The Teenaged Brain: Part 2

In our last installment (The Teenaged Brain: Part 1), we discussed a familiar finding from the National Comorbidity Survey Replication (NCS-R): the peak age of onset for any mental health disorder is about 14 years. In an attempt to explain these data, we are exploring some of the known developmental changes in the teenaged brain at the level of gene, cell, and behavior.

We discussed in the last column a number of issues, ranging from alterations in gray matter volume to changes in adolescent executive function. Does a more complete understanding of these maturational processes provide enough hints to explain the NCS-R data?

Here we will attempt to answer this question. Three psychopathologies will be examined: affective disorders, anxiety disorders, and risk-taking activities—behaviors that may underlie substance abuse issues. As we go through some fairly recent findings, there may be an intellectual temptation to explain the NCS-R findings in terms of mutational (genetic) alterations inside otherwise normally functioning adolescent-related developmental processes.

As we will discover, demonstrating that this is indeed the biological basis for their numbers has proved to be surprisingly elusive. The relationship between the onset of psychiatric disorders and the typical changes seen in the developing brain of adolescents is complex, indirect, and not well understood. There is some evidence that certain disorders exist because of an exaggeration of otherwise typically functioning processes. But these are only hints. We are only in the beginning stages of our understanding of the relationship between adolescence and mental health. To date, no genetic anomalies have been shown to be responsible for the peak onset findings revealed by NCS-R in any mental health–related disorder.

Major depression is a serious and commonly experienced fact of life for many adolescents. Puzzling to some researchers, the adolescent-onset form often carries the most severe, most disabling symptoms of any form of human depression. Anxiety-related symptoms often precede the disorder, acting like a harbinger, and often first presenting in childhood.

Are there any cellular or even molecular explanations for these data? Unruly and wildly fluctuating hormonal changes are usually invoked to account for some of the risk associated with the adolescent-related affective disorders. That invocation may be well founded, with some of the strongest data coming from epidemiological investigations.

It is well established, for example, that changes in the prevalence for female depressive and anxiety disorders first show up midway through adolescence. The prepubertal ratio (female to male) is 1:1. By the time the adolescents have transited through Tanner stage III, that ratio has changed to 2:1. (As you may recall, the Tanner system [stages I through V] is devised to describe the typical transit through puberty for both males and females [See Table]). Corresponding to specific anatomical and hormonal events, the 5 stages are named prepubertal, beginning pubertal, midpubertal, advanced pubertal, and postpubertal. The sex-based change in the prevalence of these psychopathologies, first observed in the midpubertal stage, is stable into adulthood.

Are there any genetic explanations for this consistent observation? The answer is clearly “no,” or at least “not yet.” There is certainly reason to believe that hope may be on the horizon, however—mostly related to mouse studies examining the biochemistry of tetrahydroprogesterone (THP).

As you may recall, THP is released during stress. Normally, it provides an anxiolytic effect on mouse behavior. This behavioral change is mediated by the binding and subsequent activation of γ-aminobutyric acid, type A (GABAA) receptors—the same receptors activated by benzodiazepines and alcohol. Oddly enough, a specific subtype of the GABAA receptor, called an a4b2d receptor, is associated with an extraordinarily different response. If THP binds to this subtype, it increases anxiety in the animal, mediating a response directly opposed to the typical GABAA receptor behaviors. Researchers have recently shown that the expression of this subtype is greatly increased as the mouse transits through puberty. The increase is region-specific, most prevalent in the CA1 region of the hippocampus (known to be involved in memory formation). Convincingly, the increase in normally observable anxiety is blocked if the animal is prevented from making THP!

Though these hints are tantalizing, they say little about human behavior. For that we have to turn to examining the living brain, and these days that means functional MRI (fMRI). Do noninvasive brain-imaging studies reveal linkages to data from these images? Do they say anything about the anxiety-ridden or depressed teenaged brain? The answer to the first question is “no,” but the answer to the second question is a tentative “maybe.”

There is clear evidence that adolescents with both anxiety and depression have odd amygdala-associated reactions to typical social stimuli when compared with controls. The data are unsatisfying, mostly because they are associative. But combined with other research, an interesting picture may be emerging of the manner in which emotional stimuli are perceived in these youthful populations. Researchers have found evidence for anomalous adolescent cortical responses to emotional stimuli, for example.

Typical experiments (which usually involve both adults and adolescents in fMRI studies) consist of 2 phases:

• While their brains are being imaged, the subjects are asked to make emotional evaluations of faces bearing various kinds of emotion-competent expressions.

• While still in the machine, subjects are asked to make nonemotional statements about those same faces. When subjects encounter a joyous face, they might be asked, “How happy do you feel after seeing this?” Then they might be asked, “What color is the hair?”

The results are consistent: the adults in these studies actively engage the orbitofrontal cortex whenever this switch occurs. The adolescents do not. When these studies are combined with other data, the picture emerges that adolescents are abnormally engaging specific brain regions to externally presented emotionally competent stimuli. There are hints that these youngsters consistently provide unreal-istic evaluations of these emotions wherever they perceive them. These appraisals may act as triggering responses to depressive and anxiety-related disorders.

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