Identifying and Contextualizing Pre-Diagnostic Psychiatric Risk States using Brain-Based and Population-Level Evidence

Abstract

Mental illness is very common, with an estimated 12-month prevalence in the United States of about 30%, and typically chronic, leading to extensive disability affecting both the individual and society at large. Obstacles to effective treatment include a typical delay in receiving care by several years and imprecise diagnostic labels based on empirical symptom groupings. While for decades both the clinical and research efforts in psychiatry were focused largely on those with established, conventional diagnoses, more recent work has begun exploring psychiatric illness through a dimensional lens. Traditional models of disease have been extended to include those at risk for a diagnosable mental illness, who may have subthreshold symptoms but do not yet meet diagnostic criteria. Specifically, staging models of psychiatric illness have been developed, in which illness is conceptualized as existing on a spectrum ranging from a pre-symptomatic risk stage defined by genetic and environmental vulnerability, to an unspecified subthreshold symptom stage, to a stage that more closely aligns with symptom patterns of current diagnostic labels, and to ultimately meeting DSM-V criteria for a diagnosable illness. At the forefront of such a staging approach has been the early intervention paradigm for psychotic disorders, in which treatment begins during the prodromal phase of illness in an attempt to adjust its course to one that is milder and less life-altering. This highlights the potential value of studying mental illness in the subthreshold stages, as advancements in this area could inform the development of population-level programs to identify those most seriously at risk for the more severe stages of illness. Earlier intervention can then mitigate the personal and societal burden of psychiatric illness. It has further been shown that the earlier, less specific stages of psychosis-proneness not only signal risk for future psychotic disorders, but a broader, transdiagnostic risk for psychopathology. These transdiagnostic risk stages thus provide an avenue for the study of mental illness that is not constrained by empirical symptom groupings. Examining how psychopathology differentiates over the course of development can provide insight into environmental and biological mechanisms, ultimately facilitating the development of treatment approaches based on mechanistic understanding instead of empirical diagnostic labels. This dissertation employs this subthreshold, transdiagnostic lens to better understand environmental, biological and practical dimensions of mental illness development. Most psychiatric illnesses have an onset in mid adolescence to young adulthood, a time of important emotional, social and cognitive development that may create a period of heightened vulnerability. Therefore, Chapter 2 examines year-to-year patterns in psychotic experiences and associated risk factors in early adolescence to better understand early and rather undifferentiated stages of psychopathology. In this community sample, most remained at low symptom levels, but higher levels were associated with an increased likelihood that psychotic experiences would persist as well as with the presence of risk factors, in particular recent stressful events, bullying, and alcohol experimentation. Chapter 3 then focuses on identifying neural markers shared across disorder-specific risk states through a meta-analysis of task-based functional neuroimaging studies involving adolescents and young adults. This work revealed transdiagnostic aberrant activation in the left dorsolateral prefrontal cortex, which undergoes active development in late adolescence and constitutes a node in the frontoparietal control network, as well as in nodes of the salience and default mode networks. Finally, Chapter 4 is a case study on how adults with self-reported psychiatric symptoms, who may be at risk for worsening psychopathology, may attempt to address their symptoms with cannabis. In line with prior work highlighting the lack of symptomatic improvement in this participant group, no significant changes in task-based brain activation were found after yearlong cannabis use.