The storm and stress of adolescence: insights from human imaging and mouse genetics

Abstract

The characterization of adolescence as a time of "storm and stress" remains an open debate. Intense and frequent negative affect during this period has been hypothesized to explain the increased rates of affective disorders, suicide, and accidental death during this time of life. Yet some teens emerge from adolescence with minimal turmoil. We provide a neurobiological model of adolescence that proposes an imbalance in the development of subcortical limbic (e.g., amygdala) relative to prefrontal cortical regions as a potential mechanism for heightened emotionality during this period. Empirical support for this model is provided from recent behavioral and human imaging studies on the development of emotion regulation. We then provide examples of environmental factors that may exacerbate imbalances in amygdala-ventrofrontal function increasing risk for anxiety related behaviors. Finally we present data from human and mouse studies to illustrate how genetic factors may enhance or diminish this risk. Together, these studies provide a converging methods approach for understanding the highly variable stress and turmoil experienced in adolescence.

Figure 1

Neurobiological model depicting later development of top down prefrontal regions relative to subcortical limbic regions involved in emotional processes. This imbalance in development of these systems is suggested to be at the core of aberrant teen behavior in contrast to the popular view of adolescent behavior being due to the protracted development of the prefrontal cortex alone (Adapted from Somerville et al., 2010).

Figure 2. Exaggerated Amydala Response in Adolescents

Amygdala response to empty threat (fearful faces) as a function of age. Adapted from Hare et al., 2008

Figure 3. Habituation of Amygdala Response is associated with Anxiety and Less vPFC activity

Trait anxiety scores were negatively correlated with habituation (decrease from early to late trials) of amygdale activity (r=.447; p .001). Amygdala habituation was calculated by subtracting activity in late trials from activity in early trials. (A) Region of the left amygdala that correlated with trait anxiety. (B) Scatter plot of the correlation between trait anxiety and amygdala habituation. The y-axis represents MR signal in the left amygdala for early_late trials. The x-axis represents trait anxiety score. There was negative functional coupling between the amygdala and the ventral prefrontal cortex (vPFC). The magnitude of activity in vPFC and the strength of the connectivity between vPFC and the amygdala were negatively correlated with amygdala habituation (r =.559 p .001). (Right) Scatterplot of vPFC-amygdala connectivity values versus amygdala habituation. The y-axis represents MR signal in the left amygdala for early-late trials. The x-axis represents Z-scored vPFC-amygdala connectivity values. Adapted from Hare et al. 2008.

Figure 4. Amygdala activity and proximity to the WTC on September 11th, 2001

Fearful emotional faces elicited greater left (top panel) and right (bottom panel) amygdale activity in the 9/11-exposed group relative to a comparison group (p < 05). Amygdala activity was negatively correlated with time since worst trauma in lifetime in left (r = .46, p < .05 and right amygdale ((r = .45, p < .06). Adapted from Ganzel et al. (2007).

Figure 5. Altered behavior and neural circuitry underlying extinction in mice and humans with BDNF Val66Met

Impaired extinction in Met allele carriers (Val/Met and Met/Met) as a function of time in 68 mice (A) and 72 humans (B) as indexed by percent time freezing in mice and skin conductance response (SCR) in humans to the conditioned stimulus when it was no longer paired with the aversive stimulus. (C) Brain activity as indexed by percent change in MR signal during extinction in the ventromedial prefrontal cortex (vmPFC) by genotype (xyz = −4, 24, 3), with Met allele carriers having significantly less activity than Val/Val homozygotes [VM < VV = blue], image threshold p < 0.05, corrected. (D) Genotypic differences in left amygdala activity during extinction (xyz = −25, 2, −20) in 70 humans, with Met allele carriers having significantly greater activity than Val/Val homozygotes [VM > VV = orange], image threshold p < 0.05, corrected. *p < 0.05. **MM were included in the analysis with VM, but plotted separately to see dose response. All results are presented as a mean ± SEM. VV = Val/Val; VM = Val/Met; MM = Met/Met (From Soliman et al. 2010).