Leaders of the Lifespan Brain Institute (LiBI) brought together experts in child and adult psychiatry, and basic and translational science, to delve into the origins of mental illness, during the Institute’s first symposium, “Pathological Antecedents to Neuropsychiatric Disorders.” Throughout the day, 200 attendees learned about how the typical trajectory of brain development and function is derailed in psychiatric disorders at various points throughout life — perhaps as early as in the womb.
LiBI is uniquely positioned as a broad collaboration between Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania that supports research across the fetal-adult continuum, which is a pillar of CHOP Research Institute’s strategic plan.
Led by Director Raquel Gur, MD, PhD, professor of Psychiatry Neurology and Radiology at Penn, and Associate Director Stewart Anderson, MD, a CHOP research psychiatrist and professor of Psychiatry at Penn, LiBI has assembled large data sets that allow researchers from multiple specialties to study the underlying genetic, molecular, cellular, system, and behavioral functions that likely intersect with environmental factors and contribute to the development of psychiatric illnesses. Better understanding of these complexities will help researchers to develop, test, and implement new approaches to get those processes back on track in children before they develop symptoms, which mainly appear during adolescence and early adulthood.
“‘LiBI’ means heart in Hebrew,” said Maria Oquendo, MD, PhD, chair of Psychiatry at Penn Medicine. “That is a compelling image for this. We know the bulk of conditions we treat have roots in adolescence, and the best way to improve mental illnesses is preventing them, and the way to prevent them is to find out how they develop.”
In the general population, about every four to five youth have a lifetime mental disorder, according to youth.gov. Yet, there is a dearth in scientific literature about children and youth with psychiatric illnesses compared to that of adults, pointed out Tami Benton, MD, psychiatrist-in-chief at CHOP. And though suicide rates and the number of children prescribed psychotropic medications have increased, Dr. Benton remarked that high rates of resistance and relapse remain — along with limited use of psychosocial, evidence-based interventions for children.
Prenatal Health and Schizophrenia Risk
During his morning keynote address, Daniel Weinberger, MD, director and CEO of the Lieber Institute for Brain Development, and professor of Psychiatry, Neurology, Neuroscience at The Institute of Genetic Medicine, Johns Hopkins University School, suggested that gene-environment interactions that influence placental biology may be part of the neurodevelopmental underpinnings of schizophrenia.
About 100 loci, or regions, of the genome have been associated with increased risk of schizophrenia. Dr. Weinberger suggested that if scientists can demonstrate that gene sets found in these loci are strongly related to how the brain is built at its earliest stages, then fetal development potentially could be considered a more a vulnerable time in terms of risk for schizophrenia than what happens to the brain after an individual is born. Pointing toward that concept, he presented the audience with several snapshots of genomic data that suggest the overall gene set linked to schizophrenia is more abundantly expressed in fetal life than during adult life. Dr. Weinberger also showed many of the loci that have been identified as risk factors for schizophrenia appear to influence the environmental sensitivity of the genome early in life. In another series of studies, he explored differences in how these genes are regulated in the placenta during perinatal adversity, such when a serious obstetrical complication occurs.
“What makes us most interested in this new frontier is that preserving prenatal health may represent a primary form of prevention of schizophrenia,” Dr. Weinberger said.
New Insights From Bench-Neuroscience
A series of bench-neuroscience presentations followed Dr. Weinberger’s, including a fascinating presentation from Larry Singh, PhD, a research scientists with CHOP’s Center for Mitochondrial and Epigenomic Medicine. CHOP has one of the world’s largest clinics for people lacking about 40 genes on one copy of their chromosome 22. About one-quarter of those affected with this mutation will develop schizophrenia. Drs. Singh and Anderson are using human stem cell derived neurons and human genetics to determine whether additional mutations in mitochondrial-functioning genes, genes that are critical to a cell’s energetics, are associated with risk or with resilience to developing schizophrenia.
In the next presentation, Doug Coulter, PhD, a neurology researcher at CHOP and a professor of Neurology and Neuroscience at Penn, along with graduate student Julia Kahn described a research project that demonstrated that mice with nearly the same mutation as found in 22q deletion syndrome-affected people have a subregion of the forebrain, the ventral hippocampus, that is abnormally excitable. These mice also have abnormalities in social perception.
Amazingly, injection into the ventral hippocampus of a non-toxic virus that carries a genetic construct that decreases neuronal activity when the animal is provided a specific drug, corrects the social perception abnormality in adult mice. This type of study shows a future direction of translational neuroscience research and maybe neuropsychiatric medicine itself — the study of specific brain circuitry whose abnormal activity is associated with abnormal behaviors, and the correction of both the activity and behavior by manipulation of that specific circuitry.
A Rich Resource: The Philadelphia Neurodevelopmental Cohort
Throughout the afternoon, researchers illustrated how data from the Philadelphia Neurodevelopmental Cohort (PNC) allowed them to conduct longitudinal analyses and dig deep the neurobiological development of mental illness. Funded by the National Institutes of Mental Health, the PNC is a collaboration between the Center for Applied Genomics at CHOP and the Brain Behavior Laboratory at the University of Pennsylvania. The cohort includes a population-based sample of over 9,500 individuals, ranging from 8 to 21 years old, who received medical care at the CHOP network.
“With the PNC, every day I feel like a kid in a candy store because of the huge amount of data,” said Ran Barzilay, MD, PhD, a research associate at LiBI, child and adolescent psychiatrist, and symposium speaker. “There are limitations, but you can ask any question and [the cohort] can get you closer to answering it.”
Dr. Barzilay’s presentation focused on how exposure to traumatic stress affects cognition and psychopathology. Using traumatic stress evaluations conducted in children through the PNC, he found that nearly 1,000 participants reported experiencing three or more traumatic stress events. This exposure to stress appeared to have a robust association with four factors, or features, of participants’ mental health: anxious-misery, fear, psychosis, and externalizing (behavioral). Even after controlling for post-traumatic stress disorder and depression, traumatic exposure was still associated with these four domains. Dr. Barzilay also found that the highest stress exposure was associated with worse cognitive performance, such as executive function.
“We all go through stressors in life — some of us will go on to be resilient, but a large number are at risk,” explained Dr. Barzilay, describing the developmental path of every child as a railroad that can branch out in many different directions. His research mission is to dissect the “very complex trajectories” and find clinical and cognitive biomarkers along these tracks to tell us where a particular pediatric patient is going. “We need to learn more about resilience to learn how to change the trajectory. Learning about resilience is a key aspect in learning about mental illness.”
Waxing and Waning Symptoms
For another presenter, Monica Calkins, PhD, director of Clinical Research Assessment at LiBI, PNC data provided a “window” into the psychosis of young people of different ages. This allowed her to gain key insights into how prodrome symptoms (symptoms that precede the actual onset of a mental illness) wax and wane throughout a child’s early life. She found, for example, that 11-year-olds endorsed higher levels of symptoms than older children, and that the rate of symptoms appeared to lower with older age. By conducting follow-ups of a cohort of participants, Dr. Calkin also found that even some people who were classified as “resilient” at one time point of the study still had increasing and decreasing clinical symptoms over time. Similarly, some symptoms emerged then remitted between two time points of study.
“The symptoms are not stagnant,” Dr. Calkins said. “There is a waxing and waning over time, even in this early threshold stage.” The results, she continued, suggest that “varying trajectories of psychosis spectrum symptoms” are evident early on in U.S. youth and underscore the existence of a wide developmental window of opportunity to study risk and resilience factors associated with varying clinical outcomes.
Neuro Targets for Bipolar Disorder
The symposium wrapped up with a presentation from keynote speaker, Mary L. Phillips, MD, director of the Mood and Brain Laboratory at the University of Pittsburgh School of Medicine. Dr. Phillips addressed the steps that her lab has taken to integrate neuroscience and clinical frameworks, as well as identify neuro targets for developing illnesses like bipolar disorder. Though often neglected as an illness, bipolar disorder is the fourth leading cause of disability in the world.
“[BD] is not a trivial disease at all, and it affects people across the lifespan,” Dr. Phillips said.
Her lab investigates the key question of what particular circuits in the brain are aberrant functionally and structurally in the condition. Though researchers already know something about the neural biomarkers of emotional dysregulation, a key feature of bipolar disorder, Dr. Phillips pointed out that it is a feature of a range of anxiety and mood disorders, not just BD. Thus, her research investigates the potential biomarkers of another behavior, impulsive sensation seeking (ISS), that has been evident in adults with BD. ISS is a combination of impulsivity and sensation-seeking, defined as the tendency and willingness to seek and take risks.
“We know little of the neurobiology of ISS,” Dr. Phillips said.
Through developing a reward task, she is learning key insights into reward circuitry, particularly about brain activity in an area potentially associated with uncertain rewards and outcome expectancy: the left ventrolateral prefrontal cortex (VLPFC). The VLPFC, Dr. Phillips explained, may play a role in reward anticipation paradigms, including how a person makes decisions about the future in ambiguous contexts.