)

• Board Certification, Psychiatry, American Board of Psychiatry and Neurology (2009)

• Board Certification, Child and Adolescent Psychiatry, ABPN (2010)

Community and International Work

• Tropical Pediatrics in Africa, Ndola, Zambia

  Topic

  Preventing the spread of infection through education

  Partnering Organization(s)

  Arthur Davison Hospital

  Populations Served

  Children across Zambia

  Location

  International

  Ongoing Project

  No

  Opportunities for Student Involvement

  Yes

Contact

Additional Info

Current Research and Scholarly Interests

Dr. Singh’s research investigates the developmental psychopathology, pathophysiology, and treatment of pediatric mood disorders, as well as methods to protect and preserve function before and after the onset of depression or mania. Using an integration of clinical, neuroimaging, genetic, and neuroendocrine tools, her research aims to explore the complex risk factors associated with the development of serious mood disorders in children and adolescents. Dr. Singh and her collaborators have also been actively exploring pharmacological and psychotherapeutic methods of treating mood symptoms associated with and leading up to these disorders in youth. Through national collaborations, she is examining the benefits of a combination of family focused psychotherapy with medication in youth offspring of parents with bipolar disorder to reduce mood symptoms and family stress. In addition, she and her group have been conducting studies examining the neuroimaging effects pharmacological and psychosocial interventions – specifically exploring whether such interventions can reduce limbic hyperactivity and increase prefrontal cognitive control. These areas of research aspire to advance understanding of the core mechanisms, endophenotypes, and early interventions for pediatric onset mood disorders. Dr. Singh has been awarded several NIMH awards integrating innovative neuroimaging techniques and mechanisms of emotion regulation to understand the neurodevelopmental basis of mood disorders among children.

Dr. Singh has received many honors through the course of her career, including the NARSAD Young Investigator Award, the Klingenstein Third Generation Foundation Depression Fellowship, the American Psychiatric Association’s Young Minds in Psychiatry Award and Blanche F. Ittleson Award for Research in Child/Adolescent Psychiatry, Michigan State University’s Distinguished Young Alumni Award,and the American Academy of Child and Adolescent Psychiatry's Virginia Q. Anthony Outstanding Woman Leader Award. She was also selected as the Akiko Yamazaki and Jerry Yang Faculty Scholar in Pediatric Translational Medicine.

Dr. Singh earned her MD at Michigan State University and her MS at University of Michigan. She completed her combined residency in Pediatrics, Psychiatry, and Child and Adolescent Psychiatry at Cincinnati Children’s Hospital Medical Center. After two years of neuroimaging training at the Center for Interdisciplinary Brain Sciences Research at Stanford University, she joined the faculty at Stanford in 2009.

Clinical Trials

• A Study of the Relationship of Psychosocial Function With Mood Symptoms in Offspring of Parents With Bipolar Disorder Not Recruiting

  The primary purpose of this study is to compare, over 24 months, the time spent with clinically significant mood symptoms (ie, mania, depression), as measured by the Longitudinal Interval Follow-Up Evaluation (LIFE) and the Psychiatric Status Rating Scale (PSR), in offspring of bipolar parents with and without at least mild impairment in psychosocial functioning.

  Stanford is currently not accepting patients for this trial. For more information, please contact Spectrum Child Health, 650-724-1175.

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• iTBS in Refractory Pediatric Depression Not Recruiting

  This work will mark the first step in understanding the neural targets for rTMS in youth with difficult to treat depressive symptoms, creating benchmarks for optimizing the safety and efficacy of rTMS for pediatric populations through precision targeting, and encourage funding applications for larger sham- controlled randomized clinical studies.

  Stanford is currently not accepting patients for this trial. For more information, please contact Romina Nejad, BS, 650-497-3933.

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• Mechanism of Antidepressant-Related Dysfunctional Arousal in High-Risk Youth Not Recruiting

  A 16-week double blind, placebo-controlled investigation of escitalopram in adolescents with depression and/or anxiety with a family history of Bipolar Disorder. Subjects will be evaluated using semi-structured diagnostic interviews and symptom ratings, participate in a MRI scan and then randomized to treatment. Following randomization, high-risk youth will have visits every week for the first 4 weeks of treatment then biweekly up to 16 weeks during which time tolerability and ratings will be performed. MRI scan will be repeated at week 4.

  Stanford is currently not accepting patients for this trial. For more information, please contact Manpreet K Singh, MD MS, 650-725-5922.

  View full details

Projects

• MOMENTUM - Measuring Obesity and Mood Effects on Neurobehavioral ThroUgh Maturation, Stanford University (September 16, 2015 - June 30, 2020)

  Depression and obesity are reaching epidemic proportions in American youth today, and when they co-occur, they may have compounding deleterious effects, including the development of impaired insulin sensitivity toward insulin resistance (a precursor to diabetes in which cells fail to respond to the normal actions of the hormone insulin). Traditionally, depression and impaired insulin sensitivity have been compartmentalized as separate emotional and physical health syndromes. However, recent evidence suggests interactions and common neurobehavioral pathways between these syndromes that can lead to worsening depressive symptoms. To date, no study has investigated the underlying mechanisms or risk factors for developing worsening of depressive symptoms in youth with depression and impaired insulin sensitivity.
  There is a pressing clinical need to better identify which youth with depression and impaired insulin sensitivity are most likely to develop worsening depressive symptoms, as current pharmacological and dietary/lifestyle strategies to overcome the burgeoning threat of lifelong depression and obesity are of limited efficacy, have adverse side effects, and in most cases are not curative. Compelling recent data have shown that depressed youth, independent of changes in weight, have early disruptions of neurobiological systems critical for the response and regulation of reward, most notably in the nucleus accumbens, anterior cingulate cortex, insula, and amygdala neural reward circuit. This Research has implicated involvement of the Approach Motivation construct of the NIMH Research Domain Criteria (RDoC) Positive Valence Systems, which describes fundamental aspects of reward dysfunction when youth with depression engage in unhealthy lifestyle behaviors (e.g. overeating) that place them at high risk for progressively worsening depressive symptoms.
  This proposal aims to use an RDoC framework in the first prospective study to investigate the mechanisms and risk factors for worsening depressive symptoms that are associated with dysfunctional Approach Motivation in youth with depression and impaired insulin sensitivity. To accomplish these aims, 120 overweight girls and boys (ages 9-15 years) seeking treatment for moderate to severe depressive symptoms, will be assessed at baseline, 6 months, and 24 months with cognitive and behavioral markers of Approach Motivation, serum markers of insulin sensitivity, and clinical markers of depression. Youth will be scanned with multimodal MRI at baseline and at 6 months. We aim to determine whether worsening depressive symptoms in youth with depression and impaired insulin sensitivity is mediated by changes in neural reward circuitry, and to identify clinical, demographic, and familial risk factors for developing worsening depression in these youth. This knowledge will be vitally important to mental health and primary care professionals who have limited empirical evidence on which to base their practice. It also has potential to inform the pathophysiology of other disorders associated with dysfunctional approach motivation and to catalyze the development of novel treatment targets.

  Location

  Stanford, CA

  Collaborators

  • Natalie Rasgon, Dr, Department of Psychiatry and Behavioral Sciences
  • Cara Bohon, Clinical Assistant Professor, Stanford University
  • Booil Jo, Prof, Stanford University
  • Jack Yanovski, Chief, Section on Growth and Obesity, PDEGEN, National Institute of Child Health and Human Development

• Risk and Resilience (R&R) Study, Stanford University (September 1, 2013 - August 31, 2018)

  The conceptual overview for this study is based on 4 key challenges: (a) family history is the strongest risk factor for developing mood disorders in childhood, including major depressive (MDD) or bipolar (BD) disorder, but the mechanisms underlying this risk are unknown; (b) mood disorders in childhood are complicated by diagnostic confusion, which can lead to improper or delayed treatments; (c) multivariate analyses have been underutilized for differentiating etiological risks of BD from MDD or for predicting outcome, and (d) not all youth of parents with BD or MDD develop symptoms suggesting that some are resilient to developing mood disorders. However, the neurobiological basis of resilience from mood disorders is unknown. This project aims to provide innovative solutions to these challenges by charting the evolution of mood symptoms in youth at risk starting from health in order to understand ideal times and methods for intervention. To accomplish these aims, we are conducting an integrative study of 150 families comprised of fathers, mothers, and gender balanced healthy youth, ages 8-15 years: 50 healthy offspring will be of parents with BD, 50 healthy offspring will be of parents with MDD, and 50 healthy controls will have no family history of psychopathology. After screening for eligibility, youth will complete interviews and questionnaires confirming absence of any symptoms of psychopathology and neurocognitive assessments at baseline; they will also do home collection of diurnal cortisol over 2 days, and then return to the lab for an MRI scan. Youth will return for an 18-month clinical follow-up.

  Location

  401 Quarry Road, Stanford, CA 94305

• Mechanisms of Antidepressant Related Dysfunctional Arousal in High Risk Youth, Stanford University and University of Cincinnati (September 23, 2015 - July 31, 2020)

  Antidepressants are commonly prescribed medications used by American youth today to treat a variety of childhood onset psychiatric disorders. However, serious psychiatric adverse events may also emerge from antidepressant use including irritability, agitation, elevated mood, and other adverse events associated with increased dysfunctional emotional arousal. For some youth, these adverse events lead to the development of lifelong psychopathologies such as bipolar disorder. Importantly, the mechanisms through which antidepressants increase risk for developing these adverse events are largely unknown. Moreover, there is a pressing clinical need to better identify which youth taking antidepressants will develop adverse outcomes.
  Youth who are highly likely to develop adverse responses to antidepressants are those who are already vulnerable to developing dysfunctional emotional arousal. Compelling data from family studies have shown that youth with a family history of bipolar disorder have high rates of major mood and other disorders of emotional arousal, and demonstrate early disruptions of neurobiological systems critical for the regulation of emotional arousal, most notably in the amygdala and ventrolateral prefrontal cortex (VLPFC) neural circuit. Antidepressants are commonly used to treat dysfunctional emotional arousal in high-risk youth; however, they may also increase and accelerate the onset of mood disorders in some of these youth.
  Research has implicated involvement of the Arousal construct of the NIMH Research Domain Criteria (RDoC) Arousal and Regulatory Systems, which describes fundamental aspects of emotional dysfunction when youth experience an adverse antidepressant-related psychiatric event. This proposal aims to use an RDoC framework in a randomized trial to investigate the etiological mechanisms and risk factors associated with antidepressant-related dysfunctional emotional arousal in high-risk youth. To accomplish these aims, 150 (75/site) high-risk youth, i.e. having at least one first- or second-degree relative with bipolar I disorder, who have moderate to severe depression or anxiety symptoms, will be randomized to receive double-blind treatment either with psychotherapy plus escitalopram or psychotherapy plus placebo. Prior to randomization, we will collect baseline magnetic resonance imaging (MRI), behavioral, and physiological measures of arousal. After randomization, youth will undergo a second MRI scan at 4 weeks, and then will be clinically assessed for up to 16 weeks to evaluate for changes in arousal. We aim to determine whether antidepressant-related changes in arousal are mediated by changes in amygdala-VLPFC circuitry, and to identify neurobiological risk factors for developing dysfunctional arousal. This knowledge will be vitally important to mental health professionals who have limited empirical evidence on which to base their treatment of youth most vulnerable for emotion dysregulation. It also has potential to inform the pathophysiology of disorders associated with dysfunctional emotional arousal and the development of novel targets for treating this complex problem.

  Location

  401 Quarry Road, Stanford, CA 94305

  Collaborators

  • Allan Reiss, Stanford University
  • Booil Jo, Prof, Stanford University
  • Kiki Chang, Professor, Stanford University
  • Gary Glover, Professor of Radiology (General Radiology) and, by courtesy, of Psychology and of Electrical Engineering, Stanford University
  • Melissa DelBello, Professor and Chair of Psychiatry , University of Cincinnati
  • David Miklowitz, Professor, UCLA

• Neurodevelopmental Features of Sexual Dimorphism in Pediatric Psychopathology, Stanford University (August 4, 2015 - July 31, 2016)

  Sex differences in psychiatric disorders are common and occur early in development. The etiologic pathways that lead to sex differences in psychiatric disorders stem from complex interactions among clinical, cognitive, genetic, and neural factors that vary as a function of developmental stage. Past studies have been insufficiently powered in the size of their samples and the number of measures assessed to model these risk factors systematically within or between girls and boys, within or across multiple psychiatric disorders, or across developmental stages. Because of these limitations, we do not have a comprehensive understanding of the neurobiology of sex differences in childhood-onset psychiatric disorders, which has hindered timely diagnosis and treatment.
  Given that current pharmacological and psychotherapeutic strategies to address the burgeoning threat of lifelong psychiatric disorders are of limited efficacy, have adverse side-effects, and in most cases are not curative, there is a pressing clinical need to identify early risk factors for the development of psychiatric disorders. Compelling recent data in children have implicated anomalies throughout development in neural circuitry that is critical for cognitive processing, most notably in prefrontal, limbic, and striatal neural circuits, that may be transdiagnostic and conditioned on sex. Moreover, advances in genetic pathways associated with key cognitive regulatory functions have been translated into increased characterization of the neurocircuitry that subserves psychiatric disorders.
  This proposal aims to leverage the large multimodal dataset of the Philadelphia Neurodevelopmental Cohort (PNC) to address the pressing questions of which core risk factors predict specific psychiatric disorders conditioned on sex (i.e., within girls and within boys), which factors explain sexual dimorphism in childhood-onset psychiatric disorders, and when sex differences in psychiatric disorders emerge. To accomplish these aims, we will use state-of-the-art high-dimensional modeling methods to develop a parsimonious risk model that integrates clinical, cognitive, genetic, and neural factors in the PNC database to predict sex differences in childhood-onset psychiatric disorders. We will model clinical, cognitive, and genetic data from a large cohort of almost 10,000 boys and girls who are between the ages of 8-21 years, and neuroimaging data in a subset of ~1,500 youth. The PNC database includes measures of normal and abnormal functioning across a wide age range to enable comparisons of outcomes in psychiatric disorders across age and in developmental subgroups. Understanding how clinical, cognitive, genetic, and neural factors interact in the development of sex differences in psychiatric disorders will provide more precise neurobiologically-informed treatment targets.

  Location

  401 Quarry Road, Stanford, CA 94305

  Collaborators

  • Joachim Hallmayer, Associate Professor of Psychiatry and Behavioral Sciences, Stanford University
  • Ian Gotlib, Stanford University

2022-23 Courses

• Independent Studies (8)
  • Directed Reading in Psychiatry
    PSYC 299 (Aut, Win, Spr, Sum)
  • Graduate Research
    NEPR 399 (Aut, Win, Spr, Sum)
  • Graduate Research
    PSYC 399 (Aut, Win, Spr, Sum)
  • Medical Scholars Research
    PSYC 370 (Aut, Win, Spr, Sum)
  • Out-of-Department Directed Reading
    BIO 198X (Aut)
  • Research in Human Biology
    HUMBIO 193 (Aut, Win)
  • Teaching in Psychiatry
    PSYC 290 (Aut, Win, Spr, Sum)
  • Undergraduate Research
    PSYC 199 (Aut, Win, Spr, Sum)

Stanford Advisees

• Med Scholar Project Advisor
  Kevin Sun

Graduate and Fellowship Programs

• Child Psychiatry (Fellowship Program)

All Publications

• A Double-Blind Randomized Trial to Investigate Mechanisms of Antidepressant-Related Dysfunctional Arousal in Depressed or Anxious Youth at Familial Risk for Bipolar Disorder. Journal of personalized medicine Honeycutt, D. C., DelBello, M. P., Strawn, J. R., Ramsey, L. B., Patino, L. R., Hinman, K., Welge, J., Miklowitz, D. J., Jo, B., Blom, T. J., Bruns, K. M., Hamill Skoch, S. K., Starace, N., Tallman, M. J., Singh, M. K. 2022; 12 (6)

  Abstract

  Antidepressants are standardly used to treat moderate to severe symptoms of depression and/or anxiety in youth but may also be associated with rare but serious psychiatric adverse events such as irritability, agitation, aggression, or suicidal ideation. Adverse events are especially common in youth with a family history of bipolar disorder (BD) who are at heightened risk for dysfunction in neurobiological systems that regulate emotion and arousal. To further understand this phenomenon, this study will examine (a) baseline risk factors associated with dysfunctional arousal in a sample of youth at high-risk for BD treated with or without an antidepressant, (b) whether antidepressant-related changes in arousal are mediated by changes in prefrontal-limbic circuitry, and (c) whether pharmacogenetic factors influence antidepressant-related changes in arousal. High-risk youth (aged 12-17 years with moderate to severe depressive and/or anxiety symptoms and at least one first-degree relative with bipolar I disorder) will be randomized to receive psychotherapy plus escitalopram or psychotherapy plus placebo. Neuroimaging and behavioral measures of arousal will be collected prior to randomization and at 4 weeks. Samples for pharmacogenetic analysis (serum escitalopram concentration, CYP2C19 metabolizer phenotype, and HTR2A and SLC6A4 genotypes) will be collected at 8 weeks. Youth will be followed for up to 16 weeks to assess change in arousal measures.

  View details for DOI 10.3390/jpm12061006

  View details for PubMedID 35743790

• Editorial: Weighing Benefits and Risks While Treating Irritability and Emotional Dysregulation in Autism. Journal of the American Academy of Child and Adolescent Psychiatry 2022
• Impact of vision impairment and ocular morbidity and their treatment on depression and anxiety in children: A systematic review. Ophthalmology Li, D., Chan, V. F., Virgili, G., Piyasena, P., Negash, H., Whitestone, N., O'Connor, S., Xiao, B., Clarke, M., Cherwek, D. H., Singh, M. K., She, X., Wang, H., Boswell, M., Prakalapakorn, S. G., Patnaik, J. L., Congdon, N. 2022

  Abstract

  TOPIC: This systematic review and meta-analysis summarizes existing evidence to establish whether vision impairment, ocular morbidity and their treatment are associated with depression and anxiety in children.CLINICAL RELEVANCE: Understanding and quantifying these associations support early detection and management of mental health symptoms in children with vision impairment and ocular morbidity. Additionally, this review provides evidence in favour of insurance coverage for timely strabismus surgery.METHODS: We searched nine electronic databases from inception to February 18, 2021, including observational and interventional studies assessing whether vision impairment and/or ocular morbidity and their treatment are associated with depression and/or anxiety in children. We used narrative synthesis and meta-analysis with the residual maximum likelihood method. A protocol was registered and published on The International Prospective Register of Systematic Reviews (PROSPERO, CRD42021233323).RESULTS: Among 28,992 studies, 28,956 (99.9%) were excluded as duplicates or unrelated content. Among 36 remaining studies, 21 (58.3%) were observational studies concerning vision impairment, eight (22.2%) were observational studies concerning strabismus, and seven (19.4%) were interventional studies. Vision-impaired children experienced significantly higher scores of depression (Standard Mean Difference [SMD] 0.57, 95% Confidence Interval (CI) 0.26-0.89, 11 studies) and anxiety (SMD 0.61, 95% CI 0.40-0.821, 14 studies) than normally-sighted children. In particular, myopic children experienced higher scores of depression (SMD 0.59, 95% CI 0.36-0.81, six studies) than normally-sighted children. Strabismus surgery significantly improved symptoms of depression (SMD: 0.59 95% CI 0.12-1.06, three studies) and anxiety (SMD: 0.69 95% CI 0.24-1.14, four studies) in children.DISCUSSION: Among children, vision impairment is associated with greater symptoms of depression and anxiety. Surgical treatment of strabismus improved these symptoms. Further randomized controlled trials exploring the impact of public health measures for myopia correction on mental health in children are needed. Scaling up access to strabismus surgery could improve the mental health of affected children.

  View details for DOI 10.1016/j.ophtha.2022.05.020

  View details for PubMedID 35660416

• Can Translational Social Neuroscience Research offer Insights to Mitigate Structural Racism in America? Biological psychiatry. Cognitive neuroscience and neuroimaging Singh, M. K., Nimarko, A., Bruno, J., Anand, K. J., Singh, S. P. 2022

  Abstract

  Social isolation and conflict due to structural racism may result in human suffering and loneliness across the lifespan. Given the rising prevalence of these problems in America, combined with disruptions experienced during the COVID-19 pandemic, the neurobiology of affiliative behaviors may offer practical solutions to the pressing challenges associated with structural racism. Controlled experiments across species demonstrate that social connections are critical to survival, although strengthening individual resilience is insufficient to address the magnitude and impact of structural racism. In contrast, the multi-level construct of social resilience, defined by the power of groups to cultivate, engage in, and sustain positive relationships that endure and recuperate from social adversities, offers unique insights that may have greater impact, reach, and durability than individual-level interventions. Here, we review the putative social resilience-enhancing interventions and, when available, their biological mediators, with the hope to stimulate discovery of novel approaches to mitigate structural racism. We will first explore the social neuroscience principles underlying psychotherapy and other psychiatric interventions. Then, we will explore translational efforts across species to tailor treatments that increase social resilience, with context and cultural sensitivity in mind. Finally, we will conclude with some practical future directions for understudied areas that may be essential for progress in biological psychiatry, including ethical ways to increase representation in research and developing social paradigms that inform dynamics toward or away from socially resilient outcomes.

  View details for DOI 10.1016/j.bpsc.2022.05.005

  View details for PubMedID 35609781

• The Intriguing Role of Thalamic Structure and Function in Youth With and at Familial Risk for Bipolar Disorder Singh, M., Gorelik, A., Gorelik, M., Chang, K., Gotlib, I., Reiss, A., Nimarko, A. ELSEVIER SCIENCE INC. 2022: S38
• Real-Time fMRI Neurofeedback Augmented Mindfulness Training in Maltreated Youth: A Randomized Sham-Controlled Trial Kirlic, N., Cohen, Z., Tsuchiyagaito, A., Cochran, G., Yu, X., Singh, M., Aupperle, R., Misaki, M., Paulus, M. ELSEVIER SCIENCE INC. 2022: S355
• Parenting centers and caregiver mental health: Evidence from a large-scale randomized controlled trial in China. Child development Jiang, Q., Dill, S., Sylvia, S., Singh, M. K., She, X., Wang, E., Medina, A., Rozelle, S. 2022

  Abstract

  This study conducts an exploratory analysis of the impacts of a center-based early childhood development intervention on the mental health of caregivers, using data from a cluster-randomized controlled trial of 1664 caregivers (Mage =36.87years old) of 6- to 24-month-old children in 100 villages in rural China. Caregivers and children in 50 villages received individual parenting training, group activities and open play space in village parenting centers. The results show no significant overall change in caregiver-reported mental health symptoms after 1year of intervention. Subgroup analyses reveal heterogeneous effects by caregiver socioeconomic status and identity (mother vs. grandmother). Findings suggest that early childhood development interventions without targeted mental health components may not provide sufficient support to improve caregiver mental health.

  View details for DOI 10.1111/cdev.13782

  View details for PubMedID 35481708

• Depressive and Anxiety Symptoms among Children and Adolescents in Rural China: A Large-Scale Epidemiological Study. International journal of environmental research and public health Jiang, Q., She, X., Dill, S., Sylvia, S., Singh, M. K., Wang, H., Boswell, M., Rozelle, S. 2022; 19 (9)

  Abstract

  Although children living in low- and middle-income countries (LMICs) account for 90% of the global population of children, depression, and anxiety among children in LMICs have been understudied. This study examines the prevalence of depression and anxiety and their associations with biological and psychosocial factors among children across China, with a focus on rural areas. We conducted a large-scale epidemiological study of depression and anxiety among 53,421 elementary and junior high school-aged children across China. The results show that 20% are at risk for depression, 6% are at risk for generalized anxiety, and 68% are at risk for at least one type of anxiety. Girls and junior high school students show a higher risk for both depression and anxiety symptoms, while socioeconomic status has varying associations to depression and anxiety symptoms. Our results also show consistent correlations between depression and anxiety symptoms and standard math test scores. These findings underscore the importance of identification, prevention, and treatment of youth depression and anxiety in underdeveloped areas. As China constitutes 15% of the global population of children under age 18, this study offers valuable information to the field of global mental health.

  View details for DOI 10.3390/ijerph29095026

  View details for PubMedID 35564422

• Narrative Review: Impairing Emotional Outbursts: What They Are and What we Should do About Them. Journal of the American Academy of Child and Adolescent Psychiatry Carlson, G. A., Singh, M. K., Amaya-Jackson, L., Benton, T. D., Althoff, R. R., Bellonci, C., Bostic, J. Q., Chua, J. D., Findling, R. L., Galanter, C. A., Gerson, R. S., Sorter, M. T., Stringaris, A., Waxmonsky, J. G., McClellan, J. M. 2022

  Abstract

  Impairing emotional outbursts, defined by extreme anger or distress in response to relatively ordinary frustrations and disappointments, impact all mental health systems of care, emergency departments, schools and juvenile justice programs. However, the prevalence, outcome and impact of outbursts are difficult to quantify because they are transdiagnostic and not explicitly defined by our current nosology. Research variably addresses outbursts under the rubrics of tantrums, anger, irritability, aggression, rage attacks and/or emotional and behavioral dysregulation. Consistent methods for identifying and assessing impairing emotional outbursts across development or systems of care are lacking.The American Academy of Child and Adolescent Psychiatry Presidential Task Force (2019-2021), conducted a narrative review addressing impairing emotional outbursts within the limitations of the existing literature and independent of diagnosis.Extrapolating from the existing literature, best estimates suggest that outbursts occur in 4 - 10% of community children (preschoolers through adolescents). Impairing emotional outbursts may respond to successful treatment of the primary disorder, especially for some children with attention deficit hyperactivity disorder whose medications have been optimized. However, outbursts are generally multidetermined and often represent maladaptive or deficient coping strategies and responses.Evidence-based strategies are necessary to address factors that trigger, reinforce or excuse the behaviors, and to enhance problem-solving skills. Unfortunately, currently available interventions yield only modest effect sizes for treatment effect. More specific definitions and measures are needed to track and quantify outbursts, and to design and assess the effectiveness of interventions. We clearly need better treatments.

  View details for DOI 10.1016/j.jaac.2022.03.014

  View details for PubMedID 35358662

• Mood Instability in Youth at High Risk for Bipolar Disorder. Journal of the American Academy of Child and Adolescent Psychiatry Miklowitz, D. J., Weintraub, M. J., Singh, M. K., Walshaw, P. D., Merranko, J. A., Birmaher, B., Chang, K. D., Schneck, C. D. 2022

  Abstract

  OBJECTIVE: Mood instability is associated with the onset of bipolar disorder (BD) in youth with a family history of the illness. In a clinical trial with youth at high risk for BD, we examined the association between mood instability and symptomatic, psychosocial, and familial functioning over an average of two years.METHOD: Youth (ages 9-17 yrs.) with major depressive disorder or other specified BD, current mood symptoms, and a family history of BD were rated by parents on a mood instability scale. Participants were randomly assigned to four months of family-focused therapy or enhanced care psychoeducation, both with medication management as needed. Independent evaluators rated youth every four to six months for up to four years on symptom severity and psychosocial functioning, while parents rated youths' mood instability and levels of family conflict.RESULTS: High risk youth (N=114; mean age 13.3+2.6 years; 72 female) were followed for an average of 104.3+65.8 weeks (range 0-255) following randomization. Youth with other specified BD (vs. major depressive disorder), younger age, earlier symptom onset, more severe mood symptoms, lower psychosocial functioning, and more familial conflict over time had higher mood instability ratings throughout the study period. Mood instability mediated the association between baseline diagnosis and mother/offspring conflict at follow-up (Z=2.88, p=0.004, alphabeta=0.19, 95% CI=0.06-0.32). Psychosocial interventions did not moderate these associations.CONCLUSION: A questionnaire measure of mood instability tracked closely with symptomatic, psychosocial, and family functioning in youth at high risk for BD. Interventions that are successful in reducing mood instability may enhance long-term outcomes among high risk youth.

  View details for DOI 10.1016/j.jaac.2022.03.009

  View details for PubMedID 35307538

• Association Between Strabismus and Children's Mental Health. JAMA ophthalmology Prakalapakorn, S. G., Singh, M. K., Congdon, N. 2022
• Neurofeedback-Augmented Mindfulness Training Elicits Distinct Responses in the Subregions of the Insular Cortex in Healthy Adolescents. Brain sciences Yu, X., Cohen, Z. P., Tsuchiyagaito, A., Cochran, G., Aupperle, R. L., Stewart, J. L., Singh, M. K., Misaki, M., Bodurka, J., Paulus, M. P., Kirlic, N. 2022; 12 (3)

  Abstract

  Mindfulness training (MT) reduces self-referential processing and promotes interoception, the perception of sensations from inside the body, by increasing one's awareness of and regulating responses to them. The posterior cingulate cortex (PCC) and the insular cortex (INS) are considered hubs for self-referential processing and interoception, respectively. Although MT has been consistently found to decrease PCC, little is known about how MT relates to INS activity. Understanding links between mindfulness and interoception may be particularly important for informing mental health in adolescence, when neuroplasticity and emergence of psychopathology are heightened. We examined INS activity during real-time functional magnetic resonance imaging neurofeedback-augmented mindfulness training (NAMT) targeting the PCC. Healthy adolescents (N = 37; 16 female) completed the NAMT task, including Focus-on-Breath (MT), Describe (self-referential processing), and Rest conditions, across three neurofeedback runs and two non-neurofeedback runs (Observe, Transfer). Regression coefficients estimated from the generalized linear model were extracted from three INS subregions: anterior (aINS), mid (mINS), and posterior (pINS). Mixed model analyses revealed the main effect of run for Focus-on-Breath vs. Describe contrast in aINS [R2 = 0.39] and pINS [R2 = 0.33], but not mINS [R2 = 0.34]. Post hoc analyses revealed greater aINS activity and reduced pINS activity during neurofeedback runs, and such activities were related to lower self-reported life satisfaction and less pain behavior, respectively. These findings revealed the specific involvement of insula subregions in rtfMRI-nf MT.

  View details for DOI 10.3390/brainsci12030363

  View details for PubMedID 35326319

• Intrinsic connectivity and family dynamics: Striato-limbic markers of risk and resilience in youth at familial risk for mood disorders. Biological psychiatry. Cognitive neuroscience and neuroimaging Fischer, A. S., Holt-Gosselin, B., Hagan, K. E., Fleming, S. L., Nimarko, A. F., Gotlib, I. H., Singh, M. K. 2022

  Abstract

  BACKGROUND: Characterizing (1) functional connectivity (FC) markers of risk and resilience in emotion and reward networks and (2) how family dynamics in youth at high familial risk for bipolar disorder (HR-BD) and major depressive disorder (HR-MDD) are related to FC may advance our understanding of the neural underpinnings of mood disorders and lead to more effective interventions.METHODS: 139 youth (43 HR-BD, 46 HR-MDD, and 50 low risk [LR]) aged 12.9+/-2.7 years were followed for 4.5+/-2.4 years. We characterized differences in striato-limbic FC that distinguished HR-BD, HR-MDD and LR; and resilience (RES) versus conversion to psychopathology (CVT). We then examined whether risk status moderated FC-family function associations. Finally, we examined whether baseline differences in FC between HR-BD, HR-MDD and LR predicted RES versus CVT at follow-up.RESULTS: HR-BD had greater amygdala-middle frontal gyrus and dorsal striatum-middle frontal gyrus FC, and HR-MDD had lower amygdala-fusiform gyrus and dorsal striatum-precentral gyrus FC (voxel-level p<0.001, cluster-level FDR-corrected p<0.05). RES had greater amygdala-orbitofrontal cortex and ventral striatum-dorsal anterior cingulate cortex FC relative to CVT (voxel-level p<0.001, cluster-level FDR-corrected p<0.05). Greater family rigidity was inversely associated with amygdala-fusiform gyrus FC across all groups (FDR-corrected p=0.017), with a moderating effect of bipolar risk status (HR-BD vs. HR-MDD p<0.001; HR-BD versus LR p=0.005). Baseline FC differences did not predict RES versus CVT.CONCLUSIONS: Findings represent neural signatures of risk and resilience in emotion and reward processing networks in youth at familial risk for mood disorders that may be targets for novel interventions tailored to the family context.

  View details for DOI 10.1016/j.bpsc.2022.02.009

  View details for PubMedID 35272095

• Effects of Family Intervention on Psychosocial Functioning and Mood Symptoms of Youth at High Risk for Bipolar Disorder JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY Weintraub, M. J., Schneck, C. D., Posta, F., Merranko, J. A., Singh, M. K., Chang, K. D., Miklowitz, D. J. 2022

  Abstract

  Family-focused therapy (FFT) is associated with reduced rates of mood episodes among youth at high risk for bipolar disorder (BD). In a randomized trial of FFT compared to a psychoeducation-only treatment (enhanced care, EC), we sought to determine if changes in psychosocial functioning mediate mood improvements among high-risk youth.119 youths with active mood symptoms and a family history of BD were randomized to either 4 months of FFT or EC. Participants were rated on mood symptom severity and provided self-ratings of psychosocial functioning across domains of family, social-emotional, and school functioning. Repeated measures mixed modeling and bootstrapped mediational analyses evaluated the effects of treatment conditions and psychosocial functioning on mood improvements immediately posttreatment and over 2 years of follow-up.Youths in FFT reported greater improvements in family functioning over 24 months compared to those in EC, F(5, 76.8) = 3.1, p < .05. Improvements in family functioning partially mediated participants' improvements in depressive symptoms, B = -0.22, p < .01; 95% CI [-0.55, -0.02]. The effects of FFT versus EC on family functioning were stronger among youth with comorbid anxiety and externalizing disorders than among youth without these comorbid disorders.The findings suggest a temporal link between changes in youths' perceptions of family functioning and improvements in depressive symptoms among high-risk youth in FFT. Family conflict and cohesion are important treatment targets for youth who present with early signs of BD. Future studies should examine whether changes in observational measures of family interaction precede improvements in mood among high-risk youth. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

  View details for DOI 10.1037/ccp0000708

  View details for Web of Science ID 000746937000001

  View details for PubMedID 35084893

• Neural correlates of reward processing distinguish healthy youth at familial risk for bipolar disorder from youth at familial risk for major depressive disorder. Translational psychiatry Nimarko, A. F., Gorelik, A. J., Carta, K. E., Gorelik, M. G., Singh, M. K. 1800; 12 (1): 31

  Abstract

  Youth at familial risk for bipolar disorder (BD-risk) and major depressive disorder (MDD-risk) have aberrant reward processing, a core feature of these mood disorders. Whether BD risk differentiates from MDD risk in reward processing merits further study. We compared neural activation and connectivity during anticipation and outcome of monetary gain and loss during fMRI using the Monetary Incentive Delay (MID) Task among BD-risk (n=40), MDD-risk (n=41), and healthy comparison youth (HC) (n=45), in the absence of any lifetime or current history of psychopathology [mean age 13.09±2.58, 56.3% female]. Participants completed the MID task at baseline and were followed for behavioral and clinical outcomes over 4.37±2.29 years. Region-of-interest (ROI) analyses conducted using anatomically defined thalamus, ventrolateral prefrontal cortex, nucleus accumbens, and putamen seeds showed that relative to MDD-risk and HC, BD-risk had decreased activation of the thalamus during anticipation of monetary gain [F(2,118)=4.64, p=0.01 (FDR-corrected p=0.04)]. Psychophysiological interaction analyses revealed that BD-risk had less connectivity between the thalamus and left middle frontal gyrus (Z>3.1, p<0.001) and left-superior temporal gyrus (Z>3.1, p<0.05) compared with MDD-risk. Voxelwise, BD-risk had decreased activation in the cerebellum during anticipation and outcome of monetary gain relative to MDD-risk and HC (Z>3.1, p<0.001; Z>3.1, p<0.01). In BD-risk, decreased thalamic connectivity was associated with increased impulsivity at baseline and reduced prosocial behavior at follow-up. Reduced thalamic activation and connectivity during reward processing may distinguish familial risk for BD from familial risk for MDD and represent early markers of vulnerability that may herald social dysfunction later in adolescence.

  View details for DOI 10.1038/s41398-022-01800-9

  View details for PubMedID 35075136

• Self-regulation of the posterior cingulate cortex with real-time fMRI neurofeedback augmented mindfulness training in healthy adolescents: A nonrandomized feasibility study. Cognitive, affective & behavioral neuroscience Kirlic, N., Cohen, Z. P., Tsuchiyagaito, A., Misaki, M., McDermott, T. J., Aupperle, R. L., Stewart, J. L., Singh, M. K., Paulus, M. P., Bodurka, J. 2022

  Abstract

  Mindfulness training (MT) promotes the development of one's ability to observe and attend to internal and external experiences with objectivity and nonjudgment with evidence to improve psychological well-being. Real-time functional MRI neurofeedback (rtfMRI-nf) is a noninvasive method of modulating activity of a brain region or circuit. The posterior cingulate cortex (PCC) has been hypothesized to be an important hub instantiating a mindful state. This nonrandomized, single-arm study examined the feasibility and tolerability of training typically developing adolescents to self-regulate the posterior cingulate cortex (PCC) using rtfMRI-nf during MT. Thirty-four adolescents (mean age: 15 years; 14 females) completed the neurofeedback augmented mindfulness training task, including Focus-on-Breath (MT), Describe (self-referential thinking), and Rest conditions, across three neurofeedback and two non-neurofeedback runs (Observe, Transfer). Self-report assessments demonstrated the feasibility and tolerability of the task. Neurofeedback runs differed significantly from non-neurofeedback runs for the Focus-on-Breath versus Describe contrast, characterized by decreased activity in the PCC during the Focus-on-Breath condition (z = -2.38 to -6.27). MT neurofeedback neural representation further involved the medial prefrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex, posterior insula, hippocampus, and amygdala. State awareness of physical sensations increased following rtfMRI-nf and was maintained at 1-week follow-up (Cohens' d = 0.69). Findings demonstrate feasibility and tolerability of rtfMRI-nf in healthy adolescents, replicates the role of PCC in MT, and demonstrate a potential neuromodulatory mechanism to leverage and streamline the learning of mindfulness practice. ( ClinicalTrials.gov identifier #NCT04053582; August 12, 2019).

  View details for DOI 10.3758/s13415-022-00991-4

  View details for PubMedID 35292905

• Thalamic Structure and Function in Youth With and At Familial Risk for Bipolar Disorder Singh, M., Gorelik, A., Carta, K., Gorelik, M., Chang, K., Bruno, J., Nimarko, A. SPRINGERNATURE. 2021: 285-286
• Examining the Relation between Caregiver Mental Health and Student Outcomes in Rural China. International journal of environmental research and public health Wang, H., Cousineau, C., Hu, Y. A., Hu, G., Qi, S., Sun, A., Wu, H., Rozelle, S., Singh, M. 2021; 18 (23)

  Abstract

  Research continues to highlight the central relationship between caregivers' mental health and their children's development. This study examined the relation between primary caregivers' mental health and school-aged children's outcomes, including student mental health, resilience, and academic performance, in rural China. Using cross-sectional data from economically poor areas in the Gansu province, 2989 students (mean age = 11.51, 53.33% male, 46.67% female) and their primary caregivers (74.2% female) completed the 21-item, self-report Depression Anxiety Stress Scale. Students also completed the 25-item Connor-Davidson Resilience Scale and a standardized math test. The results indicated a high prevalence of caregiver depression (31%), stress (39%), and anxiety (24%). Characteristics that were significantly correlated with caregiver mental health issues included being a grandparent, having a low socioeconomic status and low education level, and living in a household with at least one migrant worker. Apart from caregiver stress and student resilience, caregiver mental health issues were negatively correlated with all student outcomes, including student mental health, resilience, and academic performance. Although additional empirical research is needed to investigate the associations between caregiver mental health and student outcomes, our results suggest that rural communities could benefit greatly from programs focused on improving the mental health of caregivers and this, in turn, may have a positive impact on student outcomes.

  View details for DOI 10.3390/ijerph282312613

  View details for PubMedID 34886336

• A Commentary on Youth Onset Bipolar Disorder. Bipolar disorders Singh, M. K., Post, R. M., Miklowitz, D. J., Birmaher, B., Youngstrom, E., Goldstein, B., Soutullo, C., Axelson, D., Chang, K. D., DelBello, M. P. 2021

  Abstract

  AIM: Given ongoing disagreement about the diagnosis of pediatric bipolar disorder, we sought to illuminate key empirical findings regarding the condition in children and adolescents.METHODS: We conducted a review of extant studies of the diagnosis, course, and treatment bipolar disorder in children and adolescents.RESULTS: Bipolar disorder is a lifelong, familial condition with frequent onset in childhood or adolescence. Secular trends indicate that globally, the onset of puberty is occurring earlier, which may contribute to increased identification of mood disorders in younger populations. Despite opinions to the contrary, bipolar disorder has been observed in youth around the world, not just in the U.S. Discrete and episodic manic symptoms occur on a continuum/spectrum of severity and duration. Clinicians may be just as likely to miss mania (false negatives) as over-call it (false positives). As is true in adults, periodicity and heterogeneity are defining features of early-onset bipolar disorder. Youth who are misdiagnosed and undiagnosed tend to do poorly over the long-term. Youth with and at risk for bipolar disorder are frequently exposed to maltreatment, abuse, and bullying. Fortunately, there are now many evidence-based interventions that have been studied in thousands of youth with or at high risk for bipolar disorder, demonstrating large effect sizes for evaluated treatments versus comparative treatments.CONCLUSION: Identifying optimal methods for evaluation and treatment of bipolar disorder in children and adolescents represent important advances in the field. Recognizing the occurrence of mania symptoms in youth is pivotal for improving outcomes in patients living with bipolar disorder.

  View details for DOI 10.1111/bdi.13148

  View details for PubMedID 34689401

• Genetic and demographic predisposing factors associated with pediatric sleepwalking in the Philadelphia Neurodevelopmental Cohort. Journal of the neurological sciences Chiba, Y., Phillips, O. R., Takenoshita, S., Ollila, H. M., Hallmayer, J. F., Nishino, S., Singh, M. K. 2021; 430: 119997

  Abstract

  OBJECTIVES: Sleepwalking is a parasomnia associated with non-rapid eye movement (NREM) sleep and is formally diagnosed using polysomnography (PSG). However, PSG are difficult to perform on children or adolescents due to needed compliance. To understand this condition in youth, few studies have been conducted on a large cohort of youths with a diverse distribution of ages and races to characterize it better in the absence of PSG. The present study aimed to evaluate the prevalence of sleepwalking in youth, as well as associated demographic and genetic characteristics, using questionnaires in a large pediatric cohort.METHODS: Data from the Philadelphia Neurodevelopmental Cohort (PNC) of 7515 youths aged between 8 and 22years were used in analyses. Demographic and clinical data, including age, sex, and race, and genetic data from 2753 African American (AA) and 4762 European American (EA) subjects were investigated. The age-wise prevalence of sleepwalking in AA and EA subjects was evaluated. Finally, race-specific genome-wide association (GWAS) analyses of sleepwalking were also performed (N=155 AA cases and 2598 AA controls; N=512 EA cases and 4250 EA controls).RESULTS: Lifetime history of sleepwalking correlated with male sex and EA race. A genetic risk locus that reached genome-wide significance was detected at rs73450744 on chromosome 18 in AA, but not EA youth.CONCLUSION: The present results suggest that male sex, EA race, and genetic factors may be associated with higher rates of sleepwalking among youth. Future studies should consider these variables to advance understanding of the complex pathogenesis of sleepwalking.

  View details for DOI 10.1016/j.jns.2021.119997

  View details for PubMedID 34563919

• Expanding bipolar outreach during college. Journal of affective disorders Singh, M. K., Miller, S., Hooshmand, F., Wang, P. W., Chang, L., Ketter, T. A. 2021; 295: 28-32

  Abstract

  OBJECTIVES: To assess feasibility and clinical significance of tracking mania and depression in community college students before and after early identification and intervention.METHODS: From Affective Illness to Recovery: STudent Access to Rapid Treatment (FAIRSTART) is an early intervention program to provide diagnostic therapeutic consultation, short-term care, and community ongoing care referral for 18-28 year-old outpatient community college students (mean age 22.9±4.0 years) experiencing manic symptoms. Over three years, 54 FAIRSTART participants (70% with DSM-IV bipolar I/II/not otherwise specified disorder, BDI/II/NOS) were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation (ADE) and followed (range: one-time consult to 4.3±3.6 visits over 3-6 month follow-up) with the STEP-BD Clinical Monitoring Form.RESULTS: 38/54 patients (70%) had BDI/II/NOS, 11 unipolar depression (20%), 1 psychosis spectrum disorder (2%), 2 dysthymia/persistent depressive disorder (4%), and 2 incomplete intake with mood disorder diagnosis undetermined (4%). Average illness duration was 9.1±5.3 years. Among the 38 BD I/II/NOS patients, depression (SUM-D, t(30)=6.5; p<0.001) and mania (SUM-M, t(30)=4.7; p<0.001) scores improved significantly from baseline to last visit, with 17 (44.7%) reporting recovery by time transitioned from FAIRSTART to community care (after 4.3±3.6 visits).CONCLUSIONS: Short-term, early intervention in community college students with mood symptoms appeared feasible and yielded significant improvements in depression and mania scores. However, additional studies, with longer-term follow-ups, larger sample sizes, and comparison to current care standards, are needed to determine this early intervention program's impact on trajectory of mania symptoms in transitional age young adult populations.

  View details for DOI 10.1016/j.jad.2021.08.001

  View details for PubMedID 34391959

• Emotion Dysregulation in Children and Adolescents: Part II. Child and adolescent psychiatric clinics of North America Singh, M. K., Carlson, G. A. 2021; 30 (3): xiii-xiv
• Preventing Irritability and Temper Outbursts in Youth by Building Resilience. Child and adolescent psychiatric clinics of North America Singh, M. K., Hu, R., Miklowitz, D. J. 2021; 30 (3): 595-610

  Abstract

  Severe irritability and temper outbursts are risk factors for the onset of serious and lifelong mood disorders. In treating children and adolescents with severe irritability, clinicians should evaluate and address safety issues before acute stabilization of symptoms. Then, clinicians can initiate interventions to prevent the onset or relapses of the undesired behavior and its functional consequences. This review summarizes primary, secondary, and tertiary relapse prevention strategies, with an emphasis on strategies that build resilience in youth that mitigate the onset, recurrence, and progression of emotion dysregulation.

  View details for DOI 10.1016/j.chc.2021.04.009

  View details for PubMedID 34053688

• Attention Deficit Hyperactivity Disorder (ADHD) among elementary students in rural China: Prevalence, correlates, and consequences. Journal of affective disorders Pang, X., Wang, H., Dill, S., Boswell, M., Pang, X., Singh, M., Rozelle, S. 2021; 293: 484-491

  Abstract

  BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a widely recognized mental health problem in developed countries but remains under-investigated in developing settings. This study examines the prevalence, correlates, and consequences of ADHD symptoms among elementary school students in rural China.METHODS: Cross-sectional data were collected from 6,719 students across 120 rural primary schools in China on ADHD symptoms, demographic characteristics, and academic performance in reading and math. ADHD symptoms were evaluated using the caregiver-reported ADHD Rating Scale-IV.RESULTS: The prevalence of ADHD symptoms was 7.5% in our sample. Male students, students in lower grade levels, and students with lower cognitive ability showed a significantly higher prevalence of ADHD symptoms (ORs=2.56, 2.06, and 1.84, respectively; p<0.05). Left-behind children showed a significantly lower prevalence of ADHD symptoms than did children who were living with their parents (OR=0.74, p < 0.05). Adjusted regressions show that students with ADHD symptoms scored 0.12 standardized deviations lower in reading (p < 0.05) and 0.19 standardized deviations lower in math (p < 0.01).LIMITATIONS: The ADHD Rating Scale-IV is a screening scale rather than a diagnostic test. Caregiver self-report measures also may underestimate ADHD symptoms for our sample.CONCLUSIONS: ADHD is a common disorder among rural students in China and appears to be contributing to poor academic outcomes. The higher prevalence of ADHD among students with low cognitive ability also suggests that many rural children in China face multifactorial learning challenges. Taken together, the findings indicate a need for educators and policymakers in rural China to develop programs to reduce risk and support students with ADHD symptoms.

  View details for DOI 10.1016/j.jad.2021.06.014

  View details for PubMedID 34280772

• Building on the science of risk and resilience in youth at familial risk for bipolar disorder Singh, M. WILEY. 2021: 39-40
• Subthreshold manic symptoms (sleep disturbance and irritability) and response to lurasidone in children and adolescents with bipolar depression Singh, M., Tocco, M., Siu, C., Pikalov, A. WILEY. 2021: 59
• Why are we debating the reality of pediatric bipolar disorder? Singh, M. WILEY. 2021: 9
• Symptomatic, Functional, and Brain Connectivity Changes Before and After Family Focused Therapy Versus Standard Psychoeducation Among Youth at Familial Risk for Bipolar Disorder Singh, M., Nimarko, A., Garrett, A., Walshaw, P., Chang, K., Miklowitz, D. ELSEVIER SCIENCE INC. 2021: S80-S81
• Extracurricular Activities, Screen Media Activity, and Sleep May Be Modifiable Factors Related to Children's Cognitive Functioning: Evidence From the ABCD Study. Child development Kirlic, N., Colaizzi, J. M., Cosgrove, K. T., Cohen, Z. P., Yeh, H., Breslin, F., Morris, A. S., Aupperle, R. L., Singh, M. K., Paulus, M. P. 2021

  Abstract

  This study used a machine learning framework in conjunction with a large battery of measures from 9,718 school-age children (ages 9-11) from the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study to identify factors associated with fluid cognitive functioning (FCF), or the capacity to learn, solve problems, and adapt to novel situations. The identified algorithm explained 14.74% of the variance in FCF, replicating previously reported socioeconomic and mental health contributors to FCF, and adding novel and potentially modifiable contributors, including extracurricular involvement, screen media activity, and sleep duration. Pragmatic interventions targeting these contributors may enhance cognitive performance and protect against their negative impact on FCF in children.

  View details for DOI 10.1111/cdev.13578

  View details for PubMedID 33900639

• Emotion Dysregulation and Outbursts in Children and Adolescents: Part I. Child and adolescent psychiatric clinics of North America Carlson, G. A., Singh, M. K. 2021; 30 (2): xiii-xvi
• Long-Term Effectiveness of Lurasidone in Pediatric Bipolar Depression: Response, Remission and Recovery. CNS spectrums Singh, M., Tocco, M., Schweizer, E., Pikalov, A. 2021; 26 (2): 148

  Abstract

  BACKGROUND: Bipolar disorder frequently has an early onset, with an estimated 1.8% prevalence of bipolar I disorder in children and adolescents. Childhood onset of bipolar disorder is typically associated with a chronic, severe, and disabling course of illness. Relatively few prospective studies are available that evaluate the long-term efficacy of atypical antipsychotics in achieving and sustaining response or remission in pediatric patients with bipolar depression. Lurasidone has been approved by the FDA as monotherapy for bipolar depression in pediatric patients ages 10-17 years. The aim of the current post-hoc analysis was to evaluate the long-term efficacy of lurasidone in achieving response or remission in children and adolescents with bipolar depression followed over a two-year period.METHOD: Patients 10-17 years with bipolar I depression who completed a 6-week double-blind (DB) study of lurasidone vs. placebo were eligible to enroll in a two-year, open-label (OL) extension study in which patients were continued on flexibly-dosed lurasidone (20-80 mg/d) or switched from placebo to lurasidone. Efficacy measures included the Children's Depression Rating Scale, Revised (CDRS-R) and the Clinical Global Impression, Bipolar Depression Severity scale (CGI-BP-S). Functioning was evaluated utilizing the Clinician-rated Children's Global Assessment Scale (CGAS) score, with a score >70 indicating no clinically meaningful functional impairment. Responder criteria were met if a patient achieved criteria = 50% reduction from DB baseline in the CDRS-R total score: remission criteria were met if a patient achieved a CDRS-R Total Score =28 and a YMRS total score =8 and CGI-BP-S depression score =3, and a patient was considered to have met recovery criteria if they achieved remission with a CGAS score >70. In addition, a more stringent outcome, sustained remission, was also analyzed, which required a patient to meet remission criteria for =24 consecutive weeks.RESULTS: A total of 306 patients completed the 6-week DB study and entered the extension study; 195 (63.7%) patients completed one year of treatment and 168 (54.9%) patients completed two years of treatment. Responder rates at OL baseline, one year, and two years were: 51.0%, 88.4% and 91.1%, respectively; remission rates were 24.3%, 61.3%, and 75.6%, respectively; and recovery rates were 17.7%, 53.8%, and 73.8%. On a Pearson correlation analysis, there was a strong inverse relationship (r = -0.71) between CDRS-R total score, and global functioning as measured by the CGAS. Sustained remission was achieved by 37.2% of patients at one year and 57% of patients after two years.CONCLUSIONS: In children and adolescents with bipolar depression, up to 2 years of treatment with lurasidone was associated with continued improvement in depressive symptoms, resulting in progressively higher rates of response, remission, recovery, and the more rigorously calculated outcome of sustained remission.FUNDING: Sunovion Pharmaceuticals Inc.

  View details for DOI 10.1017/S1092852920002345

  View details for PubMedID 34127107

• Prefrontal cortex and amygdala anatomy in youth with persistent levels of harsh parenting practices and subclinical anxiety symptoms over time during childhood. Development and psychopathology Suffren, S., La Buissonniere-Ariza, V., Tucholka, A., Nassim, M., Seguin, J. R., Boivin, M., Kaur Singh, M., Foland-Ross, L. C., Lepore, F., Gotlib, I. H., Tremblay, R. E., Maheu, F. S. 2021: 1–12

  Abstract

  Childhood adversity and anxiety have been associated with increased risk for internalizing disorders later in life and with a range of brain structural abnormalities. However, few studies have examined the link between harsh parenting practices and brain anatomy, outside of severe maltreatment or psychopathology. Moreover, to our knowledge, there has been no research on parenting and subclinical anxiety symptoms which remain persistent over time during childhood (i.e., between 2.5 and 9 years old). Here, we examined data in 94 youth, divided into four cells based on their levels of coercive parenting (high / low) and of anxiety (high / low) between 2.5 and 9 years old. Anatomical images were analyzed using voxel-based morphometry (VBM) and FreeSurfer. Smaller gray matter volumes in the prefrontal cortex regions and in the amygdala were observed in youth with high versus low levels of harsh parenting over time. In addition, we observed significant interaction effects between parenting practices and subclinical anxiety symptoms in rostral anterior cingulate cortical thickness and in amygdala volume. These youth should be followed further in time to identify which youth will or will not go on to develop an anxiety disorder, and to understand factors associated with the development of sustained anxiety psychopathology.

  View details for DOI 10.1017/S0954579420001716

  View details for PubMedID 33745487

• Social impairment in relation to clinical symptoms in youth at high risk for bipolar disorder. Early intervention in psychiatry Weintraub, M. J., Keenan-Miller, D., Schneck, C. D., Forgey Borlik, M., Suddath, R. L., Marvin, S. E., Singh, M. K., Chang, K. D., Miklowitz, D. J. 2021

  Abstract

  AIM: Social impairment is common in individuals with bipolar disorder (BD), although its role in youths at high-risk for BD (i.e., mood symptoms in the context of a family history of BD) is not well understood. Social impairment takes many forms including social withdrawal, relational aggression, physical aggression, and victimization. The aim of this study was to explore the links between social impairment and clinical symptoms in youth at high-risk for BD.METHODS: The sample included 127 youths with elevations in mood symptoms (depression or hypomania) and at least one first and/or second degree relative with BD. Measures of youths' current psychopathology (i.e., depressive and manic severity, suicidality, anxiety, and attention-deficit/hyperactivity disorder [ADHD]) were regressed onto youths' self-reports of social impairment (i.e., social withdrawal, relational aggression, physical aggression, and victimization).RESULTS: Depressive symptoms, suicidal ideation, and anxiety symptoms were related to social withdrawal. Suicidal ideation was also related to reactive aggression. ADHD symptoms related to reactive and proactive aggression as well as relational victimization. Manic symptoms were not associated with social impairment in this sample.CONCLUSIONS: Although cross-sectional, study findings point to potential treatment targets related to social functioning. Specifically, social withdrawal should be a target for treatment of childhood depressive and anxiety symptoms. Treatments that focus on social skills and cognitive functioning deficits associated with BD may also have clinical utility.

  View details for DOI 10.1111/eip.13124

  View details for PubMedID 33559355

• Default mode and salience network alterations in suicidal and non-suicidal self-injurious thoughts and behaviors in adolescents with depression. Translational psychiatry Ho, T. C., Walker, J. C., Teresi, G. I., Kulla, A., Kirshenbaum, J. S., Gifuni, A. J., Singh, M. K., Gotlib, I. H. 2021; 11 (1): 38

  Abstract

  Suicidal ideation (SI) and non-suicidal self-injury (NSSI) are two distinct yet often co-occurring risk factors for suicide deaths in adolescents. Elucidating the neurobiological patterns that specifically characterize SI and NSSI in adolescents is needed to inform the use of these markers in intervention studies and to develop brain-based treatment targets. Here, we clinically assessed 70 adolescents-49 adolescents with depression and 21 healthy controls-to determine SI and NSSI history. Twenty-eight of the depressed adolescents had a history of SI and 29 had a history of NSSI (20 overlapping). All participants underwent a resting-state fMRI scan. We compared groups in network coherence of subdivisions of the central executive network (CEN), default mode network (DMN), and salience network (SN). We also examined group differences in between-network connectivity and explored brain-behavior correlations. Depressed adolescents with SI and with NSSI had lower coherence in the ventral DMN compared to those without SI or NSSI, respectively, and healthy controls (all ps<0.043, uncorrected). Depressed adolescents with NSSI had lower coherence in the anterior DMN and in insula-SN (all ps<0.030, uncorrected), and higher CEN-DMN connectivity compared to those without NSSI and healthy controls (all ps<0.030, uncorrected). Lower network coherence in all DMN subnetworks and insula-SN were associated with higher past-month SI and NSSI (all ps<0.001, uncorrected). Thus, in our sample, both SI and NSSI are related to brain networks associated with difficulties in self-referential processing and future planning, while NSSI specifically is related to brain networks associated with disruptions in interoceptive awareness.

  View details for DOI 10.1038/s41398-020-01103-x

  View details for PubMedID 33436537

• Neural Changes in Youth at High-Risk for Bipolar Disorder Undergoing Family-Focused Therapy or Psychoeducation. Bipolar disorders Garrett, A. S., Chang, K. D., Singh, M. K., Armstrong, C. C., Walshaw, P. D., Miklowitz, D. J. 2021

  Abstract

  BACKGROUND: Patients with mood disorders may benefit from psychosocial interventions through changes in brain networks underlying emotion processing. In this study, we used functional magnetic resonance imaging (fMRI) to investigate treatment-related changes in emotion processing networks in youth at familial high risk for bipolar disorder (BD).METHODS: Youth, ages 9-17, were randomly assigned to family-focused therapy for high-risk youth (FFT-HR) or an active comparison treatment, Enhanced Care (EC). Before and after these 4-month treatments, participants underwent fMRI while viewing happy, fearful, and calm facial expressions. Twenty youth in FFT-HR and 20 in EC were included in analyses of pre- to post-treatment changes in activation across the whole brain. Significant clusters were assessed for correlation with mood symptom improvement.RESULTS: In the dorsolateral prefrontal cortex (DLPFC), activation increased from pre- to post-treatment in the FFT-HR group and decreased in the EC group. Insula activation decreased in the FFT-HR group and did not change in the EC group. Across both treatments, decreasing activation in the hippocampus and amygdala was correlated with pre- to post-treatment improvement in hypomania, while increasing activation in the DLPFC was correlated with pre- to post-treatment improvement in depression.DISCUSSION: Psychosocial treatment addresses abnormalities in emotion regulation networks in youth at high risk for BD. Increased prefrontal cortex activation suggests enhanced emotion regulation from pre to post-treatment with FFT-HR. Improvements in family interactions may facilitate the development of prefrontal resources that provide protection against future mood episodes.

  View details for DOI 10.1111/bdi.13045

  View details for PubMedID 33432670

• Visual memory improvement in adolescents at high risk for suicide who are receiving psychotherapy at a community clinic. Psychiatry research Santamarina-Perez, P. n., Mendez, I. n., Eiroa-Orosa, F. J., Singh, M. K., Gorelik, A. n., Picado, M. n., Font, E. n., Moreno, E. n., Martínez, E. n., Morer, A. n., Cordovilla, C. n., Romero, S. n. 2021; 298: 113796

  Abstract

  The current study aims to: 1) investigate cognitive differences among adolescents at risk for suicide versus healthy controls (HC) and 2) identify cognitive changes associated with response to psychotherapy among adolescents at high risk for suicide. Thirty-five adolescents at high risk for suicide (HR), and 14 HC adolescents were recruited. Clinical and cognitive assessments were conducted in both groups at baseline and 16 weeks later (after the patients completed psychotherapy). HR and HC adolescents were compared at baseline and at completion of the study. We also conducted further analysis by separating into two groups the HR adolescents who responded to psychotherapy (n=17) and those who did not (n=11). At baseline, the HR group had significantly lower performance on verbal memory and processing speed than the HC group. At week 16, HR adolescents performed as well as HC adolescents in all cognitive domains. Among patients, better performance on visual memory was observed in those who responded to psychotherapy compared to those who did not. We concluded that lower performance on verbal memory and processing speed may be associated with a high risk for suicide among adolescents. Improvement in visual memory might be related to a lower risk for suicide in adolescents.

  View details for DOI 10.1016/j.psychres.2021.113796

  View details for PubMedID 33609921

• Neuroimaging Biomarkers in Pediatric Mood Disorders MOOD DISORDERS Packer, M., Tang, W., Singh, M. K., Selvaraj, S., Brambilla, P., Soares, J. C. 2021: 28-38
• BIPOLAR DISORDER IN YOUTH: NEW FINDINGS ON BIOMARKERS, ILLNESS COURSE, AND TREATMENT Miklowitz, D. J., Singh, M. K. ELSEVIER SCIENCE INC. 2021: S261
• OUTBURSTS IN THE AFTERTIME: WHERE DO WE GO FROM HERE? Singh, M. K. ELSEVIER SCIENCE INC. 2021: S136
• Longitudinal relationship between maternal distress and pediatric mood symptoms in youth with mood disorders. Journal of psychiatric research Weintraub, M. J., Schneck, C. D., Singh, M. K., Walshaw, P. D., Chang, K. D., Sullivan, A. E., Miklowitz, D. J. 2021; 144: 353-359

  Abstract

  Parents of a child with a mood disorder report significant levels of distress and burden from caregiving. This study examined whether maternal distress varies over time with levels of mood symptoms in youth with mood disorders, and whether expressed emotion (EE) and family functioning moderate these associations. We recruited youth (ages 9-17 years) with mood disorders and familial risk for bipolar disorder (BD) for a randomized trial of family-focused therapy compared to standard psychoeducation. Participants were assessed every 4-6 months for up to 4 years. Using repeated-measures mixed effects modeling, we examined the longitudinal effects of youths' mood symptoms and maternal distress concurrently, as well as whether each variable predicted the other in successive study intervals. Secondary analyses examined the moderating effects of EE and ratings of family cohesion and adaptability on maternal distress. In sample of 118 youth-mother dyads, levels of self-reported parental distress decreased over time, with no differences between treatment conditions. Youths' depressive symptoms and, most strongly, mood lability were associated with greater maternal distress longitudinally; however, maternal distress did not predict youths' mood symptoms or lability. The effect of youth symptoms on maternal distress was greater among mothers who were high EE. Family cohesion was associated with reduced concurrent ratings of maternal distress, whereas family adaptability was associated with reduced maternal distress at successive follow-ups. While maternal distress decreases over time as youths' symptoms decrease, mothers of youth with mood disorders experience significant distress that is directly linked to the youths' depressive symptom severity and lability. Improved family functioning appears to be an important mechanism by which to intervene.

  View details for DOI 10.1016/j.jpsychires.2021.10.041

  View details for PubMedID 34735839

• The Impact of COVID-19 on Adolescent Mental Health: Preliminary Findings From a Longitudinal Sample of Healthy and At-Risk Adolescents. Frontiers in pediatrics Cohen, Z. P., Cosgrove, K. T., DeVille, D. C., Akeman, E., Singh, M. K., White, E., Stewart, J. L., Aupperle, R. L., Paulus, M. P., Kirlic, N. 2021; 9: 622608

  Abstract

  Background: The COVID-19 pandemic has brought on far-reaching consequences for adolescents. Adolescents with early life stress (ELS) may be at particular risk. We sought to examine how COVID-19 impacted psychological functioning in a sample of healthy and ELS-exposed adolescents during the pandemic. Methods: A total of 24 adolescents (15 healthy, nine ELS) completed self-report measures prior to and during the COVID-19 pandemic. The effect of COVID-19 on symptoms of depression and anxiety were explored using linear mixed-effect analyses. Results: With the onset of the pandemic, healthy but not ELS-exposed adolescents evidenced increased symptoms of depression and anxiety (ps < 0.05). Coping by talking with friends and prioritizing sleep had a protective effect against anxiety for healthy adolescents (t = -3.76, p = 0.002). Conclusions: On average, this study demonstrated large increases in depression and anxiety in adolescents who were healthy prior to the COVID-19 pandemic, while ELS-exposed adolescents evidenced high but stable symptoms over time.

  View details for DOI 10.3389/fped.2021.622608

  View details for PubMedID 34169046

• Perinatal Mental Health Problems in Rural China: The Role of Social Factors. Frontiers in psychiatry Jiang, Q., Guo, Y., Zhang, E., Cohen, N., Ohtori, M., Sun, A., Dill, S., Singh, M. K., She, X., Medina, A., Rozelle, S. D. 1800; 12: 636875

  Abstract

  Background: Perinatal mental health is important for the well-being of the mother and child, so the relatively high prevalence of perinatal mental health problems in developing settings poses a pressing concern. However, most studies in these settings focus on the demographic factors associated with mental health problems, with very few examing social factors. Hence, this study examines the prevalence of the depressive, anxiety and stress symptoms among pregnant women and new mothers in rural China, and the associations between these mental health problems and social factors, including decision-making power, family conflicts, and social support. Methods: Cross-sectional data were collected from 1,027 women in their second trimester of pregnancy to 6 months postpartum in four low-income rural counties in Sichuan Province, China. Women were surveyed on symptoms of mental health problems using the Depression, Anxiety, and Stress Scale (DASS-21) and social risk factors. Multivariate logistic regression analyses were conducted to examine social risk factors associated with maternal mental health problems, with results reported as odds ratios (OR) and 95% confidence intervals (CI). Results: Among all respondents, 13% showed symptoms of depression, 18% showed symptoms of anxiety, 9% showed symptoms of stress, and 23% showed symptoms of any mental health problem. Decision-making power was negatively associated with showing symptoms of depression (OR = 0.71, CI: 0.60-0.83, p < 0.001) and stress (OR = 0.76, CI: 0.63-0.90, p = 0.002). Family conflict was positively associated with depression (OR = 1.53, CI: 1.30-1.81, p < 0.001), anxiety (OR = 1.34, CI: 1.15-1.56, p < 0.001), and stress (OR = 1.68, CI: 1.41-2.00, p < 0.001). In addition, social support was negatively associated with depression (OR = 0.56, CI: 0.46-0.69, p < 0.001), anxiety (OR = 0.76, CI: 0.63-0.91, p = 0.002), and stress (OR = 0.66, CI: 0.53-0.84, p < 0.001). Subgroup analyses revealed that more social risk factors were associated with symptoms of anxiety and stress among new mothers compared to pregnant women. Conclusion: Perinatal mental health problems are relatively prevalent among rural women in China and are strongly associated with social risk factors. Policies and programs should therefore promote individual coping methods, as well as target family and community members to improve the social conditions contributing to mental health problems among rural women.

  View details for DOI 10.3389/fpsyt.2021.636875

  View details for PubMedID 34950062

• Letter to the Editor: Measurement-Based Care in Youth-Feasibility and Acceptance. Journal of child and adolescent psychopharmacology Fristad, M. A., Bell, Z., Dopp, R., Ghaziuddin, N., Leffler, J., Schneck, C. D., Singh, M. K., Sullivan, A., Weinstein, S., Miller, L. 2020
• Variable Neurobehavioral Outcomes in Youth at Familial Risk for Mood Disorders Singh, M. SPRINGERNATURE. 2020: 45–46
• Study Protocol for Teen Inflammation Glutamate Emotion Research (TIGER) FRONTIERS IN HUMAN NEUROSCIENCE Walker, J. C., Teresi, G. I., Weisenburger, R. L., Segarra, J. R., Ojha, A., Kulla, A., Sisk, L., Gu, M., Spielman, D. M., Rosenberg-Hasson, Y., Maecker, H. T., Singh, M. K., Gotlib, I. H., Ho, T. C. 2020; 14
• Study Protocol for Teen Inflammation Glutamate Emotion Research (TIGER). Frontiers in human neuroscience Walker, J. C., Teresi, G. I., Weisenburger, R. L., Segarra, J. R., Ojha, A., Kulla, A., Sisk, L., Gu, M., Spielman, D. M., Rosenberg-Hasson, Y., Maecker, H. T., Singh, M. K., Gotlib, I. H., Ho, T. C. 2020; 14: 585512

  Abstract

  This article provides an overview of the study protocol for the Teen Inflammation Glutamate Emotion Research (TIGER) project, a longitudinal study in which we plan to recruit 60 depressed adolescents (ages 13-18 years) and 30 psychiatrically healthy controls in order to examine the inflammatory and glutamatergic pathways that contribute to the recurrence of depression in adolescents. TIGER is the first study to examine the effects of peripheral inflammation on neurodevelopmental trajectories by assessing changes in cortical glutamate in depressed adolescents. Here, we describe the scientific rationale, design, and methods for the TIGER project. This article is intended to serve as an introduction to this project and to provide details for investigators who may be seeking to replicate or extend these methods for other related research endeavors.

  View details for DOI 10.3389/fnhum.2020.585512

  View details for PubMedID 33192421

  View details for PubMedCentralID PMC7604389

• Broad white matter impairment in multiple system atrophy. Human brain mapping Del Campo, N., Phillips, O., Ory-Magne, F., Brefel-Courbon, C., Galitzky, M., Thalamas, C., Narr, K. L., Joshi, S., Singh, M. K., Peran, P., Pavy-LeTraon, A., Rascol, O. 2020

  Abstract

  Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by the widespread aberrant accumulation of alpha-synuclein (alpha-syn). MSA differs from other synucleinopathies such as Parkinson's disease (PD) in that alpha-syn accumulates primarily in oligodendrocytes, the only source of white matter myelination in the brain. Previous MSA imaging studies have uncovered focal differences in white matter. Here, we sought to build on this work by taking a global perspective on whole brain white matter. In order to do this, in vivo structural imaging and diffusion magnetic resonance imaging were acquired on 26 MSA patients, 26 healthy controls, and 23 PD patients. A refined whole brain approach encompassing the major fiber tracts and the superficial white matter located at the boundary of the cortical mantle was applied. The primary observation was that MSA but not PD patients had whole brain deep and superficial white matter diffusivity abnormalities (p <.001). In addition, in MSA patients, these abnormalities were associated with motor (Unified MSA Rating Scale, Part II) and cognitive functions (Mini-Mental State Examination). The pervasive whole brain abnormalities we observe suggest that there is widespread white matter damage in MSA patients which mirrors the widespread aggregation of alpha-syn in oligodendrocytes. Importantly, whole brain white matter abnormalities were associated with clinical symptoms, suggesting that white matter impairment may be more central to MSA than previously thought.

  View details for DOI 10.1002/hbm.25227

  View details for PubMedID 33064319

• ABERRANT REWARD FUNCTION AND STRUCTURE IS ASSOCIATED WITH SUICIDAL IDEATION AND BEHAVIOR IN YOUTH WITH DEPRESSION AND OBESITY Singh, M. K., Nimarko, A., Nrusimha, A., Gorelik, A., Rodriguez, N., Carta, K., Lu, Y., Kaur, J., Hagan, K., Fischer, A. ELSEVIER SCIENCE INC. 2020: S278
• LONG-TERM EFFICACY OF LURASIDONE IN PEDIATRIC BIPOLAR DEPRESSION: POST HOC ANALYSIS OF RESPONSE, REMISSION, AND RECOVERY Singh, M. K., Tocco, M., Schweizer, E., Pikalov, A. A. ELSEVIER SCIENCE INC. 2020: S169
• NEURAL CORRELATES OF REWARD PROCESSING DISTINGUISH HEALTHY YOUTH AT FAMILIAL RISK FOR BIPOLAR DISORDER FROM YOUTH AT FAMILIAL RISK FOR MDD Nimarko, A. F., Fischer, A. S., Hagan, K. E., Carta, K. E., Gorelik, A. J., Nrusimha, A., Kaur, J., Rodriguez, N. S., Singh, M. K. ELSEVIER SCIENCE INC. 2020: S170
• RELATIONS BETWEEN INFLAMMATION AND REWARD-SEEKING BEHAVIORS IN YOUTH WITH DEPRESSION AND OBESITY Nrusimha, A., Hagan, K. E., Nimarko, A. F., Rodriguez, N. S., Kaur, J., Carta, K. E., Gorelik, A. J., Singh, M. K. ELSEVIER SCIENCE INC. 2020: S179
• Isn't the evidence base for pediatric bipolar disorder already sufficient to inform clinical practice? Bipolar disorders Singh, M. K., Chang, K. D., Goldstein, B., Miklowitz, D. J., Soutullo, C., Youngstrom, E., Birmaher, B., Axelson, D., Post, R. M., DelBello, M. P. 2020

  Abstract

  In the May 6th Issue of the Australia and New Zealand Journal of Psychiatry, Malhi et al. published a Reflection1 asserting that the use of the term paediatric bipolar disorder (PBD) should be abandoned. Referencing unreplicated studies and dated citations, the authors incorrectly infer from administrative database studies that rates of bipolar disorder diagnoses are rising among youth, critically missing that the number of visits with a bipolar diagnosis increased markedly, not necessarily the number of children with the diagnosis.

  View details for DOI 10.1111/bdi.12987

  View details for PubMedID 32844555

• Changes in Intrinsic Brain Connectivity in Family-Focused Therapy Versus Standard Psychoeducation Among Youth at High Risk for Bipolar Disorder. Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K., Nimarko, A. F., Garrett, A. S., Gorelik, A. J., Roybal, D. J., Walshaw, P. D., Chang, K. D., Miklowitz, D. J. 2020

  Abstract

  OBJECTIVE: We compared intrinsic network connectivity in symptomatic youth at high risk (HR) for bipolar disorder (BD) and healthy comparison (HC) youth, and, in HR youth, investigated treatment-related changes in intrinsic connectivity following family focused therapy for high-risk youth (FFT-HR) versus standardized family psychoeducation.METHOD: HR youth (N=34; age 9-17 years; mean 14 years, 56% girls) with depressive and/or hypomanic symptoms and at least one first- or second-degree relative with BD I or II were randomly assigned to 4 months of FFT-HR (12 sessions of psychoeducation, communication, and problem-solving skills training) or Enhanced Care (EC; 3 family and 3 individual psychoeducation sessions). Before and after 4-months of treatment, participants underwent resting state functional magnetic resonance imaging (rs-fMRI). A whole brain independent component analysis compared rs-fMRI networks in HR youth and 30 age-matched HC youth at a pretreatment baseline. Then, we identified pretreatment to post-treatment (4-month) changes in network connectivity in HR youth receiving FFT-HR (n=16) or EC (n=18) and correlated these changes with depression improvement.RESULTS: At baseline, HR youth had greater connectivity between the ventrolateral prefrontal cortex (VLPFC) and the anterior default mode network (aDMN) than did HCs (p=.004). Over 4 months of treatment, FFT-HR-assigned HR youth had increased VLPFC-aDMN connectivity from pre- to post-treatment (p=.003), whereas HR youth in EC showed no significant change over time (p=.11) (treatment by time interaction, [t(31)=3.33, CI 95% [0.27, 1.14], p=.002]. Reduction in depression severity over 4 months inversely correlated with enhanced anterior DMN (r= -.71) connectivity in the FFT-HR but not in the EC (r=-.07) group (z=-2.17, p=.015).CONCLUSION: Compared to standard psychoeducation, FFT-HR is associated with stronger connectivity between the VLPFC and aDMN, suggesting possible enhancements of self- and illness awareness and emotion regulation.

  View details for DOI 10.1016/j.jaac.2020.07.892

  View details for PubMedID 32745598

• Neural Correlates of Positive Emotion Processing That Distinguish Healthy Youth at Familial Risk for Bipolar Versus Major Depressive Disorder. Journal of the American Academy of Child and Adolescent Psychiatry Nimarko, A. F., Fischer, A. S., Hagan, K. E., Gorelik, A. J., Lu, Y., Young, C. J., Singh, M. K. 2020

  Abstract

  OBJECTIVE: Familial risk for bipolar (BD) or major depressive (MDD) disorder may lead to differential emotion processing signatures, resulting in unique neural vulnerability.METHOD: Healthy offspring of a parent with BD (n=29, "BD-risk") or MDD (n=44, "MDD-risk") and youth without any personal or family psychopathology (n=28, "HC") ages 8-17 (13.64 ± 2.59) completed an implicit emotion perception functional magnetic resonance imaging task. Whole-brain voxel-wise and psychophysiological interaction analyses examined neural differences in activation and connectivity during emotion processing. Regression modeling tested for neural associations with behavioral strengths and difficulties and conversion to psychopathology at follow-up (3.71 ± 1.91 years).RESULTS: BD-risk youth showed significantly reduced bilateral putamen activation, and decreased connectivity between the left putamen and the left ventral anterior cingulate cortex (vACC) and the right posterior cingulate cortex (PCC) during positive-valence emotion processing compared to MDD-risk and HC (Z >2.3; p <.001). Decreased left putamen- right PCC connectivity correlated with subsequent peer problems in BD-risk (beta = -2.90; p <.05) and MDD-risk (beta = -3.64; p <.05). Decreased left (beta = -.09; p < .05) and right putamen activation (beta = -.07; p = .04) were associated with conversion to a mood or anxiety disorder in BD-risk. Decreased left putamen-right PCC connectivity was associated with a higher risk of conversion in BD-risk (HR = 8.28 , p < .01) and MDD-risk (HR = 2.31, p = .02).CONCLUSION: Reduced putamen activation and connectivity during positive emotion processing appear to distinguish BD-risk youth from MDD-risk and HC youth, and may represent a marker of vulnerability.

  View details for DOI 10.1016/j.jaac.2020.07.890

  View details for PubMedID 32738282

• Effects of family-focused therapy on suicidal ideation and behavior in youth at high risk for bipolar disorder. Journal of affective disorders Miklowitz, D. J., Merranko, J. A., Weintraub, M. J., Walshaw, P. D., Singh, M. K., Chang, K. D., Schneck, C. D. 2020; 275: 14–22

  Abstract

  BACKGROUND: Youth who are at clinical and familial risk for bipolar disorder (BD) often have significant suicidal ideation (SI). In a randomized trial, we examined whether family-focused therapy (FFT) is associated with reductions in SI and suicidal behaviors in high-risk youth.METHODS: Participants (ages 9-17 years) met diagnostic criteria for unspecified BD or major depressive disorder with active mood symptoms and had at least one relative with BD type I or II. Participants were randomly allocated to 12 sessions in 4 months of FFT or 6 sessions in 4 months of psychoeducation (enhanced care, EC), with pharmacotherapy as needed. Clinician- and child-rated assessments of mood, suicidal thoughts and behaviors, and family conflict were obtained at baseline and 4-6 month intervals over 1-4 years.RESULTS: Participants (N=127; mean 13.2±2.6 yrs., 82 female) were followed over an average of 105.9±64.0 weeks. Youth with high baseline levels of SI who received FFT had lower levels of (and fewer weeks with) SI at follow-up compared to youth with high baseline SI who received EC. Participants in FFT had longer intervals without suicidal behaviors than participants in EC. Youths' ratings of family conflict significantly mediated the effects of treatment on SI at follow-up.LIMITATIONS: Family conflict was based on questionnaires rather than observer ratings of family interactions.CONCLUSIONS: Family psychoeducation with skill training can be an effective deterrent to suicidal thoughts and behaviors in youth at high risk for BD. Reducing parent/offspring conflict should be a central objective of psychosocial interventions for high-risk youth with SI.

  View details for DOI 10.1016/j.jad.2020.06.015

  View details for PubMedID 32658817

• Cannabis and the Developing Adolescent Brain. Current treatment options in psychiatry Fischer, A. S., Tapert, S. F., Lee Louie, D., Schatzberg, A. F., Singh, M. K. 2020; 7 (2): 144–61

  Abstract

  Purpose of Review: This review summarizes (1) recent trends in delta-9-tetrahydrocannabionol [THC] and cannabidiol (CBD) content in cannabis products, (2) neurobiological correlates of cannabis use on the developing adolescent brain, (3) effects of cannabis on psychiatric symptoms and daily functioning in youth (i.e., academic performance, cognition, sleep and driving), (4) cannabis products used to relieve or treat medical issues in youth, and (5) available treatments for cannabis use disorder in adolescence.Recent findings: Despite marked increases in THC content and availability of cannabis, there has been a decline in perceived risk and an increase in use of THC extract products among youth in the United States. The primary psychiatric symptoms associated with cannabis use in youth are increased risk for addiction, depressive, and psychotic symptoms. Cannabis alters endocannabinoid system function which plays a central role in modulating the neurodevelopment of reward and stress systems. To date, few studies have examined neurobiological mechanisms underlying the psychiatric sequalae of cannabis exposure in youth. Adolescent cannabis exposure results in impaired cognition, sleep, and driving ability. There are very limited FDA-approved cannabinoid medications, none of them supporting their use for the treatment of psychiatric symptoms. Behavioral therapies are currently the mainstay of treating cannabis misuse, with no pharmacotherapies currently approved by the FDA for cannabis use disorder in youth.Summary: Here, we summarize the most up-to-date knowledge on the neurobiological psychiatric, and daily function effects of the most commonly used cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We then review FDA approved medical use of cannabinoid treatments as well as pharmacological and psychological treatments for cannabis use disorder in youth. Our current understanding of the effects of cannabis on the developing brain and treatments for cannabis misuse in youth remain limited. Future research aimed at examining the neurobiological effects of cannabis, with objective measures of exposure, over the course of pediatric development and in relation to psychiatric symptoms are needed.

  View details for DOI 10.1007/s40501-020-00202-2

  View details for PubMedID 32714742

• Long-term efficacy of lurasidone in pediatric bipolar depression: Response, remission and recovery Singh, M., Tocco, M., Schweizer, E., Pikalov, A. WILEY. 2020: 99
• Family Dynamics and Emotion Processing: Functional Connectivity Biomarkers of Risk and Resilience in Youth at Familial Risk for Mood Disorders Fischer, A., Holt-Gosselin, B., Nimarko, A., Carta, K., Kaur, J., Lu, Y., Rodriguez, N., Takada, C., Gotlib, I., Singh, M. ELSEVIER SCIENCE INC. 2020: S288
• Variable Neurobehavioral Outcomes in Youth at Familial Risk for Mood Disorders Singh, M., Nimarko, A., Hagan, K., Fischer, A. ELSEVIER SCIENCE INC. 2020: S68
• Is There an Ace Up Our Sleeve? A Review of Interventions and Strategies for Addressing Behavioral and Neurobiological Effects of Adverse Childhood Experiences in Youth. Adversity and resilience science Kirlic, N., Cohen, Z. P., Singh, M. K. 2020; 1 (1): 5-28

  Abstract

  Exposure to early life adversity (ELA) is a major public health crisis posing as a significant risk of immediate and sustained mental and physical health consequences. While a remarkable body of knowledge has been amassed showing psychological, cognitive, social, developmental, and neurobiological consequences of ELA exposure, little has been done to improve the long-term mental and physical health outcomes for youth exposed to ELA. Furthermore, neurobiological processes underlying poor outcomes in this population have been largely left out of prevention and intervention target efforts. In this review, we first describe ELA-related alterations across psychological and neurobiological systems in children and adolescents. Next, we describe existing evidence-based interventions targeting ELA-related outcomes. We then turn to experimental studies examining individual differences in mechanistic functioning consequent to ELA exposure, and strategies that target these mechanisms and modulate disrupted functioning. Finally, we highlight areas of future research that may be promising in engaging behavioral and neurobiological targets through novel preventive interventions or augmentation of existing interventions, thereby reducing negative mental and physical health outcomes later in life.

  View details for DOI 10.1007/s42844-020-00001-x

  View details for PubMedID 34278327

  View details for PubMedCentralID PMC8281391

• Characteristics of youth at high risk for bipolar disorder compared to youth with bipolar I or II disorder. Journal of psychiatric research Weintraub, M. J., Schneck, C. D., Walshaw, P. D., Chang, K. D., Singh, M. K., Axelson, D. A., Birmaher, B., Miklowitz, D. J. 2020; 123: 48–53

  Abstract

  Significant efforts have been undertaken to characterize the phenomenology of the high-risk period for bipolar disorder (BD) through the examination of youth at familial risk (i.e., having a first- or second-degree relative with BD) or clinical high risk for the disorder (i.e., youth with BD Not Otherwise Specified [NOS] or major depressive disorder [MDD]). However, little is known about the phenomenology of youth at both familial and clinical high risk for BD. In this study, we examined the clinical and psychosocial characteristics of youth at familial and clinical high risk (HR) for BD, and compared these characteristics to those of youth with BD I and II. Both groups were recruited based on current, active mood symptoms from separate randomized trials of family therapy. A total of 127 HR youth were evaluated: 52 (40.9%) were diagnosed with BD-NOS and 75 (59.1%) were diagnosed with MDD. Compared to adolescents with BD I and II (n=145), HR youth had higher rates of anxiety disorders, and comparable rates of attention-deficit/hyperactivity disorder and oppositional defiant disorder/conduct disorder. Manic symptom severity and psychosocial functioning were progressively more impaired consistent with diagnostic severity: BD I>BD II>BD-NOS>MDD. Nonetheless, HR youth exhibited depressive symptom severity that was comparable to adolescents with BD I. These results provide further support for the high rates of anxiety disorders and premorbid dysfunction in addition to active mood symptoms for youth at risk for BD, and suggest anxiety is an important phenomenological characteristic and treatment target in the high-risk period.

  View details for DOI 10.1016/j.jpsychires.2020.01.010

  View details for PubMedID 32036073

• Effects of Family-Focused Therapy vs Enhanced Usual Care for Symptomatic Youths at High Risk for Bipolar Disorder: A Randomized Clinical Trial. JAMA psychiatry Miklowitz, D. J., Schneck, C. D., Walshaw, P. D., Singh, M. K., Sullivan, A. E., Suddath, R. L., Forgey Borlik, M., Sugar, C. A., Chang, K. D. 2020

  Abstract

  Importance: Behavioral high-risk phenotypes predict the onset of bipolar disorder among youths who have parents with bipolar disorder. Few studies have examined whether early intervention delays new mood episodes in high-risk youths.Objective: To determine whether family-focused therapy (FFT) for high-risk youths is more effective than standard psychoeducation in hastening recovery and delaying emergence of mood episodes during the 1 to 4 years after an active period of mood symptoms.Design, Settings, and Participants: This multisite randomized clinical trial included referred youths (aged 9-17 years) with major depressive disorder or unspecified (subthreshold) bipolar disorder, active mood symptoms, and at least 1 first- or second-degree relative with bipolar disorder I or II. Recruitment started from October 6, 2011, and ended on September 15, 2016. Independent evaluators interviewed participants every 4 to 6 months to measure symptoms for up to 4 years. Data analysis was performed from March 13 to November 3, 2019.Interventions: High-risk youths and parents were randomly allocated to FFT (12 sessions in 4 months of psychoeducation, communication training, and problem-solving skills training; n=61) or enhanced care (6 sessions in 4 months of family and individual psychoeducation; n=66). Youths could receive medication management in either condition.Main Outcomes and Measures: The coprimary outcomes, derived using weekly psychiatric status ratings, were time to recovery from prerandomization symptoms and time to a prospectively observed mood (depressive, manic, or hypomanic) episode after recovery. Secondary outcomes were time to conversion to bipolar disorder I or II and longitudinal symptom trajectories.Results: All 127 participants (82 [64.6%] female; mean [SD] age, 13.2 [2.6] years) were followed up for a median of 98 weeks (range, 0-255 weeks). No differences were detected between treatments in time to recovery from pretreatment symptoms. High-risk youths in the FFT group had longer intervals from recovery to the emergence of the next mood episode (chi2=5.44; P=.02; hazard ratio, 0.55; 95% CI, 0.48-0.92;), and from randomization to the next mood episode (chi2=4.44; P=.03; hazard ratio, 0.59; 95% CI, 0.35-0.97) than youths in enhanced care. Specifically, FFT was associated with longer intervals to depressive episodes (log-rank chi2=6.24; P=.01; hazard ratio, 0.53; 95% CI, 0.31-0.88) but did not differ from enhanced care in time to manic or hypomanic episodes, conversions to bipolar disorder, or symptom trajectories.Conclusions and Relevance: Family skills-training for youths at high risk for bipolar disorder is associated with longer times between mood episodes. Clarifying the relationship between changes in family functioning and changes in the course of high-risk syndromes merits future investigation.Trial Registration: ClinicalTrials.gov identifier: NCT01483391.

  View details for DOI 10.1001/jamapsychiatry.2019.4520

  View details for PubMedID 31940011

• Adapted Dialectical Behavior Therapy for Adolescents with a High Risk of Suicide in a Community Clinic: A Pragmatic Randomized Controlled Trial. Suicide & life-threatening behavior Santamarina-Perez, P. n., Mendez, I. n., Singh, M. K., Berk, M. n., Picado, M. n., Font, E. n., Moreno, E. n., Martínez, E. n., Morer, A. n., Borràs, R. n., Cosi, A. n., Romero, S. n. 2020

  Abstract

  This study is a pragmatic randomized controlled trial, which compares the effectiveness of an adapted form of Dialectical Behavior Therapy for Adolescents (DBT-A) and treatment as usual plus group sessions (TAU + GS) to reduce suicidal risk for adolescents in a community health mental clinic.Thirty-five adolescents from a community outpatient clinic, with repetitive NSSI alone or with SA over the last 12 months and with current high suicide risk as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS), were enrolled. Participants were randomly assigned to undergo either DBT-A (n = 18) or TAU + GT (n = 17) treatments over a 16-week period. Primary outcomes were the difference between NSSI and SA recorded during the first 4 weeks and the final 4 weeks of treatment. Secondary outcomes included changes in Children's Global Assessment Scale (C-GAS), Suicidal Ideation Questionnaire (SIQ-JR), and Beck Depression Inventory-II (BDI-II).Dialectical Behavior Therapy for Adolescents was more effective than TAU + GS at reducing NSSI, use of antipsychotics, and improving C-GAS. No SAs were reported in the two groups at the end of the treatment. Both treatments were equally effective in decreasing SIQ-JR and BDI-II scores.These findings support the feasibility and effectiveness of DBT-A for adolescents at high risk of suicide in community settings.

  View details for DOI 10.1111/sltb.12612

  View details for PubMedID 31944371

• Longitudinal trajectories of mood symptoms and global functioning in youth at high risk for bipolar disorder. Journal of affective disorders Weintraub, M. J., Schneck, C. D., Walshaw, P. D., Chang, K. D., Sullivan, A. E., Singh, M. K., Miklowitz, D. J. 2020; 277: 394–401

  Abstract

  Little is known about the longitudinal course of mood symptoms and functioning in youth who are at high risk for bipolar disorder (BD). Identifying distinct course trajectories and predictors of those trajectories may help refine treatment approaches.This study examined the longitudinal course of mood symptoms and functioning ratings in 126 youth at high risk for BD based on family history and early mood symptoms. Participants were enrolled in a randomized trial of family-focused therapy and followed longitudinally (mean 2.0 years, SD = 53.6 weeks).Using latent class growth analyses (LCGA), we observed three mood trajectories. All youth started the study with active mood symptoms. Following the index mood episode, participants were classified as having a "significantly improving course" (n = 41, 32.5% of sample), a "moderately symptomatic course" (n = 21, 16.7%), or a "predominantly symptomatic course" (n = 64, 50.8%) at follow-up. More severe depression, anxiety, and suicidality at the study's baseline were associated with a poorer course of illness. LCGA also revealed three trajectories of global functioning that closely corresponded to symptom trajectories; however, fewer youth exhibited functional recovery than exhibited symptomatic recovery.Mood trajectories were assessed within the context of a treatment trial. Ratings of mood and functioning were based on retrospective recall.This study suggests considerable heterogeneity in the course trajectories of youth at high risk for BD, with a significant proportion (32.5%) showing long-term remission of symptoms. Treatments that enhance psychosocial functioning may be just as important as those that ameliorate symptoms in youth at risk for BD.

  View details for DOI 10.1016/j.jad.2020.08.018

  View details for PubMedID 32861841

• Lurasidone in Children and Adolescents with Bipolar Depression Presenting with Mixed (Subsyndromal Hypomanic) Features: Post Hoc Analysis of a Randomized Placebo-Controlled Trial. Journal of child and adolescent psychopharmacology Singh, M. K., Pikalov, A. n., Siu, C. n., Tocco, M. n., Loebel, A. n. 2020

  Abstract

  Objectives: To evaluate the efficacy and safety of lurasidone in the treatment of children and adolescents with bipolar depression presenting with mixed (subsyndromal hypomanic) features. Methods: Patients, 10-17 years of age, with a Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5), diagnosis of bipolar I depression were randomized to 6 weeks of double-blind treatment with once-daily flexible doses of lurasidone 20-80 mg or placebo. The presence of mixed (subsyndromal hypomanic) features in this pediatric bipolar depression trial was defined as a Young Mania Rating Scale score of 5 or greater at study baseline. Key efficacy measures included change from baseline to week 6 in the Children's Depression Rating Scale-Revised (CDRS-R) score (primary endpoint) and Clinical Global Impressions-Bipolar Severity (CGI-BP-S) score, using a mixed model for repeated measures analysis. Results: At baseline, subsyndromal hypomanic features were present in 54.2% of patients. Treatment with lurasidone (vs. placebo) was associated with significantly greater reductions in CDRS-R scores at week 6, independent of the presence (-21.5 vs. -15.9, p < 0.01; effect size d = 0.43) or absence (-20.5 vs. -14.9, p < 0.01; d = 0.44) of subsyndromal hypomanic features. Likewise, lurasidone (vs. placebo) was associated with significantly greater reductions in CGI-BP-S scores at week 6, independent of the presence (-1.6 vs. -1.1, p < 0.001, d = 0.51) or absence (-1.3 vs. -1.0, p = 0.05; d = 0.31) of these subsyndromal hypomanic features. Rates of protocol-defined treatment-emergent hypomania or mania were similar for lurasidone and placebo in patients with (lurasidone 8.2% vs. placebo 9.0%) or without subsyndromal hypomanic features (lurasidone 1.3% vs. placebo 3.7%). Conclusions: In this post hoc analysis of a randomized placebo-controlled trial, lurasidone was found to be efficacious in the treatment of child and adolescent patients with bipolar depression who presented with mixed (subsyndromal hypomanic) features. No differences in safety profile, including the risk of treatment-emergent mania, were observed in patients with or without subsyndromal hypomanic features in this study.

  View details for DOI 10.1089/cap.2020.0018

  View details for PubMedID 32392455

• Cultivating Hope. JAMA Singh, M. K. 2020; 323 (18): 1781–82
• Smaller caudate gray matter volume is associated with greater implicit suicidal ideation in depressed adolescents. Journal of affective disorders Ho, T. C., Teresi, G. I., Ojha, A. n., Walker, J. C., Kirshenbaum, J. S., Singh, M. K., Gotlib, I. H. 2020; 278: 650–57

  Abstract

  Objective biomarkers of cognitive vulnerabilities related to suicidal ideation (SI) may assist in early prevention in adolescents. Previously, we found that smaller gray matter volumes (GMVs) of the dorsal striatum prospectively predicted implicit SI, measured using a computerized implicit association test (IAT) assessing associations between "self" and "death," in a community sample of adolescents. Here, we sought to replicate these findings in an independent sample of depressed adolescents.53 depressed adolescents who varied in severity of suicidal thoughts and behaviors completed high-resolution structural MRI. Caudate, putamen, and nucleus accumbens GMVs were estimated using FreeSurfer 6.0. Robust linear regressions were used to examine associations between striatal GMVs and implicit and explicit SI, covarying for sex, age, total intracranial volume, medication use, and depression severity. Significance was determined using Bonferroni correction. Finally, LASSO regression was used to identify which striatal GMV contributed most to prediction of implicit SI.Smaller bilateral caudate and right nucleus accumbens GMVs were associated with higher IAT scores (all ps<0.001). Smaller putamen and nucleus accumbens GMVs were not associated with implicit or explicit SI. Our LASSO analysis indicated that right caudate GMV contributed most to the prediction of IAT scores.This study is the first to demonstrate that caudate GMVs are significantly associated with implicit self-associations with death in a sample of depressed adolescents. When considered with our previous work, smaller caudate GMVs may be a robust biomarker of implicit SI in adolescents, with clinical implications for early identification of youth at risk for engaging in suicidal behaviors.

  View details for DOI 10.1016/j.jad.2020.09.046

  View details for PubMedID 33039875

• Insulin Resistance and Structural Change in the Anterior Cingulate Cortex in Youth With Depression and Obesity Hagan, K., Fischer, A., Nrusimha, A., Nimarko, A., Gorelik, A., Bohon, C., Rasgon, N., Singh, M. NATURE PUBLISHING GROUP. 2019: 143–44
• Functional Connectivity Biomarkers of Emotion Regulation That Distinguish Risk for Bipolar Versus Unipolar Depression in Clinically Asymptomatic High-Risk Youth Fischer, A., Nimarko, A., Hagan, K., Gotlib, I., Singh, M. NATURE PUBLISHING GROUP. 2019: 434–35
• REWARD PROCESSING IN DEPRESSED AND OBESE CHILDREN Angal, S., Fischer, A. S., Bohon, C., Nimarko, A. F., Rolle, C. E., Lu, Y., Pan, T., Kuramkote, S. R., Rasgon, N. L., Singh, M. K. ELSEVIER SCIENCE INC. 2019: S274
• UNDERSTANDING HOW TO TREAT AND PREVENT PEDIATRIC BIPOLAR DISORDER Delbello, M. P., Singh, M. K., Carlson, G. A. ELSEVIER SCIENCE INC. 2019: S335
• ANTIPSYCHOTIC MEDICATIONS: USE AND MISUSE Campbell, P., Singh, M. K. ELSEVIER SCIENCE INC. 2019: S104–S105
• LIMBIC INTRINSIC CONNECTIVITY IN DEPRESSED AND HIGH-RISK YOUTH Singh, M. K. ELSEVIER SCIENCE INC. 2019: S125
• ARE RISK FOR AND RESILIENCE FROM BIPOLAR DISORDER TWO SIDES OF THE SAME NEUROBIOLOGY? Delbello, M. P., Singh, M. K. ELSEVIER SCIENCE INC. 2019: S361
• MECHANISMS AND RISK FACTORS UNDERLYING ADVERSE EVENTS FROM TREATING YOUTH WITH OR AT RISK FOR BIPOLAR DISORDER Singh, M. K., Angal, S., Nimarko, A., Tallman, M., Hinman, K., Zalpuri, I., Duran, L., Blom, T., Delbello, M. P. ELSEVIER SCIENCE INC. 2019: S335–S336
• MECHANISMS OF PHARMACOLOGICAL TREATMENT EFFICACY IN PEDIATRIC BIPOLAR DISORDERS Delbello, M. P., Duran, L., Tallman, M., Klein, C., Klein, C., Strawn, J., Welge, J., Sweeney, J., Blom, T., Zhang, W. ELSEVIER SCIENCE INC. 2019: S335
• DISSOCIABLE NEURAL NETWORK MARKERS OF RISK AND RESILIENCE IN PEDIATRIC BIPOLAR DISORDER Fischer, A., Nimarko, A., Fonseca, C., Angal, S., Singh, M. K. ELSEVIER SCIENCE INC. 2019: S362
• Time Spent with Parents Predicts Change in Depressive Symptoms in Adolescents with Major Depressive Disorder JOURNAL OF ABNORMAL CHILD PSYCHOLOGY Manczak, E. M., Ordaz, S. J., Singh, M. K., Goyer, M. S., Gotlib, I. H. 2019; 47 (8): 1401–8
• Neural correlates of emotion processing predict resilience in youth at familial risk for mood disorders DEVELOPMENT AND PSYCHOPATHOLOGY Nimarko, A. F., Garrett, A. S., Carlson, G. A., Singh, M. K. 2019; 31 (3): 1037–52
• Beyond a Binary Classification of Sex: An Examination of Brain Sex Differentiation, Psychopathology, and Genotype JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Phillips, O. R., Onopa, A. K., Hsu, V., Ollila, H., Hillary, R., Hallmayer, J., Gotlib, I. H., Taylor, J., Mackey, L., Singh, M. K. 2019; 58 (8): 787–98
• Fronto-Limbic Connectivity as a Predictor of Improvement in Nonsuicidal Self-Injury in Adolescents Following Psychotherapy. Journal of child and adolescent psychopharmacology Santamarina-Perez, P., Romero, S., Mendez, I., Leslie, S. M., Packer, M. M., Sugranyes, G., Picado, M., Font, E., Moreno, E., Martinez, E., Morer, A., Romero, M., Singh, M. K. 2019

  Abstract

  Objectives: Key neurobiological factors contribute to vulnerability to nonsuicidal self-injury (NSSI) among adolescents and how they respond to treatment targeted to reduce such behaviors. This study aims to examine differences in intrinsic functional connectivity between adolescents with NSSI and healthy controls (HCs) and to identify baseline connectivity markers that predict improvements in NSSI after psychotherapy. Methods: Adolescents aged 12-17 (n=24) with repetitive NSSI along with demographically similar HCs (n=16) underwent resting-state functional MRI scanning after which patients received up to 4 months of psychological treatment. A seed-based approach was used to examine baseline between-group differences in intrinsic functional connectivity of the amygdala and the medial prefrontal cortex (mPFC). Further analyses examined the associations between intrinsic functional connectivity at baseline and improvement in NSSI after psychological treatment. Results: Compared with HCs, adolescents with NSSI showed significantly reduced connectivity between the amygdala and the anterior cingulate cortex, subcallosal cortex, and paracingulate gyrus, as well as between the amygdala and a cluster encompassing the right planum temporale and right insula. Adolescents with NSSI, compared with HCs, also showed reduced connectivity between the mPFC and two clusters: one located in the precentral and postcentral gyri and another in the left insula. After treatment, 50% of patients reported fewer NSSI episodes compared to baseline, which was considered as improvement. Stronger negative amygdala-prefrontal connectivity was associated with greater posttreatment improvement in NSSI. Conclusions: Adolescents with NSSI may have aberrant amygdala and mPFC connectivity compared with HCs. Furthermore, stronger baseline negative amygdala-prefrontal connectivity may predict greater improvement in NSSI after psychological intervention. Given that no prior study has used resting-state functional connectivity to predict response to psychological treatment in adolescents with NSSI, replication of these findings is needed.

  View details for DOI 10.1089/cap.2018.0152

  View details for PubMedID 31225733

• Clinical Conundrum: How do you treat youth with depression and a family history of bipolar disorder? BIPOLAR DISORDERS Angal, S., DelBello, M., Zalpuri, I., Singh, M. K. 2019; 21 (4): 383–86
• Nucleus Accumbens Volume Predicts Allostatic Load and is Moderated by Sex and Treatment Modality in Youth With Depression and Obesity Ridout, K., Nimarko, A., Packer, M., Tang, W., Rah, E., Fonseca, C., Lu, Y., Angal, S., Rasgon, N., Singh, M. ELSEVIER SCIENCE INC. 2019: S262
• The Relation Between Tanner Stage and Age is Moderated by Trauma in Youth With Depression and Obesity Ridout, S., Ridout, K., Nimarko, A., Packer, M., Tang, W., Rah, E., Fonseca, C., Lu, Y., Angal, S., Rasgon, N., Singh, M. ELSEVIER SCIENCE INC. 2019: S315–S316
• The Relation Between Hippocampal Volume and Allostatic Load is Moderated by Tanner Stage, Sex, and Adversity in Youth With Depression and Obesity Ridout, K., Nimarko, A., Packer, M., Tang, W., Fonseca, C., Rah, E., Lu, Y., Angal, S., Singh, M. ELSEVIER SCIENCE INC. 2019: S318
• Neural Correlates of Emotion Processing in Youth at Familial Risk for Mood Disorders Nimarko, A., Angal, S., Fonseca, C., Rah, E., Tang, W., Lu, Y., McDonnell, D., Singh, M. ELSEVIER SCIENCE INC. 2019: S262–S263
• Emotion Network Predictors of Clinical Outcome in Youth at High Risk for Bipolar Disorder Singh, M., Nimarko, A., Leslie, S., Fischer, A. ELSEVIER SCIENCE INC. 2019: S2
• Early intervention for youth at high risk for bipolar disorder: A multisite randomized trial of family-focused treatment EARLY INTERVENTION IN PSYCHIATRY Miklowitz, D. J., Schneck, C. D., Walshaw, P. D., Garrett, A. S., Singh, M. K., Sugar, C. A., Chang, K. D. 2019; 13 (2): 208–16
• Using Screening Tools and Diagnosing Bipolar Disorder in Pediatric Patients. The Journal of clinical psychiatry Singh, M. K. 2019; 80 (1)

  Abstract

  At least half of the cases of bipolar disorder begin in childhood or adolescence. How do you decide whether a young patient's symptoms indicate bipolar disorder? Read this CME Brief Report to learn about reliable tools and methods to identify bipolar disorder in pediatric patients.

  View details for DOI 10.4088/JCP.SU18023BR1C

  View details for PubMedID 30865786

• Time Spent with Parents Predicts Change in Depressive Symptoms in Adolescents with Major Depressive Disorder. Journal of abnormal child psychology Manczak, E. M., Ordaz, S. J., Singh, M. K., Goyer, M. S., Gotlib, I. H. 2019

  Abstract

  Research with community samples suggests that non-affective features of families, such as the amount of time parents and adolescents spend together, affect depressive symptoms in adolescents. It is possible, however, that spending time with parents not only protects against the onset of depressive symptoms, but also reduces symptoms in adolescents who are already depressed. The current study was designed to test this formulation while also examining whether affective dimensions of family functioning - specifically parental warmth - accounted for or moderated observed associations. Finally, we tested the reverse direction of the associations, examining whether greater severity of depression in adolescents results in parents spending less time with them. Forty-one adolescents (ages 14 to 17years) who met criteria for a current major depressive episode participated in the present study with one parent. Once each month for six time points, dyads completed reports of depressive symptoms and the amount of time parents and adolescents spent with each other. Participants also completed measures of parental warmth. Results of lagged multilevel modeling indicated that spending more time with a parent predicted fewer depressive symptoms in adolescents at the following assessment relative to their mean; in contrast, greater severity of depressive symptoms did not predict spending less time with a parent at the following assessment. In contrast, parental warmth did not account for or moderate the association between time together and depressive symptoms. These results suggest that non-affective dimensions of family life, specifically spending more time with parents, have beneficial effects on depressive symptoms in adolescents diagnosed with depression.

  View details for PubMedID 30847667

• Double trouble: Weekend sleep changes are associated with increased impulsivity among adolescents with bipolar I disorder BIPOLAR DISORDERS Gershon, A., Johnson, S. L., Thomas, L., Singh, M. K. 2019; 21 (2): 132-141
• Brain and behavioral correlates of insulin resistance in youth with depression and obesity HORMONES AND BEHAVIOR Singh, M. K., Leslie, S. M., Packer, M., Zaiko, Y. V., Phillips, O. R., Weisman, E. F., Wall, D. M., Jo, B., Rasgon, N. 2019; 108: 73–83
• Clinical Conundrum: How do you treat youth with depression and a family history of bipolar disorder? Bipolar disorders Angal, S. n., DelBello, M. n., Zalpuri, I. n., Singh, M. n. 2019

  Abstract

  We present a hypothetical case based on clinical encounters common in our practice. No specific patient data was presented. We have not published or submitted any related papers from this study. This article is protected by copyright. All rights reserved.

  View details for PubMedID 31025454

• Principles of Treatment of Mood Disorders Across Development CLINICAL HANDBOOK FOR THE DIAGNOSIS AND TREATMENT OF PEDIATRIC MOOD DISORDERS Zalpuri, I., Singh, M., Singh, M. K. 2019: 83–104
• Principles of Assessment of Mood Disorders in Childhood CLINICAL HANDBOOK FOR THE DIAGNOSIS AND TREATMENT OF PEDIATRIC MOOD DISORDERS Singh, M., Singh, M. K. 2019: 3–22
• CLINICAL HANDBOOK FOR THE DIAGNOSIS AND TREATMENT OF PEDIATRIC MOOD DISORDERS Preface CLINICAL HANDBOOK FOR THE DIAGNOSIS AND TREATMENT OF PEDIATRIC MOOD DISORDERS Singh, M., Singh, M. K. 2019: XVII-XIX
• Resources and Readings CLINICAL HANDBOOK FOR THE DIAGNOSIS AND TREATMENT OF PEDIATRIC MOOD DISORDERS Singh, M., Singh, M. K. 2019: 517–19
• Quick Reference Facts for the Treatment of Pediatric Mood Disorders CLINICAL HANDBOOK FOR THE DIAGNOSIS AND TREATMENT OF PEDIATRIC MOOD DISORDERS Singh, M., Singh, M. K. 2019: 521–42
• Pharmacological Approaches for Treating Suicidality in Adolescents EVIDENCE-BASED TREATMENT APPROACHES FOR SUICIDAL ADOLESCENTS: TRANSLATING SCIENCE INTO PRACTICE Zalpuri, I., Singh, M. K., Berk, M. 2019: 293–331
• Neural correlates of liraglutide effects in persons at risk for Alzheimer's disease BEHAVIOURAL BRAIN RESEARCH Watson, K. T., Wroolie, T. E., Tong, G., Foland-Ross, L. C., Frangou, S., Singh, M., McIntyre, R. S., Roat-Shumway, S., Myoraku, A., Reiss, A. L., Rasgon, N. L. 2019; 356: 271–78
• Neural correlates of emotion processing predict resilience in youth at familial risk for mood disorders. Development and psychopathology Nimarko, A. F., Garrett, A. S., Carlson, G. A., Singh, M. K. 2019: 1–16

  Abstract

  Aberrant face emotion processing has been demonstrated in youth with and at a familial risk for bipolar and major depressive disorders. However, the neurobiological factors related to emotion processing that underlie resilience from youth-onset mood disorders are not well understood. Functional magnetic resonance imaging data during an implicit emotion processing task were collected at baseline from a sample of 50 youth, ages 8-17, who were healthy but also familially at high risk for either bipolar disorder or major depressive disorder, and 24 healthy controls with no family history of psychopathology (HCL). Participants were reevaluated 3 years later and classified into three groups for analysis: high-risk youth who converted to a psychiatric diagnosis (CVT; N = 23), high-risk youth who were resilient from developing any psychopathology (RES; N = 27), and HCL youth (N = 24) who remained healthy at follow-up. For happy > calm faces, the CVT and RES groups had significantly lower activation in the left inferior parietal lobe (IPL), while the RES group had lower activation in the right supramarginal gyrus. For fear > calm faces, the RES group had lower activation in the right precuneus and inferior frontal gyrus (IFG) compared to the CVT group. Connectivity analyses revealed the RES group exhibited higher left IPL connectivity with visual cortical regions for happy > calm faces, and higher IFG connectivity with frontal, temporal, and limbic regions for fear > calm faces. These connectivities were correlated with improvements in prosocial behaviors and global functioning. Our findings suggest that differential activation and connectivity in the IPL, IFG, and precuneus in response to emotional stimuli may represent distinct resilience and risk markers for youth-onset mood disorders.

  View details for PubMedID 31064610

• Using Screening Tools and Diagnosing Bipolar Disorder in Pediatric Patients JOURNAL OF CLINICAL PSYCHIATRY Singh, M. K. 2019; 80 (1)
• Neural and Endocrine Correlates of Early Life Abuse in Youth With Depression and Obesity FRONTIERS IN PSYCHIATRY Sun, K. L., Watson, K. T., Angal, S., Bakkila, B. F., Gorelik, A. J., Leslie, S. M., Rasgon, N. L., Singh, M. K. 2018; 9
• Neural and Endocrine Correlates of Early Life Abuse in Youth With Depression and Obesity. Frontiers in psychiatry Sun, K. L., Watson, K. T., Angal, S., Bakkila, B. F., Gorelik, A. J., Leslie, S. M., Rasgon, N. L., Singh, M. K. 2018; 9: 721

  Abstract

  Depression and insulin resistance are becoming increasingly prevalent in younger populations. The origin and consequence of insulin resistance in depressed youth may, in part, be rooted in exposure to environmental stressors, such as early life abuse, that may lead to aberrant brain motivational networks mediating maladaptive food-seeking behaviors and insipient insulin resistance. In this paper, we aimed to investigate the impact of early life abuse on the development of insulin resistance in depressed and overweight youth aged 9 to 17 years. We hypothesized that youth with the greatest burden of early life abuse would have the highest levels of insulin resistance and corresponding aberrant reward network connectivities. To test this hypothesis, we evaluated sixty-nine depressed and overweight youth aged 9 to 17, using multimodal assessments of early life abuse, food-seeking behavior, and insulin resistance. Based on results of the Childhood Trauma Questionnaire (CTQ), we separated our study participants into two groups: 35 youth who reported high levels of the sum of emotional, physical, or sexual abuse and 34 youth who reported insignificant or no levels of any abuse. Results of an oral glucose tolerance test (OGTT) and resting state functional connectivity (RSFC), using the amygdala, insula, and nucleus accumbens (NAcc) as seed-based reward network regions of interest, were analyzed for group differences between high abuse and low abuse groups. High abuse youth exhibited differences from low abuse youth in amygdala-precuneus, NAcc-paracingulate gyrus, and NAcc-prefrontal cortex connectivities, that correlated with levels of abuse experienced. The more different their connectivity from of that of low abuse youth, the higher were their fasting glucose and glucose at OGTT endpoint. Importantly, level of abuse moderated the relation between reward network connectivity and OGTT glucose response. In contrast, low abuse youth showed hyperinsulinemia and more insulin resistance than high abuse youth, and their higher OGTT insulin areas under the curve correlated with more negative insula-precuneus connectivity. Our findings suggest distinct neural and endocrine profiles of youth with depression and obesity based on their histories of early life abuse.

  View details for DOI 10.3389/fpsyt.2018.00721

  View details for PubMedID 30622489

  View details for PubMedCentralID PMC6308296

• The Role of the Nucleus Accumbens as a Treatment Marker in Pediatric Depression and Obesity Singh, M. NATURE PUBLISHING GROUP. 2018: S4-S5
• Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project AUSTRALIAN AND NEW ZEALAND JOURNAL OF PSYCHIATRY Parker, G., Tavella, G., Macqueen, G., Berk, M., Grunze, H., Deckersbach, T., Dunner, D. L., Sajatovic, M., Amsterdam, J. D., Ketter, T. A., Yatham, L. N., Kessing, L., Bassett, D., Zimmerman, M., Fountoulakis, K. N., Duffy, A., Alda, M., Calkin, C., Sharma, V., Anand, A., Singh, M. K., Hajek, T., Boyce, P., Frey, B. N., Castle, D. J., Young, A. H., Vieta, E., Rybakowski, J. K., Swartz, H. A., Schaffer, A., Murray, G., Bayes, A., Lam, R. W., Bora, E., Post, R. M., Ostacher, M. J., Lafer, B., Cleare, A. J., Burdick, K. E., O'Donovan, C., Ortiz, A., Henry, C., Kanba, S., Rosenblat, J. D., Parikh, S. V., Bond, D. J., Grunebaum, M. F., Frangou, S., Goldberg, J. F., Orum, M., Osser, D. N., Frye, M. A., McIntyre, R. S., Fagiolini, A., Manicavasagar, V., Carlson, G. A., Malhi, G. S. 2018; 52 (12): 1173–82
• Reduced dorsal striatal gray matter volume predicts implicit suicidal ideation in adolescents SOCIAL COGNITIVE AND AFFECTIVE NEUROSCIENCE Ho, T. C., Cichocki, A. C., Gifuni, A. J., Camacho, M., Ordaz, S. J., Singh, M. K., Gotlib, I. H. 2018; 13 (11): 1215-1224
• Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project. The Australian and New Zealand journal of psychiatry Parker, G., Tavella, G., Macqueen, G., Berk, M., Grunze, H., Deckersbach, T., Dunner, D. L., Sajatovic, M., Amsterdam, J. D., Ketter, T. A., Yatham, L. N., Kessing, L. V., Bassett, D., Zimmerman, M., Fountoulakis, K. N., Duffy, A., Alda, M., Calkin, C., Sharma, V., Anand, A., Singh, M. K., Hajek, T., Boyce, P., Frey, B. N., Castle, D. J., Young, A. H., Vieta, E., Rybakowski, J. K., Swartz, H. A., Schaffer, A., Murray, G., Bayes, A., Lam, R. W., Bora, E., Post, R. M., Ostacher, M. J., Lafer, B., Cleare, A. J., Burdick, K. E., O'Donovan, C., Ortiz, A., Henry, C., Kanba, S., Rosenblat, J. D., Parikh, S. V., Bond, D. J., Grunebaum, M. F., Frangou, S., Goldberg, J. F., Orum, M., Osser, D. N., Frye, M. A., McIntyre, R. S., Fagiolini, A., Manicavasagar, V., Carlson, G. A., Malhi, G. S. 2018: 4867418808382

  Abstract

  OBJECTIVE:: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations.METHOD:: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified.RESULTS:: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders.CONCLUSION:: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

  View details for PubMedID 30378461

• Beyond a Binary Classification of Sex: An Examination of Brain Sex Differentiation, Psychopathology, and Genotype. Journal of the American Academy of Child and Adolescent Psychiatry Phillips, O. R., Onopa, A. K., Hsu, V., Ollila, H. M., Hillary, R. P., Hallmayer, J., Gotlib, I. H., Taylor, J., Mackey, L., Singh, M. K. 2018

  Abstract

  OBJECTIVE: Sex differences in the brain are traditionally treated as binary. We present new evidence that a continuous measure of sex differentiation of the brain can explain sex differences in psychopathology. The degree of sex differentiated brain features (ie, features that are more common in one sex) may predispose individuals toward sex-biased psychopathology and may also be influenced by the genome. We hypothesized that individuals with a female-biased differentiation score would have greater female-biased psychopathology (internalizing symptoms, such as anxiety and depression), whereas individuals with a male-biased differentiation score would have greater male-biased psychopathology (externalizing symptoms, such as disruptive behaviors).METHOD: Using the Philadelphia Neurodevelopmental Cohort database acquired from database of Genotypes and Phenotypes, we calculated the sex differentiation measure, a continuous data-driven calculation of each individual's degree of sex differentiating features extracted from multimodal brain imaging data (Magnetic resonance imaging (MRI) /Diffusion MRI) from the imaged participants (n=866, 407F/459M).RESULTS: In males, higher differentiation scores were correlated with higher levels of externalizing symptoms (r=0.119, p=0.016). The differentiation measure reached genome-wide association study significance (p<5*10-8) in males with single nucleotide polymorphisms Chromsome5:rs111161632:RASGEF1C and Chromosome19:rs75918199:GEMIN7, and in females with Chromosome2:rs78372132:PARD3B and Chromosome15:rs73442006:HCN4.CONCLUSION: The sex differentiation measure provides an initial topography of quantifying male and female brain features. This demonstration that the sex of the human brain can be conceptualized on a continuum has implications for both the presentation of psychopathology and the relation of the brain with genetic variants that may be associated with brain differentiation.

  View details for PubMedID 30768381

• Limbic Intrinsic Connectivity in Depressed and High-Risk Youth. Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K., Leslie, S. M., Packer, M. M., Weisman, E. F., Gotlib, I. H. 2018; 57 (10): 775

  Abstract

  OBJECTIVE: Depression runs in families and has been associated with dysfunctional limbic connectivity. Whether aberrant limbic connectivity is a risk factor for or a consequence of depression is unclear. To examine this question, we compared resting state functional connectivity (RSFC) in youth with depressive disorders (DEP), healthy offspring of parents with depression (DEP-risk), and healthy comparison (HC) youth.METHOD: Magnetic resonance imaging at rest was acquired from 119 youth, aged 8 to 17 years (DEP, n= 41, DEP-risk, n= 39, and HC, n= 39) and analyzed using seed-based RSFC in bilateral amygdala and nucleus accumbens (NAcc), covarying for age, IQ, and sex.RESULTS: We found distinct risk- and disorder-specific patterns of RSFC across groups. DEP-risk and DEP youth shared reduced negative amygdala-right frontal cortex RSFC and reduced positive amygdala-lingual gyrus RSFC compared to HC youth (p< .001). DEP-risk youth had weaker negative amygdala-precuneus RSFC compared to DEP and HC youth (p< .001), suggesting a resilience marker for depression. In contrast, DEP youth had increased positive NAcc-left frontal cortex RSFC and reduced positive NAcc-insula RSFC compared to DEP-risk and HC youth (p<.001), suggestive of disorder-specific features of depression. Greater depression severity was correlated with disorder-specific amygdala and NAcc RSFC (p< .05).CONCLUSION: RSFC in the amygdala and NAcc may represent selective disorder- and risk-specific markers in youth with, and at familial risk for, depression. Longitudinal studies are needed to determine whether these patterns predict long-term clinical outcomes.

  View details for PubMedID 30274652

• PHARMACOLOGICAL STRATEGIES FOR MANAGING PEDIATRIC DEPRESSION Singh, M. K. ELSEVIER SCIENCE INC. 2018: S120
• INSULIN RESPONSE MEDIATES THE EFFECT OF FAMILY HISTORY OF DEPRESSION ON CONSUMMATORY PLEASURE IN YOUTH WITH DEPRESSION AND OBESITY Sun, K. L., Watson, K. T., Packer, M., Wall, D. M., Staver, A. C., Leslie, S. M., Bahl, N. E., Nimarko, A. F., Rasgon, N. L., Singh, M. K. ELSEVIER SCIENCE INC. 2018: S241–S242
• Limbic Intrinsic Connectivity in Depressed and High-Risk Youth JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Singh, M. K., Leslie, S. M., Packer, M. M., Weisman, E. F., Gotlib, I. H. 2018; 57 (10): 775-+
• Reduced dorsal striatal gray matter volume predicts implicit suicidal ideation in adolescents. Social cognitive and affective neuroscience Ho, T. C., Cichocki, A., Gifuni, A. J., Catalina Camacho, M., Ordaz, S. J., Singh, M. K., Gotlib, I. H. 2018

  Abstract

  Suicidal ideation (SI), a potent risk factor for suicide attempts, increases in adolescence. While alterations in dopaminergic functioning have been implicated in suicidal acts-particularly in adults-we do not know whether morphological alterations in dopamine-rich regions of the brain, such as the striatum, are vulnerability factors for the emergence of SI in adolescents. At baseline, a community sample of 152 adolescents (89 female; mean age: 11.41 ± 1.01 years) completed an MRI scan that was used to estimate gray matter volumes (GMV) of three striatal structures: caudate, nucleus accumbens, and putamen. At a 24-month follow-up session, participants completed a self-report measure of suicidal ideation frequency (SIQ) and the death-version of the Implicit Association Test (IAT). Robust linear regression models were conducted to predict SIQ and IAT scores from striatal GMV. Bilateral putamen and left caudate GMV significantly predicted IAT scores (all ps<0.03). No other associations were significant (all ps>0.05). Our finding of reduced dorsal striatal GMV predicting implicit SI may indicate that downstream dopaminergic dysfunction is implicated in the development of overt suicidal behaviors. Self-reported SI was not associated with striatal GMV, suggesting that biological correlates of suicide risk may correlate specifically with objective measurements of SI in adolescents.

  View details for PubMedID 30256980

• Neural correlates of liraglutide effects in persons at risk for Alzheimer's Disease. Behavioural brain research Watson, K. T., Wroolie, T. E., Tong, G., Foland-Ross, L. C., Frangou, S., Singh, M., McIntyre, R., Roat-Shumway, S., Myoraku, A., Reiss, A. L., Rasgon, N. L. 2018

  Abstract

  Insulin resistance (IR) is a metabolic state preceding development of type 2 diabetes (DM2), cardiovascular disease, and neurodegenerative disorders, including Alzheimer's Disease (AD). Liraglutide, a glucagon-like peptide-1 (GLP) agonist, is an insulin-sensitizing agent with neuroprotective properties, as shown in animal studies. The purpose of this double-blinded, placebo-controlled study was to examine the neural effects of administration of liraglutide in cognitively normal late middle-aged individuals with subjective cognitive complaints (half of subjects had family history of AD). Seed-based resting state connectivity using functional magnetic resonance imaging (fMRI) conducted before and after 12 weeks of liraglutide treatment or placebo. Neuropsychological testing was conducted before and after treatment to determine whether there were any potential behavioral correlates to neural changes.RESULTS: At baseline (time point 1), higher fasting plasma glucose (FPG) was associated with decreased connectivity between bilateral hippocampal and anterior medial frontal structures. At time point 2, we observed significant improvement in intrinsic connectivity within the default mode network (DMN) in the active group relative to placebo. There were no detectable cognitive differences between study groups after this duration of treatment. To our knowledge, this is the first placebo-controlled study to report neural effects of liraglutide in a middle-aged population with subjective cognitive complaints. Larger and longer duration studies are warranted to determine whether liraglutide has neuroprotective benefit for individuals at risk for AD.

  View details for PubMedID 30099030

• Insulin resistance is associated with smaller brain volumes in a preliminary study of depressed and obese children PEDIATRIC DIABETES Phillips, O. R., Onopa, A. K., Zaiko, Y. V., Singh, M. K. 2018; 19 (5): 892-897
• Neurofunctional Correlates of Response to Quetiapine in Adolescents with Bipolar Depression. Journal of child and adolescent psychopharmacology Chang, K., DelBello, M., Garrett, A., Kelley, R., Howe, M., Adler, C., Welge, J., Strakowski, S. M., Singh, M. 2018

  Abstract

  OBJECTIVES: Prior studies have shown that youth with bipolar disorder demonstrate neurofunctional changes in key prefrontal and subcortical brain regions implicated in emotional regulation following treatment with pharmacological agents. We recently reported a large response rate (>60%) to quetiapine (QUET) for treating depressive symptoms in adolescents with bipolar depression. This study investigates the neurofunctional effects of QUET using functional magnetic resonance imaging (fMRI).METHODS: Thirty-three unmedicated subjects, 10-17 years of age, with a current depressive episode (Children's Depression Rating Scale-Revised [CDRS-R] > 40) associated with bipolar I or II disorder were recruited in a two-site randomized, placebo (PBO)-controlled trial of QUET monotherapy for treatment of bipolar depression in adolescents. Twenty-three of these participants (nine male) underwent an MRI scan at baseline, then were randomized to QUET or PBO, followed for 8 weeks, and at the end of their study participation underwent another MRI scan. During the fMRI scan, subjects viewed negative and neutral pictures and rated the valence of each picture.RESULTS: Sixteen subjects had usable data at both time points: 10 subjects randomized to QUET, and 6 randomized to PBO. For QUET subjects, lower baseline activation in the left dorsolateral prefrontal cortex (p<0.005) and higher baseline activation in the left ventrolateral prefrontal cortex (p=0.0024) predicted greater improvement in CDRS-R scores from baseline to follow-up. When QUET and PBO groups were combined (n=16), region-of-interest activation did not significantly predict change in CDRS-R.CONCLUSIONS: Baseline activation patterns in dorsal and ventral portions of the prefrontal cortex that are critical for the regulation of emotion-predicted response, but only within the QUET group. Thus, specific medications may be more effective in the context of specific prefrontal activation patterns in youth with bipolar depression. Larger studies of these youth would help to clarify the effects of QUET on brain activation.

  View details for PubMedID 29847157

• Neurofunctional Correlates of Response to Quetiapine in Adolescents with Bipolar Depression JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Chang, K., DelBello, M., Garrett, A., Kelley, R., Howe, M., Adler, C., Welge, J., Strakowski, S. M., Singh, M. 2018; 28 (6): 379-386
• Allostatic Load Predictors of Treatment Response in Patients With Unremitted Depression Rasgon, N., Watson, K., Singh, M., Wroolie, T., Myoraku, A., Roat-Shumway, S. ELSEVIER SCIENCE INC. 2018: S36–S37
• Superficial white matter damage in anti-NMDA receptor encephalitis JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Phillips, O., Joshi, S. H., Narr, K. L., Shattuck, D. W., Singh, M., Di Paola, M., Ploner, C. J., Pruss, H., Paul, F., Finke, C. 2018; 89 (5): 518–25

  Abstract

  Clinical brain MRI is normal in the majority of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, extensive deep white matter damage wasrecently identifiedin these patients using diffusion weighted imaging. Here, our aim was to study a particularly vulnerable brain compartment, the late myelinating superficial white matter.Forty-six patients with anti-NMDAR encephalitis were included. Ten out of these were considered neurologically recovered (modified Rankin scale of zero), while 36 patients were non-recovered. In addition, 30 healthy controls were studied. MRI data were collected from all subjects and superficial white matter mean diffusivity derived from diffusion tensor imaging was compared between groups in whole brain, lobar and vertex-based analyses. Patients underwent comprehensive cognitive testing, and correlation analyses were performed between cognitive performance and superficial white matter integrity.Non-recovered patients showed widespread superficial white matter damage in comparison to recovered patients and healthy controls. Vertex-based analyses revealed that damage predominated in frontal and temporal lobes. In contrast, the superficial white matter was intact in recovered patients. Importantly, persistent cognitive impairments in working memory, verbal memory, visuospatial memory and attention significantly correlated with damage of the superficial white matter in patients.Anti-NMDAR encephalitis is associated with extensive superficial white matter damage in patients with incomplete recovery. The strong association with impairment in several cognitive domains highlights the clinical relevance of white matter damage in this disorder and warrants investigations of the underlying pathophysiological mechanisms.

  View details for PubMedID 29101253

• Neural and Behavioral Phenotypes in Children of Parents With Mood Disorders Singh, M., Packer, M., Onopa, A., Leslie, S., Zaiko, Y., Wall, D., Staver, A., Weisman, E., Phillips, O. ELSEVIER SCIENCE INC. 2018: S23–S24
• Brain and behavioral correlates of insulin resistance in youth with depression and obesity. Hormones and behavior Singh, M. K., Leslie, S. M., Packer, M. M., Zaiko, Y. V., Phillips, O. R., Weisman, E., Wall, D., Jo, B., Rasgon, N. L. 2018

  Abstract

  Depression, together with insulin resistance, is increasingly prevalent among youth. These conditions have traditionally been compartmentalized, but recent evidence suggests that a shared brain motivational network underlies their co-occurrence. We posit that, in the context of depressive symptoms, insulin resistance is associated with aberrant structure and functional connectivity in the Anterior Cingulate Cortex (ACC) and hippocampus. This motivational neural circuit underlies dysfunctional behavioral responses and increased sensitivity to rewarding aspects of ingesting high calorie food that lead to disinhibition of eating even when satiated. To investigate this shared mechanism, we evaluated a sample of forty-two depressed and overweight (BMI > 85th%) youth aged 9 to 17. Using ACC and hippocampus structural and seed-based regions of interest, we investigated associations between insulin resistance, depression, structure (ACC thickness, and ACC and hippocampal area), and resting-state functional connectivity (RSFC). We predicted that aberrant associations among these neural and behavioral characteristics would be stronger in insulin resistant compared to insulin sensitive youth. We found that youth with greater insulin resistance had higher levels of anhedonia and more food seeking behaviors, reduced hippocampal and ACC volumes, and greater levels of ACC and hippocampal dysconnectivity to fronto-limbic reward networks at rest. For youth with high levels of insulin resistance, thinner ACC and smaller hippocampal volumes were associated with more severe depressive symptoms, whereas the opposite was true for youth with low levels of insulin resistance. The ACC-hippocampal motivational network that subserves depression and insulin resistance separately, may represent a critical neural interaction that link these syndromes together.

  View details for PubMedID 29596854

• Insulin resistance is associated with smaller brain volumes in a preliminary study of depressed and obese children. Pediatric diabetes Phillips, O. R., Onopa, A. K., Zaiko, Y. V., Singh, M. K. 2018

  Abstract

  OBJECTIVE: During childhood, the brain can consume up to 65% of total calories, and a steady supply of the brain's main fuel glucose needs to be maintained. Although the brain itself is not dependent on insulin for the uptake of glucose, insulin plays an important role in energy homeostasis. Thus, the risk for insulin resistance during brain development may negatively impact the whole brain volume.METHODS: We investigated the link between the insulin resistance and the whole brain volume as measured by structural Magnetic resonance imaging (MRI) in 46 unmedicated depressed and overweight youths between the ages of 9 and 17years.RESULTS: Smaller whole brain volumes were associated with insulin resistance independent of age, sex, depression severity, body mass index, socioeconomic status, Tanner Stage, and Intelligence quotient (IQ) (r = 0.395, P = .014) CONCLUSIONS: There may be a significant cost for developing insulin resistance on the developing brain. Disentangling the precise relationship between the insulin resistance and the developing brain is critical.

  View details for PubMedID 29569318

• Network basis of suicidal ideation in depressed adolescents JOURNAL OF AFFECTIVE DISORDERS Ordaz, S. J., Goyer, M. S., Ho, T. C., Singh, M. K., Gotlib, I. H. 2018; 226: 92–99

  Abstract

  Suicidal ideation rates rise precipitously in adolescence, contributing to risk for attempts. Although researchers are beginning to explore the brain basis of attempts in depressed adolescents, none have focused on the basis of ideation, which has implications for prevention. This study examined the association between intrinsic neural network coherence and the severity of suicidal ideation in depressed adolescents.Forty adolescents diagnosed with Major Depressive Disorder were administered the Columbia-Suicide Severity Rating Scale and underwent resting-state fMRI. We quantified within-network coherence in the executive control (ECN), default mode (DMN), and salience (SN) networks, and in a non-relevant network consisting of noise signal. We associated coherence in each of these networks with the greatest lifetime severity of suicidal ideation experienced, covarying for motion, age of depression onset, and severity of current depressive and anxious symptoms.Lower coherence in the left ECN, anterior DMN, and SN were independently associated with greater lifetime severity of suicidal ideation. When including all three significant networks and covariates in a single model, only the left ECN significantly predicted suicidal ideation.Studies with a larger sample size are needed to verify our findings.Our finding of hypoconnectivity in multiple networks extends emerging evidence for hypoconnectivity in adolescent suicidality and is consistent with theoretical conceptualizations of suicidal ideation as a complex set of cognitions associated with cognitive control, self-referential thinking, and processing salient information. While multiple networks could be targets for effective early interventions, those targeting ECN functionality (cognitive control) may be particularly beneficial.

  View details for PubMedID 28968564

• Double trouble: weekend sleep changes are associated with increased impulsivity among adolescents with bipolar I disorder. Bipolar disorders Gershon, A. n., Johnson, S. L., Thomas, L. n., Singh, M. K. 2018

  Abstract

  Both sleep disruption and impulsivity are important predictors of the course of bipolar disorder (BD). Although sleep disruption has been shown to intensify impulsivity, little research has considered how these two important domains interact within BD. Adolescence is a critical period for the onset of BD, and is often associated with increases in impulsivity and substantial changes in sleep. We tested the hypothesis that disruptions in sleep would increase impulsivity among adolescents, and that this effect would be more pronounced among those with BD.Thirteen- to nineteen-year-olds diagnosed with BD-I (n = 33, age [mean ± standard deviation (SD)] 16.2 ± 1.66 years, 54.5% female) and psychiatrically healthy controls (n = 26, age [mean ± SD] 15.5 ± 1.45 years, 55.6% female) reported their past-week bedtime, rise time, and sleep duration, separately for school days and weekends, and completed a self-report questionnaire on impulsivity. Stepwise regression was used to examine the effects of sleep on impulsivity, and the moderation of this effect by BD status.Adolescents with BD reported significantly higher impulsivity, later and more variable rise time, and more variable time in bed and sleep duration on school days than did controls. Greater change in sleep duration between school days and weekends was associated with significantly more impulsivity among adolescents with BD as compared to controls.These findings highlight the important effect of sleep on impulsivity among adolescents with BD and add to the growing evidence that establishing sleep routines may be an important therapeutic target for youth with BD.

  View details for PubMedID 29781205

• Vulnerabilities in sequencing and task switching in healthy youth offspring of parents with mood disorders JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Singh, M. K., Leslie, S. M., Bhattacharjee, K., Gross, M., Weisman, E. F., Soudi, L. M., Phillips, O. R., Onopa, A. 2018; 40 (6): 606–18

  Abstract

  Visuospatial processing and task switching are impaired in individuals with mood disorders. It is unknown whether early deficits are present before mood symptom on set or are related to risk for a specific type of mood disorder. To investigate, we compared visual attention and task switching during sequencing among never-disordered youth with parental family histories of bipolar (BD) and major depressive disorders (MDD) and healthy controls (HC) with no personal or family history of psychopathology.8-17-year-old youth of parents with BD (n = 31, "BD-risk"), youth of parents with MDD (n = 49, "MDD-risk"), and demographically similar HC (n = 31, "HC") were examined using the Delis-Kaplan Executive Functioning System Trail Making Test. Seed-based resting-state functional connectivity (RSFC) was collected from a subset of 88 participants (25 BD-risk, 37 MDD-risk, 26 HC) to investigate group differences in RSFC related to visuospatial processing.BD-risk and MDD-risk offspring had impaired sequencing and task switching, demonstrated by reduced scores on visual scanning, F(2, 108) = 4.12, p = .02, number sequencing, F(2, 88) = 4.75, p = .01, letter sequencing, F(2, 108) = 4.24, p = .02, and number-letter sequencing, F(2, 108) = 4.66, p = .01, compared to scores in HC. RSFC between the posterior cingulate (PCC) and clusters in the subcallosal cortex, amygdala, and hippocampus significantly differed among HC, BD-risk, and MDD-risk groups. PCC-subcallosal/limbic RSFC was positively coupled in the MDD-risk and BD-risk groups and negatively coupled in HCs.Youth at familial risk for mood disorders demonstrate visuospatial deficits early in the processing stream. Improved methods for identifying at-risk children with the earliest possible neurocognitive impairments may inform remediation strategies that could prevent mood disorders.

  View details for PubMedID 29168420

• Association of Fasting Insulin Levels and Depression Severity With Resting-State Functional Connectivity in Depressed Adolescents Leslie, S., Weisman, E., Staver, A., Wall, D., Andrade, A., Zaiko, Y., Onopa, A., Packer, M., Phillips, O., Rasgon, N., Singh, M. NATURE PUBLISHING GROUP. 2017: S381
• A Pharmacologic Algorithm for Youth Who Are at High Risk for Bipolar Disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Schneck, C. D., Chang, K. D., Singh, M. K., DelBello, M. P., Miklowitz, D. J. 2017; 27 (9): 796–805

  Abstract

  Depression and brief periods of manic symptoms are linked to a significant risk of progression to bipolar disorder (BD) in children who have a first-degree relative with BD I or II. However, little evidence exists to guide the pharmacologic management of children with these high-risk phenotypes. We propose a pharmacological treatment algorithm for high-risk youth and present results on its use in a study of children with a first-degree relative with BD.Subjects were 40 youth (mean 12.7 years, range 9-17 years) who had (1) a first-degree relative with lifetime history of BD I or II, (2) DSM-IV-TR diagnoses of BD not otherwise specified, major depressive disorder or cyclothymic disorder, and (3) active symptoms of depression, mania, or hypomania. Participants and their families were enrolled in a randomized trial examining the effects of two psychosocial interventions on the 1-year course of mood disorder. At study intake, participants received a psychiatric evaluation and were offered medications or had existing medications optimized to decrease symptom severity. During the 1-year study, psychiatrists treated participants using a medication algorithm to treat depressive or manic symptoms as well as comorbid anxiety and/or attention-deficit/hyperactivity disorder.At study entry, 25 of 40 (62.5%) of the participants were taking at least one psychiatric medication. At 1 year, nearly an identical proportion were taking medications (22 of 35, 63%). Independent ratings indicated that in 84.7% of the study visits, physicians maintained adherence to the algorithm. No patients experienced antidepressant- or stimulant-induced mania during the study.An algorithmic approach to pharmacologic interventions may aid in the management of youth (i.e., age <18) at high risk for BD. Future studies should compare outcomes in high-risk patients receiving algorithm-prescribed treatment versus those receiving treatment as usual.Early Family-Focused Treatment for Youth at Risk for Bipolar Disorder; www.clinicaltrials.gov/ ; NCT00943085.

  View details for PubMedID 28731778

  View details for PubMedCentralID PMC5689113

• Anomalous prefrontal-limbic activation and connectivity in youth at high risk for bipolar disorder JOURNAL OF AFFECTIVE DISORDERS Chang, K., Garrett, A., Kelley, R., Howe, M., Sanders, E., Acquaye, T., Bararpour, L., Li, S., Singh, M., Jo, B., Hallmayer, J., Reiss, A. 2017; 222: 7–13

  Abstract

  Abnormal prefrontal-limbic brain activation in response to facial expressions has been reported in pediatric bipolar disorder (BD). However, it is less clear whether these abnormalities exist prior to onset of mania, thus representing a biomarker predicting development of BD.We examined brain activation in 50 youth at high risk for BD (HR-BD), compared with 29 age- and gender-matched healthy control (HC) subjects. HR-BD was defined as having a parent with BD, as well as current mood or attentiondeficit/ hyperactivity disorder (ADHD) symptoms, or a history of at least one depressive episode. FMRI data were collected during an implicit emotion perception task using facial expression stimuli. Activation to fearful faces versus calm faces was compared between HR-BD and HC groups, including analyses of functional connectivity, and comparison of allele subgroups of the serotonin transporter (5-HTTLPR) gene.While viewing fearful versus calm faces, HR-BD youth had significantly greater activation than HC youth in the right amygdala, ventrolateral prefrontal cortex (VLPFC), superior frontal cortex, cerebellum, and lingual gyrus. HR-BD youth, relative to HC youth, had greater functional connectivity between the right amygdala and the VLPFC as well as visual cortical regions Within the HR-BD group, youth with the s-allele had a trend for greater activation in the right amygdala and subgenual cingulate cortex CONCLUSIONS: Similar to youth with BD, youth at high risk for BD have greater activation than healthy controls in the amygdala and ventrolateral prefrontal cortex in response to fearful faces, as well greater functional connectivity between these regions. HR-BD youth with the s-allele of the 5-HTTLPR gene may be at greatest risk for developing BD.

  View details for PubMedID 28667891

• PHARMACOTHERAPY IN YOUTH AT HIGH RISK FOR BIPOLAR DISORDER Singh, M. K., Staver, A., Hinman, K., Goldsmith, M., Chang, K. ELSEVIER SCIENCE INC. 2017: S342
• SYMPTOM IMPROVEMENT ASSOCIATED WITH LURASIDONE TREATMENT OF CHILDREN AND ADOLESCENTS WITH BIPOLAR I DEPRESSION: RESULTS OF A SHORT-TERM PLACEBO-CONTROLLED TRIAL Singh, M. K., Goldman, R., Tocco, M., Pikalov, A. A., Deng, L., Cucchiaro, J., Loebel, A. ELSEVIER SCIENCE INC. 2017: S271-S272
• NEUROBEHAVIORAL PHENOTYPES IN YOUTH OFFSPRING OF PARENTS WITH MOOD DISORDERS Singh, M. K. ELSEVIER SCIENCE INC. 2017: S314
• NEUROIMAGING TO PREDICT TREATMENT RESPONSE IN YOUTH WITH AND AT RISK FOR BIPOLAR DISORDER Chang, K., Garrett, A., Howe, M. E., Singh, M. K. ELSEVIER SCIENCE INC. 2017: S324
• RESEARCH SYMPOSIUM: SOCIAL NEUROSCIENCE AND CHILD AND ADOLESCENT PSYCHIATRY RESEARCH PRIORITIES AT THE NATIONAL INSTITUTE OF MENTAL HEALTH Singh, M. K. ELSEVIER SCIENCE INC. 2017: S307-S308
• Early intervention for youth at high risk for bipolar disorder: A multisite randomized trial of family-focused treatment. Early intervention in psychiatry Miklowitz, D. J., Schneck, C. D., Walshaw, P. D., Garrett, A. S., Singh, M. K., Sugar, C. A., Chang, K. D. 2017

  Abstract

  AIMS: Despite the considerable public health impact of bipolar disorder (BD), no psychosocial interventions have been systematically evaluated in its early prodromal stages. We describe the rationale, design and analytic methods for a 3-site randomized trial of family-focused treatment for youth at high risk (FFT-HR) for BD.METHODS: Participants (ages 9-17years) have a diagnosis of unspecified BD or major depressive disorder, current mood symptoms and at least one first- or second-degree relative with a lifetime history of BD I or II. Participants are randomly assigned to FFT-HR (12 sessions in 4months of family psychoeducation and skills training) or enhanced care (EC; 6 individual and family sessions over 4months), with pharmacotherapy provided as needed. A subset of participants undergo pre- and post-treatment functional MRI (fMRI) scans while performing face-rating and family problem-solving tasks designed to activate corticolimbic circuitry. Independent evaluators assess participants' status every 4 to 6months for up to 4years.RESULTS: We hypothesize that FFT-HR will be more effective than EC in reducing the severity of mood symptoms (primary outcome) and the hazard of a first manic episode (secondary) over 4years. Secondarily, we will explore whether FFT-HR is associated with greater decreases in amygdala activation and increases in dorsolateral, ventrolateral or anterior medial prefrontal cortex activation from pre- to post-treatment. Clinical characteristics of 133 subjects enrolled at baseline are described.CONCLUSIONS: This study will test a novel intervention to reduce the early symptoms of BD, and identify neural and behavioural mechanisms that may help refine future treatments.

  View details for PubMedID 28776930

• Hyperactivation in Cognitive Control and Visual Attention Brain Regions During Emotional Interference in Adolescent Depression. Biological psychiatry. Cognitive neuroscience and neuroimaging Colich, N. L., Ho, T. C., Foland-Ross, L. C., Eggleston, C., Ordaz, S. J., Singh, M. K., Gotlib, I. H. 2017; 2 (5): 388-395

  Abstract

  Individuals with Major Depressive Disorder (MDD) are characterized by biases in attention to negative emotional material. While there is evidence that anomalous functioning in frontocingulate regions may underlie these biases, we know little about the neural correlates of negative emotional biases in depressed adolescents.Eighteen adolescents diagnosed with MDD and 21 matched healthy control (CTL) adolescents underwent fMRI while performing an emotional distractor task. On each trial participants were presented with task-relevant house pairs and task-irrelevant face pairs. Participants indicated whether the house pairs were identical while ignoring the face pairs, which were either fearful, sad, or neutral.Despite equivalent behavioral performance (response time and accuracy) between groups, adolescents with MDD exhibited greater activation in frontocingulate regions, including dorsal anterior cingulate cortex (dACC) and inferior frontal gyrus/middle frontal gyrus (IFG/MFG), and occipitoparietal regions, including lateral occipital cortex and superior parietal lobule when ignoring fearful versus neutral faces. Response times to these trial conditions also correlated negatively with activation in IFG/MFG and lateral occipital cortex suggesting these regions are recruited in order to effectively ignore emotional distractors. Groups did not differ when ignoring sad versus neutral faces or fearful versus sad faces.Adolescents with MDD recruit both cognitive control and visual attention regions to a greater degree than do CTL adolescents, reflecting greater cognitive demand when downregulating threat-related stimuli.

  View details for DOI 10.1016/j.bpsc.2016.09.001

  View details for PubMedID 28890942

  View details for PubMedCentralID PMC5586219

• The neuroscience of depression: Implications for assessment and intervention (vol 62, pg 60, 2014) BEHAVIOUR RESEARCH AND THERAPY Singh, M. K., Gotlib, I. H. 2017; 92: 106
• Inhibited Temperament and Hippocampal Volume in Offspring of Parents with Bipolar Disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Kim, E., Garrett, A., Boucher, S., Park, M., Howe, M., Sanders, E., Kelley, R. G., Reiss, A. L., Chang, K. D., Singh, M. K. 2017; 27 (3): 258-265

  Abstract

  Prior studies have suggested that inhibited temperament may be associated with an increased risk for developing anxiety or mood disorder, including bipolar disorder. However, the neurobiological basis for this increased risk is unknown. The aim of this study was to examine temperament in symptomatic and asymptomatic child offspring of parents with bipolar disorder (OBD) and to investigate whether inhibited temperament is associated with aberrant hippocampal volumes compared with healthy control (HC) youth.The OBD group consisted of 45 youth, 24 of whom had current psychiatric symptoms (OBD(+)s) and 21 without any psychiatric symptoms (OBD(-)s), and were compared with 24 HC youth. Temperament characteristics were measured by using the Revised Dimensions of Temperament Survey. Magnetic resonance imaging was used to measure hippocampal volumes. The association between temperament and hippocampal volumes was tested by using multiple regression analysis.Compared with the OBD(-)s group, the OBD(+)s group had significantly more inhibited temperament traits, less flexibility, more negative mood, and less regular rhythm in their daily routines. In contrast, the OBD(-)s group was more likely to approach novel situations compared with OBD(+)s or HC groups. Within the OBD(+)s group, a more inhibited temperament was associated with smaller right hippocampal volumes.In this study, symptomatic OBD were characterized by an inhibited temperament that was inversely correlated with hippocampal volume. Additional longitudinal studies are needed to determine whether inverse correlations between hippocampal volume and inhibited temperament represent early markers of risk for later developing bipolar disorder.

  View details for DOI 10.1089/cap.2016.0086

  View details for Web of Science ID 000399535900007

• Inhibited Temperament and Hippocampal Volume in Offspring of Parents with Bipolar Disorder. Journal of child and adolescent psychopharmacology Kim, E., Garrett, A., Boucher, S., Park, M., Howe, M., Sanders, E., Kelley, R. G., Reiss, A. L., Chang, K. D., Singh, M. K. 2017; 27 (3): 258-265

  Abstract

  Prior studies have suggested that inhibited temperament may be associated with an increased risk for developing anxiety or mood disorder, including bipolar disorder. However, the neurobiological basis for this increased risk is unknown. The aim of this study was to examine temperament in symptomatic and asymptomatic child offspring of parents with bipolar disorder (OBD) and to investigate whether inhibited temperament is associated with aberrant hippocampal volumes compared with healthy control (HC) youth.The OBD group consisted of 45 youth, 24 of whom had current psychiatric symptoms (OBD(+)s) and 21 without any psychiatric symptoms (OBD(-)s), and were compared with 24 HC youth. Temperament characteristics were measured by using the Revised Dimensions of Temperament Survey. Magnetic resonance imaging was used to measure hippocampal volumes. The association between temperament and hippocampal volumes was tested by using multiple regression analysis.Compared with the OBD(-)s group, the OBD(+)s group had significantly more inhibited temperament traits, less flexibility, more negative mood, and less regular rhythm in their daily routines. In contrast, the OBD(-)s group was more likely to approach novel situations compared with OBD(+)s or HC groups. Within the OBD(+)s group, a more inhibited temperament was associated with smaller right hippocampal volumes.In this study, symptomatic OBD were characterized by an inhibited temperament that was inversely correlated with hippocampal volume. Additional longitudinal studies are needed to determine whether inverse correlations between hippocampal volume and inhibited temperament represent early markers of risk for later developing bipolar disorder.

  View details for DOI 10.1089/cap.2016.0086

  View details for PubMedID 27768380

• Interpretation Bias Training in Depressed Adolescents: Near- and Far-Transfer Effects. Journal of abnormal child psychology LeMoult, J., Colich, N., Joormann, J., Singh, M. K., Eggleston, C., Gotlib, I. H. 2017

  Abstract

  Depressed adolescents are characterized by negative interpretation biases. Although investigators have used cognitive bias modification for interpretation (CBM-I) to experimentally manipulate interpretation biases in depressed adults, the near- and far-transfer effects are not well understood in adolescents diagnosed with Major Depressive Disorder (MDD). In this study, we extend previous research by investigating the near- and far-transfer effects of 6 sessions of Positive versus Neutral CBM-I on independent measures of interpretation bias (near-transfer effects) and on attention biases and clinical symptoms (far-transfer effects) in a sample of adolescents with MDD (n = 46). At post-training, adolescents who received Positive CBM-I interpreted ambiguous scenarios more positively than did participants who received Neutral CBM-I, providing evidence of training effectiveness. There was no evidence, however, of near- or far-transfer effects. These findings raise concerns about the malleability of interpretation biases in adolescent depression and suggest that further work is needed to establish the clinical utility of CBM-I for adolescents with MDD.

  View details for DOI 10.1007/s10802-017-0285-6

  View details for PubMedID 28299526

• Hyperactivation in cognitive control and visual attention brain regions during emotional interference in adolescent depression Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Colich, N., Ho, T., Foland-Ross, L., Eggleston, C., Ordaz, S., Singh, M., Gotlib, I. 2017
• Treatment of psychiatric symptoms among offspring of parents with bipolar disorder. Current treatment options in psychiatry Zalpuri, I. n., Singh, M. K. 2017; 4 (4): 341–56

  Abstract

  Bipolar disorder is highly familial and has a protracted and diagnostically confusing prodrome. This review critically evaluates recently published literature relevant to the treatment of psychiatric symptoms in high-risk offspring of parents with Bipolar Disorder.Non-pharmacological treatment options including psychotherapy, resilience promotion through good sleep, diet, and exercise hygiene, and omega-3 fatty acid supplementation are important first line interventions for high-risk offspring. There has been some success in treating this population with open-label trials with mood stabilizers and atypical antipsychotics; however, these results have not been replicated in randomized controlled trails.Despite some progress in early identification of symptoms in offspring of parents with Bipolar Disorder, there is scarce evidence supporting the treatment of these high-risk youth to prevent psychiatric symptoms from progressing to threshold bipolar or other psychiatric disorders. There is a need for prospective and randomized trials and research that identifies reliable biomarkers to individualize treatments for these youth.

  View details for PubMedID 29503793

  View details for PubMedCentralID PMC5831272

• Sleep in Adolescents With Bipolar I Disorder: Stability and Relation to Symptom Change JOURNAL OF CLINICAL CHILD AND ADOLESCENT PSYCHOLOGY Gershon, A., Singh, M. K. 2017; 46 (2): 247-257

  Abstract

  Sleep disturbances are common features of bipolar disorder (BD), yet little is known about trajectories of sleep disturbances in youth with BD. Using longitudinal data, this study assessed the stability of sleep disturbances and their ability to predict symptom progression in adolescents diagnosed with BD compared to controls. Thirteen- to 19-year-olds meeting diagnostic criteria for BD I (n = 19, 16.2 ± 1.75 years, 57.9 % female, 68.4% Caucasian) and psychiatrically healthy age-comparable controls (n = 21, 15.7 ± 1.48 years. 52.4% female, 57.1% Caucasian) were assessed for sleep onset latency, number of awakenings, and wake time, separately for weekdays and weekends using a self-report questionnaire. Sleep indices and symptoms of mania (Young Mania Rating Scale) and depression (Children's Depression Rating Scale) were assessed at two time points, T1 and T2, approximately 12 months apart. Correlations were used to examine stability of sleep indices across time points and regression models to examine the effects of T1 sleep on T2 symptoms. Adolescents with BD showed low stability on most sleep indices, whereas controls showed high stability on all sleep indices. After controlling for T1 depression symptoms, more T1 weekend awakenings and weekend wake time predicted significantly greater T2 depression symptoms in youth with BD but not in controls. No significant associations were found between T1 sleep and T2 mania symptoms. These findings suggest that increased awakenings and wakefulness on weekends may represent an important therapeutic target for reducing depression in adolescents with BD.

  View details for DOI 10.1080/15374416.2016.1188699

  View details for Web of Science ID 000396778500008

• Fractional Anisotropy in Cingulum-Hippocampus Tracts Predicts Suicidal Ideation in Young Adolescents Ho, T., Ordaz, S., Leong, J., Lowet, D., Goyer, M., Singh, M., Gotlib, I. NATURE PUBLISHING GROUP. 2016: S295–S296
• Neurobehavioral Markers of Aberrant Approach Motivation in Pediatric Depression Singh, M. NATURE PUBLISHING GROUP. 2016: S115
• Intrinsic Brain Connectivity in Youth With Depression at High Risk for Insulin Insensitivity Singh, M., Leslie, S., Foland-Ross, L., Weisman, E., Bhattacharjee, K., Onopa, A., Soudi, L., Staver, A., Bohon, C., Rasgon, N. NATURE PUBLISHING GROUP. 2016: S185–S186
• GENETIC AND BRAIN MORPHOMETRIC PREDICTORS OF ANTIDEPRESSANT-INDUCED MANIA IN YOUTH AT HIGH-RISK FOR BIPOLAR DISORDER Chang, K. D., Singh, M. K., Garrett, A., Kelley, R., Howe, M. E. ELSEVIER SCIENCE INC. 2016: S298
• RESTING-STATE FUNCTIONAL CONNECTIVITY OF THE AMYGDALA IN HEALTHY OFFSPRING OF PARENTS WITH MOOD DISORDERS Leslie, S. M., Foland-Ross, L., Bhattacharjee, K., Soudi, L., Onopa, A., Singh, M. K. ELSEVIER SCIENCE INC. 2016: S132
• TRAJECTORIES AND TREATMENT NEUROSCIENCE IN PEDIATRIC MANIA Singh, M. K., Frazier, J. A. ELSEVIER SCIENCE INC. 2016: S297-S298
• FUNCTIONAL CONNECTIVITY OF THE DORSOLATERAL PREFRONTAL CORTEX IS MODULATED BY PSYCHOTHERAPY FOR YOUTH WITH MOOD DYSREGULATION AT HIGH-RISK FOR BIPOLAR DISORDER Garrett, A., Miklowitz, D. J., Hernandez, J. M., Walshaw, P. D., Singh, M. K., DeGeorge, D., Chang, K. D. ELSEVIER SCIENCE INC. 2016: S300-S301
• LONGITUDINAL THALAMIC NEUROANATOMY IN ADOLESCENTS WITH BIPOLAR I DISORDER Singh, M. K., Wei, M., Soudi, L., Raman, M., Foland-Ross, L., DeGeorge, D., Chang, K. D. ELSEVIER SCIENCE INC. 2016: S299
• EARLY MARKERS OF STRESS IN HIGH-RISK OFFSPRING Singh, M. K., Bhattacharjee, K., Soudi, L., Ghosh, P., Foland-Ross, L., Gotlib, I., Chang, K. D. ELSEVIER SCIENCE INC. 2016: S300
• NEURAL AND BEHAVIORAL CHARACTERISTICS OF RISK AND RESILIENCE IN YOUTH OFFSPRING OF PARENTS WITH BIPOLAR DISORDER Singh, M. K., Chang, K. D., Bhattacharjee, K., Rossallini, B., Kelley, R., Kim, E., Gotlib, I. ELSEVIER SCIENCE INC. 2016: S285
• Sleep in Adolescents With Bipolar I Disorder: Stability and Relation to Symptom Change. Journal of clinical child and adolescent psychology Gershon, A., Singh, M. K. 2016: 1-11

  Abstract

  Sleep disturbances are common features of bipolar disorder (BD), yet little is known about trajectories of sleep disturbances in youth with BD. Using longitudinal data, this study assessed the stability of sleep disturbances and their ability to predict symptom progression in adolescents diagnosed with BD compared to controls. Thirteen- to 19-year-olds meeting diagnostic criteria for BD I (n = 19, 16.2 ± 1.75 years, 57.9 % female, 68.4% Caucasian) and psychiatrically healthy age-comparable controls (n = 21, 15.7 ± 1.48 years. 52.4% female, 57.1% Caucasian) were assessed for sleep onset latency, number of awakenings, and wake time, separately for weekdays and weekends using a self-report questionnaire. Sleep indices and symptoms of mania (Young Mania Rating Scale) and depression (Children's Depression Rating Scale) were assessed at two time points, T1 and T2, approximately 12 months apart. Correlations were used to examine stability of sleep indices across time points and regression models to examine the effects of T1 sleep on T2 symptoms. Adolescents with BD showed low stability on most sleep indices, whereas controls showed high stability on all sleep indices. After controlling for T1 depression symptoms, more T1 weekend awakenings and weekend wake time predicted significantly greater T2 depression symptoms in youth with BD but not in controls. No significant associations were found between T1 sleep and T2 mania symptoms. These findings suggest that increased awakenings and wakefulness on weekends may represent an important therapeutic target for reducing depression in adolescents with BD.

  View details for PubMedID 27472039

• Resting State Neural Functional Connectivity is Associated With Suicidal Ideation and Behavior in Depressed Adolescents Goyer, M. S., Singh, M., Ordaz, S., Gotlib, I. H. ELSEVIER SCIENCE INC. 2016: 193S–194S
• Neurobiological Markers of Stress in Youth Offspring of Parents with Mood Disorders Singh, M. K., Phillips, O., Bhattacharjee, K., Hernandez, J., Foland-Ross, L., Gotlib, I. ELSEVIER SCIENCE INC. 2016: 31S
• Neural Aspects of Inhibition Following Emotional Primes in Depressed Adolescents. Journal of clinical child and adolescent psychology Colich, N. L., Foland-Ross, L. C., Eggleston, C., Singh, M. K., Gotlib, I. H. 2016; 45 (1): 21-30

  Abstract

  Adults diagnosed with major depressive disorder (MDD) have been found to be characterized by selective attention to negative material and by impairments in their ability to disengage from, or inhibit the processing of, negative stimuli. Altered functioning in the frontal executive control network has been posited to underlie these deficits in cognitive functioning. We know little, however, about the neural underpinnings of inhibitory difficulties in depressed adolescents. We used functional magnetic resonance imaging in 18 adolescents diagnosed with MDD and 15 age- and gender-matched healthy controls (CTLs) while they performed a modified affective Go/No-Go task that was designed to measure inhibitory control in the presence of an emotional distractor. Participants were presented with either a happy or a sad face, followed by a go or a no-go target to which they either made or inhibited a motor response. A group (MDD, CTL) by valence (happy, sad) by condition (go, no-go) analysis of variance indicated that MDD adolescents showed attenuated BOLD response in the right dorsolateral prefrontal cortex (DLPFC) and in the occipital cortex bilaterally, to no-go targets that followed a sad, but not a happy, face. Adolescents diagnosed with MDD showed anomalous recruitment of prefrontal control regions during inhibition trials, suggesting depression-associated disruption in neural underpinnings of the inhibition of emotional distractors. Given that the DLPFC is associated with the maintenance of goal-relevant information, it is likely that sad faces differentially capture attention in adolescents with MDD and interfere with task demands requiring inhibition.

  View details for DOI 10.1080/15374416.2014.982281

  View details for PubMedID 25635920

  View details for PubMedCentralID PMC4520793

• Cognitive Predictors of Sexual Dimorphism in Pediatric Depression Singh, M., Mackey, L., Gotlib, I., Hallmayer, J. NATURE PUBLISHING GROUP. 2015: S334–S335
• Neurofunctional Characteristics of Risk and Resilience in Youth Offspring of Bipolar Parents Singh, M. NATURE PUBLISHING GROUP. 2015: S40
• Amygdalar volumetric correlates of social anxiety in offspring of parents with bipolar disorder. Psychiatry research Park, M., Garrett, A., Boucher, S., Howe, M., Sanders, E., Kim, E., Singh, M., Chang, K. 2015; 234 (2): 252-258

  Abstract

  The prevalence of social anxiety disorder is high in offspring of parents with bipolar disorder (BD) and anxiety may be a significant risk factor in these youth for developing BD. We compared social anxiety symptoms between BD offspring with mood symptoms (high-risk group for developing BD I or II: HR) and healthy controls (HC). We also explored the correlations between the amygdalar volumes and social anxiety symptoms in the HR group with high social anxiety scores (HRHSA) due to the potential involvement of the amygdala in the pathophysiology of both BD and social anxiety. Youth participating in the study included 29h and 17HC of comparable age and gender. To assess social anxiety symptoms, we used the Multidimensional Anxiety Scale for Children (MASC) social anxiety subscale. The HR group's MASC social anxiety score was significantly higher than that of the HC group. Among the 29h, 17 subjects (58.6%) showed high social anxiety and they were classified as the HRHSA group. No significant difference was observed in amygdalar volume between the HRHSA and HC groups. However, there were significant negative correlations between amydalar volumes and MASC social anxiety score in the HRHSA group. These findings have implications for the link between amygdalar structure and both anxiety and mood control. This link may serve to implicate high social anxiety as a risk marker for future BD development.

  View details for DOI 10.1016/j.pscychresns.2015.09.018

  View details for PubMedID 26472294

• Predicting first onset of depression in young girls: Interaction of diurnal cortisol and negative life events. Journal of abnormal psychology LeMoult, J., Ordaz, S. J., Kircanski, K., Singh, M. K., Gotlib, I. H. 2015; 124 (4): 850-859

  Abstract

  Interactions between biological vulnerability and environmental adversity are central to the pathophysiology of depression. Given evidence that the hypothalamic-pituitary-adrenal (HPA) axis influences biological responses to environmental events, in the current longitudinal study the authors examined HPA-axis functioning, negative life events, and their interaction as predictors of the first onset of depression. At baseline, girls ages 9 to 14 years provided saliva samples to assess levels of diurnal cortisol production, quantified by total cortisol production (area under the curve with respect to ground; AUCg) and the cortisol awakening response (CAR). The authors then followed these participants until they reached age 18 in order to assess their subsequent experience of negative life events and the onset of a depressive episode. They found that the influence of negative life events on the subsequent onset of depression depended on HPA-axis functioning at baseline. Specifically, negative life events predicted the onset of depression in girls with higher levels of AUCg, but not in girls with lower levels of AUCg. In contrast, CAR did not predict the onset of depression either alone or in interaction with negative life events. These findings suggest that elevated total cortisol production in daily life potentiates susceptibility to environmental adversity and signals the need for early intervention.

  View details for DOI 10.1037/abn0000087

  View details for PubMedID 26595472

  View details for PubMedCentralID PMC4662047

• Intrinsic Amygdala Functional Connectivity in Youth With Bipolar I Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Singh, M. K., Kelley, R. G., Chang, K. D., Gotlib, I. H. 2015; 54 (9): 763-770

  Abstract

  Bipolar disorder (BD) commonly begins during adolescence and may continue into adulthood. Studies in adults with BD suggest that disruptions in amygdalar neural circuitry explain the pathophysiology underlying the disorder. Importantly, however, amygdala subregion networks have not yet been examined in youth close to mania onset. The goal of this study was to compare resting state functional connectivity patterns in amygdala subregions in youth with bipolar I disorder with patterns in healthy controls.Centromedial, laterobasal, and superficial amygdala subdivisions were assessed during rest and examined in relation to clinical measures of mania in youth (14-20 years old) with bipolar I disorder who experienced only a single episode of mania (BD; n = 20) and age-matched healthy comparison youth without any personal or family history of DSM-IV Axis I disorders (HC; n = 23).Relative to HC youth, youth with BD exhibited decreased connectivity between the laterobasal subdivision of the amygdala and the hippocampus and precentral gyrus, and increased connectivity between the laterobasal subdivision and the precuneus. Connectivity between the right laterobasal amygdala and right hippocampus was positively correlated with levels of anxiety in BD but not in HC youth, and connectivity between the right laterobasal amygdala and right precuneus was negatively correlated with insight about bipolar illness.Youth with BD have abnormal amygdala resting state network connections to regions that are critical for emotional processing and self-awareness. Longitudinal studies are needed to determine whether these aberrant patterns in youth with BD can be altered with intervention and can influence the course of disorder.

  View details for DOI 10.1016/j.jaac.2015.06.016

  View details for Web of Science ID 000360259500011

  View details for PubMedCentralID PMC4548854

• Intrinsic Amygdala Functional Connectivity in Youth With Bipolar I Disorder. Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K., Kelley, R. G., Chang, K. D., Gotlib, I. H. 2015; 54 (9): 763-770

  Abstract

  Bipolar disorder (BD) commonly begins during adolescence and may continue into adulthood. Studies in adults with BD suggest that disruptions in amygdalar neural circuitry explain the pathophysiology underlying the disorder. Importantly, however, amygdala subregion networks have not yet been examined in youth close to mania onset. The goal of this study was to compare resting state functional connectivity patterns in amygdala subregions in youth with bipolar I disorder with patterns in healthy controls.Centromedial, laterobasal, and superficial amygdala subdivisions were assessed during rest and examined in relation to clinical measures of mania in youth (14-20 years old) with bipolar I disorder who experienced only a single episode of mania (BD; n = 20) and age-matched healthy comparison youth without any personal or family history of DSM-IV Axis I disorders (HC; n = 23).Relative to HC youth, youth with BD exhibited decreased connectivity between the laterobasal subdivision of the amygdala and the hippocampus and precentral gyrus, and increased connectivity between the laterobasal subdivision and the precuneus. Connectivity between the right laterobasal amygdala and right hippocampus was positively correlated with levels of anxiety in BD but not in HC youth, and connectivity between the right laterobasal amygdala and right precuneus was negatively correlated with insight about bipolar illness.Youth with BD have abnormal amygdala resting state network connections to regions that are critical for emotional processing and self-awareness. Longitudinal studies are needed to determine whether these aberrant patterns in youth with BD can be altered with intervention and can influence the course of disorder.

  View details for DOI 10.1016/j.jaac.2015.06.016

  View details for PubMedID 26299298

• Using neuroimaging to evaluate and guide pharmacological and psychotherapeutic treatments for mood disorders in children CNS SPECTRUMS Singh, M. K., Garrett, A. S., Chang, K. D. 2015; 20 (4): 359-368

  Abstract

  Mood disorders are increasing in childhood, and often require multimodal and comprehensive treatment plans to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for treatment and stabilization. Current evidence supports the use of a number of interventions in children and adolescents diagnosed with DSM-5 mood spectrum disorders, which are associated with impairments in prefrontal-striatal-limbic networks, which are key for emotional functioning and regulation. Yet, little is known about the neurobiological effects of interventions on the developing brain. This chapter provides a synopsis of the literature demonstrating the neural effects of psychotropic medications and psychotherapy in youth with depressive or bipolar spectrum disorders. Additional longitudinal and biological studies are warranted to characterize the effects of these interventions on all phases and stages of mood illness development in children and adolescents.

  View details for DOI 10.1017/S1092852914000819

  View details for PubMedID 25659836

• Association of Anxiety Symptoms in Offspring of Bipolar Parents with Serotonin Transporter-Linked Polymorphic Region (5-HTTLPR) Genotype JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Park, M., Sanders, E., Howe, M., Singh, M., Hallmayer, J., Kim, E., Chang, K. 2015; 25 (6): 458-466

  Abstract

  Offspring of parents with bipolar disorder (BD) have been shown to be at high risk for BD. Anxiety symptoms, even at subclinical levels, have been associated with increased risk for BD in these youth. The s-allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in the pathophysiology of both BD and anxiety disorders and has been associated with pharmacological treatment response and increased risk for antidepressant side effects. Therefore, we aimed to explore 1) whether anxiety symptoms in offspring of BD parents were associated with presence of the 5-HTTLPR s-allele and 2) whether anxiety symptoms in the offspring of BD parents according to the 5-HTTLPR genotypes are related to antianxiety medication status.A total of 64 offspring of BD parents (mean age: 13.7 years) and 51 healthy controls (HC) (mean age: 13.7 years) were compared genetically and on the Multidimensional Anxiety Scale for Children (MASC).Offspring of BD parents showed higher levels of overall anxiety than did the HC group. Only antianxiety medication naïve offspring of BD parents were found to have an association between 5-HTTLPR genotypes and anxiety symptoms. The antianxiety medication naïve offspring of BD parents with the s-allele showed higher level of overall anxiety than offspring of BD parents with the l/l genotype. No significant differences in anxiety symptoms or their association with the 5-HTTLPR genotype were found in the HC group.This study indicated that there may be an association between 5-HTTLPR genotypes and anxiety symptoms in offspring of BD parents, and that antianxiety medication status may affect anxiety symptoms in the offspring of BD patients according to genotype.

  View details for DOI 10.1089/cap.2014.0115

  View details for PubMedID 26218602

• Is there validity to the bipolar prodrome? journal of clinical psychiatry Singh, M. K. 2015; 76 (5): e655-6
• Interaction of Hippocampal Volume Trajectories and Negative Life Events in Youth with and At Risk for Mood Disorders Singh, M. K., Kelley, R. G., Chang, K. D., Gotlib, I. H. ELSEVIER SCIENCE INC. 2015: 314S
• Inattentive achievement: the challenges and opportunities of learning with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K. 2015; 54 (5): 348-349
• Preliminary study of anxiety symptoms, family dysfunction, and the brain-derived neurotrophic factor (BDNF) Val66Met genotype in offspring of parents with bipolar disorder. Journal of psychiatric research Park, M., Chang, K. D., Hallmayer, J., Howe, M. E., Kim, E., Hong, S. C., Singh, M. K. 2015; 61: 81-88

  Abstract

  Several genetic and environmental factors place youth offspring of parents with bipolar disorder (BD) at high risk for developing mood and anxiety disorders. Recent studies suggest that anxiety symptoms, even at subclinical levels, have been associated with an increased risk for developing BD. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the pathophysiology of both BD and anxiety disorders. We aimed to explore whether anxiety in BD offspring was associated with the BDNF Val66Met polymorphism. 64 BD offspring (mean age: 13.73 (S.D. 3.45) M = 30, F = 34) and 51 HC (mean age: 13.68 (S.D. 2.68) M = 23, F = 28) were compared on presence of the met allele and on scores from the Multidimensional Anxiety Scale for Children (MASC). To assess family function, we used the Family Adaptability and Cohesion Evaluation Scales (FACES-IV). The Baron & Kenny method was the statistical approach used to examine the moderating effects between variables. BD offspring showed higher levels of overall anxiety than did the HC group. BD offspring with the val/val genotype showed higher levels of anxiety than BD offspring with other genotypes. No significant levels of anxiety or its association with BDNF genotype were found in the HC group. BD offspring group showed significantly more family dysfunction when compared with the HC group and the family dysfunction moderated the association between the BDNF genotype and anxiety symptoms. This study demonstrated the potential interplay of three factors: BD offspring, anxiety symptoms and family dysfunction.

  View details for DOI 10.1016/j.jpsychires.2014.11.013

  View details for PubMedID 25498133

• Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY Garrett, A. S., Miklowitz, D. J., Howe, M. E., Singh, M. K., Acquaye, T. K., Hawkey, C. G., Glover, G. H., Reiss, A. L., Chang, K. D. 2015; 56: 215-220

  Abstract

  Psychotherapy for youth with mood dysregulation can help stabilize mood and improve functioning, but the neural mechanisms of this improvement are not known. In this study we investigated the changes in brain activation underlying improvement in mood symptoms.Twenty-four subjects (ages 13-17) participated: 12 patients with clinically significant symptoms of depression and/or mania, and 12 healthy comparison subjects (HC) matched for age and sex. All subjects completed functional magnetic resonance imaging while viewing facial expressions. The patients then received up to 4 months of psychotherapy and were rescanned at end of treatment. Whole brain differences between patient and control groups were assessed with a voxel-wise analysis. Changes in activation from pre- to post-treatment within the patient group were tested for correlation with changes in mood symptoms.At baseline the patient group had hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and hyperactivation in the posterior cingulate cortex compared to the HC group. Between pre- and post-treatment activation increased in the DLPFC and decreased in the amygdala. Increases in DLPFC activation were significantly correlated with improvement in mania symptoms.Enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation in pediatric patients at familial risk for bipolar disorder.

  View details for DOI 10.1016/j.pnpbp.2014.09.007

  View details for Web of Science ID 000345526400030

  View details for PubMedCentralID PMC4258439

• Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder. Progress in neuro-psychopharmacology & biological psychiatry Garrett, A. S., Miklowitz, D. J., Howe, M. E., Singh, M. K., Acquaye, T. K., Hawkey, C. G., Glover, G. H., Reiss, A. L., Chang, K. D. 2015; 56: 215-220

  Abstract

  Psychotherapy for youth with mood dysregulation can help stabilize mood and improve functioning, but the neural mechanisms of this improvement are not known. In this study we investigated the changes in brain activation underlying improvement in mood symptoms.Twenty-four subjects (ages 13-17) participated: 12 patients with clinically significant symptoms of depression and/or mania, and 12 healthy comparison subjects (HC) matched for age and sex. All subjects completed functional magnetic resonance imaging while viewing facial expressions. The patients then received up to 4 months of psychotherapy and were rescanned at end of treatment. Whole brain differences between patient and control groups were assessed with a voxel-wise analysis. Changes in activation from pre- to post-treatment within the patient group were tested for correlation with changes in mood symptoms.At baseline the patient group had hypoactivation in the dorsolateral prefrontal cortex (DLPFC) and hyperactivation in the posterior cingulate cortex compared to the HC group. Between pre- and post-treatment activation increased in the DLPFC and decreased in the amygdala. Increases in DLPFC activation were significantly correlated with improvement in mania symptoms.Enhancement of frontal executive control brain regions may underlie improvement in mood dysregulation in pediatric patients at familial risk for bipolar disorder.

  View details for DOI 10.1016/j.pnpbp.2014.09.007

  View details for PubMedID 25283342

• Association between insulin resistance and cognition in patients with depressive disorders: Exploratory analyses into age-specific effects JOURNAL OF PSYCHIATRIC RESEARCH Wroolie, T. E., Kenna, H. A., Singh, M. K., Rasgon, N. L. 2015; 60: 65-72

  Abstract

  The current preliminary cross sectional study sought to examine the effects of insulin resistance (IR) and body mass index (BMI) on cognitive performance in adult patients with a history depression, currently not in an acute Major Depressive Episode (MDD). As an exploratory post hoc investigation, special consideration was given to adults <45 years and ≥45 years old. Subjects included men and women ages 19-71 (N = 39) with a history of a non-psychotic, non-melancholic MDD. All subjects underwent an insulin suppression test to determine Steady-State Plasma Glucose (SSPG), a battery of neuropsychological tests, and measurement of BMI. Multiple linear regressions were conducted to determine whether there were differential effects of direct (SSPG) and indirect (BMI) measures on cognition in the whole sample and within dichotomized age groups (<45 and ≥45 years). Preliminary results showed that in the sample as a whole, SSPG was not associated with worse performance on any cognitive variables, while higher BMI was associated with worse dominant hand fine motor skills. Within age groups, differential effects on cognition were found in relation to SSPG and BMI. Higher SSPG was associated with worse cognitive flexibility in the group <45 years, whereas higher BMI was associated with worse estimate of global intelligence in the group ≥45 years. The potential negative impact of IR in younger adults with depression raises concerns regarding the long-term impact on cognition and risk for Alzheimer's disease in undiagnosed younger adults with IR and depression. These negative consequences may not be seen with indirect measures of IR in younger adult populations. Overweight and obesity in older adults with a history of depression appear to have further negative impacts on cognition similar to deficits seen in patients with diabetes.Clinical Trial NCT01106313.

  View details for DOI 10.1016/j.jpsychires.2014.10.001

  View details for Web of Science ID 000347268500008

• Association between insulin resistance and cognition in patients with depressive disorders: exploratory analyses into age-specific effects. Journal of psychiatric research Wroolie, T. E., Kenna, H. A., Singh, M. K., Rasgon, N. L. 2015; 60: 65-72

  Abstract

  The current preliminary cross sectional study sought to examine the effects of insulin resistance (IR) and body mass index (BMI) on cognitive performance in adult patients with a history depression, currently not in an acute Major Depressive Episode (MDD). As an exploratory post hoc investigation, special consideration was given to adults <45 years and ≥45 years old. Subjects included men and women ages 19-71 (N = 39) with a history of a non-psychotic, non-melancholic MDD. All subjects underwent an insulin suppression test to determine Steady-State Plasma Glucose (SSPG), a battery of neuropsychological tests, and measurement of BMI. Multiple linear regressions were conducted to determine whether there were differential effects of direct (SSPG) and indirect (BMI) measures on cognition in the whole sample and within dichotomized age groups (<45 and ≥45 years). Preliminary results showed that in the sample as a whole, SSPG was not associated with worse performance on any cognitive variables, while higher BMI was associated with worse dominant hand fine motor skills. Within age groups, differential effects on cognition were found in relation to SSPG and BMI. Higher SSPG was associated with worse cognitive flexibility in the group <45 years, whereas higher BMI was associated with worse estimate of global intelligence in the group ≥45 years. The potential negative impact of IR in younger adults with depression raises concerns regarding the long-term impact on cognition and risk for Alzheimer's disease in undiagnosed younger adults with IR and depression. These negative consequences may not be seen with indirect measures of IR in younger adult populations. Overweight and obesity in older adults with a history of depression appear to have further negative impacts on cognition similar to deficits seen in patients with diabetes.Clinical Trial NCT01106313.

  View details for DOI 10.1016/j.jpsychires.2014.10.001

  View details for PubMedID 25455511

• Preparing and Presenting Effective Abstracts and Posters in Psychiatry ACADEMIC PSYCHIATRY Singh, M. K. 2014; 38 (6): 709-715

  Abstract

  Presenting an abstract and a poster gives scientists from all fields, including psychiatry, an important opportunity to introduce their research to others. Researchers and mental health professionals at all levels of career development can use several media resources to assist them with the technical aspects of preparing an abstract or a poster. This article will focus on major principles associated with preparing and presenting an abstract and a poster at a scientific meeting. A literature search using NIH PubMed was conducted to identify peer and nonpeer-reviewed articles that provide methods for effective abstract and poster presentation for the period of 1966 to June 2014. First, the author reviews the purpose and relative importance of abstracts and posters in academic settings. Next, the author describes the qualities of an effective abstract and poster and common pitfalls that may occur. Finally, the author presents a systematic approach to preparing and presenting an abstract and a poster in a scientific setting. Several sources consistently suggest that readability, organization, and succinctness are qualities that make an effective and successful abstract and poster. Mental health professionals in all stages of their career development may benefit from following these guidelines in presenting their scientific work.

  View details for DOI 10.1007/s40596-014-0190-z

  View details for PubMedID 25085499

• Association Between Direct and Indirect Measures of Insulin Resistance and Cognition in Euthymic Adults with Histories of Major Depressive Disorder Wroolie, T., Kenna, H., Singh, M., Rasgon, N. NATURE PUBLISHING GROUP. 2014: S282
• Distinguishing bipolar disorder from other psychiatric disorders in children. Current psychiatry reports Singh, M. K., Ketter, T., Chang, K. D. 2014; 16 (12): 516-?

  Abstract

  Pediatric onset bipolar disorder (BD) is a challenging diagnosis with potentially debilitating outcomes. This review aims to critically evaluate recently published literature relevant to the diagnosis of BD in youth, emphasizing interesting and important new findings characterizing pediatric BD and reporting updates in the diagnostic and statistical manual relevant to this disorder in youth. Challenges regarding the diagnosis of BD will be discussed, in addition to important distinctions with other childhood disorders, including other bipolar spectrum disorders; major depressive disorder; dysthymia; disruptive mood dysregulation disorder (DMDD); attention-deficit/hyperactivity disorder (ADHD) and other disruptive behavioral disorders; anxiety disorders, including post-traumatic stress disorder (PTSD); psychotic disorders; autism spectrum disorders; substance use disorders; and borderline personality disorder. The review concludes with a comment on past research limitations and future directions in the field.

  View details for DOI 10.1007/s11920-014-0516-2

  View details for PubMedID 25315116

• Distinguishing Bipolar Disorder From Other Psychiatric Disorders in Children CURRENT PSYCHIATRY REPORTS Singh, M. K., Ketter, T., Chang, K. D. 2014; 16 (12)

  Abstract

  Pediatric onset bipolar disorder (BD) is a challenging diagnosis with potentially debilitating outcomes. This review aims to critically evaluate recently published literature relevant to the diagnosis of BD in youth, emphasizing interesting and important new findings characterizing pediatric BD and reporting updates in the diagnostic and statistical manual relevant to this disorder in youth. Challenges regarding the diagnosis of BD will be discussed, in addition to important distinctions with other childhood disorders, including other bipolar spectrum disorders; major depressive disorder; dysthymia; disruptive mood dysregulation disorder (DMDD); attention-deficit/hyperactivity disorder (ADHD) and other disruptive behavioral disorders; anxiety disorders, including post-traumatic stress disorder (PTSD); psychotic disorders; autism spectrum disorders; substance use disorders; and borderline personality disorder. The review concludes with a comment on past research limitations and future directions in the field.

  View details for DOI 10.1007/s11920-014-0516-2

  View details for Web of Science ID 000343893600004

• Early signs of anomalous neural functional connectivity in healthy offspring of parents with bipolar disorder. Bipolar disorders Singh, M. K., Chang, K. D., Kelley, R. G., Saggar, M., Reiss, A. L., Gotlib, I. H. 2014; 16 (7): 678-689

  Abstract

  Bipolar disorder (BD) has been associated with dysfunctional brain connectivity and with family chaos. It is not known whether aberrant connectivity occurs before illness onset, representing vulnerability for developing BD amidst family chaos. We used resting-state functional magnetic resonance imaging (fMRI) to examine neural network dysfunction in healthy offspring living with parents with BD and healthy comparison youth.Using two complementary methodologies [data-driven independent component analysis (ICA) and hypothesis-driven region-of-interest (ROI)-based intrinsic connectivity], we examined resting-state fMRI data in 8-17-year-old healthy offspring of a parent with BD (n = 24; high risk) and age-matched healthy youth without any personal or family psychopathology (n = 25; low risk).ICA revealed that, relative to low-risk youth, high-risk youth showed increased connectivity in the ventrolateral prefrontal cortex (VLPFC) subregion of the left executive control network (ECN), which includes frontoparietal regions important for emotion regulation. ROI-based analyses revealed that high-risk versus low-risk youth had decreased connectivities between the left amygdala and pregenual cingulate, between the subgenual cingulate and supplementary motor cortex, and between the left VLPFC and left caudate. High-risk youth showed stronger connections in the VLPFC with age and higher functioning, which may be neuroprotective, and weaker connections between the left VLPFC and caudate with more family chaos, suggesting an environmental influence on frontostriatal connectivity.Healthy offspring of parents with BD show atypical patterns of prefrontal and subcortical intrinsic connectivity that may be early markers of resilience to or vulnerability for developing BD. Longitudinal studies are needed to determine whether these patterns predict outcomes.

  View details for DOI 10.1111/bdi.12221

  View details for PubMedID 24938878

• The neuroscience of depression: implications for assessment and intervention. Behaviour research and therapy Singh, M. K., Gotlib, I. H. 2014; 62: 60-73

  Abstract

  Major Depressive Disorder (MDD) is among the most prevalent of all psychiatric disorders and is the single most burdensome disease worldwide. In attempting to understand the profound deficits that characterize MDD across multiple domains of functioning, researchers have identified aberrations in brain structure and function in individuals diagnosed with this disorder. In this review we synthesize recent data from human neuroimaging studies in presenting an integrated neural network framework for understanding the impairments experienced by individuals with MDD. We discuss the implications of these findings for assessment of and intervention for MDD. We conclude by offering directions for future research that we believe will advance our understanding of neural factors that contribute to the etiology and course of depression, and to recovery from this debilitating disorder.

  View details for DOI 10.1016/j.brat.2014.08.008

  View details for PubMedID 25239242

  View details for PubMedCentralID PMC4253641

• The neuroscience of depression: Implications for assessment and intervention BEHAVIOUR RESEARCH AND THERAPY Singh, M. K., Gotlib, I. H. 2014; 62: 60-73

  Abstract

  Major Depressive Disorder (MDD) is among the most prevalent of all psychiatric disorders and is the single most burdensome disease worldwide. In attempting to understand the profound deficits that characterize MDD across multiple domains of functioning, researchers have identified aberrations in brain structure and function in individuals diagnosed with this disorder. In this review we synthesize recent data from human neuroimaging studies in presenting an integrated neural network framework for understanding the impairments experienced by individuals with MDD. We discuss the implications of these findings for assessment of and intervention for MDD. We conclude by offering directions for future research that we believe will advance our understanding of neural factors that contribute to the etiology and course of depression, and to recovery from this debilitating disorder.

  View details for DOI 10.1016/j.brat.2014.08.008

  View details for Web of Science ID 000345471000007

  View details for PubMedCentralID PMC4253641

• Early signs of anomalous neural functional connectivity in healthy offspring of parents with bipolar disorder BIPOLAR DISORDERS Singh, M. K., Chang, K. D., Kelley, R. G., Saggar, M., Reiss, A. L., Gotlib, I. H. 2014; 16 (7): 678-689

  Abstract

  Bipolar disorder (BD) has been associated with dysfunctional brain connectivity and with family chaos. It is not known whether aberrant connectivity occurs before illness onset, representing vulnerability for developing BD amidst family chaos. We used resting-state functional magnetic resonance imaging (fMRI) to examine neural network dysfunction in healthy offspring living with parents with BD and healthy comparison youth.Using two complementary methodologies [data-driven independent component analysis (ICA) and hypothesis-driven region-of-interest (ROI)-based intrinsic connectivity], we examined resting-state fMRI data in 8-17-year-old healthy offspring of a parent with BD (n = 24; high risk) and age-matched healthy youth without any personal or family psychopathology (n = 25; low risk).ICA revealed that, relative to low-risk youth, high-risk youth showed increased connectivity in the ventrolateral prefrontal cortex (VLPFC) subregion of the left executive control network (ECN), which includes frontoparietal regions important for emotion regulation. ROI-based analyses revealed that high-risk versus low-risk youth had decreased connectivities between the left amygdala and pregenual cingulate, between the subgenual cingulate and supplementary motor cortex, and between the left VLPFC and left caudate. High-risk youth showed stronger connections in the VLPFC with age and higher functioning, which may be neuroprotective, and weaker connections between the left VLPFC and caudate with more family chaos, suggesting an environmental influence on frontostriatal connectivity.Healthy offspring of parents with BD show atypical patterns of prefrontal and subcortical intrinsic connectivity that may be early markers of resilience to or vulnerability for developing BD. Longitudinal studies are needed to determine whether these patterns predict outcomes.

  View details for DOI 10.1111/bdi.12221

  View details for Web of Science ID 000344373100002

• Reward Processing in Healthy Offspring of Parents With Bipolar Disorder JAMA PSYCHIATRY Singh, M. K., Kelley, R. G., Howe, M. E., Reiss, A. L., Gotlib, I. H., Chang, K. D. 2014; 71 (10): 1148-1156

  Abstract

  Bipolar disorder (BD) is highly familial and characterized by deficits in reward processing. It is not known, however, whether these deficits precede illness onset or are a consequence of the disorder.To determine whether anomalous neural processing of reward characterizes children at familial risk for BD in the absence of a personal history of a psychopathologic disorder.This study compared neural activity and behaviors of children at high and low risk for mania while they anticipate and respond to reward and loss. The study was performed from September 15, 2009, through February 17, 2012, in a university functional magnetic resonance imaging facility and included 8- to 15-year-old children without disorders born to a parent with BD (n = 20 high-risk children) and demographically matched healthy comparison children (n = 25 low-risk children).Neural activity, as measured with functional magnetic resonance imaging, during anticipation and receipt of reward and loss during a monetary incentive delay task.While anticipating losses, high-risk children had less activation in the pregenual cingulate than did their low-risk counterparts (t19 = -2.44, P = .02). When receiving rewards, high-risk children had greater activation in the left lateral orbitofrontal cortex than did low-risk children (t43 = -3.04, P = .004). High-risk children also had weaker functional connectivity between the pregenual cingulate and the right ventrolateral prefrontal cortex while anticipating rewards than did low-risk children (t19 = -4.38, P < .001) but had a stronger connectivity between these regions while anticipating losses (t24 = 2.76, P = .01). Finally, in high- but not low-risk children, novelty seeking was associated with increased striatal and amygdalar activation in the anticipation of losses, and impulsivity was associated with increased striatal and insula activation in the receipt of rewards.Aberrant prefrontal activations and connectivities during reward processing suggest mechanisms that underlie early vulnerabilities for developing dysfunctional regulation of goal pursuit and motivation in children at high risk for mania. Longitudinal studies are needed to examine whether these patterns of neural activation predict the onset of mania and other mood disorders in high-risk children.

  View details for DOI 10.1001/jamapsychiatry.2014.1031

  View details for Web of Science ID 000342900200009

• Neurobiological Clues of Risk for Bipolar Disorder Development PSYCHIATRIC ANNALS Chang, K. D., Garrett, A., Singh, M. 2014; 44 (10): 466-470
• Reward processing in healthy offspring of parents with bipolar disorder. JAMA psychiatry Singh, M. K., Kelley, R. G., Howe, M. E., Reiss, A. L., Gotlib, I. H., Chang, K. D. 2014; 71 (10): 1148-1156

  Abstract

  Bipolar disorder (BD) is highly familial and characterized by deficits in reward processing. It is not known, however, whether these deficits precede illness onset or are a consequence of the disorder.To determine whether anomalous neural processing of reward characterizes children at familial risk for BD in the absence of a personal history of a psychopathologic disorder.This study compared neural activity and behaviors of children at high and low risk for mania while they anticipate and respond to reward and loss. The study was performed from September 15, 2009, through February 17, 2012, in a university functional magnetic resonance imaging facility and included 8- to 15-year-old children without disorders born to a parent with BD (n = 20 high-risk children) and demographically matched healthy comparison children (n = 25 low-risk children).Neural activity, as measured with functional magnetic resonance imaging, during anticipation and receipt of reward and loss during a monetary incentive delay task.While anticipating losses, high-risk children had less activation in the pregenual cingulate than did their low-risk counterparts (t19 = -2.44, P = .02). When receiving rewards, high-risk children had greater activation in the left lateral orbitofrontal cortex than did low-risk children (t43 = -3.04, P = .004). High-risk children also had weaker functional connectivity between the pregenual cingulate and the right ventrolateral prefrontal cortex while anticipating rewards than did low-risk children (t19 = -4.38, P < .001) but had a stronger connectivity between these regions while anticipating losses (t24 = 2.76, P = .01). Finally, in high- but not low-risk children, novelty seeking was associated with increased striatal and amygdalar activation in the anticipation of losses, and impulsivity was associated with increased striatal and insula activation in the receipt of rewards.Aberrant prefrontal activations and connectivities during reward processing suggest mechanisms that underlie early vulnerabilities for developing dysfunctional regulation of goal pursuit and motivation in children at high risk for mania. Longitudinal studies are needed to examine whether these patterns of neural activation predict the onset of mania and other mood disorders in high-risk children.

  View details for DOI 10.1001/jamapsychiatry.2014.1031

  View details for PubMedID 25142103

• Type and duration of subsyndromal symptoms in youth with bipolar I disorder prior to their first manic episode BIPOLAR DISORDERS Correll, C. U., Hauser, M., Penzner, J. B., Auther, A. M., Kafantaris, V., Saito, E., Olvet, D., Carrion, R. E., Birmaher, B., Chang, K. D., DelBello, M. P., Singh, M. K., Pavuluri, M., Cornblatt, B. A. 2014; 16 (5): 478-492

  Abstract

  The aim of the present study was to systematically evaluate the prodrome to mania in youth.New-onset/worsening symptoms/signs of ≥ moderate severity preceding first mania were systematically assessed in 52 youth (16.2 ± 2.8 years) with a research diagnosis of bipolar I disorder (BD-I). Youth and/or caregivers underwent semi-structured interviews, using the Bipolar Prodrome Symptom Scale-Retrospective.The mania prodrome was reported to start gradually in most youth (88.5%), with either slow (59.6%) or rapid (28.8%) deterioration, while a rapid-onset-and-deterioration prodrome was rare (11.5%). The manic prodrome, conservatively defined as requiring ≥ 3 symptoms, lasted 10.3 ± 14.4 months [95% confidence interval (CI): 6.3-14.4], being present for ≥ 4 months in 65.4% of subjects. Among prodromal symptoms reported in ≥ 50% of youth, three were subthreshold manic in nature (irritability: 61.5%, racing thoughts: 59.6%, increased energy/activity: 50.0%), two were nonspecific (decreased school/work functioning: 65.4%, mood swings/lability: 57.7%), and one each was depressive (depressed mood: 53.8%) or subthreshold manic/depressive (inattention: 51.9%). A decreasing number of youth had ≥ 1 (84.6%), ≥ 2 (48.1%), or ≥ 3 (26.9%) 'specific' subthreshold mania symptoms (i.e., elation, grandiosity, decreased need for sleep, racing thoughts, or hypersexuality), lasting 9.5 ± 14.9 months (95% CI: 5.0-14.0), 3.5 ± 3.5 months (95% CI: 2.0-4.9), and 3.0 ± 3.2 months (95% CI: 1.0-5.0) for ≥ 1, ≥ 2, or ≥ 3 specific symptoms, respectively.In youth with BD-I, a relatively long, predominantly slow-onset mania prodrome appears to be common, including subthreshold manic and depressive psychopathology symptoms. This suggests that early clinical identification and intervention may be feasible in bipolar disorder. Identifying biological markers associated with clinical symptoms of impending mania may help to increase chances for early detection and prevention before full mania.

  View details for DOI 10.1111/bdi.12194

  View details for Web of Science ID 000340381500004

  View details for PubMedID 24597782

• Brain Structures in the Fear and Reward Circuits During Adolescence: Impact of Parenting and Anxiety Suffren, S., Ariza, V., Singh, M., Gotlib, I. H., Foland-Ross, L. C., Boivin, M., Seguin, J. R., Tremblay, R. E., Lepore, F., Maheu, F. ELSEVIER SCIENCE INC. 2014: 355S
• The Impact of Early Life Stress on the Development of Neural Circuitry in Prepubertal Children: Gender Differences and Emotional and Cognitive Functioning Gotlib, I. H., Foland-Ross, L. C., Colich, N. L., Kircanski, K., Singh, M. K., Joormann, J. ELSEVIER SCIENCE INC. 2014: 299S
• Differentiating Neural Networks Underlying Risk for Depression in Youth Singh, M. K., Kelley, R. G., Howe, M., Gotlib, I., Chang, K. NATURE PUBLISHING GROUP. 2013: S225–S226
• Prospective neurochemical characterization of child offspring of parents with bipolar disorder PSYCHIATRY RESEARCH-NEUROIMAGING Singh, M. K., Jo, B., Adleman, N. E., Howe, M., Bararpour, L., Kelley, R. G., Spielman, D., Chang, K. D. 2013; 214 (2): 153-160

  Abstract

  We wished to determine whether decreases in N-acetyl aspartate (NAA) and increases in myoinositol (mI) concentrations as a ratio of creatine (Cr) occurred in the dorsolateral prefrontal cortex (DLPFC) of pediatric offspring of parents with bipolar disorder (BD) and a healthy comparison group (HC) over a 5-year period using proton magnetic resonance spectroscopy ((1)H-MRS). Paticipants comprised 64 offspring (9-18 years old) of parents with BD (36 with established BD, and 28 offspring with symptoms subsyndromal to mania) and 28 HCs, who were examined for group differences in NAA/Cr and mI/Cr in the DLPFC at baseline and follow-up at either 8, 10, 12, 52, 104, 156, 208, or 260 weeks. No significant group differences were found in metabolite concentrations at baseline or over time. At baseline, BD offspring had trends for higher mI/Cr concentrations in the right DLPFC than the HC group. mI/Cr concentrations increased with age, but no statistically significant group differences were found between groups on follow-up. It may be the case that with intervention youth at risk for BD are normalizing otherwise potentially aberrant neurochemical trajectories in the DLPFC. A longer period of follow-up may be required before observing any group differences.

  View details for DOI 10.1016/j.pscychresns.2013.05.005

  View details for Web of Science ID 000325432300009

  View details for PubMedID 24028795

  View details for PubMedCentralID PMC3796054

• Prospective neurochemical characterization of child offspring of parents with bipolar disorder. Psychiatry research Singh, M. K., Jo, B., Adleman, N. E., Howe, M., Bararpour, L., Kelley, R. G., Spielman, D., Chang, K. D. 2013; 214 (2): 153-160

  Abstract

  We wished to determine whether decreases in N-acetyl aspartate (NAA) and increases in myoinositol (mI) concentrations as a ratio of creatine (Cr) occurred in the dorsolateral prefrontal cortex (DLPFC) of pediatric offspring of parents with bipolar disorder (BD) and a healthy comparison group (HC) over a 5-year period using proton magnetic resonance spectroscopy ((1)H-MRS). Paticipants comprised 64 offspring (9-18 years old) of parents with BD (36 with established BD, and 28 offspring with symptoms subsyndromal to mania) and 28 HCs, who were examined for group differences in NAA/Cr and mI/Cr in the DLPFC at baseline and follow-up at either 8, 10, 12, 52, 104, 156, 208, or 260 weeks. No significant group differences were found in metabolite concentrations at baseline or over time. At baseline, BD offspring had trends for higher mI/Cr concentrations in the right DLPFC than the HC group. mI/Cr concentrations increased with age, but no statistically significant group differences were found between groups on follow-up. It may be the case that with intervention youth at risk for BD are normalizing otherwise potentially aberrant neurochemical trajectories in the DLPFC. A longer period of follow-up may be required before observing any group differences.

  View details for DOI 10.1016/j.pscychresns.2013.05.005

  View details for PubMedID 24028795

• Anomalous gray matter structural networks in major depressive disorder. Biological psychiatry Singh, M. K., Kesler, S. R., Hadi Hosseini, S. M., Kelley, R. G., Amatya, D., Hamilton, J. P., Chen, M. C., Gotlib, I. H. 2013; 74 (10): 777-785

  Abstract

  BACKGROUND: Major depressive disorder (MDD) is characterized by abnormalities in structure, function, and connectivity in several brain regions. Few studies have examined how these regions are organized in the brain or investigated network-level structural aberrations that might be associated with depression. METHODS: We used graph analysis to examine the gray matter structural networks of individuals diagnosed with MDD (n = 93) and a demographically similar healthy comparison group (n = 151) with no history of psychopathology. The efficiency of structural networks for processing information was determined by quantifying local interconnectivity (clustering) and global integration (path length). We also compared the groups on the contributions of high-degree nodes (i.e., hubs) and regional network measures, including degree (number of connections in a node) and betweenness (fraction of short path connections in a node). RESULTS: Depressed participants had significantly decreased clustering in their brain networks across a range of network densities. Compared with control subjects, depressed participants had fewer hubs primarily in medial frontal and medial temporal areas, had higher degree in the left supramarginal gyrus and right gyrus rectus, and had higher betweenness in the right amygdala and left medial orbitofrontal gyrus. CONCLUSIONS: Networks of depressed individuals are characterized by a less efficient organization involving decreased regional connectivity compared with control subjects. Regional connections in the amygdala and medial prefrontal cortex may play a role in maintaining or adapting to depressive pathology. This is the first report of anomalous large-scale gray matter structural networks in MDD and provides new insights concerning the neurobiological mechanisms associated with this disorder.

  View details for DOI 10.1016/j.biopsych.2013.03.005

  View details for PubMedID 23601854

• Anomalous Gray Matter Structural Networks in Major Depressive Disorder BIOLOGICAL PSYCHIATRY Singh, M. K., Kesler, S. R., Hosseini, S. M., Kelley, R. G., Amatya, D., Hamilton, J. P., Chen, M. C., Gotlib, I. H. 2013; 74 (10): 777-785
• Socio-emotional processing and functioning of youth at high risk for bipolar disorder. Journal of affective disorders Whitney, J., Howe, M., Shoemaker, V., Li, S., Marie Sanders, E., Dijamco, C., Acquaye, T., Phillips, J., Singh, M., Chang, K. 2013; 148 (1): 112-117

  Abstract

  The goal of this study was to investigate differences in socio-emotional processing and functioning in children and adolescents at high risk for bipolar disorder (BD) and healthy control participants.Children and adolescents with a parent with bipolar disorder, who had mood dysregulation but not fully syndromal BD (high risk, HR, n=24), were compared to participants with no personal or family history of psychopathology (healthy control, HC, n=27) across several neuropsychological domains. Social reciprocity was measured by the Social Responsiveness Scale, theory of mind was measured by use of the NEPSY, and affect recognition was measured by the NEPSY and the Diagnostic Test of Nonverbal Accuracy 2 (DANVA).The HR group demonstrated significant impairment in social reciprocity, including impairments in social awareness, social cognition, social communication, social motivation, and autistic mannerisms. There were no significant group differences in performance on theory of mind or affect recognition tasks.Lack of impairment in tasks associated with theory of mind or affect recognition indicate that social functioning difficulties are not likely due to impairments in these areas, or that the measures employed were not sufficiently sensitive to detect group differences.Youth at high risk for BD demonstrated impairments in numerous social domains, which may be due to innate differences in brain development governing socio-emotional functioning or may be due to disruptions in normal development caused by mood regulation difficulties.

  View details for DOI 10.1016/j.jad.2012.08.016

  View details for PubMedID 23123133

• The VAL66MET Polymorphism and Affect Recognition in Youth at Risk for Bipolar Disorder 68th Annual Scientific Meeting of the Society-of-Biological-Psychiatry Sanders, E. M., Woicicki, K., Cosgrove, V. E., Howe, M. E., Pearlstein, J., Staudenmaier, P., Garrett, A., Kelley, R., Boucher, S., Chang, K. D., Singh, M. K. ELSEVIER SCIENCE INC. 2013: 176S–176S
• In this issue. Abstract thinking: adolescence and adversity. Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K. 2013; 52 (3): 215-216
• Early Intervention for Symptomatic Youth at Risk for Bipolar Disorder: A Randomized Trial of Family-Focused Therapy JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Miklowitz, D. J., Schneck, C. D., Singh, M. K., Taylor, D. O., George, E. L., Cosgrove, V. E., Howe, M. E., Dickinson, L. M., Garber, J., Chang, K. D. 2013; 52 (2): 121-131

  Abstract

  Depression and brief periods of (hypo)mania are linked to an increased risk of progression to bipolar I or II disorder (BD) in children of bipolar parents. This randomized trial examined the effects of a 4-month family-focused therapy (FFT) program on the 1-year course of mood symptoms in youth at high familial risk for BD, and explored its comparative benefits among youth in families with high versus low expressed emotion (EE).Participants were 40 youth (mean 12.3±2.8 years, range 9-17) with BD not otherwise specified, major depressive disorder, or cyclothymic disorder who had a first-degree relative with BD I or II and active mood symptoms (Young Mania Rating Scale [YMRS]>11 or Child Depression Rating Scale>29). Participants were randomly allocated to FFT-High Risk version (FFT-HR; 12 sessions of psychoeducation and training in communication and problem-solving skills) or an education control (EC; 1-2 family sessions).Youth in FFT-HR had more rapid recovery from their initial mood symptoms (hazard ratio = 2.69, p = .047), more weeks in remission, and a more favorable trajectory of YMRS scores over 1 year than youth in EC. The magnitude of treatment effect was greater among youth in high-EE (versus low-EE) families.FFT-HR may hasten and help sustain recovery from mood symptoms among youth at high risk for BD. Longer follow-up will be necessary to determine whether early family intervention has downstream effects that contribute to the delay or prevention of full manic episodes in vulnerable youth.

  View details for DOI 10.1016/j.jaac.2012.10.007

  View details for Web of Science ID 000314430000004

  View details for PubMedID 23357439

  View details for PubMedCentralID PMC3558946

• Brain structural response in individuals at familial risk for bipolar disorder: a tale of two outcomes. Biological psychiatry Singh, M. K., Chang, K. D. 2013; 73 (2): 109-110
• Reward Processing in Adolescents With Bipolar I Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Singh, M. K., Chang, K. D., Kelley, R. G., Cui, X., Sherdell, L., Howe, M. E., Gotlib, I. H., Reiss, A. L. 2013; 52 (1): 68-83

  Abstract

  Bipolar disorder (BD) is a debilitating psychiatric condition that commonly begins in adolescence, a developmental period that has been associated with increased reward seeking. Because youth with BD are especially vulnerable to negative risk-taking behaviors, understanding the neural mechanisms by which dysregulated affect interacts with the neurobehavioral processing of reward is clearly important. One way to clarify how manic symptoms evolve in BD is to "prime" the affect before presenting rewarding stimuli. The objective of this study was to investigate the neural effects of an affective priming task designed to positively induce mood before reward processing in adolescents with and without BD.Neural activity and behaviors during the anticipation of and response to monetary reward and loss after an affective prime were compared using functional magnetic resonance imaging in 13- to 18-year-old adolescents with a recent onset of BD-I (n = 24) and demographically matched healthy comparison youth (n = 24).Compared with the healthy control youth, youth with BD had speeded reaction times and showed decreased activation in the thalamus and inferior temporal gyrus while anticipating gains after priming but increased activations in the middle frontal gyrus and parietal cortices while anticipating losses after priming. Youth with BD also showed less activation in the inferior parietal lobule, thalamus, and superior frontal gyrus while receiving losses after priming.Aberrant prefrontal and subcortical activations during reward processing suggest mechanisms that may underlie disordered self-awareness during goal pursuit and motivation in BD. Longitudinal studies are needed to examine whether this pattern of neural activation predicts a poorer long-term outcome.

  View details for DOI 10.1016/j.jaac.2012.10.004

  View details for PubMedID 23265635

• The Neural Effects of Psychotropic Medications in Children and Adolescents CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA Singh, M. K., Chang, K. D. 2012; 21 (4): 753-?

  Abstract

  Little is known about the neurobiological effects of psychotropic medications used in the treatment of children and adolescents diagnosed with a psychiatric disorder. This review provides a synopsis of the literature demonstrating the neural effects associated with exposure to psychotropic medication in youth using multimodal neuroimaging. The article concludes by illustrating how, taken together, these studies suggest that pharmacological interventions during childhood do indeed affect brain structure and function in a detectable manner, and the effects appear to be ameliorative.

  View details for DOI 10.1016/j.chc.2012.07.010

  View details for PubMedID 23040900

• Information processing in adolescents with bipolar I disorder JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY Whitney, J., Joormann, J., Gotlib, I. H., Kelley, R. G., Acquaye, T., Howe, M., Chang, K. D., Singh, M. K. 2012; 53 (9): 937-945

  Abstract

  Cognitive models of bipolar I disorder (BD) may aid in identification of children who are especially vulnerable to chronic mood dysregulation. Information-processing biases related to memory and attention likely play a role in the development and persistence of BD among adolescents; however, these biases have not been extensively studied in youth with BD.We administered the self-referent encoding task and the dot-probe task to adolescents with bipolar I disorder (BD, n = 35) and a demographically similar healthy comparison group (HC, n = 25) at baseline, and at a 1-year follow-up in a subset of this cohort (n = 22 per group).At both baseline and 1-year follow-up, there were significant interactions of group (BD, HC) and valence of stimulus (positive, negative adjective) on endorsement and recall of self-referent adjectives. HC adolescents endorsed and recalled more positive self-referent adjectives at baseline and follow-up while adolescents with BD endorsed and recalled more negative self-referent adjectives at baseline but not follow-up. Over time, depression symptomatology was associated with impaired memory for positive self-referent adjectives. There were no group differences in attentional bias at either time points.Adolescents with BD exhibit bias away from endorsement and recall of positive adjectives, which remained stable over time and independent of mood state.

  View details for DOI 10.1111/j.1469-7610.2012.02543.x

  View details for PubMedID 22390273

• In this issue/abstract thinking: update your socioeconomic status. Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K. 2012; 51 (9): 853-854
• Volumetric reductions in the subgenual anterior cingulate cortex in adolescents with bipolar I disorder BIPOLAR DISORDERS Singh, M. K., Chang, K. D., Chen, M. C., Kelley, R. G., Garrett, A., Mitsunaga, M. M., Bararpour, L., Howe, M., Reiss, A. L., Gotlib, I. H. 2012; 14 (6): 585-596

  Abstract

  A range of prefrontal and subcortical volumetric abnormalities have been found in adults and adolescents with bipolar disorder. It is unclear, however, if these deficits are present early in the onset of mania or are a consequence of multiple mood episodes or prolonged exposure to medication. The goal of this study was to examine whether youth with bipolar I disorder who recently experienced their first episode of mania are characterized by brain volumetric abnormalities.Anatomical images from magnetic resonance imaging of 26 13- to 18-year-old adolescents with bipolar I disorder and 24 age-comparable healthy controls with no personal or family history of psychopathology were analyzed using whole-brain voxel-based morphometry (VBM).Compared with healthy controls, adolescents with bipolar I disorder had significantly less gray matter volume in the left subgenual cingulate cortex [p<0.05, family-wise error (FWE)-corrected].Adolescents with a recent single episode of mania have smaller subgenual cingulate cortex volume than do their healthy counterparts, suggesting that this anomaly occurs early in the onset of, or may predate the disorder. Longitudinal studies are needed to examine the impact of this volumetric reduction on the course and outcome of this disorder.

  View details for DOI 10.1111/j.1399-5618.2012.01043.x

  View details for PubMedID 22938166

• Abnormal Amygdala and Prefrontal Cortex Activation to Facial Expressions in Pediatric Bipolar Disorder JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Garrett, A. S., Reiss, A. L., Howe, M. E., Kelley, R. G., Singh, M. K., Adleman, N. E., Karchemskiy, A., Chang, K. D. 2012; 51 (8): 821-831

  Abstract

  Previous functional magnetic resonance imaging (fMRI) studies in pediatric bipolar disorder (BD) have reported greater amygdala and less dorsolateral prefrontal cortex (DLPFC) activation to facial expressions compared to healthy controls. The current study investigates whether these differences are associated with the early or late phase of activation, suggesting different temporal characteristics of brain responses.A total of 20 euthymic adolescents with familial BD (14 male) and 21 healthy control subjects (13 male) underwent fMRI scanning during presentation of happy, sad, and neutral facial expressions. Whole-brain voxelwise analyses were conducted in SPM5, using a three-way analysis of variance (ANOVA) with factors group (BD and healthy control [HC]), facial expression (happy, sad, and neutral versus scrambled), and phase (early and late, corresponding to the first and second half of each block of faces).There were no significant group differences in task performance, age, gender, or IQ. Significant activation from the main effect of group included greater DLPFC activation in the HC group, and greater amygdala/hippocampal activation in the BD group. The interaction of Group × Phase identified clusters in the superior temporal sulcus/insula and visual cortex, where activation increased from the early to late phase of the block for the BD but not the HC group.These findings are consistent with previous studies that suggest deficient prefrontal cortex regulation of heightened amygdala response to emotional stimuli in pediatric BD. Increasing activation over time in superior temporal and visual cortices suggests difficulty processing or disengaging attention from emotional faces in BD.

  View details for DOI 10.1016/j.jaac.2012.06.005

  View details for PubMedID 22840553

• Biological evidence for a neurodevelopmental model of pediatric bipolar disorder. The Israel journal of psychiatry and related sciences Roybal, D. J., Singh, M. K., Cosgrove, V. E., Howe, M., Kelley, R., Barnea-Goraly, N., Chang, K. D. 2012; 49 (1): 28-43

  Abstract

  Bipolar disorder (BD) is a chronic illness with high morbidity and mortality. Pediatric onset BD has a more severe course of illness with higher rates of relapse and psychosocial impairment. Discovering interventions early in the course of BD in youth is paramount to preventing full illness expression and improve functioning in these individuals throughout the lifespan. It is therefore important to understand the mechanisms involved in the development of BD in order to determine which youth are at most risk and provide biological targets for early intervention. To serve this cause, we propose a neurodevelopmental model of BD, based on the existing data that implicate prefrontal-subcortical network dysfunction, caused by pre-existing genetic susceptibility and triggered by pathological reactions to stress and chronic inflammatory processes.

  View details for PubMedID 22652927

• Altered Small-World Properties of Gray Matter Networks in Major Depression 67th Annual Meeting of the Society-of-Biological-Psychiatry Singh, M. K., Kesler, S. R., Hosseini, H., Kelley, R. G., Amatya, D., Hamilton, P., Chen, M. C., Gotlib, I. H. ELSEVIER SCIENCE INC. 2012: 106S–106S
• Resting State Functional Connectivity in Healthy Offspring of Parents with Bipolar Disorder Singh, M. K., Kelley, R. G., Shoemaker, V. R., Li, S., Boucher, S., Gotlib, I. H., Reiss, A. L., Chang, K. D. ELSEVIER SCIENCE INC. 2012: 204S–205S
• In this issue/abstract thinking: of mice, monkeys, and men. Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K. 2012; 51 (3): 231-232
• A Commentary on "Recruiting Researchers in Psychiatry: The Influence of Residency vs. Early Motivation" ACADEMIC PSYCHIATRY Singh, M. K. 2012; 36 (2): 83-84
• Biological Evidence for a Neurodevelopmental Model of Pediatric Bipolar Disorder ISRAEL JOURNAL OF PSYCHIATRY AND RELATED SCIENCES Roybal, D. J., Singh, M. K., Cosgrove, V. E., Howe, M., Kelley, R., Barnea-Goraly, N., Chang, K. D. 2012; 49 (1): 28-43

  Abstract

  Bipolar disorder (BD) is a chronic illness with high morbidity and mortality. Pediatric onset BD has a more severe course of illness with higher rates of relapse and psychosocial impairment. Discovering interventions early in the course of BD in youth is paramount to preventing full illness expression and improve functioning in these individuals throughout the lifespan. It is therefore important to understand the mechanisms involved in the development of BD in order to determine which youth are at most risk and provide biological targets for early intervention. To serve this cause, we propose a neurodevelopmental model of BD, based on the existing data that implicate prefrontal-subcortical network dysfunction, caused by pre-existing genetic susceptibility and triggered by pathological reactions to stress and chronic inflammatory processes.

  View details for Web of Science ID 000308697600004

• Characterization and Factors Associated with Sleep Quality in Adolescents with Bipolar I Disorder CHILD PSYCHIATRY & HUMAN DEVELOPMENT Roybal, D. J., Chang, K. D., Chen, M. C., Howe, M. E., Gotlib, I. H., Singh, M. K. 2011; 42 (6): 724-740

  Abstract

  Sleep disturbance is an early marker for bipolar disorder (BD) onset in youth. We characterized sleep quality in adolescents experiencing mania within the last 6-12 months. We examined the association between mood and sleep in 27 adolescents with BD and 24 matched healthy controls (HC). Subjects were assessed by parent and teen report of sleep, a semi-structured clinical interview, the Young Mania Rating Scale (YMRS), and the Childhood Depression Rating Scale (CDRS-R). Average BD youth YMRS (mean 20.3 ± 7.3) and CDRS-R (mean 42.4 ± 14.1) scores indicated they were still ill at time of assessment. Compared to HCs, adolescents with BD have distinct patterns of prolonged sleep onset latency, frequent nighttime awakenings, and increased total time awake. Mood symptoms, specifically excessive guilt, self-injurious behavior, and worsening evening mood, interfered with sleep. Further studies are needed to determine whether early regulation of sleep would improve long-term outcome in BD youth.

  View details for DOI 10.1007/s10578-011-0239-0

  View details for PubMedID 21701911

• Resting State Functional Connectivity in Adolescents with Bipolar I Disorder Singh, M. K., Kelley, R. G., Sanders, E. M., Acquaye, T., Li, S., Howe, M. E., Reiss, A. L., Chang, K. D. MARY ANN LIEBERT INC. 2011: 633
• In this issue/abstract thinking: here, there, everywhere! Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K. 2011; 50 (9): 849-850
• Changes in Brain Activation Following Family-Focused Treatment in Youth At-Risk for Bipolar Disorder 66th Annual Meeting of the Society-of-Biological-Psychiatry Garrett, A. S., Reiss, A. L., Miklowitz, D. J., Acquaye, T. K., Cosgrove, V. E., Singh, M. K., Howe, M. E., Kelley, R. G., Taylor, D., George, E., Chang, K. ELSEVIER SCIENCE INC. 2011: 163S–163S
• Resting State Functional Connectivity in Adolescents with Bipolar I Disorder Singh, M. K., Kelley, R., Sanders, E. M., Li, S., Howe, M., Reiss, A. L., Chang, K. ELSEVIER SCIENCE INC. 2011: 175S
• Early Intervention Strategies and Their Biological Correlates in Children at Risk for Bipolar Disorder Singh, M. K. ELSEVIER SCIENCE INC. 2011: 175S
• In this issue/abstract thinking: back to the future. Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K. 2011; 50 (3): 205-206
• Neurochemical deficits in the cerebellar vermis in child offspring of parents with bipolar disorder BIPOLAR DISORDERS Singh, M. K., Spielman, D., Libby, A., Adams, E., Acquaye, T., Howe, M., Kelley, R., Reiss, A., Chang, K. D. 2011; 13 (2): 189-197

  Abstract

  We aimed to compare concentrations of N-acetyl aspartate, myo-inositol, and other neurometabolites in the cerebellar vermis of offspring at risk for bipolar disorder (BD) and healthy controls to examine whether changes in these neuronal metabolite concentrations occur in at-risk offspring prior to the onset of mania.A total of 22 children and adolescents aged 9-17 years with a familial risk for bipolar I or II disorder [at-risk offspring with non-bipolar I disorder mood symptoms (AR)], and 25 healthy controls (HC) were examined using proton magnetic resonance spectroscopy at 3T to study metabolite concentrations in an 8-cc voxel in the cerebellar vermis.Decreased myo-inositol and choline concentrations in the vermis were seen in the AR group compared to HC (p<0.01).Decreased cellular metabolism and interference with second messenger pathways may be present in the cerebellar vermis in youth at risk for BD as evident by decreased myo-inositol and choline concentrations in this region. These results may be limited by a cross-sectional design, co-occurring diagnoses, and medication exposure. Longitudinal studies are necessary to determine whether early neurochemical changes can predict the development of mania. Improved methods for identifying children with certain neurochemical vulnerabilities may inform preventive and early intervention strategies prior to the onset of mania.

  View details for DOI 10.1111/j.1399-5618.2011.00902.x

  View details for PubMedID 21443573

• Early psychosocial intervention for youth at risk for bipolar I or II disorder: a one-year treatment development trial BIPOLAR DISORDERS Miklowitz, D. J., Chang, K. D., Taylor, D. O., George, E. L., Singh, M. K., Schneck, C. D., Dickinson, L. M., Howe, M. E., Garber, J. 2011; 13 (1): 67-75

  Abstract

  Previous studies have identified behavioral phenotypes that predispose genetically vulnerable youth to a later onset of bipolar I or II disorder, but few studies have examined whether early psychosocial intervention can reduce risk of syndromal conversion. In a one-year open trial, we tested a version of family-focused treatment adapted for youth at high risk for bipolar disorder (FFT-HR).A referred sample of 13 children (mean 13.4±2.69 years; 4 boys, 9 girls) who had a parent with bipolar I or II disorder participated at one of two outpatient specialty clinics. Youth met DSM-IV criteria for major depressive disorder (n=8), cyclothymic disorder (n=1), or bipolar disorder not otherwise specified (n=4), with active mood symptoms in the past month. Participants were offered FFT-HR (12 sessions in four months) with their parents, plus psychotropic medications as needed. Independent evaluators assessed depressive symptoms, hypomanic symptoms, and global functioning at baseline and then every four months for one year, with retrospective severity and impairment ratings made for each week of the follow-up interval.Families were mostly adherent to the treatment protocol (85% retention), and therapists administered the FFT-HR manual with high levels of fidelity. Youth showed significant improvements in depression, hypomania, and psychosocial functioning scores on the Adolescent Longitudinal Interval Follow-up Evaluation. They also showed significant improvements in Young Mania Rating Scale and Children's Depression Rating Scale scores.FFT-HR is a promising intervention for youth at high risk for BD. Larger-scale randomized trials that follow youth into young adulthood will be necessary to determine whether early psychosocial intervention can reduce the probability of developing bipolar I or II disorder among genetically vulnerable youth.

  View details for DOI 10.1111/j.1399-5618.2011.00890.x

  View details for Web of Science ID 000287311200007

  View details for PubMedID 21320254

  View details for PubMedCentralID PMC3077951

• Antidepressants and Psychostimulants in Pediatric Populations Is there an Association with Mania? PEDIATRIC DRUGS Goldsmith, M., Singh, M., Chang, K. 2011; 13 (4): 225-243

  Abstract

  This article reviews the literature that examines whether exposure to psychostimulants or antidepressants precipitates or exacerbates manic symptoms, or decreases the age at onset of mania in pediatric populations. A PubMed search using relevant key words identified studies targeting five distinct clinical groups: (i) youth without a diagnosis of bipolar disorder (BD) at the time of exposure to psychostimulants; (ii) youth with a diagnosis of BD at the time of exposure to psychostimulants; (iii) youth without a diagnosis of BD at the time of exposure to antidepressants; (iv) youth with a diagnosis of BD at the time of exposure to antidepressants; and (v) youth who develop BD after exposure to these medications. In patients with attention-deficit hyperactivity disorder (ADHD), the risk for mania was found to be relatively low with the use of psychostimulants. For patients with BD and ADHD, effective mood stabilization is important prior to adding a stimulant. For children with depression and/or anxiety, the risk of antidepressant-induced mania (AIM) was generally low (<2%), but the risk of general 'activation' secondary to a selective serotonin reuptake inhibitor (SSRI) may be greater (2-10%). However, rates of AIM in specialty clinics appear to be much higher. SSRIs may be particularly problematic in specific populations, such as those with some symptoms of mania or a family history of BD, but the precise risk is unknown. There is no clear evidence that stimulants or SSRIs accelerate the natural course of BD development in overall samples, but in individual cases prescribers should proceed cautiously when using these agents in youth already at risk for developing BD, such as those with ADHD and mood dysregulation, a history of prior AIM, a history of psychosis, or a family history of BD.

  View details for PubMedID 21692547

• Is Developmental and Behavioral Pediatrics Training Related to Perceived Responsibility for Treating Mental Health Problems? ACADEMIC PEDIATRICS Horwitz, S. M., Caspary, G., Storfer-Isser, A., Singh, M., Fremont, W., Golzari, M., Stein, R. E. 2010; 10 (4): 252-259

  Abstract

  The aim of this study was to investigate training in developmental and behavioral pediatrics (DBP) for graduating residents, their competencies in diagnosing and treating child mental health (MH) problems, and whether the amount of DBP training and/or perceived competencies are associated with perceived responsibility for treating 3 MH problems.Data were collected from 636 residents who completed the American Academy of Pediatrics's 2007 Graduating Residents Survey. The survey included questions on training and self-rated competencies in multiple MH skill areas and perceived responsibility for identifying and treating/managing children's MH problems. Weighted multivariable logistic regression analyses examined associations between training, competencies, and perceived responsibility for treating/managing attention-deficit/hyperactivity disorder (ADHD), anxiety, and depression.Ninety percent of respondents completed a DBP rotation, with 86% reporting >3 to 4 weeks of training. Duration of DBP rotation was related to training and perceived competencies in MH skill areas, and nearly all residents who reported high competencies were trained in those skill areas. However, <50% reported their competencies as "very good" or "excellent." Residents with training and high competency in dosing with medications were most likely to agree that pediatricians should be responsible for treating/managing ADHD, anxiety, and depression.DBP training is highly associated with self-rated MH competencies, and highly assessed competencies are related to perceived responsibility for treating/managing common MH problems; yet 14% of graduating residents have <3 to 4 weeks of DBP training. These results argue for providing more high-quality educational experience with proven effectiveness to produce confident pediatricians who will be more responsive to identifying and treating MH problems of their patients.

  View details for Web of Science ID 000280074000010

  View details for PubMedID 20554260

• In this issue/Abstract thinking: Response to intervention in child psychiatry. Journal of the American Academy of Child and Adolescent Psychiatry Singh, M. K. 2010; 49 (7): 633-634
• Brain glutamatergic characteristics of pediatric offspring of parents with bipolar disorder PSYCHIATRY RESEARCH-NEUROIMAGING Singh, M., Spielman, D., Adleman, N., Alegria, D., Howe, M., Reiss, A., Chang, K. 2010; 182 (2): 165-171

  Abstract

  We wished to determine whether decreases in prefrontal glutamate concentrations occur in offspring of parents with bipolar disorder with and at high risk for mania. Sixty children and adolescents, 9-18 years old, of parents with bipolar I or II disorder (20 offspring with established history of mania, "BD", 20 offspring with symptoms subsyndromal to mania, "SS", and 20 healthy controls "HC") were examined using proton magnetic resonance spectroscopy at 3T to study glutamatergic metabolite concentrations in the anterior cingulate cortex (ACC). A signal for reductions in absolute glutamate concentrations in the ACC was seen in the BD compared with HC and SS groups. No other statistically significant differences among groups were found. Offspring of parents with BD with prior histories of mania may have disruptions in glutamatergic function compared with HC or children at risk for BD who have not yet developed mania. Longitudinal studies are necessary to confirm whether prefrontal glutamate decreases only after the onset of full mania.

  View details for DOI 10.1016/j.pscychresns.2010.01.003

  View details for PubMedID 20413280

• Prefrontal Grey Matter Volume Abnormalities in Adolescent First Episode Mania 65th Annual Convention of the Society-of-Biological-Psychiatry Singh, M. K., Chang, K. D., Reiss, A. L., Gotlib, I. H. ELSEVIER SCIENCE INC. 2010: 222S–223S
• Neural Processing of Reward and Loss in Girls at Risk for Major Depression ARCHIVES OF GENERAL PSYCHIATRY Gotlib, I. H., Hamilton, J. P., Cooney, R. E., Singh, M. K., Henry, M. L., Joormann, J. 2010; 67 (4): 380-387

  Abstract

  Deficits in reward processing and their neural correlates have been associated with major depression. However, it is unclear if these deficits precede the onset of depression or are a consequence of this disorder.To determine whether anomalous neural processing of reward characterizes children at familial risk for depression in the absence of a personal history of diagnosable disorder.Comparison of neural activity among children at low and high risk for depression as they process reward and loss.University functional magnetic resonance imaging facility.Thirteen 10- to 14-year-old never-disordered daughters of mothers with recurrent depression ("high risk") and 13 age-matched never-disordered daughters with no family history of depression ("low risk"). Main Outcome Measure Neural activity, as measured using functional magnetic resonance imaging, in key reward and attention neural circuitry during anticipation and receipt of reward and loss.While anticipating gains, high-risk participants showed less activation than did their low-risk counterparts in the putamen and left insula but showed greater activation in the right insula. When receiving punishment, high-risk participants showed greater activation in the dorsal anterior cingulate gyrus than did low-risk participants, who showed greater activation in the caudate and putamen.Familial risk for depression affects neural mechanisms underlying the processing of reward and loss; young girls at risk for depression exhibit anomalies in the processing of reward and loss before the onset of depressive symptoms. Longitudinal studies are needed to examine whether these characteristics predict the subsequent onset of depression.

  View details for PubMedID 20368513

• Neural Correlates of Response Inhibition in Pediatric Bipolar Disorder JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Singh, M. K., Chang, K. D., Mazaika, P., Garrett, A., Adleman, N., Kelley, R., Howe, M., Reiss, A. 2010; 20 (1): 15-24

  Abstract

  Pediatric bipolar disorder is characterized by core deficits in mood and executive function and commonly co-occurs with attention-deficit/hyperactivity disorder (ADHD). We aimed to examine response inhibition in this population, as an element of executive function, which, if aberrant, may interfere with learning and information processing.Children (9-18 years) with bipolar I or II disorder (BD, n = 26) and age, gender, and intelligence quotient (IQ) comparable healthy children (HC, n = 22) without any psychopathology were given a standardized Go/NoGo computerized task measuring response inhibition. A whole-brain functional magnetic resonance imaging (MRI) group analysis was performed using statistical parametric mapping software (SPM2) for comparing NoGo to Go epochs.There were no statistically significant group differences between groups in age, gender, or ethnicity. The BD group had high rates of co-morbid disorders, including 81% with ADHD, 62% with oppositional defiant disorder (ODD), and 46% with anxiety disorders. This BD group had fewer correct responses on Go (84% vs. 96%, T[46] = 3.35, p = 0.002) and overall (85% vs. 94%, T[46] = 4.12, p = 0.0002) trials as compared to the HC group. However, there were no statistically significant group differences in response inhibition on NoGo trials (p = 0.11). In the NoGo-Go contrast, the BD group showed increased neural activation in the right dorsolateral prefrontal cortex (DLPFC) compared to HC (T[46] = 4.21, p < 0.001).During accurate NoGo but impaired Go trial performance, children with BD showed increased right DLPFC activation versus controls, suggesting increased recruitment of executive control regions for accurate response inhibition. Studies relating these results to mood regulation in pediatric BD are warranted.

  View details for DOI 10.1089/cap.2009.0004

  View details for PubMedID 20166792

• Atypical Antipsychotics for Acute Manic and Mixed Episodes in Children and Adolescents with Bipolar Disorder Efficacy and Tolerability DRUGS Singh, M. K., Ketter, T. A., Chang, K. D. 2010; 70 (4): 433-442

  Abstract

  The diagnosis of bipolar disorder (BD) in children is increasing, and often requires a comprehensive treatment plan to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for the treatment and stabilization of disrupted mood. Current evidence collectively demonstrates, by randomized controlled design, that atypical antipsychotics have efficacy for the treatment of acute manic or mixed symptoms in children and adolescents with BD. Additional longitudinal and biological studies are warranted to characterize the effects of atypical antipsychotics on all phases and stages of bipolar illness development in children and adolescents.

  View details for PubMedID 20205485

• Management of Bipolar Disorders in Children and Adolescents HANDBOOK OF DIAGNOSIS AND TREATMENT OF BIPOLAR DISORDERS Chang, K. D., Singh, M. K., Wang, P. W., Howe, M., Ketter, T. A. 2010: 389–424
• Neurochemical substrates of risk in pediatric offspring of parents with bipolar disorder 8th International Conference on Bipolar Disorder Singh, M. K., Spielman, D., Kelley, R., ALEGRIA, D., Howe, M., Reiss, A., Chang, K. WILEY-BLACKWELL. 2009: 80–80
• Inhibition and attention in adolescents with nonmanic mood disorders and a high risk for developing mania JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY Singh, M. K., DelBello, M. P., Fleck, D. E., Shear, P. K., Strakowski, S. M. 2009; 31 (1): 1-7

  Abstract

  This study examines psychomotor inhibition, sustained attention, and inhibitory attentional control in adolescents (ages 12-18 years) with a nonmanic mood disorder and with a first-degree relative with bipolar I disorder (MD, N = 20) and demographically matched healthy children of parents without any psychiatric disorder (HC, N = 13). MD participants showed abnormal performance in stop signal reaction time and latency (d = 1.28 and 1.64, respectively), sustained attention response bias (d = 0.75), and color naming speed (d = 0.88). The results indicate that MD participants exhibit psychomotor disinhibition, marginal cognitive slowing and cautious response biases, but no formal deficits in sustained or selective attention.

  View details for DOI 10.1080/13803390801945038

  View details for Web of Science ID 000261739200001

  View details for PubMedID 18608697

• Temperament in Child Offspring of Parents with Bipolar Disorder 54th Annual Meeting of the American-Academy-of-Child-and-Adolescent-Psychiatry Singh, M. K., DelBello, M. P., Strakowski, S. M. MARY ANN LIEBERT INC. 2008: 589–93

  Abstract

  The aim of this study was to examine the relationship between temperament and psychopathology in child offspring of parents with bipolar disorder.The Dimensions of Temperament-Revised (DOTS-R) and the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH U K-SADS) were used to assess temperament and psychopathology, respectively in offspring (8-18 years) of parents with bipolar I disorder (OBP, n = 31) and demographically similar healthy offspring of parents without any Diagnostic and Statistical Manual of Mental Disorders, 4(th) edition (DSM-IV) diagnosis (OHC, n = 21).Compared to OHC, OBP had increased Activity Level-General scores (effect size, d = -0.78), and a trend for decreased Task Orientation (d = -0.78). OBP with mood disorders had trends for decreased Approach (d = 0.89), Flexibility-Rigidity (d = 1.01), Rhythmicity-Sleep (d = 0.79), and Task Orientation (d = 0.89) as compared to OBP without mood disorders. OBP with attention-deficit/hyperactivity disorder (ADHD) showed a trend for decreased Task Orientation scores compared with those without ADHD (d = 0.82).Although limited by parent report, specific temperaments may be important in characterizing offspring of parents with bipolar disorder. Longitudinal studies to determine if certain temperaments inform treatment response and prognosis in this population are needed.

  View details for DOI 10.1089/cap.2007.142

  View details for Web of Science ID 000261992900006

  View details for PubMedID 19108663

• Neuroanatornical characterization of child offspring of bipolar parents JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Singh, M. K., DelBello, M. P., Adler, C. M., Stanford, K. E., Strakowski, S. M. 2008; 47 (5): 526-531

  Abstract

  To examine structural differences in selected anterior limbic brain regions between at-risk children of parents with bipolar I disorder and children with healthy parents. We hypothesized that at-risk (AR) children would exhibit abnormalities in brain regions that are involved in mood regulation.Children (8-12 years old) of parents with bipolar I disorder (AR children, n = 21) and of parents without any DSM-IV Axis I disorder (healthy controls, n = 24) were evaluated using diagnostic assessments and brain magnetic resonance imaging. Morphometric analyses were used to examine group differences in the prefrontal cortical, thalamic, striatal, and amygdalar volumes.Nine (43%) of the AR children met DSM-IV-TR criteria for a nonbipolar mood disorder at the time of assessment. AR and healthy control children did not demonstrate statistically significant differences across regions of interest (Wilks lambda =.86, F4,39 = 1.64, p = .18; effect size, f = 0.19). Post hoc analyses of covariance showed the largest relative effect size was contributed by the prefrontal cortex (f = 0.26).Eight- to 12-year-old children with a familial risk for mania do not exhibit any statistically significant volumetric differences in the prefrontal cortex, thalamus, striatum, or amygdala as compared with age-matched children of parents without any psychopathology. Longitudinal studies examining whether structural changes over time may be associated with vulnerability for developing subsequent bipolar disorder are needed to clarify the underlying pathophysiology of this disorder.

  View details for DOI 10.1097/CHI.0b013e318167655a

  View details for Web of Science ID 000255261000008

  View details for PubMedID 18356766

• Prospective neurochemical characterization of child offspring of parents with bipolar disorder 63rd Annual Convention of the Society-of-Biological-Psychiatry Singh, M. K., Chang, K. D., Spielman, D. M. ELSEVIER SCIENCE INC. 2008: 191S–191S
• Obstetrical complications in children at high risk for bipolar disorder 46th Annual Meeting of the American-Academy-of-Child-and-Adolescent-Psychiatry Singh, M. K., DelBello, M. P., Soutullo, C., Stanford, K. E., McDonough-Ryan, P., Strakowski, S. M. PERGAMON-ELSEVIER SCIENCE LTD. 2007: 680–85

  Abstract

  To examine obstetrical complications as a risk factor for developing bipolar disorder (BPD). We hypothesized that children with a bipolar parent would be at greater risk for obstetrical complications than demographically matched children of healthy adults. Additionally, within this "at-risk" (AR) sample, we hypothesized that obstetrical complications would be associated with the development of psychiatric disorders.The Washington University in St. Louis Kiddie-Schedule for Affective Disorders and Schizophrenia (WASH-U KSADS) was administered to children (AR) who had at least one parent with BPD (N=36) and children of healthy parents (HC) (N=27), by raters who were blind to diagnostic category. To assess obstetrical risk history, the Rochester Research Obstetrical Scale (ROS) was administered to parents of AR and HC children.Children at familial risk for BPD had greater total (p=0.02) and prenatal (p=0.006) obstetrical complication scores than children of healthy parents. However, obstetrical complications were not associated with the development of affective, anxiety, or disruptive behavioral disorders within the at-risk group.Our data suggest that compared with children of families without BPD, children of parents with BPD may be at greater risk for obstetrical complications, particularly those that occur during the prenatal period; however, at this early follow-up period factors other than obstetrical complications appear to contribute to the differences in rates of psychiatric disorders between these groups.

  View details for DOI 10.1016/j.jpsychires.2006.02.009

  View details for Web of Science ID 000246242900009

  View details for PubMedID 16698037

• Psychopathology in children of bipolar parents 152nd Annual Meeting of the American-Psychiatric-Association Singh, M. K., DelBello, M. P., Stanford, K. E., Soutullo, C., McDonough-Ryan, P., McElroy, S. L., Strakowski, S. M. ELSEVIER SCIENCE BV. 2007: 131–36

  Abstract

  Few studies have examined the psychopathological profiles of child offspring of bipolar parents. Such investigations are useful as a first step to identifying potential prodromal manifestations of bipolar disorder.The presence of psychopathology in 37 children with at least one parent with bipolar I disorder and 29 demographically matched children with parents free of any DSM-IV Axis I psychopathology was evaluated using the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U KSADS).Twenty-nine (78%) of 37 high-risk children were diagnosed with at least one DSM-IV Axis I diagnosis as compared to seven (24%) of 29 children of healthy control parents (Fisher's exact test, p < 0.0001, odds ratio=11, 95% CI=3.33, 33). Sixteen percent (N=6) of high-risk offspring met DSM-IV criteria for bipolar I disorder as compared to none of the healthy control offspring (Fisher's exact test, p < 0.03). High-risk offspring also had statistically significant elevations in rates of other affective and disruptive behavior disorders as well as subsyndromal manifestations of psychopathology.Children of bipolar parents had an elevated risk for developing bipolar and other psychiatric disorders. The study of children of bipolar parents who are at high risk for developing bipolar disorder themselves is essential to identify potential prodromal manifestations of the disorder and to eventually establish targeted early intervention strategies. Longitudinal studies to confirm the prodromal manifestations of bipolar disorder and risk factors associated with the development of specific diagnoses in children are needed.

  View details for DOI 10.1016/j.jad.2007.01.004

  View details for Web of Science ID 000248823300016

  View details for PubMedID 17275096

• Medical management of pediatric mood disorders PEDIATRIC ANNALS Singh, M. K., Pfeifer, J. C., Barzman, D. H., Kowatch, R. A., DelBello, M. P. 2007; 36 (9): 552-563
• Pharmacotherapy for child and adolescent mood disorders PSYCHIATRIC ANNALS Singh, M. K., Pfeifer, J. C., Barzman, D., Kowatch, R. A., DelBello, M. P. 2007; 37 (7): 465-476
• Acute dystonia associated with aripiprazole in a child JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Singh, M. K., DelBello, M. P., Adler, C. M. 2007; 46 (3): 306-307
• Co-occurrence of bipolar and attention-deficit hyperactivity disorders in children BIPOLAR DISORDERS Singh, M. K., DelBello, M. P., Kowatch, R. A., Strakowski, S. M. 2006; 8 (6): 710-720

  Abstract

  Pediatric bipolar disorder (BPD) and attention-deficit hyperactivity disorder (ADHD) co-occur more frequently than expected by chance. In this review, we examine 4 potential explanations for the high rate of this common co-occurrence: (i) BPD symptom expression leads to overdiagnosis of ADHD in BPD youth; (ii) ADHD is a prodromal or early manifestation of pediatric-onset BPD; (iii) ADHD and associated factors (e.g., psychostimulants) lead to the onset of pediatric BPD; and (iv) ADHD and BPD share an underlying biological etiology (i.e., a common familial or genetic risk or underlying neurophysiology).Peer-reviewed publications of studies of children and adolescents with comorbid BPD and ADHD were reviewed.There is a bidirectional overlap between BPD and ADHD in youth, with high rates of ADHD present in children with BPD (up to 85%), and elevated rates of BPD in children with ADHD (up to 22%). Phenomenologic, genetic, family, neuroimaging, and treatment studies revealed that BPD and ADHD have both common and distinct characteristics. While there are data to support all 4 explanations postulated in this paper, the literature most strongly suggests that ADHD symptoms represent a prodromal or early manifestation of pediatric-onset BPD in certain at-risk individuals. Bipolar disorder with comorbid ADHD may thus represent a developmentally specific phenotype of early-onset BPD.The etiology of comorbid BPD and ADHD is likely multifactorial. Additional longitudinal and biological studies are warranted to clarify the relationships between BPD and ADHD since they may have important diagnostic and treatment implications.

  View details for Web of Science ID 000242373200007

  View details for PubMedID 17156157

• Pain insensitivity in schizophrenia: trait or state marker? Journal of psychiatric practice Singh, M. K., Giles, L. L., Nasrallah, H. A. 2006; 12 (2): 90-102

  Abstract

  As early as the turn of the 20th century, clinicians observed patients with schizophrenia failing to respond to the pain of a myocardial infarction, ruptured appendix, or perforated bowel. Although this pain insensitivity in individuals with psychosis has been described in the literature for many years, the phenomenon is still poorly understood. We therefore reviewed the literature for findings concerning whether pain insensitivity in schizophrenia represents a state or a trait marker.A comprehensive Medline search of the literature on pain insensitivity in subjects with schizophrenia was conducted.While the literature contains anecdotal observations, case reports, and a few rigorous clinical studies concerning patients with schizophrenia being relatively indifferent to pain, there is a dearth of empirical, well-controlled studies in this area. Although early studies that examined the response of individuals with schizophrenia to thermal or electrical pain were constrained by a variety of methodological confounders, studies on this topic suggest that the higher pain thresholds observed in schizophrenia are best explained by a complex, multifactorial model. Most intriguing are the results of one recent study that found pain insensitivity in family members of persons with schizophrenia, suggesting that this phenomenon may be a trait or endophenotype rather than being due to a psychotic state.Pain insensitivity in individuals with schizophrenia, which is associated with increased morbidity and mortality, is poorly understood. It is possible that pain insensitivity might serve as a prodromal predictor of susceptibility for schizophrenia. Future studies are needed to further clarify the neurobiology, pathophysiology, and practical clinical implications of this phenomenon.

  View details for PubMedID 16728905