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.

Most fMRI studies of amydgala reactivity have focused on stimuli with arousing and/or emotional content (e.g. faces or pictures), or novel stimuli. The studies of novel stimuli have focused on stimulus novelty, i.e. events that alter the immediate stimulus surround, for example the presentation of unfamiliar face(s) contrasted with familiar ones. Few studies have examined amygdala reactivity to conceptually novel visual stimuli, ie. images of objects that cannot exist in the real world.

Behavioral inhibition (BI) is a genetically influenced behavioral profile seen in 15–20% of 2-year-old children. Children with BI are timid with people, objects and situations that are novel or unfamiliar, and are more reactive physiologically to these challenges as evidenced by higher heart rate, pupillary dilation, vocal cord tension and higher levels of cortisol. BI predisposes to the later development of anxiety, depression and substance abuse. Reduced hippocampal volumes have been observed in anxiety disorders, depression and posttraumatic stress disorder. Animal models have demonstrated that chronic stress can damage the hippocampal formation and implicated cortisol in these effects. We, therefore, hypothesized that the hippocampi of late adolescents who had been behaviorally inhibited as children would be smaller compared with those who had not been inhibited. Hippocampal volume was measured with high-resolution structural magnetic resonance imaging in 43 females and 40 males at 17 years of age who were determined to be BI+ or BI− based on behaviors observed in the laboratory as young children. BI in childhood predicted reduced hippocampal volumes in the adolescents who were offspring of parents with panic disorder, or panic disorder with comorbid major depression. We discuss genetic and environmental factors emanating from both child and parent that may explain these findings. To the best of our knowledge, this is the first study to demonstrate a relationship between the most extensively studied form of temperamentally based human trait anxiety, BI, and hippocampal structure. The reduction in hippocampal volume, as reported by us, suggests a role for the hippocampus in human trait anxiety and anxiety disorder that warrants further investigation.

The search for unique biological features of psychiatric disorders, as defined using the reliable symptom clusters of the DSM, has had a disappointing yield in terms of fundamental novel insights to etiology or treatment. Genetic studies reveal a surprising degree of overlap in the genetic variants that confer risk for ostensibly biologically distinct disorders ( 1 Smoller J.W. Craddock N. Kendler K. Lee P.H. Neale B.M. et al. Cross-Disorder Group of the Psychiatric Genomics ConsortiumIdentification of risk loci with shared effects on five major psychiatric disorders: A genome-wide analysis. Lancet. 2013; 381: 1371-1379 Abstract Full Text Full Text PDF PubMed Scopus (2178) Google Scholar ). Thus, National Institute of Mental Health leadership has promulgated the Research Domain Criteria (RDoC), a research roadmap that focuses on dimensions. Neural Antecedents of Emotional Disorders: A Functional Magnetic Resonance Imaging Study of Subsyndromal Emotional Symptoms in Adolescent GirlsBiological PsychiatryVol. 74Issue 4PreviewEmotional symptoms (ES) emerge forme fruste in adolescence, before manifesting as fully fledged emotional disorders. Studies indicate that subsyndromal ES precede the onset of emotional disorders. We hypothesized that adolescents showing subsyndromal ES will show perturbations in the emotion regulatory frontolimbic network (FLN) during emotion processing. Full-Text PDF Patterns of Neural Connectivity During an Attention Bias Task Moderate Associations Between Early Childhood Temperament and Internalizing Symptoms in Young AdulthoodBiological PsychiatryVol. 74Issue 4PreviewBiased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area might clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood. Full-Text PDF

Mindfulness training aims to impact emotion regulation. Generalized anxiety disorder (GAD) symptoms can be successfully addressed through mindfulness-based interventions. This preliminary study is the first to investigate neural mechanisms of symptom improvements in GAD following mindfulness training. Furthermore, we compared brain activation between GAD patients and healthy participants at baseline. 26 patientswith a current DSM-IV GAD diagnosiswere randomized to an 8-week Mindfulness Based Stress Reduction (MBSR, N = 15) or a stress management education (SME, N = 11) active control program. 26 healthy participants were included for baseline comparisons. BOLD response was assessed with fMRI during affect labeling of angry and neutral facial expressions. At baseline, GAD patients showed higher amygdala activation than healthy participants in response to neutral, but not angry faces, suggesting that ambiguous stimuli reveal stronger reactivity in GAD patients. In patients, amygdala activation in response to neutral faces decreased following both interventions. BOLD response in ventrolateral prefrontal regions (VLPFC) showed greater increase in MBSR than SME participants. Functional connectivity between amygdala and PFC regions increased significantly pre-to post-intervention within the MBSR, but not SME group. Both, change in VLPFC activation and amygdala-prefrontal connectivity were correlated with change in Beck Anxiety Inventory (BAI) scores, suggesting clinical relevance of these changes. Amygdala-prefrontal connectivity turned from negative coupling (typically seen in down-regulation of emotions), to positive coupling; potentially suggesting a unique mechanism of mindfulness. Findings suggest that in GAD, mindfulness training leads to changes in fronto-limbic areas crucial for the regulation of emotion; these changes correspond with reported symptom improvements. (C) 2013 The Authors. Published by Elsevier Inc.

One of the central questions that has occupied those disciplines concerned with human development is the nature of continuities and discontinuities from birth to maturity. The amygdala has a central role in the processing of novelty and emotion in the brain. Although there is considerable variability among individuals in the reactivity of the amygdala to novel and emotional stimuli, the origin of these individual differences is not well understood. Four-month old infants called high reactive (HR) demonstrate a distinctive pattern of vigorous motor activity and crying to specific unfamiliar visual, auditory and olfactory stimuli in the laboratory. Low-reactive infants show the complementary pattern. Here, we demonstrate that the HR infant phenotype predicts greater amygdalar reactivity to novel faces almost two decades later in adults. A prediction of individual differences in brain function at maturity can be made on the basis of a single behavioral assessment made in the laboratory at 4 months of age. This is the earliest known human behavioral phenotype that predicts individual differences in patterns of neural activity at maturity. These temperamental differences rooted in infancy may be relevant to understanding individual differences in vulnerability and resilience to clinical psychiatric disorder. Males who were HR infants showed particularly high levels of reactivity to novel faces in the amygdala that distinguished them as adults from all other sex/temperament subgroups, suggesting that their amygdala is particularly prone to engagement by unfamiliar faces. These findings underline the importance of taking gender into account when studying the developmental neurobiology of human temperament and anxiety disorders. The genetic study of behavioral and biologic intermediate phenotypes (or ‘endophenotypes’) indexing anxiety-proneness offers an important alternative to examining phenotypes based on clinically defined disorder. As the HR phenotype is characterized by specific patterns of reactivity to elemental visual, olfactory and auditory stimuli, well before complex social behaviors such as shyness or fearful interaction with strangers can be observed, it may be closer to underlying neurobiological mechanisms than behavioral profiles observed later in life. This possibility, together with the fact that environmental factors have less time to impact the 4-month phenotype, suggests that this temperamental profile may be a fruitful target for high-risk genetic studies.

CONTEXTThe 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.OBJECTIVETo 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.DESIGNStructural 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.SETTINGAthinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital.PARTICIPANTSSeventy-six subjects who were high-reactive or low-reactive infants at 4 months of age.MAIN OUTCOME MEASURECortical thickness.RESULTSAdults 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.CONCLUSIONSTo 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.

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.

ABSTRACT 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.

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.

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. (C) 2003 Society of Biological Psychiatry.

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.

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.

Objective: Chess and Thomas suggested that temperament might make a contribution to social phobia and other forms of extreme social anxiety. This study provides the first investigation of the outcomes in adolescents who had been inhibited (subdued to and avoidant of novelty) or uninhibited (approaching novelty) in the second year of life, utilizing both direct interview and direct observation. Method: Seventy-nine subjects, aged 13 years, who had been classified as inhibited or uninhibited in the second year were assessed with both standardized interview and direct observation. Results: There was a significant association between earlier classification of a child as inhibited and generalized social anxiety at adolescence, but no association with specific fears, separation anxiety, or performance anxiety. The adolescents who were classified as socially anxious made fewer spontaneous comments than those without social anxiety; no relation was seen between any other type of fear and the number of spontaneous comments. Adolescent girls who had been inhibited as toddlers were more likely to be impaired by generalized social anxiety than boys. Conclusions: The interview and observational data indicate that important aspects of an inhibited temperament are preserved from the second year of life to early adolescence, which predispose an adolescent to social anxiety.

Adolescents who had been classified as behaviorally inhibited in the second year of life were given a version of the Stroop Interference test using words from three different affective categories: threatening, positive, and neutral. Examination of the longest latencies produced by each subject revealed that those adolescents who had been inhibited as young children, compared with those who had been uninhibited, had more words with threatening symbolic content among their longest latencies. This result suggests that some important aspects of the original temperamental profile have been preserved over an 11-year period. The modified Stroop Interference test may be a sensitive probe for an underlying psychological/physiological vulnerability, which is apparently present in inhibited youngsters, that may place child at risk for later anxiety disorder.

Two cohorts of adolescents who were categorized at either 21 or 31 months of age as extremely inhibited or uninhibited completed the Youth Self-Report (YSR), and their parents completed the Child Behavior Checklist (CBCL). In the second year, inhibited children typically cease ongoing behavior and vocalizing, seek comfort from a familiar person, or withdraw in response to unfamiliar situations. By contrast uninhibited children do not become subdued by novelty and are sociable and outgoing, often vocalizing, smiling, and approaching unfamiliar persons or objects. The 13-year-old adolescents who had been categorized as inhibited at 21 months of age scored significantly lower than adolescents originally classified as uninhibited on the Total Externalizing, Delinquent Behavior, and Aggressive Behavior Scales. Parental ratings of Total Externalizing and Aggressive behavior on the CBCL agreed with the Youth Self-Report. The second cohort of adolescents who had been selected at 31 months yielded similar findings, but only for males. These results suggest that important aspects of the original temperamental profile have been preserved over a 12-year period.