Trait-Like Brain Activity during Adolescence Predicts Anxious Temperament in Primates

Abstract

Early theorists (Freud and Darwin) speculated that extremely shy children, or those with anxious temperament, were likely to have anxiety problems as adults. More recent studies demonstrate that these children have heightened responses to potentially threatening situations reacting with intense defensive responses that are characterized by behavioral inhibition (BI) (inhibited motor behavior and decreased vocalizations) and physiological arousal. Confirming the earlier impressions, data now demonstrate that children with this disposition are at increased risk to develop anxiety, depression, and comorbid substance abuse. Additional key features of anxious temperament are that it appears at a young age, it is a stable characteristic of individuals, and even in non-threatening environments it is associated with increased psychic anxiety and somatic tension. To understand the neural underpinnings of anxious temperament, we performed imaging studies with 18-fluoro-deoxyglucose (FDG) high-resolution Positron Emission Tomography (PET) in young rhesus monkeys. Rhesus monkeys were used because they provide a well validated model of anxious temperament for studies that cannot be performed in human children. Imaging the same animal in stressful and secure contexts, we examined the relation between regional metabolic brain activity and a trait-like measure of anxious temperament that encompasses measures of BI and pituitary-adrenal reactivity. Regardless of context, results demonstrated a trait-like pattern of brain activity (amygdala, bed nucleus of stria terminalis, hippocampus, and periaqueductal gray) that is predictive of individual phenotypic differences. Importantly, individuals with extreme anxious temperament also displayed increased activity of this circuit when assessed in the security of their home environment. These findings suggest that increased activity of this circuit early in life mediates the childhood temperamental risk to develop anxiety and depression. In addition, the findings provide an explanation for why individuals with anxious temperament have difficulty relaxing in environments that others perceive as non-stressful.

Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates

“…With functional brain imaging, we identified the central nucleus of the amygdala (Ce) and anterior hippocampus as components of the neural circuit underlying AT (2,19). More-over, we found that young primates with high AT have increased metabolism in these regions when studied in both stressful and nonstressful contexts (2). These data set the stage for in-depth molecular studies in primates focused on understanding the mechanisms mediating the function of the brain regions underlying AT.…”

“…Using functional brain imaging in conjunction with ex vivo molecular analyses of relevant brain regions, the monkey model allows for the longitudinal study of AT and its underlying neural substrates. With functional brain imaging, we identified the central nucleus of the amygdala (Ce) and anterior hippocampus as components of the neural circuit underlying AT (2,19). More-over, we found that young primates with high AT have increased metabolism in these regions when studied in both stressful and nonstressful contexts (2).…”

“…To this end, we have optimized a model of anxious temperament (AT), the conserved at-risk phenotype, in young developing rhesus monkeys (1)(2)(3)(4). The rhesus monkey is ideal for studying the origin of human AT because these species share the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning (5)(6)(7)(8)(9)(10).…”

Neural mechanisms underlying heterogeneity in the presentation of anxious temperament

“…Clinically relevant anxiety is often accompanied and preceded by an anxious temperament (AT). AT is a trait-like phenotype that is evident early in life, stable over time, associated with increased amygdala reactivity to novelty and potential threat, and expressed similarly in children and young nonhuman primates (1)(2)(3)(4)(5)(6). Extreme dispositional anxiety and behavioral inhibition in childhood is a wellestablished risk factor for the internalizing spectrum of psychiatric disorders, including anxiety and major depression (5,7,8).…”

“…Like the internalizing disorders, childhood AT is a complex, multidimensional phenotype and children with extreme AT show varying mixtures of peripheral physiological, behavioral, and other kinds of anxiety-related symptoms (5,11,12). This diversity manifests as weak covariation among these features (2,13,14). From the perspective of diagnosis and treatment, an important unresolved question is the degree to which heterogeneity in anxious individuals' symptoms reflects fundamental differences or similarities in the underlying neurobiology.…”