The relationship between typical changes in the adolescent brain and the onset of psychopathology is not a unitary phenomenon, but an underlying theme may be conceptualized as “moving parts get broken”. Adolescence is characterized by major changes in the neural systems that subserve higher cognitive functions, reasoning and interpersonal interactions, cognitive control of emotions, risk-vs-reward appraisal and motivation. Not surprisingly, when not adequately surmounted, it is precisely these challenges that increase the risk of cognitive, affective and addictive disorders. Understanding the basis of these disorders therefore requires a comprehensive knowledge of how the brain is put together. Many advances are being made, though a lot remains to be learned.
An emerging theme from pediatric neuroimaging studies is that the journey of brain development is often as important as the destination. For example, IQ is predicted by the developmental trajectory of cortical thickness, not by the adult size100
. Large individual variability in brain anatomy and function call for longitudinal study designs that capture the nuances of heterochronous developmental curves. The first phases of longitudinal studies have mapped developmental trajectories for typical development but less so for some psychiatric illnesses. The next phases should go beyond simply mapping brain growth and begin to discern the adverse as well as protective factors that influence those trajectories.
A common initial approach to assessing causal influences on brain development is to discern the relative effects of genetic versus non-genetic factors. This is best addressed through comparisons of monozygotic and dyzygotic twins. Results from an ongoing pediatric longitudinal neuroimaging project at the Child Psychiatry Branch of the National Institute of Mental Health indicate significant age-by-heritability interactions, with gray-matter heritability generally decreasing with age and white-matter heritability generally increasing with age101
. Heritability-by-age interactions may be related to the timing of gene expression, which in turn may relate to the timing of the onset of illness. Postmortem human and animal studies indicate that ‘developmental’ genes have diverse effects at various stages of brain development. But differences in heritability in different age groups may also reflect the cumulative effect of experience on brain structure; depending on certain inherent traits (e.g. musical talents or personality), it is only with time that specific experiences start to shape the brain.
Multivariate analyses of twin data indicate that a relatively small number of shared genetic and environmental factors account for a substantial portion of the variance across multiple neuroanatomic structures102
. Ongoing studies of specific gene effects on brain maturation may help to sharpen our understanding of brain development mechanisms and provide insight into the etiologies of various pathologies. The Saguenay Youth Study, carried out in a geographically isolated population with the known founder effect, will facilitate our search for genes that influence brain and behaviour during adolescence103
. Finally, genetics may also provide biologically relevant subtypes of neuropsychiatric disorders that are obscured in current diagnostic schemes.
The marked sex differences in age of onset, prevalence and symptomatology for nearly every neuropsychiatric disorder may provide important clues as to their pathophysiology. The most obvious outward physical manifestations of puberty are caused by changing levels of hormones11
. Perhaps this has contributed to the tendency to attribute all of the cognitive and behavioral changes of adolescence to “raging hormones”104
. But the relationship between hormones, brain and behavior is complex, reciprocal and poorly understood. Steroid hormones affect neuronal activity and morphology throughout development. Most neurons have receptors for adrenal and gonadal hormones that, when these receptors are activated they can affect neurotransmitter function. Short-term effects are mediated by membrane-bound receptors, whereas long-term effects alter gene expression via intraneuronal or nuclear receptors. Conversely, the dramatic hormonal changes of puberty are triggered by alterations in excitatory and inhibitory inputs to gonadotropin-releasing hormone neurons in the pituitary. Behaviorally, hormonal effects drive aggression and sexual interest but their impact on impulse control, logical problem solving and other cognitive tasks has not been well established.
Social and cultural factors for boys and girls are profoundly different and the relationship of these differences to manifest pathology should be explored. In the biological realm, sex differences likely stem directly from different genes on the X or Y chromosomes or indirectly through the effects of different hormone levels. Studies of subjects with sex-chromosome variations (e.g. XO, XXY, XXYY, XXX, XXXXY) or anomalous hormone levels (e.g. congenital adrenal hyperplasia, androgen insensitivity syndrome, familial male precocious puberty) will be useful to sort out the relative contributions of gene and hormone effects. For instance, males with an extra X chromosome (XXY or Klinefelter’s syndrome) have a high incidence of language disorders, ADHD, and social skills deficits that are reflected in differences in cortical thickness, consistent with reports in the literature for XY subjects with those disorders105
. Girls with Congenital Adrenal Hyperplasia, which is characterized by intrauterine exposure to high levels of testosterone, have an entirely different pattern of structural findings, indicating differential effects of sex chromosomes and hormones on the brain106
Although neuroimaging is beginning to establish correlations between brain structure/physiology and behavior, the link between typical behavioral changes and psychopathology has not been firmly established. For example, the neural circuitry underlying “moodiness” in an adolescent may not be the same circuitry involved in depression or bipolar disorder. Neuroimaging data can help develop neuroanatomical models of cognitive, affective and social processes based on findings from developmental psychology107
. Imaging studies of healthy adolescents are also helping to construct age-appropriate structural and functional brain templates.
Newer imaging approaches are being developed. Magnetic Resonance Spectroscopy studies at high magnetic field can help to quantify neurotransmitter systems, such as glutamate and GABA, as well as markers of neurogenesis108
. Combining multiple imaging modalities on the same individuals, such as structural MRI, fMRI, diffusion tensor imaging, magnetization transfer imaging, EEG or MEG, will enhance our ability to interpret the signals for each of the modalities. Being able to examine simultaneously inter-individual variation from cellular to macroscopic levels will be instrumental in bridging gaps between genes, brain, and behavior.
Studies of the neural substrates of adolescent behavior and decision-making will need to be integrated better with social and educational science. Laboratory studies of teenagers using hypothetical situations in calm environments without peer influence may have little relevance for understanding real-world decision making that occurs often in the context of intense physical or emotion arousal, conflicting priorities, and in the presence of peers109
Many questions about adolescent brain development and its impact on disease can best be investigated in animal models. Modeling the adolescent phase in animals is useful for the investigation of risk for addictive and other early-onset neuropsychiatric disorders86
. While animal models that represent the full phenotypic spectrum of a psychiatric disorder, such as schizophrenia or depression, are non-existent, individual phenotypic components of disorders - such as developmental alterations that might be associated with the illness - can be used to construct animal models that are aimed at unraveling disease mechanisms and that allow testing novel interventions110
Another translational approach involves combined in vivo (e.g. MRI) and postmortem studies in animals; such studies are essential for clarifying the nature of neurobiological changes driving the MRI findings. Of immediate relevance will be studies that attempt to discern the degree to which changes in cortical gray-matter, as detected by MRI, are related to dendritic arborization, intracortical myelination or the encroachment of white matter on the inner cortical border.
Adolescence is a time of substantial neurobiological and behavioral change. These changes are usually beneficial and optimize the brain for the challenges ahead, but may also confer a vulnerability to certain types of psychopathology. The technologies to elucidate the relationship between specific neurobiological maturational processes and specific normative or pathologic changes are already in place. Applying these tools to understand when and how deviations from typical development occur may enhance our ability to prevent or treat disorders affecting a substantial number of people.