Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Structural differences in adult orbital and ventromedial prefrontal cortex predicted by infant temperament at 4 months of age.

CONTEXT: The term temperament refers to a biologically based predilection for a distinctive pattern of emotions, cognitions, and behaviors first observed in infancy or early childhood. High-reactive infants are characterized at age 4 months by vigorous motor activity and crying in response to unfamiliar visual, auditory, and olfactory stimuli, whereas low-reactive infants show low motor activity and low vocal distress to the same stimuli. High-reactive infants are biased to become behaviorally inhibited in the second year of life, defined by timidity with unfamiliar people, objects, and situations. In contrast, low-reactive infants are biased to develop into uninhibited children who spontaneously approach novel situations. OBJECTIVE: To examine whether differences in the structure of the ventromedial or orbitofrontal cerebral cortex at age 18 years are associated with high or low reactivity at 4 months of age. DESIGN: Structural magnetic resonance imaging in a cohort of 18-year-olds enrolled in a longitudinal study. Temperament was determined at 4 months of age by direct observation in the laboratory. SETTING: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital. PARTICIPANTS: Seventy-six subjects who were high-reactive or low-reactive infants at 4 months of age. MAIN OUTCOME MEASURE: Cortical thickness. RESULTS: Adults with a low-reactive infant temperament, compared with those categorized as high reactive, showed greater thickness in the left orbitofrontal cortex. Subjects categorized as high reactive in infancy, compared with those previously categorized as low reactive, showed greater thickness in the right ventromedial prefrontal cortex. CONCLUSIONS: To our knowledge, this is the first demonstration that temperamental differences measured at 4 months of age have implications for the architecture of human cerebral cortex lasting into adulthood. Understanding the developmental mechanisms that shape these differences may offer new ways to understand mood and anxiety disorders as well as the formation of adult personality.

Neuroanatomical correlates of extraversion and neuroticism.

Introversion/extraversion and neuroticism are 2 important and frequently studied dimensions of human personality. These dimensions describe individual differences in emotional responding across a range of situations and may contribute to a predisposition for psychiatric disorders. Recent neuroimaging research has begun to provide evidence that neuroticism and introversion/extraversion have specific functional and structural neural correlates. Previous studies in healthy adults have reported an association between neuroticism, introversion/extraversion, and the activity of the prefrontal cortex and amygdala. Studies of individuals with psychopathological states have also indicated that anatomic variations in these brain areas may relate to extraversion and neuroticism. The purpose of the present study was to examine selected structural correlates of neuroticism and extraversion in healthy subjects (n = 28) using neuroanatomic measures of the cerebral cortex and amygdala. We observed that the thickness of specific prefrontal cortex regions correlates with measures of extraversion and neuroticism. In contrast, no such correlations were observed for the volume of the amygdala. The results suggest that specific aspects of regional prefrontal anatomy are associated with specific personality traits.

Temperament and its implications for neuroimaging of anxiety disorders.

We review the attributes of inhibited and uninhibited infant temperaments, and their developmental trajectories into early adulthood. Inborn individual differences in infants' propensity to respond to novel people and objects are associated with persistent differences in the responsivity of the amygdala to novelty, as measured with functional magnetic resonance imaging, after more than 20 years of development. Because an inhibited temperament is a risk factor for developing later psychiatric disorders, particularly generalized social anxiety disorder, temperamental differences are confounds in neuroimaging and genetic studies. Longitudinal studies are a unique tool for understanding the developmental and temperamental risk factors for psychiatric disorder.

Antitussive activity of sigma-1 receptor agonists in the guinea-pig.

1. Current antitussive medications have limited efficacy and often contain the opiate-like agent dextromethorphan (DEX). The mechanism whereby DEX inhibits cough is ill defined. DEX displays affinity at both NMDA and sigma receptors, suggesting that the antitussive activity may involve central or peripheral activity at either of these receptors. This study examined and compared the antitussive activity of DEX and various putative sigma receptor agonists in the guinea-pig citric-acid cough model. 2. Intraperitoneal (i.p.) administration of DEX (30 mg kg(-1)) and the sigma-1 agonists SKF-10,047 (1-5 mg kg(-1)), Pre-084 (5 mg kg(-1)), and carbetapentane (1-5 mg kg(-1)) inhibited citric-acid-induced cough in guinea-pigs. Intraperitoneal administration of a sigma-1 antagonist, BD 1047 (1-5 mg kg(-1)), reversed the inhibition of cough elicited by SKF-10,047. In addition, two structurally dissimilar sigma agonists SKF-10,047 (1 mg ml(-1)) and Pre-084 (1 mg ml(-1)) inhibited cough when administered by aerosol. 3. Aerosolized BD 1047 (1 mg ml(-1), 30 min) prevented the antitussive action of SKF-10,047 (5 mg kg(-1)) or DEX (30 mg kg(-1)) given by i.p. administration and, likewise, i.p. administration of BD 1047 (5 mg kg(-1)) prevented the antitussive action of SKF-10,047 given by aerosol (1 mg ml(-1)). 4. These results therefore support the argument that antitussive effects of DEX may be mediated via sigma receptors, since both systemic and aerosol administration of sigma-1 receptor agonists inhibit citric-acid-induced cough in guinea-pigs. While significant systemic exposure is possible with aerosol administration, the very low doses administered (estimated <0.3 mg kg(-1)) suggest that there may be a peripheral component to the antitussive effect.

Inhibited and uninhibited infants "grown up": adult amygdalar response to novelty.

Infants with an inhibited temperament tend to develop into children who avoid people, objects, and situations that are novel or unfamiliar, whereas uninhibited children spontaneously approach novel persons, objects, and situations. Behavioral and physiological features of these two temperamental categories are moderately stable from infancy into early adolescence and have been hypothesized to be due, in part, to variation in amygdalar responses to novelty. We found that adults who had been categorized in the second year of life as inhibited, compared with those previously categorized as uninhibited, showed greater functional MRI signal response within the amygdala to novel versus familiar faces.

Differential amygdalar response to novel versus newly familiar neutral faces: a functional MRI probe developed for studying inhibited temperament.

BACKGROUND: As a prelude to future studies of subjects with different temperaments, we sought to develop a probe to measure differential amygdalar responses to novel versus familiar stimuli. Prior neuroimaging studies of the amygdala in humans to date have focused principally on responses to emotional stimuli, primarily aversive, rather than to novelty per se. METHODS: Eight normal subjects aged 22.4 +/- 1.3 years were scanned using functional magnetic resonance imaging (fMRI) during passive viewing of novel and familiar faces. RESULTS: Using this newly developed paradigm, we found greater fMRI blood oxygenation level dependent (BOLD) signal response within the right amygdala to novel versus familiar faces--all with neutral expression. Furthermore, although a new facial identity was always presented in the novel condition, signal in the amygdala declined over time as it did for the familiar condition. CONCLUSIONS: These results suggest that at least one primary function of the amygdala is to detect and process unexpected or unfamiliar events that have potential biological import, of which stimuli symbolic of fear or threat are but one possible example. We propose that this experimental paradigm will be useful for examining brain responses to novelty in different temperamental groups, as well as various psychiatric disorders.

Novelty responses and differential effects of order in the amygdala, substantia innominata, and inferior temporal cortex.

Recent studies of amygdala function have focused on examining responses to emotionally valenced versus neutral stimuli. However, electrophysiologic and neuroimaging studies also suggest that novel neutral faces activate the amygdala, though few investigations have examined the effects of novelty and its relation to changes in stimulus condition. To further investigate how the human amygdala and related structures react to novel neutral faces and to stimulus condition changes, we evaluated human brain responses to blocks containing multiple novel and single repeated face stimuli, presented in two different orders, using functional magnetic resonance imaging (fMRI). Significantly increased signal was present in the amygdala, substantia innominata (SI), and inferior temporal cortex (ITC) to the contrast of multiple novel versus single faces. However, these regions differed in their responses based on whether a stimulus condition was presented 1st or 2nd, with the amygdala and SI having significantly different response profiles than the ITC. Specifically, greater responses to stimuli presented 2nd (i.e., after a condition change) were found in the amygdala and SI, but not in the ITC. Furthermore, the response difference to the Multiple versus Single contrast was greatest in the amygdala and SI, when single faces were presented 1st, and multiple faces presented 2nd, but this pattern was the reverse in the ITC. We speculate that the signal changes to neutral faces in the amygdala and SI with respect to condition (multiple or single faces) and stimulus order may relate to the involvement of these structures in novelty detection and the orienting response.