A phenotype of early infancy predicts reactivity of the amygdala in male adults.

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.

Temperamental contributions to the affect family of anxiety.

The discovery of pharmacologic interventions that mute the intensity of anxiety and guilt in some individuals has been a benevolent gift to those who suffer from these disabling states. Although some commentators have wondered about the social consequences of large numbers of asymptomatic persons taking these drugs, few have questioned the advantages for the smaller group of anguished patients. It is likely, however, that, during the next century, scientists will discover a drug that eliminates the feeling components of guilt and remorse while leaving intact the semantic knowledge that certain acts are ethically improper. An individual who took this drug regularly would continue to know that deceiving a friend, lying to a client, and stealing from an employer are morally wrong but would be protected from the uncomfortable feeling of guilt or remorse that accompanies a violation of a personal moral standard. It is reasonable to wonder, therefore, whether our society would be changed in a major way if many citizens were protected from guilt and remorse. Most Western philosophers, especially Kant, made reason the bedrock of conscience. People acted properly, Kant believed, because they knew that the behavior was morally right. All individuals wish to regard the self as virtuous and try to avoid the uncertainty that follows detection of the inconsistency that is created when they behave in ways that are not in accord with their view of the self's desirable attributes. Kant believed that, although the moral emotions restrain asocial acts, they were not necessary for the conduct of a moral life. On the other hand, some philosophers, such as Peirce and Dewey, argued that anticipation of anxiety, shame, and guilt motivate a continued loyalty to one's ethical standards. A person who was certain that he or she was protected from these uncomfortable emotions would find it easier to ignore the moral imperatives acquired during childhood and adolescence. It is not obvious that a drug that blocks remorse also will eliminate the mutual social obligations that make a society habitable; nonetheless, a posture of vigilance that is appropriate for--unlike gorillas--humans can hold representations of envy, anger, and dislike toward people they have never met for a very long time. While we wait for future inquiry to resolve this issue, it is useful to acknowledge that a satisfying analysis of this problem will require a deeper appreciation of the differences between the representations of the biological events that are the foundation of an emotion and the representations that define the semantic networks for the concepts good and bad.

Further evidence of association between behavioral inhibition and social anxiety in children.

OBJECTIVE: The authors sought to examine psychopathological correlates of behavioral inhibition in young offspring of parents with panic disorder and/or major depression. METHOD: Behavioral inhibition, determined by using standard laboratory observations, was assessed in four groups of children (age 2-6 years): 129 children of parents with both panic disorder and major depression, 22 children of parents with panic disorder alone, 49 children of parents with major depression alone, and 84 comparison children of parents with neither panic disorder nor major depression. Psychopathology in children > or =5 years was compared between children with behavioral inhibition (N=64) and without (N=152). RESULTS: Social anxiety disorder (social phobia or avoidant disorder) was significantly more likely to be found in the children with behavioral inhibition (17%) than in those without (5%). Noninhibited children were significantly more likely than inhibited children to have disruptive behavior disorders (20% versus 6%, respectively) and had higher scores on the attention problems scale of the Child Behavior Checklist (mean=52.1 versus 50.8). CONCLUSIONS: This study adds to the growing literature suggesting an association between behavioral inhibition and social anxiety disorder and an inverse relationship between inhibition and disruptive behavior disorders.

Infant temperament and the brainstem auditory evoked response in later childhood.

Brainstem auditory evoked responses (BAERs) were evaluated on 10-12-year-old children (N = 56) who had been classified as high or low reactive to unfamiliar stimuli at 4 months of age. BAER measurement was selected because high reactive infants tend to become inhibited or fearful young children, and adult introverts have a faster latency to wave V of the BAER than do extroverts. Children previously classified as high reactive at 4 months had larger wave V components than did low reactive children, a finding that possibly suggests greater excitability in projections to the inferior colliculus. The fact that a fundamental feature of brainstem activity differentiated preadolescent children belonging to two early temperamental groups supports the value of gathering physiological data in temperament research.

Genetic association analysis of behavioral inhibition using candidate loci from mouse models.

Genes influence the development of anxiety disorders, but the specific loci involved are not known. Genetic association studies of anxiety disorders are complicated by the complexity of the phenotypes and the difficulty in identifying appropriate candidate loci. We have begun to examine the genetics of behavioral inhibition to the unfamiliar (BI), a heritable temperamental predisposition that is a developmental and familial risk factor for panic and phobic disorders. Specific loci associated with homologous phenotypes in mouse models provide compelling candidate genes for human BI. We conducted family-based association analyses of BI using four genes derived from genetic studies of mouse models with features of behavioral inhibition. The sample included families of 72 children classified as inhibited by structured behavioral assessments. We observed modest evidence of association (P = 0.05) between BI and the glutamic acid decarboxylase gene (65 kDA isoform), which encodes an enzyme involved in GABA synthesis. No significant evidence of association was observed for the genes encoding the adenosine A(1A) receptor, the adenosine A(2A) receptor, or preproenkephalin. This study illustrates the potential utility of using candidate genes derived from mouse models to dissect the genetic basis of BI, a possible intermediate phenotype for panic and phobic disorders.

A controlled study of behavioral inhibition in children of parents with panic disorder and depression.

OBJECTIVE: "Behavioral inhibition to the unfamiliar" has been proposed as a precursor to anxiety disorders. Children with behavioral inhibition are cautious, quiet, introverted, and shy in unfamiliar situations. Several lines of evidence suggest that behavioral inhibition is an index of anxiety proneness. The authors sought to replicate prior findings and examine the specificity of the association between behavioral inhibition and anxiety. METHOD: Laboratory-based behavioral observations were used to assess behavioral inhibition in 129 young children of parents with panic disorder and major depression, 22 children of parents with panic disorder without major depression, 49 children of parents with major depression without panic disorder, and 84 children of parents without anxiety disorders or major depression (comparison group). A standard definition of behavioral inhibition based on previous research ("dichotomous behavioral inhibition") was compared with two other definitions. RESULTS: Dichotomous behavioral inhibition was most frequent among the children of parents with panic disorder plus major depression (29% versus 12% in comparison subjects). For all definitions, the univariate effects of parental major depression were significant (conferring a twofold risk for behavioral inhibition), and for most definitions the effects of parental panic disorder conferred a twofold risk as well. CONCLUSIONS: These results suggest that the comorbidity of panic disorder and major depression accounts for much of the observed familial link between parental panic disorder and childhood behavioral inhibition. Further work is needed to elucidate the role of parental major depression in conferring risk for behavioral inhibition in children.

Temperature asymmetry and behavior.

Asymmetries in the surface temperature of the fingertips of the right and left hands were gathered on four independent samples of children ranging in age from 4 to 8 years (N = 398) while watching film clips in order to determine if the direction or magnitude of asymmetry was related to behavioral signs of fear or inhibition. The left index finger was cooler than the right index finger for all four groups. The right ring finger was cooler than the left ring finger for two of the four groups, and of similar temperature for the other two groups. There was no relation between direction of asymmetry and behavior and only a modest relation between a large temperature asymmetry between the index fingers and behavioral signs of very high fear or inhibition. There was no relation between asymmetry and fear or inhibition across all children, suggesting the utility of examining extreme scores.

Taxonic structure of infant reactivity: evidence from a taxometric perspective.

Previously, we proposed a theoretical framework that classified infants into qualitative categories of reactivity, rather than on a continuous dimension. The present research used an objective statistical procedure (maximum covariance analysis, or MAXCOV) to determine if a qualitative latent structure, consistent with our theoretical conjectures, would be found to underlie quantitative indices of reactivity to stimuli in a sample of 599 four-month-old infants. Results of the MAXCOV analysis showed clear evidence of a latent discontinuity underlying the behavioral measures of infant reactivity. The base rate of the latent class (or taxon) was estimated at 10%. Infants within the putative high-reactivity taxon, compared with infants not in the taxon, were elevated on measures of behavioral inhibition at 4.5 years. These results provide objective empirical support for a central tenet in our theoretical model by supporting the taxonicity of infant reactivity.

Early childhood predictors of adult anxiety disorders.

This paper considers the influence of temperamental factors on the development of anxious symptoms in children and adolescents. About 20 percent of healthy children are born with a temperamental bias that predisposes them to be highly reactive to unfamiliar stimulation as infants and to be fearful of or avoidant to unfamiliar events and people as young children. Experiences act on this initial temperamental bias and, by adolescence, about one-third of this group is likely to show signs of serious social anxiety. These children are also likely to have one or more biological features, including a sympathetically more reactive cardiovascular system, asymmetry of cortical activation in EEG favoring a more active right frontal area, more power in the EEG in the higher frequency range, and a narrower facial skeleton. The data imply that this temperamental bias should be conceptualized as constraining the probability of developing a consistently fearless and spontaneous profile rather than as determining an anxious or introverted phenotype.

Adolescent social anxiety as an outcome of inhibited temperament in childhood.

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.

Behavioral inhibition in children from families at high risk for developing alcoholism.

OBJECTIVE: To determine whether children at risk for the development of adult alcohol dependence would show greater "behavioral inhibition" to the unfamiliar, an early childhood temperament characteristic. METHOD: One hundred peer play evaluations were conducted blindly with preschool children from families selected to be at high or low risk for developing alcohol dependence. Each child was paired with different children (same-sex pairs) in independent sessions to determine the stability of the behavioral response. RESULTS: High-risk children spent significantly more time staring at the other child during the peer play session while refraining from engaging in play, and significantly less time speaking to the other child. Significantly more time was spent proximal to the parent, but only on the first peer play session. These behaviors have been shown to be indicators of behavioral inhibition. CONCLUSIONS: These findings suggest that the presence of behavioral inhibition to the unfamiliar in childhood may be a risk factor for later development of alcohol dependence. While there is abundant evidence that childhood externalizing behaviors are risk factors for later development of substance dependence, the present results suggest that internalizing behaviors may be a pathway as well.

Startle potentiation by threat of aversive stimuli and darkness in adolescents: a multi-site study.

In recent years, the startle reflex has become an exciting new tool to investigate affective responses to aversive stimuli in humans. The popularity of this methodology is largely based on the substantial amount of animal research available on this topic. Several procedures have been developed to examine startle potentiation in humans, but most studies have been carried out in adults and may not be appropriate for children or adolescents. The present study is a multi-site project (Yale University, Harvard University, and the University of Minnesota) investigating two new procedures to examine the potentiation of startle in adolescents. The subjects were 50 male and female aged 13-17 years old. One procedure examined fear-potentiated startle to the threat of an unpleasant airblast directed to the larynx. The second examined the facilitation of startle in darkness. Potentiation was found using each procedure and the degree of potentiation was similar across laboratories. These results suggest that both the threat of an airblast and darkness can reliably be used to examine startle potentiation in young subjects.

Infant temperament and anxious symptoms in school age children.

A group of 164 children from different infant temperament categories were seen at 7 years of age for a laboratory battery that included behavioral and physiological measurements. The major results indicated that children who had been classified as high reactive infants at 4 months of age, compared with infants classified as low reactive, (a) were more vulnerable to the development of anxious symptoms at age 7 years, (b) were more subdued in their interactions with a female examiner, (c) made fewer errors on a task requiring inhibition of a reflex, and (d) were more reflective. Further, the high reactives who developed anxious symptoms differed from the high reactives without anxious symptoms with respect to fearful behavior in the second year and, at age 7 years, higher diastolic blood pressure, a narrower facial skeleton, and greater magnitude of cooling of the temperature of the fingertips to cognitive challenge. Finally, variation in magnitude of interference to fearful or aggressive pictures on a modified Stroop procedure failed to differentiate anxious from nonanxious or high from low reactive children.

Childhood derivatives of high and low reactivity in infancy.

A group of 193 children, classified as high or low reactive to stimulation at 4 months and observed again at 14 and 21 months, were observed at 4 1/2 years of age for behavioral signs of inhibited or uninhibited behavior. Children who had been high reactive were less spontaneous and less sociable than those who had been classified as low reactive, but only a small proportion of children maintained a consistently inhibited or uninhibited phenotype at all ages.

Asymmetry of finger temperature and early behavior.

Measures of the temperature of the fingertips of eighty-three 4-year-old children revealed an unexpected asymmetry in which the index finger of the left hand but the ring finger of the right hand were the coolest digits. In addition, a subset of 20 children who had the coolest right compared with the left ring finger were more fearful to unfamiliar events and also had a cooler right than left forehead at 21 months of age.

Cardiac function and behavioral reactivity during infancy.

Longitudinal cardiac data from the end of the fetal period to 21 months of age were examined for change and stability over age and relations to the temperamental characteristics of high and low reactivity at 4 months of age and fear to the unfamiliar in the second year. Heart period and power in the cardiac spectra changed dramatically over the first 2 years, and individual differences were not preserved until 9-14 months of age. Sleep heart period at 2 weeks of age and low frequency power at 2 months of age were better predictors of the temperamental categories than later measures of the same variables, suggesting that cardiac function early in life may be an especially sensitive index of temperamental qualities.

Stable behavioral inhibition and its association with anxiety disorder.

"Behavioral inhibition to the unfamiliar" is a temperamental construct reflecting the tendency to be shy, timid, and constrained in novel situations. Previous work has suggested that it may be associated with anxiety disorders in children. Psychopathology was assessed in children from a nonclinical sample originally identified as behaviorally inhibited or uninhibited at 21 months and followed through 7 1/2 years. Children who remained inhibited at 4, 5 1/2 and 7 1/2 years (Stable Inhibited) had higher rates of anxiety disorders than children who were not consistently inhibited. Their parents had higher rates of multiple childhood anxiety disorders and of continuing anxiety disorder. These results suggest that the association between behavioral inhibition and anxiety disorder is accounted for by children who have stable behavioral inhibition.

Temperamental factors in human development.

The initial dispositions to approach or to avoid unfamiliar events are 2 temperamental characteristics of children--among the many that have been described--that appear to be moderately stable over time and associated with distinct, physiological profiles that may be under partial genetic control. The display of high versus low levels of both motor activity and crying to unfamiliar in 4-month-old infants predicts these 2 temperamental profiles in the 2nd year. This fact implies, but does not prove, that variation in the excitability of those brain areas that mediate motor activity and crying participates in the actualization of the temperamental categories called inhibited and uninhibited to the unfamiliar.

Temperament and allergic symptoms.

Two independent studies of the first and second degree relatives of extremely shy versus sociable children revealed greater prevalence of hayfever and social anxiety among the relatives of the former group of children. These data, which are in accord with other research, imply a genetically mediated relation between social anxiety and selected atopic allergies.