Adolescent Development and Risk for Serious Psychopathology

The Mittal lab is working to develop an early identification program aimed at examining markers of susceptibility for the onset and course of serious mental illness, such as schizophrenia.

In a neural diathesis-stress conceptualization of psychosis, individuals with a biological susceptibility (i.e., from inherited genes, and/or mutations, and/or an early prenatal teratogen/insult(s)) often exhibit subtle signs of impairment from infancy (e.g., delayed achievement of milestones such as walking/talking/toilet training; motor abnormalities; poor social skills and affective responsivity; broad cognitive deficits).
Much later, these vulnerabilities interact with the substantial environmental stressors and dramatic neural and endocrine maturational factors that occur during adolescence (e.g., normative age related increases in sex hormones synergistically affect neurotransmitters and modulate gene expression; marked neural reorganization affects both connectivity and intercommunication between key brain structures and networks), and/or substance abuse, contributing to emerging subtle attenuated psychotic symptoms (e.g., finding a greater degree of meaning in everyday coincidences; seeing shadows out of the corner of one’s eye; mild grandiosity; feeling vaguely suspicious of friends and family; experiencing increasing difficulty in getting one’s point across), a decline in functioning (e.g., difficulty concentrating; feeling less motivated; social withdraw), an array of dysfunctional behaviors (e.g., adopting unusual interests; exhibiting clumsiness; becoming “thrown-off” more by every day stressors) and eventually, the onset of formal psychosis (e.g., schizophrenia, bipolar disorder with psychotic features, depression with psychotic features).


 

While the Artist Louis Wain was developing a psychotic disorder, his perceptions of reality changed, at first subtly, and then more severely. This change is illustrated by paintings made of his favorite subject matter, cats. Detecting these gradual changes early on, can have significant ramifications for implementing affective treatments and improving the course of illness.

 

 

 

 

 

 

This period of transition during adolescence (i.e., the prodromal or high-risk period), immediately before the formal onset of psychosis, holds the unique potential to both inform etiological conceptualizations of psychoticdisorders, and serve as a viable point for early intervention and/or prevention.

This figure illustrates our conception of the interacting genetic, environmental, and developmental factors contributing to the onset of psychosis (which typically occurs during the transition from adolescence to early adulthood). As depicted, the adolescence period is characterized by a complex and dynamic intersection of these contributing factors. However, more empirical evidence is sorely needed to bolster our understanding of the links in this largely theoretical model.

 

 

 

 

A Research Priority: Early Identification and Intervention

The available research has consistently shown that roughly 35% of adolescents exhibiting a prodromal or high-risk syndrome (i.e., based on the course, frequency, and severity of a combination of the symptoms and characteristics noted above) will convert to a psychotic disorder within a two-year period.

 
A growing body of evidence also suggests that early intervention (e.g., psychoeducation; social skills training; psychosocial interventions for the individual and family; pharmacological agents) may be helpful for those at risk for psychopathology. Specifically, forming relationships with treatment providers prior to serious illness, adopting strategies prior to when severe and acute symptoms can interfere with the acquisition and assimilation of psychotherapy skills (e.g., stress management), engaging family members in both reducing the stressful environment and helping to monitor the subtle changing symptoms, and/or beginning low-dose treatment with psychotropic medications (i.e., which may have a neuroprotective effect) can ameliorate course of illness, and may help to delay or even prevent onset of a psychotic disorder.
 
Unfortunately, although we know that approximately 1/3rd of high-risk individuals will convert to an Axis I psychotic disorder in a short period of time, we are not certain whom among the at-risk group is most likely to fall into this category. As blanket treatment for all high-risk individuals is not a feasible method for intervention (i.e., therapeutic treatments are costly and timely; the available medications have significant and serious side-effects), identifying those individuals at highest risk for this conversion is a urgent and important research priority.
 

Biomarkers and Risk for Mental Illness

The Mittal lab’s research in this area has involved working with adolescents and young adults exhibiting high-risk syndromes or genetic susceptibility, and conducting prospective longitudinal studies of these populations to assess a variety of biopsychosocial variables.

Dr. Mittal, as well as his collaborators and students, study a range of characteristics and behaviors that may be used to enhance identification and treatment of high-risk individuals, and concurrently, refine etiological understanding of the pathophysiology underlying psychotic disorders. To date, the lab has specialized in several distinct, but mechanistically related susceptibility markers including movement abnormalities, obste

trical complications, neurocognitive deficits, structural irregularities (e.g., temporal changes in subcortical and medial temporal lobe regions), and neuroendocrine dysregulation/psychosocial stress. We have focused on these phenomena because they appear to interact with developmental and genetic factors, share related neurological underpinnings which also characterize psychosis, and are readily quantifiable, potentially enabling a clinical system of identification and preventive intervention. Within this same context, Dr. Mittal is also fascinated by the use of social media (e.g., cooperative on-line games, networking sites) by high-risk adolescents, and how this may pertain to potential interventions, and/or progressive deterioration in mental health and global/social functioning.

 

Dermatoglyphic asymmetries (non-matching prints between corresponding left and right hand fingers) are indicative of an early prenatal insult. Among those adolescents at heightened risk for developing a psychotic disorder, the Mittal lab has found that a history of obstetric complications, and/or prenatal exposure to a viral teratogen (see adjacent) is associated with a significant greater likelihood of eventual conversion to schizophrenia.

 

 

 

  

 

Using Bayesian shape and appearance models, we have highlighted subcortical structures (i.e., the caudate and putamen) associated with both neuromotor abnormalities and psychotic symptoms in a prodromal adolescent participant. In this project, we will track annual changes in these structures and compare this data with both developing symptoms and emergent dyskinetic movements.

 

Since starting his own Laboratory in Boulder, Dr. Mittal has developed several innovative lines of related research, each tied to the overarching theme of examining subcortical influences (e.g., striatum, cerebellum, hippocampus) on higher order function, related biomarkers, and treatment targets within the context of adolescent neurodevelopment. Dr. Mittal's recent interests are in the four noted domains: 1) frontostriatal based impairment and associated biomarkers, 2) the role of the cerebellar and CTCC circuit dysfunction in motor behavior and cognition (forwarding a cognitive dysmetria based etiological conception), 3) abnormalities in inhibitory interneurons and resulting influence on executive function, and 4) targeting hippocampal deficits (cognitive, symptoms, and functional) with an exercise based intervention designed to improve medial temporal health and synaptic plasticity. In addition to working in these areas, graduate and postdoctoral students in the lab continue to develop their own lines of inquiry as well (e.g., classification, emotional processing, HPA reactivity, functional connectivity).

Research and Treatment Goals: the ADAPT Program

Over the next several years, the Mittal lab will continue this research at the Adolescent Development and Preventive Treatment (ADAPT) program at the University of Colorado at Boulder designed to increase the understanding of healthy development and mental illness among adolescents, young adults, and their families.


The University of Colorado at Boulder’s Adolescent Development and Preventive Treatment (ADAPT) research program is dedicated to promoting the understanding of factors that influence healthy development and mental health in adolescents and young adults.