Bullet point summary:

• Adolescence is the peak period for the incidence of anxiety disorders. Recent findings have revealed the immaturity of neural networks underlying emotional regulation in this population. Brain vulnerability to anxiety in adolescence is related to the unsynchronised development of anxiety-relevant brain functional systems.
• However, our current knowledge on brain deficits in adolescent anxiety is mainly borrowed from studies on adults. Understanding adolescent-specific brain deficitsis essential for developing biomarkers and brain-based therapies targeting adolescent anxiety.
• This article reviews and compares recent neuroimaging literature on anxiety-related brain structural and functional deficits between adolescent and adult populations, and proposes a model highlighting the differences between adolescence and adulthood in anxiety-related brain networks.
• This model emphasises that in adolescence the emotional control system tends to be hypoactivated, the fear conditioning system is immature, and the reward and stress response systems are hypersensitive.
• Furthermore, the striatum’s functional links to the amygdala and the prefrontal cortex are strengthened, while the link between the prefrontal cortex and the amygdala is weakened in adolescence.
• This model helps to explain why adolescents are vulnerable to anxiety disorders and provides insights into potential brain-based approaches to intervene in adolescent anxiety disorders.

What are anxiety disorders?

Anxiety disorders mainly manifest as excessive fear, worry and avoidance that induce severe emotional distress, somatic diseases, and cognitive and behavioural impairments, and in turn damage normal social functioning and negatively affect quality of life. Often, anxiety disorders have an early onset, which may be related to the developmental trajectory of the adolescent brain. The brain structure changes significantly from childhood to adolescence in terms of myelination and synapse pruning. Hormones of puberty, together with pressures from the external environment, reshape the central neural system. These developmental processes and abnormalities may trigger and/or mediate the onset and progression of anxiety disorders in adolescence.

What is the goal of the current article?

In this article, we would review anxiety-relevant abnormalities in the developing brain and attempt to propose a psychopathological model of neural systems underlying anxiety disorders for adolescence, emphasising the differences between adoles- cents and adults.

What brain structures are associated with anxiety disorders?

Previous studies have shown that the amygdala, prefrontal cortex, bed nucleus of the stria terminalis (BNST), hippocampus, striatum, anterior insula, anterior cingulate cortex and hypothalamus were closely related to anxiety disorders. Notably, the functional connectivity between the amygdala and the anterior insula is associated with the degree of avoidance. These structures, which are closely related to anxiety, may play unique roles in the development of cognitive and emotional capabilities among adolescents.

• Previous literature supports that the amygdala is related to fear learning and that its pathological increase in volume is a sign of anxiety disorders.
• The activation of the medial prefrontal cortex (mPFC) in adolescents is weakened during extinction recall. The activation of the mPFC of anxious adolescents, however, is stronger than that of the healthy group during negative emotion processing. High levels of anxiety symptoms are related to delayed development of the neural circuits including the prefrontal cortex in children and adolescents.
• In adolescents, decreased hippocampus volume is one of the risk factors for anxiety disorders.
• The BNST mediates the regulation of anxiety by neural circuits underlying substance abuse.
• The striatum contributes to anxiety symptoms and anxiety-related bias in emotional, motivational and attentional processes, since it has vital contributions to these processes, and striatum-based functional connectivity differs between anxious adolescents and healthy adolescents.
• The hypothalamus is a critical structure involved in the anxiety circuit. It is also a central part of the HPA axis responsible for regulating emotions, defensive behaviour, aggression and stress responses. The dysregulation of HPA axis activities during adolescence increases the risk of developing anxiety disorders.

What neural networks underlie adolescent anxiety?

Several neural networks underlie anxiety disorders in adolescents:

• The neural circuit between the mPFC and the amygdala is closely related to cognitive control. In adolescence, the maturation of the mPFC is later than that of the amygdala, and the ability of top-down regulation is immature and weak. Hence, insufficient inhibition of the amygdala neurons may provide a potential neural basis for adolescent anxiety disorders.
• The ventral hippocampus, basolateral amygdala and the mPFC form an interconnected circuit that plays a vital role in fear learning and extinction. The ventral hippocampus and the basolateral amygdala rely on each other coding fear-related memories. Glutamatergic inputs from the basolateral amygdala to the ventral hippocampus pyramidal neurons increase individual anxiety, while inhibition of this projection reduces anxiety-related behaviours.
• The neural networks that include the BNST, amygdala and prefrontal cortex participate in the anticipation of uncertain threats. The excessive and persistent anxiety response of patients with anxiety disorders to uncertain information may be underlain with neural projections from the basolateral amygdala to the BNST.
• Reward representations are available to the ventral striatum that participates in forming motivational and goal-oriented behaviours. The amyg- dala actively regulates the striatum. The direct projection from the amygdala to the striatum supports ‘fight or flight’ motor responses, as well as avoidance learning.
• Under stressful conditions, amygdala- to-hypothalamic outputs maintain anxiety behaviours.

How do differences in brain networks vary across subtypes of anxiety disorders?

Morphologically, patients with social anxiety disorder (SAD) have a larger grey matter volume in the dorsal striatum. They have reduced frontal lobe volume and increased amygdala volume relative to healthy controls. Patients with generalised anxiety disorder (GAD) have reduced ventromedial prefrontal cortex volume and hypothalamus volume. Patients with panic disorder (PD) have smaller grey matter volumes in the amygdala, the hippocampus, the prefrontal cortex and the bilateral striatum.

How does adolescence influence the increased risk on anxiety disorders?

Several developments in adolescence influence the increased risk on anxiety disorders in this period.

• From adolescence to adulthood, the neural connections in anxiety neural networks change dramatically. Functional and structural connections between the prefrontal cortex and the amygdala are reorganised during adolescent development. Reduced functional connectivity between the amygdala and the prefrontal cortex indicates failure of top-down control in the prefrontal cortex, which is a potential pathological factor for anxiety disorders in both adolescents and adults.
• Hippocampal volume increases and then decreases from adolescence to adulthood. During adolescence, the structural connections between the amygdala and the mPFC develop, which is related to fear conditioning. For adolescents, excessive functional connectivity between the prefrontal cortex, the amygdala and the hippocampus is associated with a higher risk of anxiety disorders. For adults, the lack of hippocampal inhibition of the prefrontal cortex, which is common in typically developing adolescents, may increase the risk of mood disorders in adults.
• The relationship between the development of the BNST and anxiety disorders in adolescents, as well as the neural connections of the BNST and their functions during adolescence, is underdocumented and needs further investigation.
• Then, the functional connectivity between the amygdala and the striatum in response to emotional cues is declining during development, and is associated with enhanced cognitive control. Adolescents with GAD show increased functional connectivity between the striatum and the amygdala, accompanying higher sensitivity to reward-related stimuli.
• Lastly, for adolescents, experiencing stress leads to overexpres- sion of corticotropin-releasing factor receptor in the hypothalamus, the amygdala and the prefrontal cortex, causing abnormalities in the HPA axis that will persist into adulthood. Significantly increased responses to stress in adolescents compared with adults, as evidenced by prolonged hormonal exposure, are possibly responsible for the increased vulnerability to psychiatric disorders seen during adolescence.

What are the most important conclusions about the developing adolescent brain in relation to anxiety disorders?

This article reviewed and compared recent neuroimaging literature on anxiety- related brain structural and functional deficits between adolescent and adult populations, and proposes a model highlighting the differences between adolescence and adulthood in anxiety-related brain networks. This model emphasises that in adolescence the emotional control system tends to be hypoactivated, the fear conditioning system is immature, and the reward and stress response systems are hypersensitive. Furthermore, the striatum’s functional links to the amygdala and the prefrontal cortex are strengthened, while the link between the prefrontal cortex and the amygdala is weakened in adolescence. This model helps to explain why adolescents are vulnerable to anxiety disorders and provides insights into potential brain-based approaches to intervene in adolescent anxiety disorders.