Leah H. Somerville

A time of change: Behavioral and neural correlates of adolescent sensitivity to appetitive and aversive environmental cues

Adolescence is a developmental period that entails substantial changes in affective and incentive-seeking behavior relative to both childhood and adulthood, including a heightened propensity to engage in risky behaviors and experience persistent negative and labile mood states. This review discusses the emotional and incentive-driven behavioral changes in adolescents and their associated neural mechanisms, focusing on the dynamic interactions between the amygdala, ventral striatum, and prefrontal cortex. Common behavioral changes during adolescence may be associated with a heightened responsiveness to incentives and emotional cues while the capacity to effectively engage in cognitive and emotion regulation is still relatively immature. We highlight empirical work in humans and animals that addresses the interactions between these neural systems in adolescents relative to children and adults, and propose a neurobiological model that may account for the nonlinear changes in adolescent behavior. Finally, we discuss other influences that may contribute to exaggerated reward and emotion processing associated with adolescence, including hormonal fluctuations and the role of the social environment.

A Genetic Variant BDNF Polymorphism Alters Extinction Learning in Both Mouse and Human

Of Mice and Men Just how closely must mouse models replicate the known features of human disorders to be accepted as useful for mechanistic and therapeutic studies? Soliman et al. (p. 863, published online 14 January) compared mice that vary only in their allelic composition at one position within the gene encoding brain-derived neurotrophic factor (BDNF) with humans exhibiting the same range of allelic variation. Individuals (mice and humans) carrying the allele that codes for a methionine-containing variant of BDNF retained a fearful response to a threatening stimulus even after its removal in comparison to those with the valine variant. Furthermore, in both cases, this linkage was mediated by diminished activity in the ventral-medial region of the prefrontal cortex. This deficit in extinction learning may contribute to differential responses to extinction-based therapies for anxiety disorders. A common genetic variation affecting fear learning and extinction operates through the same pathways in mice and men. Mouse models are useful for studying genes involved in behavior, but whether they are relevant to human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy.

Developmental neurobiology of cognitive control and motivational systems.

One form of cognitive control is the ability to resist temptation in favor of long-term goal-oriented behavior. Historically, the development of cognitive control capacity has been described by a linear function from infancy to adulthood. However, the context in which control is required impacts behavioral regulation abilities, such that emotionally charged or rewarding contexts can diminish control. More recently, studies have begun to examine the development of cognitive control in contexts that vary in motivation. These studies suggest specific windows of development in which cognitive control capacity is more vulnerable to incentive-based modulation. In this review we highlight the most recent work on neurobiological changes supporting motivational and cognitive development, underscoring the importance of functional organization and development of the underlying circuitry implicated in these processes, and provide a theoretical perspective that moves away from discussing singular functional regions toward considering functional circuitry.

Contextual Modulation of Amygdala Responsivity to Surprised Faces

We recently demonstrated a functional relationship between fMRI responses within the amygdala and the medial prefrontal cortex based upon whether subjects interpreted surprised facial expressions positively or negatively. In the present fMRI study, we sought to assess amygdalamedial prefrontal cortex responsivity when the interpretations of surprised faces were determined by contextual experimental stimuli, rather than subjective judgment. Subjects passively viewed individual presentations of surprised faces preceded by either a negatively or positively valenced contextual sentence (e.g., She just found 500 vs. She just lost 500). Negative and positive sentences were carefully matched in terms of length, situations described, and arousal level. Negatively cued surprised faces produced greater ventral amygdala activation compared to positively cued surprised faces. Responses to negative versus positive sentences were greater within the ventrolateral prefrontal cortex, whereas responses to positive versus negative sentences were greater within the ventromedial prefrontal cortex. The present study demonstrates that amygdala response to surprised facial expressions can be modulated by negatively versus positively valenced verbal contextual information. Connectivity analyses identified candidate corticalsubcortical systems subserving this modulation.

Anterior cingulate cortex responds differentially to expectancy violation and social rejection

This study investigated human anterior cingulate cortex (ACC) involvement during a task that dissociated expectancy violation from social rejection. Across two studies, participants underwent functional magnetic resonance imaging while making social judgments and receiving fictitious feedback that was either positive or negative and consistent or inconsistent with their expectations. The results demonstrate that the dorsal ACC is sensitive to expectancy violations, whereas the ventral ACC is differentially responsive to social feedback.

Human amygdala responses during presentation of happy and neutral faces: correlations with state anxiety.

BACKGROUND Previous functional imaging studies demonstrating amygdala response to happy facial expressions have all included the presentation of negatively valenced primary comparison expressions within the experimental context. This study assessed amygdala response to happy and neutral facial expressions in an experimental paradigm devoid of primary negatively valenced comparison expressions. METHODS Sixteen human subjects (eight female) viewed 16-sec blocks of alternating happy and neutral faces interleaved with a baseline fixation condition during two functional magnetic resonance imaging scans. RESULTS Within the ventral amygdala, a negative correlation between happy versus neutral signal changes and state anxiety was observed. The majority of the variability associated with this effect was explained by a positive relationship between state anxiety and signal change to neutral faces. CONCLUSIONS Interpretation of amygdala responses to facial expressions of emotion will be influenced by considering the contribution of each constituent condition within a greater subtractive finding, as well as 1) their spatial location within the amygdaloid complex; and 2) the experimental context in which they were observed. Here, an observed relationship between state anxiety and ventral amygdala response to happy versus neutral faces was explained by response to neutral faces.

Human Bed Nucleus of the Stria Terminalis Indexes Hypervigilant Threat Monitoring

BACKGROUND Though a key symptom underlying many anxiety disorders is hypervigilant threat monitoring, its biological bases in humans remain poorly understood. Animal models suggest that anxious processes such as hypervigilant threat monitoring are distinct from cued fear-like responses and mediated by the bed nucleus of the stria terminalis (BNST). Here, we applied psychophysiological and neuroimaging methodologies sensitive to sustained arousal-based responses to test the role of the human BNST in mediating environmental threat monitoring, a potential experimental model for sustained anxiety symptoms. METHODS Healthy participants (n = 50) with varying trait anxiety performed an environmental threat-monitoring task during functional magnetic resonance imaging where a stimulus line continuously fluctuated in height, providing information relevant to subsequent risk for electric shocks. Skin conductance was collected in a separate cohort (n = 47) to validate task-evoked modulation of physiological arousal. RESULTS A forebrain region consistent with the BNST showed greater overall recruitment and exaggerated tracking of threat proximity in individuals with greater anxiety. The insular cortex tracked threat proximity across all participants, showed exaggerated threat proximity responding with greater anxiety, and showed enhanced recruitment when threat proximity was ostensibly controllable. CONCLUSIONS Activity in the BNST and insula continuously monitored changes in environmental threat level and also subserved hypervigilant threat-monitoring processes in more highly trait anxious individuals. These findings bridge human and animal research informing the role of the BNST in anxious-related processes. In addition, these findings suggest that continuous functional magnetic resonance imaging paradigms offer promise in further elucidating the neural circuitries supporting sustained anticipatory features of anxiety.

The Teenage Brain: Sensitivity to Social Evaluation

Relative to childhood, peer relationships take on a heightened importance during adolescence. Might adolescents be highly attuned to information that concerns when and how they are being evaluated and what their peers think of them? This review evaluates how continuing brain development—which influences brain function—partially explains and reflects adolescents’ attunement to social evaluation. Though preliminary, evidence is mounting to suggest that while processing information relevant to social evaluation and the internal states of other people, adolescents respond with heightened emotional intensity and corresponding nonlinear recruitment of socioaffective brain circuitry. This review highlights research findings that relate trajectories of brain development to social behavior and discusses promising avenues of future research that will inform how brain development might lead adolescents to be sensitized to social evaluation.

A functional magnetic resonance imaging predictor of treatment response to venlafaxine in generalized anxiety disorder.

BACKGROUND Functional magnetic resonance imaging (fMRI) holds promise as a noninvasive means of identifying neural responses that can be used to predict treatment response before beginning a drug trial. Imaging paradigms employing facial expressions as presented stimuli have been shown to activate the amygdala and anterior cingulate cortex (ACC). Here, we sought to determine whether pretreatment amygdala and rostral ACC (rACC) reactivity to facial expressions could predict treatment outcomes in patients with generalized anxiety disorder (GAD). METHODS Fifteen subjects (12 female subjects) with GAD participated in an open-label venlafaxine treatment trial. Functional magnetic resonance imaging responses to facial expressions of emotion collected before subjects began treatment were compared with changes in anxiety following 8 weeks of venlafaxine administration. In addition, the magnitude of fMRI responses of subjects with GAD were compared with that of 15 control subjects (12 female subjects) who did not have GAD and did not receive venlafaxine treatment. RESULTS The magnitude of treatment response was predicted by greater pretreatment reactivity to fearful faces in rACC and lesser reactivity in the amygdala. These individual differences in pretreatment rACC and amygdala reactivity within the GAD group were observed despite the fact that 1) the overall magnitude of pretreatment rACC and amygdala reactivity did not differ between subjects with GAD and control subjects and 2) there was no main effect of treatment on rACC-amygdala reactivity in the GAD group. CONCLUSIONS These findings show that this pattern of rACC-amygdala responsivity could prove useful as a predictor of venlafaxine treatment response in patients with GAD.

Stability of amygdala BOLD response to fearful faces over multiple scan sessions

We used fMRI to examine amygdala activation in response to fearful facial expressions, measured over multiple scanning sessions. 15 human subjects underwent three scanning sessions, at 0, 2 and 8 weeks. During each session, functional brain images centered about the amygdala were acquired continuously while participants were shown alternating blocks of fearful, neutral and happy facial expressions. Intraclass correlation coefficients calculated across the sessions indicated stability of response in left amygdala to fearful faces (as a change from baseline), but considerably less left amygdala stability in responses to neutral expressions and for fear versus neutral contrasts. The results demonstrate that the measurement of fMRI BOLD responses in amygdala to fearful facial expressions might be usefully employed as an index of amygdala reactivity over extended periods. While signal change to fearful facial expressions appears robust, the experimental design employed here has yielded variable responsivity within baseline or comparison conditions. Future studies might manipulate the experimental design to either amplify or attenuate this variability, according to the goals of the research.