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.

Figure 1. Animals were tested two times: screening (a) and FDG-PET (b).

Behavioral and physiological screening were performed on separate days. During each behavioral screening animals were left alone in the test cage (ALN, blue) for 10-minutes, followed by a 10-minute exposure to a human intruder presenting her profile to the monkey while making No Eye Contact (NEC, pink) (a-1). To obtain a physiological measure of stress, plasma cortisol was collected after exposure to 30 minutes of restraint stress (a-2). Approximately 4 months later, animals were assessed on separate days with four FDG-PET scans, two in stressful conditions (ALN & NEC) and two conditions in the security of their home-cage (seen in orange); one condition in which they were alone (H-ALN) and one condition where their cage-mate was present (H-CM). On each test day, animals were injected with FDG (b-1) and exposed to 30-minutes of the behavioral paradigm. During stressful conditions, behavior was monitored (b-2) and plasma cortisol was collected after the cessation of the stress (b-3). FDG-uptake associated with in condition brain metabolism was assessed after completion of the behavioral paradigm, (b-4).

Figure 2. Anxious temperament, defined as increased freezing during NEC, decreased cooing during ALN and increased stress-induced cortisol, assessed during screening was significantly correlated with a similar measure taken 4-months later during FDG-PET testing.

Figure 3

a) Significant (p<.05, two-tailed multi-FDR corrected) relationships between regions of the amygdala (outlined in blue) and anxious temperament (Time 2) during the ALN (cyan) and NEC (pink) conditions are overlaid on coronal (green-border) and axial (yellow-border) slices of the study-specific MRI template (see Supplementary Methods). The areas of the brain demonstrating significant correlations in both the NEC and ALN conditions are shown in purple. b) Scatter-plots show anxious temperament (Time 2) to be correlated with z-scored residual metabolism in this overlapping region of the amygdala (after accounting for age and gray-matter probability) in both the NEC (pink, left) and ALN (cyan, right) conditions. Coordinates are in millimeters relative to the anterior commisure.

Figure 4. Regions where anxious temperament (Time 2) was significantly (p<.005, two-tailed uncorrected, two-condition logical AND conjunction) related to metabolism in both of the two stressful conditions [Alone (ALN) and No Eye Contact (NEC)] are shown overlaid on coronal slices of the study-specific MRI template in purple.

Regions where anxious temperament (Time 2) was significantly (p<.005, two-tailed uncorrected, four-condition logical AND conjunction) related with brain metabolism in the stressful conditions as well as while animals were in the security of their home-cage [Home Alone (H-ALN) and Home with their Cage Mate (H-CM)] are shown in orange. Coordinates are in millimeters relative to the anterior commisure.