From the Early Emergence of Psychiatry to Stem Cells and Neural Organoids

This issue of the Journal brings together papers that highlight how far we have come as a field in conceptualizing, investigating, and understanding the factors that lead to the development and treatment of psychiatric disorders. The papers in this issue cover a broad array of topics, beginning with a historical perspective by Dr. Ken Kendler and colleagues that discusses concepts and practices, beginning in the 17th century, that influenced the emergence of modern psychiatry (1). At the other end of the continuum, we include an extremely informative overview by Dr. Kristen Brennand updating us on how human stem cell models can be used to explore genetic mechanisms underlying psychiatric illnesses with the potential to guide the development of new treatments (2). The original research papers presented in this issue focus on understanding 1) how structural brain alterations are related to outcomes in individuals with autism spectrum disorder (ASD) and in individuals at risk to develop bipolar disorder, 2) the association between long-term continuous cannabis use and reductions in hippocampal volume, and 3) how human cerebral organoids can be used to model the effects of stress via glucocorticoids on fetal brain development.

In addition to these papers, we include a Priority Data Letter authored by Dr. Sarah Pedersen and colleagues (3) that is highly relevant to the Journal’s diversity, equity, and inclusivity efforts. This paper reports the results of a survey of 125 scientific papers that were published in the American Journal of Psychiatry in 2019 and 2020, characterizing the extent to which the following were included in each scientific report: 1) sociodemographic parameters relevant to underrepresented minorities, 2) a discussion related to how the sample did or did not reflect the demographics of the population, and 3) whether the paper was focused on health care inequities. The results are eye opening and need to be addressed. Among the findings, the authors found that only 43% of the published papers reported the race or ethnicity composition of their sample, and across these studies 94.6% of the study participants were characterized as White or Caucasian. Other issues that were uncovered related to not including the specific methods used to query one’s racial, ethnic, and sexual identity. Additionally, only two out of the 125 papers were considered to be focused on health care inequities. These data point to critical deficiencies that the Deputy Editors and I are in the process of addressing. We are very grateful to Dr. Pedersen et al. for this contribution, which we will rely on as we move forward with our efforts to use the Journal to improve research and clinical efforts focused on health care disparities and inequities.

Changes in Functional Capacity Associated With Brain Structure in Autism Spectrum Disorder

ASD is a neurodevelopmental disorder that as a diagnostic category encompasses diverse conditions with marked heterogeneity in symptom presentation, longitudinal course, and functional capabilities. Common to individuals with ASD are deficits in social functioning and communication skills along with repetitive and restricted behavioral patterns and interests. Additionally, individuals with ASD frequently have intellectual and language impairments as well as comorbid psychiatric illnesses such as ADHD and anxiety disorders. A better understanding of the pathophysiological factors underlying ASD symptom heterogeneity as they relate to function and their longitudinal course will provide a foundation for the development of subtype-specific treatments with the promise of greater efficacy. To this end, Pretzsch et al. (4) used neuroimaging and behavioral data from the Longitudinal European Autism Project to discern the brain structural correlates (i.e., cortical volume, cortical thickness, and surface area) that are associated with developmentally related changes in adaptive behavior in individuals with ASD. Behavioral data from 204 individuals with ASD and 279 neurotypical individuals, collected at two time points between 1 and 2 years apart, were used to assess changes in functional capacities across numerous domains. Based on changes in the functional capacity composite score, individuals with ASD were categorized into three adaptive outcome groups—improved, no change, or declined. When comparing among the adaptive outcome subgroups, the baseline neuroanatomical data revealed differences in cortical volume, thickness, and surface area measures across various brain regions, some of which have been linked to ASD (e.g., prefrontal cortex, temporal lobe) as well as other regions linked to cognitive, social/emotional, and behavioral processes affected in ASD. Additionally, at the individual level, a neuroanatomical “atypicality index” was calculated that was based on that individual’s structural deviation from the control group. Individual differences in this measure were found to be associated with individual differences in ASD-related adaptive change trajectories, such that greater atypicality was correlated with poorer adaptive outcomes. Finally, gene expression data from the Allen Human Brain Atlas was used to identify gene expression patterns in the brain regions that differed between the ASD adaptive subgroups. These analyses revealed enriched expression patterns for genes known to be associated with ASD in many of the brain regions that differed between the subgroups, with the strongest findings emerging when examining individuals whose adaptive capacities increased compared to those whose adaptive capacities decreased. Additionally, the researchers found that a polygenic risk score for each individual, derived from the set of genes identified from the Allen Institute data, was predictive of an individual’s neuroanatomical atypicality index. Taken together, these findings point to using neuroanatomical and genetic data as a means to make predictions about longer-term adaptive outcomes in individuals with ASD.

Developmentally Associated Alterations in Brain Structural Connectivity in Individuals at Risk to Develop Bipolar Disorder

Numerous studies have examined structural brain changes that are associated with bipolar disorder, demonstrating alterations in various regions including those involved in the expression of emotion, cognition, and emotion regulation. Roberts et al. (5) build on previous findings with a longitudinal neuroimaging study that assessed brain structural connectivity in individuals 12–30 years old at familial risk to develop bipolar disorder. Diffusion-weighted magnetic resonance imaging to assess white matter connectivity was performed initially and then 2 years later in a cohort of 97 unaffected individuals who had a first-degree relative with bipolar disorder. These data were compared with imaging data collected from a group of 86 control participants. By longitudinally studying parameters of structural connectivity across the adolescent to young adult age range, the researchers sought to characterize patterns of aberrant brain maturation that are potentially associated with the risk to develop bipolar disorder. A key result was the demonstration that at-risk individuals failed to show the normal developmental pattern of increasing structural connectivity strength in a network that included regions of the left inferior and lateral cortical regions (e.g., left insula and left inferior frontal gyrus) as well as the thalamus and posterior cortical regions. In addition, the researchers used a computational method to estimate “network controllability,” a putative indicator of the flexibility of brain states. From this analysis the authors conclude that individuals at risk for bipolar disorder have a developmental decrease in the “controllability” of the aforementioned network of interest. The authors suggest that these altered maturational patterns of brain connectivity could be important in understanding the marked alterations in emotion regulation that underlie the expression of affective symptoms in individuals with bipolar disorder.

Long-Term Cannabis Use Linked to Cognitive Alterations and Decreased Hippocampal Volume

Understanding the consequences of cannabis use on cognition, behavior, and brain structure/function is relevant to cannabis use-related psychopathology, especially in individuals that regularly use significant amounts of cannabis over the long term. This is the focus of the study by Meier et al. (6) that examined, from the well characterized New Zealand Dunedin sample, the relationship of amount and length of cannabis use with cognitive capacities and hippocampal volume. The Dunedin Study began in 1972 with an original sample of 1,037 participants who were assessed at multiple time points from birth into adulthood with various measures related to development and health. Data used in the current study involved assessments of cannabis use in 938 individuals collected at 18, 21, 26, 38, and 45 years of age; structural MRIs were performed in 875 of these participants at 45 years of age. To understand the specificity and “dose response” issues associated with cannabis use, the researchers compared data from long-term cannabis users to five other groups of individuals derived from the Dunedin sample: lifelong nonusers of cannabis, midlife recreational cannabis users, cannabis quitters, long-term tobacco users, and long-term alcohol users. It is noteworthy that individuals in the cannabis user groups also commonly used alcohol and tobacco for which the authors covaried in their statistical analyses. When assessing IQ changes from childhood to adulthood, the data revealed that long-term cannabis users had significantly greater reductions in IQ when compared to lifetime nonusers and long-term alcohol or tobacco users. Long-term cannabis users also tended to perform more poorly on other neuropsychological tests when assessed at age 45 and were reported by others to have memory and attentional issues. The authors point out that this was not the case for midlife recreational cannabis users. In relation to hippocampal volume, long-term cannabis users had decreased volume of the total hippocampus as well as various hippocampal subfields, including the dentate gyrus, when compared to cannabis nonusers. Although the hippocampus plays an important role in memory functions, the statistical analyses that were performed did not support a role for the reductions in hippocampal volume in mediating the association between long-term cannabis use and the cannabis-related neuropsychological alterations. In their discussion, the authors speculate that these significant cannabis-related changes in cognition and hippocampal volume could predispose affected individuals to further cognitive decline, possibly increasing their risk to develop dementia. In her editorial (7), Dr. Patricia Conrod from the University of Montreal emphasizes the importance of the findings and other research in this area. She also brings attention to other possible factors related to the cannabis use findings such as comorbid depression and effects on educational attainment.

Using Cerebral Organoids to Understand Glucocorticoid Effects on Neural Development With Implications for Stress Exposure and the Development of Psychopathology

Activation of the pituitary-adrenal system is a critical component of the stress response, which, via increased release of cortisol from the adrenal gland, serves to facilitate adaptive physiological and behavioral responses that are aimed at promoting survival. Cortisol and other glucocorticoids mediate their effects primarily by interacting with two glucocorticoid receptors. The higher affinity mineralocorticoid receptor is bound by nonstress levels of cortisol and also binds mineralocorticoids such as aldosterone, whereas the lower affinity glucocorticoid receptor binds cortisol when levels are higher such as at the peak in the circadian rhythm and during stress. In addition to the importance of the pituitary-adrenal system for survival, this system, with the activation of glucocorticoid receptors, plays an essential role in guiding normal fetal development. In this regard alterations in glucocorticoids during critical fetal stages have been linked to an increased risk of developing various physical and mental health-related problems. Cruceanu et al. (8) provide further insights into the mechanisms underlying the effects of glucocorticoid receptor activation on human fetal brain development by using human cerebral organoids derived from induced pluripotent stem cells as a model of fetal brain development. After developing cerebral organoids from three different donors, the researchers first demonstrated that at 70 days old, organoids show patterns of gene expression that are similar to early fetal human brain. Glucocorticoid receptors were found across all cell types and increased with increasing organoid age. Next, the researchers performed experiments exposing the organoids at various stages of development to the potent synthetic glucocorticoid dexamethasone. By activating glucocorticoid receptors with this method, the findings revealed effects in neurons and progenitor cells on the regulation of genes that are linked to differentiation and maturation. Additionally, within neurons, the effects of glucocorticoid receptor activation appeared to be enriched for modulating the expression of genes that from GWAS studies are known to be associated with various behavioral traits and some neurodevelopmental disorders, such as ASD. Taken together, these findings support the use of this in vitro human cerebral organoid model as a means to understand normal early fetal brain development as well as to elucidate the mechanisms underlying the effects of glucocorticoids and glucocorticoid receptor activation on promoting normal and aberrant brain development. This is particularly relevant when considering the well-known associations between maternal perinatal stress, early life trauma, excess glucocorticoids, and offsprings’ later risk to develop psychopathology. In their editorial (9), Drs. Jennifer Erwin and Daniel Weinberger from the Lieber Institute and John Hopkins University discuss the remarkable developments leading to the use of human cerebral organoids, their potential for future research related to brain development, and the relevance of the glucocorticoid findings from this study.

Conclusions

Looking back, it is amazing to reflect on the distance traveled in our understanding of the science underlying behavior, cognition, and emotion—from ancient medical views attributing the cause of behavioral and emotional disorders to humoral factors such as an excess of black bile, then recognizing that the brain is a critical organ in the expression of psychiatric symptoms, to imaging the structure and function of the brain, and now the ability to directly study the regulation of genes within neurons derived from stem cells collected from individuals affected with a specific psychiatric illness.

This issue of the Journal puts these scientific achievements in context as it combines an early historical perspective on the emergence of modern psychiatry with modern neuroscientific and clinical research aimed at investigating the neural and genetic underpinnings of psychiatric illnesses. The overview on the use of stem cells in psychiatry is a particularly important contribution as it explains how cutting edge in vitro methods can be used to study genes, molecules, and cells involved in psychopathology and in new treatment development. The article by Cruceanu et al. is directly related to this overview, introducing the value of cerebral organoids as a tool to uncover mechanisms underlying neurodevelopmental psychiatric disorders. Specific findings from this study address mechanisms by which glucocorticoid receptor activation, and presumably stress, influences the function of genes critical to fetal neural development. Moving from these translational neuroscience studies, the clinical research papers in this issue provide new insights into 1) the relation between outcomes in ASD patients with variation in cortical structure and genetic risk, 2) brain structural connectivity maturational alterations and the risk for developing bipolar disorder, and 3) the association between long-term cannabis use and reduced hippocampal volume.

Finally, Pedersen et al. demonstrate insufficient reporting of study sample sociodemographic data related to race and ethnicity in papers published in this journal. Of the studies that did report these data, study samples were overwhelmingly White. I want to emphasize that the Deputy Editors and myself are currently working on making changes that will address the issues raised in this paper. It is our plan that in the September 2022 issue we will update our readership with these changes as well as report on other changes that we have made to the Journal as we continue our ongoing efforts to combat racism, social injustice, and health care inequities (10).