Microbiome–Gut–Brain axis: Important link in adolescent mental health

*Flannery, J., Callaghan, B., Sharpton, T., Fisher, P., & Pfeifer, J. (2019). Is adolescence the missing developmental link in Microbiome–Gut–Brain axis communication?. Developmental psychobiology.

Gut microbial research has recently opened new frontiers in neuroscience and potentiated novel therapies for mental health problems (Mayer, et al., 2014). Much of our understanding of the gut microbiome’s role in brain function and behavior, however, has been largely derived from research on nonhuman animals. Even less is known about how the development of the gut microbiome influences critical periods of neural and behavioral development, particularly adolescence. In this review, we first discuss why the gut microbiome has become increasingly relevant to developmental cognitive neuroscience and provide a synopsis of the known connections of the gut microbiome with social–affective brain function and behavior, specifically highlighting human developmental work when possible. We then focus on adolescence, a key period of neurobiological and social–affective development. Specifically, we review the links between the gut microbiome and six overarching domains of change during adolescence: (a) social processes, (b) motivation and behavior, (c) neural development, (d) cognition, (e) neuroendocrine function, and (f) physical health and wellness. Using a developmental science perspective, we summarize key changes across these six domains to underscore the promise for the gut microbiome to bidirectionally influence and transform adolescent development.

Neural correlates of social exclusion in adolescence

*Cheng, T., Vijayakumar, N., Flournoy, J. C., de Macks, Z. O., Peake, S. J., *Flannery, J. E., … & Pfeifer, J. H. (2019). Feeling left out or just surprised? Neural correlates of social exclusion and expectancy violations in adolescence. bioRxiv, 524934.

Social belonging and affiliation are important human drives that impact decision-making and health outcomes. While neural responses to social exclusion are increasingly well-characterized, studies rarely identify whether these responses reflect the affective distress or expectancy violation associated with exclusion. The present study compares neural responses to exclusion and over-inclusion, a similarly unexpected social occurrence that violates fair play expectations, but does not involve rejection, with a focus on implications for models of dorsal anterior cingulate cortex (dACC) function. In an fMRI adaptation of the Cyberball paradigm with human adolescents 11.1-17.7 years of age (N=69), we employed parametric modulators to examine scaling of neural signal with cumulative exclusion and inclusion events. The use of parametric modulators overcomes arbitrary definitions of condition onsets and offsets imposed on fluid, continuous gameplay. In support of the notion that the dACC plays a role in processing affective distress, this region exhibited greater signal with cumulative exclusion than cumulative inclusion events. However, this difference was partly driven by diminished signal accompanying cumulative inclusion, a finding that does not conform to either affective distress or expectancy violation model predictions. Additionally, we found that signal in the insula and dorsomedial prefrontal cortex scaled uniquely with social exclusion and over-inclusion, respectively, while conjunction analyses revealed that the rostromedial prefrontal cortex and left intraparietal sulcus responded similarly to both conditions. These findings shed light on which neural regions may exhibit patterns of differential sensitivity to exclusion or over-inclusion, as well as those that are more broadly engaged by both types of social interaction.

Implications for adolescent risk-taking in novel MRI task

de Macks, Z. A. O., *Flannery, J. E., Peake, S. J., *Flournoy, J. C., *Mobasser, A., *Alberti, S. L., … & Pfeifer, J. H. (2018). Novel insights from the Yellow Light Game: Safe and risky decisions differentially impact adolescent outcome-related brain function. NeuroImage, 181, 568-581.

Changes across the span of adolescence in the adolescent reward system are thought to increase the tendency to take risks. While developmental differences in decision and outcome-related reward processes have been studied extensively, existing paradigms have largely neglected to measure how different types of decisions modulate reward-related outcome processes. We modified an existing decision-making paradigm (the Stoplight Task; Chein et al., 2011) to create a flexible laboratory measure of decision-making and outcome processing, including the ability to assess modulatory effects of safe versus risky decisions on reward-related outcome processes: the Yellow Light Game (YLG). We administered the YLG in the MRI scanner to 81 adolescents, ages 11–17 years, recruited from the community. Results showed that nucleus accumbens activation was enhanced for (1) risky > safe decisions, (2) positive > negative outcomes, and (3) outcomes following safe decisions compared to outcomes following risky decisions, regardless of whether these outcomes were positive or negative. Outcomes following risky decisions (compared to outcomes following safe decisions) were associated with enhanced activity in cortical midline structures. Furthermore, while there were no developmental differences in risk-taking behavior, more pubertally mature adolescents showed enhanced nucleus accumbens activation during positive > negative outcomes. These findings suggest that outcome processing is modulated by the types of decisions made by adolescents and highlight the importance of investigating processes involved in safe as well as risky decisions to better understand the adolescent tendency to take risks.

Does choice enhance craving regulation?

*Cosme, D., *Mobasser, A., Zeithamova, D., Berkman E. T., & Pfeifer, J. H. (2018) Choosing to regulate: Does choice enhance craving regulation?. Social Cognitive and Affective Neuroscience, 13(3), 300-309. 

Goal-directed behavior and lifelong well-being often depend on the ability to control appetitive motivations, such as cravings. Cognitive reappraisal is an effective way to modulate emotional states, including cravings, but is often studied under explicit instruction to regulate. Despite the strong prediction from Self-Determination Theory that choice should enhance task engagement and regulation success, little is known empirically about whether and how regulation is different when participants choose (vs are told) to exert control. To investigate how choice affects neural activity and regulation success, participants reappraised their responses to images of personally-craved foods while undergoing functional neuroimaging. Participants were either instructed to view or reappraise (‘no-choice’) or chose freely to view or reappraise (‘yes-choice’). Choice increased activity in the frontoparietal control network. We expected this activity would be associated with increased task engagement, resulting in better regulation success. However, contrary to this prediction, choice slightly reduced regulation success. Follow-up multivariate functional neuroimaging analyses indicated that choice likely disrupted allocation of limited cognitive resources during reappraisal. While unexpected, these results highlight the importance of studying upstream processes such as regulation choice, as they may affect the ability to regulate cravings and other emotional states.

Neural Reactivity to Emotions Supports Link Between Empathy in Late Childhood and Prosocial Behavior in Early Adolescence

*Flournoy J.C., Pfeifer J.H., *Moore W. E. III, *Tackman A. Mazziotta J.C., Iacoboni M., Dapretto M. (2016). Neural reactivity to emotional expressions mediates the relationship between childhood empathy and adolescent prosocial behavior. Child Development. 

When one is faced with the emotional distress of another person, one’s response often falls somewhere between distress and concern. Importantly, these initial, visceral responses can lead to very different decisions: the distressed person disengages, while the concerned person may be motivated to help ease the suffering of the other. The brain processes that let us make sense of the emotional states of others sometimes overlap with the systems that generate our own emotions. As children transition into adolescence, their brains and their tendency to respond with empathic concern or distress are changing rapidly. We investigated how the sensitivity of different empathy-related brain regions is related to these changes in empathic tendencies, and whether development in both areas predict real-world prosocial behavior — specifically, regular volunteering in the community.

Age-related changes in reappraisal of appetitive cravings during adolescence

Giuliani, N. R., & Pfeifer, J. H. (2015) Age-related changes in reappraisal of appetitive cravings during adolescence. NeuroImage, 108, 173-181. 

The ability to regulate temptation is an important aspect of healthy adolescent development, but the brain systems underlying this process are understudied. In the present study, 60 healthy females between the ages of 10 and 23 used cognitive regulation to decrease their desire for personally-craved and not craved unhealthy foods. Viewing personally-craved foods (versus not craved foods) elicited activity in brain regions known to be involved in reward processing, and regulating those desires recruited brain regions classically involved in top-down self-regulation regions, including the lateral prefrontal cortex (PFC). Individual differences in this activity include relatively more PFC activity during the regulation of their personally-craved foods in older participants compared to younger ones. This study is the first to investigate age-related changes in temptation regulation. Therefore, cognitive regulation of food craving in particular may be an effective way to teach teenagers to manage the desire for the temptations encountered in adolescence, including alcohol, drugs, and unhealthy food.

But do you think I’m cool? Brain differences in adolescent and adult self-processing

*Jankowski, K. F., *Moore, W. E. III, *Merchant, J. S., *Kahn, L. E., & Pfeifer, J. H. (2014). But do you think I’m cool? Developmental differences in striatal recruitment during direct and reflected social self-evaluations. Developmental Cognitive Neuroscience, 8, 40-54. pdf

This study explored differences in brain patterns during early adolescent and young adult self-evaluations. Eighteen adolescents (11-14 years) and 19 adults (21-31 years) evaluated if academic, physical, and social traits described themselves, their best friend, or themselves from their best friend’s perspective. Adolescents and adults activated cortical midline structures associated with social cognition during all three types of evaluations. Uniquely, when making social self-evaluations from their best friend’s perspective, adolescents showed greatest activation within striatal regions associated with reward-processing, and this activity increased with pubertal status. This study highlights the importance of peers in adolescent self-perceptions; it demonstrates that inferred social self-evaluations made from the perspective of a close peer may be especially salient or rewarding to adolescent self-processing, particularly throughout pubertal development.

Neural Processing of Dynamic Peer Emotions: Developmental Trajectories and Adolescent Well-Being

*Flannery, J.E., Giuliani, N. R., *Flournoy J.C., Pfeifer J.H. (in preparation). 

Emotional processes are critical to our daily functioning. We constantly use our own and others’ emotions to assess our physical and social environment, and adapt our behavior. Research would suggest that this developmental process is particularly important and undergoes major changes in adolescence due to a myriad of factors including: onset of puberty, increased hormonal production, increased neural plasticity, and social reorientation away from parents toward peers. We extended prior research by assessing brain activity during understudies aspects of affect, motivation, and control: viewing and labeling dynamic peer emotional displays. Observing and identifying dynamic peer expressions recruited expected networks implicated in emotion processing and regulation, including bilateral amygdala, medial orbitofrontal cortex (mOFC), and lateral prefrontal cortex (LPFC). However, developmental trajectories in recruitment of these regions and associations with individual differences in well-being varied from prior cross-sectional fMRI studies. This suggests existing models may need refinement to more adequately capture neurobiological foundations of adolescent-emergent and adolescent-specific patterns of behavior and mental health. 

* = student authors