Behavioural inhibition and the development of childhood anxiety disorders

Jaap Oosterlaan
Children differ in their initial reactions to novel circumstances. Some children show a propensity to react consistently to novelty and unfamiliarity with initial restraint and avoidance. These children are referred to as temperamentally behaviourally inhibited. In this chapter, the suggestion is explored that behavioural inhibition (hereafter called inhibition) may predispose a child to the development of anxiety disorders. After reviewing research on the temperamental quality of inhibition, three areas of research are described that bear on the relation between inhibition and childhood anxiety disorders. First, studies are described which have examined the hypothesized predictive relation between temperamental inhibition and anxiety disorders. Second, the Behavioural Inhibition System (BIS; Gray, 1987, 1988, 1991) is proposed as a plausible neuropsychological substrate for the predictive association between temperamental inhibition and childhood anxiety disorders. Specifically, it is suggested that an overactive BIS seems to underlie the temperamental quality of inhibition as well as pathological anxiety. Third, research is reviewed which bears on the overactive BIS hypothesis for childhood anxiety disorders. The literature on the relation between temperamental inhibition and anxiety disorders has been reviewed by others (Biederman et al., 1995; Pollock et al., 1995; Rosenbaum et al., 1993; Turner, Beidel & Wolff, 1996). This chapter reviews the more recent findings and focuses in particular on childhood anxiety disorders. Further, the chapter attempts to link the literature on the temperamental construct of inhibition with the notion of the BIS. Inhibition as a temperamental construct Inhibition may be defined as a temperamentally based predisposition of children to react consistently to novel and unfamiliar events, both social and nonsocial, with initial restraint and avoidance together with signs of wariness 45 and fear (Reznick et al., 1992). In response to encounters with unfamiliar objects, people and situations, these children show a tendency to become quiet, cease activity, retreat, and seek proximity to a familiar person. Uninhibited children show the opposite behavioural pattern. Inhibited and uninhibited behaviour have been regarded as early manifestations of adult introversion and extroversion, respectively (Broberg, Lamb & Hwang, 1990; Kagan, 1989a; Matheny, 1989; Robinson et al., 1992). The concept of temperamental inhibition shows considerable overlap with notions such as withdrawn, shy, fearful, timid, unsociable, vigilant and cautious (Gersten, 1989). Studies investigating the temperamental trait of inhibition in children have mostly relied on direct observations in laboratory situations. Different situations have been used to study inhibition across development. For example, 4-month-old infants have been studied for inhibition using visual stimuli and auditory stimuli presented in

increasing intensity (Snidman et al., 1995). Children of about 2 years have been observed for their interaction with a strange adult and for their response to presentation with a robot (Reznick et al., 1989). Studies of older children have typically used social situations to elicit inhibited behaviour, for example a play group consisting of same sex and age peers (Kagan, 1989a). The resultant measures of temperamental inhibition are approximately normally distributed. Studies have selected the top and bottom parts of the distribution to represent inhibited and uninhibited children, respectively. Among studies, the percentage of children classified as inhibited varies between the top 1040% of the distribution (Kagan, Reznick & Gibbons, 1989; Scarpa et al., 1995). It is noted in passing, however, that there is debate about whether the concept of inhibition should be approached dimensionally or categorically (Kagan & Snidman, 1991b; Reznick et al., 1989). According to the dimensional approach, inhibition refers to a continuous trait such that any child can be ordered on a continuum or dimension that ranges from extremely inhibited to extremely uninhibited behaviour. Such an approach makes definitions of inhibited and uninhibited behaviour arbitrary. In contrast, according to the categorical approach, children who display inhibited or uninhibited behavior represent qualitatively distinct groups. In favour of the latter view, some physiological correlates of inhibition show a noncontinuous distribution (Kagan et al., 1989; Kagan, Reznick & Snidman, 1987, 1988; Kagan & Snidman, 1991b; Snidman et al., 1995). The most extensive research conducted on the temperamental quality of inhibition in childhood, has been the longitudinal research begun by Garcia- Coll and continued by Kagan and colleagues (for critical reviews see Rothbart & Mauro, 1990; Turner et al., 1996; also see Gersten, 1989; Kagan, 1989a,b; Kagan et al., 1987, 1988). These investigators have prospectively studied inhibition in two samples of inhibited and uninhibited children. One sample was studied from 21 months onward, the second from 31 months onward. Both samples were studied through to 7.5 years of age. Findings indicated moderate stability of temperamental inhibition over time and cross-situational consistency for widely varying contexts, including the laboratory, the school and the home. Kagan (1989b) claimed that three-quarters of the children classified as either inhibited or uninhibited in their second year of life, exhibited signs of this classification through their 8th year. This finding is remarkable given the differences in the indices of inhibition used across follow-up. However, results also suggested that inhibition is not an irreversible attribute. Several studies have essentially replicated these results using samples of temperamentally inhibited and uninhibited children (Kagan & Snidman, 1991b; Kagan, Snidman & Arcus, 1992; Mullen, Snidman & Kagan, 1993; Snidman et al., 1995) as well as nonselected samples (Asendorpf, 1990; Broberg et al., 1990; Kagan et al., 1989; Matheny, 1989; Reznick et al., 1989; Robinson et al., 1992; Scarpa et al., 1995). Together these studies span the age range of 0 to 11 years of age. Stability of inhibition is higher in children who demonstrate extremely inhibited or extremely uninhibited behaviour than in nonselected samples. Several studies have found that more girls than boys show temperamentally inhibited behaviour (Reznick et al., 1989; Robinson et al., 1992; Scarpa et al., 1995). Moreover, girls were found to be overrepresented in children who remain consistently inhibited over time (Scarpa et al., 1995). Probably, these

findings reflect prevailing sex-role stereotypes of girls expected to be more inhibited and boys expected to display less inhibited behaviour. Two studies with infants, however, have failed to find gender differences (Broberg et al., 1990; Kagan & Snidman, 1991a). Results of studies with twins indicate that there is an important genetic influence on temperamental inhibition in samples of 1- to 2.5-year-old children (DiLalla, Kagan & Reznick, 1994; Emde et al., 1992; Matheny, 1989; Robinson et al., 1992). Heritability reflects the extent to which the observed variance in inhibition can be attributed to genetic influences. Twin studies use monozygotic twin pairs, who are genetically identical, and dizygotic twin pairs, who on average share half the genetic material passed to them from their mother and father. An estimate of heritability (h2) can be obtained by doubling the difference between the correlations for inhibited behaviour in monozygotic twins and in dizygotic twins. Estimates of heritability in nonselected samples range from h2 = 0.42 (Robinson et al., 1992) to h2 =0.70 (DiLalla et al., 1994), indicating modest to high genetic influence. Findings suggest that heritability may be particularly salient for extremely temperamentally inhibited and uninhibited behavior (DiLalla et al., 1994; Robinson et al., 1992). Studies have also found evidence for substantial genetic contributions to continuity and change in inhibited behavior over time, and to stability across situations. That is, monozygotic twins showed greater similarity in changes in inhibited behaviour over time and across situations than dizygotic twins (Matheny, 1989; Robinson et al., 1992). Kagan and colleagues (Kagan et al., 1987, 1988) have suggested that extreme temperamentally inhibited behaviour may be related to enhanced excitability of the limbic system, and especially the amygdala and hypothalamus. On the basis of this hypothesis, inhibited children are expected to show greater reactivity in the systems that are controlled by these structures. Three such systems are: the sympathetic nervous system, the reticular formation with its projections to the skeletal muscles, and the hypothalamic-pituitary-adrenal axis. Findings with temperamentally inhibited children have yielded support for increased reactivity in the sympathetic nervous system. Compared with uninhibited children, inhibited children demonstrate higher and more stable heart rates, as well as larger heart rate accelerations, larger diastolic blood pressure, larger pupillary dilation, and higher levels of norepinephrine to specific challenges. Furthermore, inhibited children evidence greater skeletal muscle tension and higher levels of salivary cortisol. These results support the idea of increased activity in the reticular formation and the hypothalamic-pituitaryadrenal axis, respectively (Kagan et al., 1987, 1988, 1989). Evidence for greater sympathetic reactivity has also been found in infants who showed signs indicative of temperamentally inhibited behaviour at age 4 months. Specifically, these children showed greater sympathetic reactivity in the cardiovascular system 2 weeks before birth and at later follow-up assessments compared with infants who did not show evidence of inhibition (Kagan, 1997; Kagan & Snidman, 1991b; Snidman et al., 1995).

To summarize, temperamental inhibition can already be observed in infants and seems to be fairly stable over the years of childhood. This behavioural tendency seems to be under powerful genetic control and is associated with specific physiological correlates, such as increased sympathetic reactivity. Temperamental inhibition: a precursor of (childhood) anxiety disorders? In this section, studies investigating the hypothesized predictive relation between temperamental inhibition and anxiety disorders are reviewed. Table 3.1 summarizes the pertinent studies in terms of aim of the studies, subjects, results and methodological issues. Six of the studies used a cross-sectional design; three studies reported a longitudinal investigation of inhibited children. With the exception of the Reznick et al. (1992) and Caspi et al. (1996) studies, all research has been conducted by Kagan and colleagues. Kagan and colleagues have utilized two different samples. The first sample(here referred to as the clinical sample) consisted of 56 children in the age range of 2 to 7 years, who were stratified into four groups: 13 children had a parent with panic disorder and agoraphobia (PDAG), 10 children had a parent with major depressive disorder (MDD), 20 children had a parent with a combination of PDAG and MDD, and 13 children had a parent neither diagnosed with PDAG, nor with MDD (non-PDAG/non-MDD group). Children from the clinical sample were classified either as inhibited or as not-inhibited and have been involved in different studies, including a 3-year follow-up study (Biederman et al., 1993). The second sample comprised children from the two cohorts of children described earlier (see p. 47) who were characterized as inhibited or uninhibited at 21 or 31 months of age and followed longitudinally to age 7.5 years (here referred to as the nonclinical sample). Note that the definition of children without inhibition differed for the clinical and nonclinical samples. In the nonclinical sample, children were selected for not being inhibited (i.e. these children demonstrated the opposite behaviour to unfamiliarity compared with inhibited children). In contrast, in the clinical sample, this group comprised children who did not show inhibited behaviour to unfamiliarity rather than uninhibited behaviour. Hence, these children were labelled not-inhibited. The first study that investigated the association between temperamental inhibition and anxiety disorders is the study by Rosenbaum et al. (1988). These authors argued that, if inhibition reflects a predisposition for anxiety disorders, inhibition would be more prevalent in children at risk for these disorders than in children who are not at risk. Using the previously described clinical sample, it was found that children at risk for anxiety disorders (i.e. those with a parent in the PDAG or PDAG+MDD group), demonstrated higher rates of inhibition than children not at risk (i.e. children with a parent in the non-PDAG/non- MDD group). In a subsequent study, Biederman et al. (1990) investigated whether inhibited children have an increased risk for anxiety disorders compared with children not classified as inhibited. This study used the nonclinical sample, the clinical sample and a group of normal control children. The results showed that inhibited children indeed had an increased risk for childhood anxiety disorders. In a third study, Rosenbaum et al. (1991) reasoned that, if inhibition is linked with a familial

predisposition to anxiety disorders, parents and siblings of inhibited children should be at increased risk for anxiety disorders. Using the nonclinical sample, it was found that parents of inhibited children had higher rates of anxiety disorders than parents of children who are uninhibited and parents of normal control children. However, similar differences were not noted for siblings. Not all inhibited children develop anxiety disorders. Hirshfeld et al. (1992) argued that, if inhibition reflects an enhanced vulnerability to develop anxiety disorders, children who remain consistently inhibited over time would have a greater risk for anxiety disorders than children who fail to do so. In addition, they hypothesized that, if inhibition is an expression of a familial predisposition, the relatives of children who remain consistently inhibited over time should show a higher prevalence of anxiety disorders than the relatives of children who do not remain consistently inhibited over time. Using children from the nonclinical sample, both hypotheses were supported: children who remained inhibited over a period of 5 years were more likely than other children to have anxiety disorders themselves and to have relatives with an anxiety disorder. No such differences were noted between children who did not remain consistently inhibited over time and children classified as (consistently) uninhibited. In a subsequent study, Rosenbaum et al. (1992) hypothesized that the risk for anxiety disorders in inhibited children should be greater in those children who have in addition parents with anxiety disorders than in children whose parents do not have anxiety disorders. To test this hypothesis, Rosenbaum et al. stratified children from both the clinical and the nonclinical sample into three groups on the basis of the presence or absence of inhibition and anxiety disorder. In an attempt to increase the specificity of the diagnosis of anxiety disorders, this diagnosis was made only if diagnostic criteria for two or more anxiety disorders were met on a structured diagnostic interview. Thus, three groups were included in the Rosenbaum et al. study: (1) inhibited children with anxiety disorders, (2) children whomanifested inhibition alone, and (3) children with neither inhibition nor anxiety disorders. These three groups were compared for the presence or absence of anxiety disorder in their parents. The results showed that parents of inhibited children with anxiety disorders had higher rates of anxiety disorders than the other two groups of parents. No differences were noted between parents of inhibited children without an anxiety disorder and parents of children who were neither inhibited nor had an anxiety disorder. Parental anxiety disorders may thus help to identify those inhibited children at increased risk to develop anxiety disorders. One of the studies that has yielded the most powerful support for inhibition as a predictor of later anxiety disorders is the longitudinal study by Biederman et al. (1993). In this study, inhibited children and children not classified as inhibited were followed for 3 years. Children came from both the clinical and nonclinical sample. At follow-up, inhibited children showed higher rates of anxiety disorders than not-inhibited children. Importantly, among inhibited children the rates of anxiety disorders increased from baseline to follow-up. The most recent study by the Kagan group investigated parent-and selfreported psychiatric correlates at 10- to 11-years follow-up in the nonclinical sample (Schwartz, Snidman & Kagan, 1996). Based on the findings of previous studies (Biederman et al., 1990; Hirshfeld et al., 1992), it was

hypothesized that inhibited children would show more internalizing symptoms, whereas uninhibited children were predicted to show more externalizing symptoms. In contrast to what was hypothesized, the two groups did not differ for internalizing symptoms. However, support was found for the hypothesis that uninhibited children would show more externalizing symptoms than inhibited children. Besides Kagan and colleagues, only Reznick et al. (1992) and Caspi et al. (1996) have studied the hypothesized predictive association between inhibition and anxiety disorders. Reznick et al. studied undergraduate students and three groups of adults, including a panic disorder group, a depression group and a normal control group. Using a newly developed questionnaire, a retrospective self-report of childhood inhibition was obtained. For the undergraduates, inhibition was associated with self-reported mental health problems (questions about whether they had ever used psychopharmacological medication, and whether they had ever been diagnosed as having depression or an anxiety disorder), and with self-reports of state anxiety and depression. The association with anxiety and depression wasmediated by those subjects who continued to be inhibited through adulthood. Furthermore, it was found that adults with either panic disorder or depression reported more childhood inhibition than normal controls. However, the panic disorder group reported more childhood inhibition than the depression group. Thus inhibition was not specifically related to anxiety. Caspi et al. (1996) reported a 18-year follow-up study of a large representative sample of children, known as the New Zealand, Dunedin cohort. On the basis of behavioural observations at age 3 years, these children were classified as either inhibited, uninhibited or well-adjusted. At age 21 years, inhibited and uninhibited children were compared with well-adjusted children for anxiety disorders, mood disorders, antisocial personality disorder and alcohol dependence. In contrast to what was hypothesized, groups did not differ for the rates of anxiety disorders. Inhibited children, however, were more likely to meet diagnostic criteria for depression. Uninhibited children (Caspi et al. used the notion undercontrolled), were more likely to meet diagnostic criteria for antisocial personality disorder and to be involved in crime. Both groups were more likely to attempt suicide, and both groups had alcohol-related problems. To summarize, although most studies support the idea that temperamental inhibition is a possible precursor for anxiety disorders, some studies have failed to do so. The risk for anxiety disorders seems to be most pronounced in children who remain consistently inhibited over time and in children who have parents with anxiety disorders. However, the present findings should be interpreted with caution for several reasons. First, to investigate the role of temperamental inhibition as a precursor of anxiety disorders, a longitudinal design is needed. Other designs do not allow conclusions to be drawn about the direction of causation (i.e. whether inhibition really antecedes anxiety disorders). Only three of the eight studies employed a longitudinal design. Of these three studies, only one (Biederman et al., 1993) has yielded support for the hypothesis that inhibited children are at increased risk for anxiety disorders. Second, the results of these longitudinal studies seem to suggest that temperamental inhibition is only predictive of anxiety disorders across relatively short periods of time (Biederman et al., 1993), but not across relatively long periods of time (Caspi et al., 1996; Schwartz

et al., 1996). Third, the studies by Kagan et al. have capitalized on the same samples and utilized relatively small groups. Fourth, the full spectrum of psychiatric disorders was not assessed in any of these studies. Most studies have focused on the assessment of internalizing psychopathology, and on the assessment of anxiety disorders in particular. Where reported, the assessment of externalizing disorders was limited in nature, and in none of these studies was the possible presence of conduct disorder checked (Biederman et al., 1990; Caspi et al., 1996; Hirshfeld et al., 1992; Rosenbaum et al., 1991; Schwartz et al., 1996). Consequently, no clear conclusions can be drawn about the specificity of the relation between temperamental inhibition and anxiety disorders. Another drawback of the limited assessment of psychopathology is that the association between uninhibited behaviour and psychopathology remains largely unexplored. The available evidence suggests, however, that uninhibited behaviour is predictive of externalizing psychopathology. For example, Biederman et al. (1990) and Hirshfeld et al. (1992), studying the nonclinical sample, found that rates of oppositional defiant disorder (ODD) were higher in uninhibited children than in inhibited children. Schwartz et al. (1996) found that uninhibited children obtained higher self-and parent-reports of externalizing symptoms. In the Caspi et al. (1996) study, uninhibited children, compared with well-adjusted children, were more likely to meet diagnostic criteria for antisocial personality disorder and to be involved in crime. Finally, studies differed in the time-window in which disorders were assessed. Six of the eight studies reported lifetime prevalences of disorders. Caspi et al. (1996) studied the rates of disorders across a period of 12 months, whereas Schwartz et al. (1996) used a time-window of 6 months. In the latter two studies, inhibited children were not found to be at increased risk for anxiety disorders. Thus the chance of finding support for the predictive association between temperamental inhibition and anxiety disorders could be related to the time-window in which disorders were assessed. All in all, the current findings await replication and more attention should be devoted to the specificity of the association between temperamental inhibition and anxiety disorders. Grays neuropsychological conceptualization of inhibition: the Behavioural Inhibition System This section attempts to link the literature on the temperamental construct of inhibition with the notion of the BIS (Gray, 1987, 1988, 1991). It is suggested that an overactive BIS is a plausible neuropsychological conceptualization of temperamental inhibition. Furthermore, the BIS offers one possibility to explain the predictive link between temperamental inhibition and anxiety disorders: activity in the BIS is associated with anxiety, and overactivity in this brain system is associated with pathological anxiety. Extrapolating primarily from animal research, Gray has developed a neuropsychological

model of brain functioning (Gray, 1987, 1988, 1991). In this model, two primary and separate brain systems are distinguished that control behaviour: the BIS and the behavioural activation system (BAS). The BIS and the BAS each respond to a separate set of events with a specific set of behaviours. Both brain systems will be described briefly. The BIS responds to three classes of stimuli: (1) novel stimuli, (2) signals of impending punishment, and (3) stimuli which signal nonreward, i.e. the omission of anticipated reward or the termination of reward. Signals of punishment and nonreward have also been referred to as threatening or aversive stimuli. Activity in the BIS gives rise to three behavioural changes: (1) inhibition of all ongoing behaviour, (2) an increment in attention to the environment, such that more information is taken in, especially concerning novel features of the environment, and (3) an increment in the level of arousal, causing an increased readiness for action. Much of the empirical evidence for the existence and the working of the BIS is derived from studies investigating the effects of anxiolytic drugs. These drugs have been found to antagonize the operation of the BIS. According to Gray, activity in the BIS is accompanied by anxiety and overfunctioning of the BIS results in pathological anxiety. The core neurological structures that discharge the functions of the BIS are the septohippocampal system (septal area and hippocampus), the ascending noradrenergic fibres to the septohippocampal system that originate in the locus coeruleus, and the serotonergic afferents to the septohippocampal system originating in the median raphe in the brainstem. Other structures involved are the Papez loop, the entorhinal cortex which projects to the hippocampus, and the prefrontal cortex which projects to the entorhinal cortex and cingulated cortex. The BAS is sensitive to signals of reward and stimuli that signal the termination or omission of punishment (i.e. appetitive stimuli). This brain system serves to maximize reward (by approach to reward) and to minimize punishment (by escape from punishment or active avoidance of punishment). Activity in the BAS is suggested to give rise to positive emotional states. The key anatomical structures that discharge the functions of the BAS are the basal ganglia, the dopaminergic fibres that ascend from the mesencephalon to innervate the basal ganglia, the thalamic nuclei closely linked to the basal ganglia, and similarly the neocortical areas closely linked to the basal ganglia. To summarize briefly: In Grays model, behaviour is explained in terms of the activity of two opposing brain systems, the BIS, which is sensitive to novel stimuli as well as to signals of punishment and nonreward (threatening or aversive stimuli), and the BAS, which is sensitive to signals of reward and nonpunishment (appetitive stimuli). The BIS serves to inhibit behaviour, whereas the BAS controls the activation of behaviour. There are reciprocally inhibitory links between the two brain systems: activity in each of the systems tends to suppress activity in the other. According to Gray, individual differences in the strength of the BIS and the BAS, and their interaction, determine temperament. Gray uses the terms temperament and personality interchangeably. Individuals with high activity in the BIS would show

high levels of inhibition, as well as enhanced sensitivity to novelty and threatening or aversive stimuli. In contrast, individuals with high activity in the BAS would show high levels of behavioural activation and increased sensitivity to appetitive stimuli. According to Gray, individual differences in the intensity of the functioning of the BIS correspond to differences in trait anxiety, such that high BIS activity corresponds with high levels of trait anxiety. Individual differences in the intensity of the functioning of the BAS correspond to differences in impulsivity, such that high BAS activity corresponds with high levels of impulsivity. For the present discussion, it is important to emphasize that the BIS produces, amongst others, inhibition in response to novelty, i.e. the behaviours that characterize temperamental inhibition. In addition to inhibition, activity in the BIS is associated with anxiety, and overfunctioning of this brain system is linked with pathological anxiety. The BIS thereby provides a plausible neuropsychological basis for the predictive association between temperamental inhibition and childhood anxiety disorders. From this the extrapolation of Grays model to childhood anxiety disorders is straightforward, as has been noted by Quay (Quay, 1988a,b): These disorders may be traced back to overfunctioning of the BIS. Quay, however, has also used Grays neuropsychological model for the explanation of two other major childhood psychopathological disorders: attention deficit hyperactivity disorder (ADHD) and conduct disorder. Specifically, Quay has suggested that ADHD reflects a persistently underactive BIS (Quay, 1988a,b, 1997). Children with conduct disorder were proposed to have an overactive BAS that dominates the BIS (Quay, 1988a,b, 1993). Quays model has stimulated research into the functioning of the BIS and the BAS in children with ADHD and conduct disorder (for review see Quay, 1993, 1997). However, few studies have explored the validity of the overactive BIS hypothesis in childhood anxiety disorders. Evidence for the overfunctioning BIS hypothesis in childhood anxiety Disorders In this section, research will be reviewed which bears on the overactive BIS hypothesis for childhood anxiety disorders, including: (a) studies investigating inhibition, (b) a study investigating sensitivity to punishment and reward and (c) a study measuring salivary cortisol. A series of studies has employed the so-called stop task (Logan & Cowan,1984; Logan, Cowan & Davis, 1984) to investigate inhibition in diverse child psychopathological groups. Although the primary aim of these studies was to investigate inhibitory control in children with ADHD, children with other disorders, including children with anxiety disorders, were incorporated in these studies as comparison groups. The stop task is purported to measure the ability to stop a current course of action and has been suggested as a direct measure of BIS functioning (Daugherty & Quay, 1991). Briefly, the stop task requires fast and accurate execution of a reaction time task. Occasionally, a stop signal is presented, which requires the child to inhibit

the response. Stop signals are presented at different intervals before the subjects expected response. The shorter the interval, the more difficult it becomes to inhibit a response. Usually, the intervals are chosen such that the shortest interval will yield a probability of inhibition close to 0, whereas the longest interval will produce a probability of inhibition close to 1. There are two main dependent measures in the stop task: (a) the inhibition function, which reflects the efficiency of the inhibitory mechanism controlling for betweensubjects differences in the speed of responding, and (b) stop signal reaction time, which is an estimate of latency of the inhibitory process. Due to their hypothetically overactive BIS, children with anxiety disorders are expected to display a particularly strong capability for inhibition in the stop task. From Quays model, contrasting predictions could be made for children with ADHD and children with conduct disorder. Specifically, children with ADHD are expected to show inhibitory deficits due to their hypothetically underactive BIS (Quay, 1988a,b, 1997). In children with conduct disorder, the excessive BAS activity causes a strong tendency to activate behaviour that interferes with the capability for inhibition (Quay, 1988a,b, 1993). Thus, according to Quay, both ADHD and conduct disorder (CD) are associated with inhibitory deficits. However, the dysfunction underlying poor inhibition for these two groups of children is different. In a recent meta-analysis of studies with the stop task (Oosterlaan, Logan & Sergeant, 1998), strong evidence was found for the existence of an inhibitory deficit in children with ADHD and CD: both groups had flatter inhibition functions than normal control children. The impairment in inhibition was traced back to a slow inhibitory process. These findings lend support for Quays prediction that both ADHD and CD are associated with poor inhibition. Four studies have investigated inhibitory control in children with anxiety using the stop task. In two of these studies (Daugherty, Quay & Ramos, 1993; Oosterlaan & Sergeant, 1996), no support was obtained for the hypothesis that anxiety disorders are associated with enhanced levels of inhibition. Daugherty et al. (1993) studied 9- to 13-year-old children, including a small group of anxious children (n= 12). Subjects were selected from regular schools on the basis of a single teacher questionnaire. Consequently, the level of impairment in their anxious children may have been insufficient to find evidence for strong inhibition. Oosterlaan & Sergeant (1996) studied children in the age range 6 to 12 years. In this study, a group of 20 anxious children participated (including 13 boys), consisting of children who obtained scores above the 95th percentile on at least two questionnaire measures of anxiety administered to the parent, the teacher and the child. However, these children also obtained elevated parent and teacher ratings of ADHD and CD symptoms. Because ADHD and CD are associated with inhibitory deficits, the presence of associated ADHD and CD symptomsmay have attenuated the hypothesized enhanced levels of inhibition in these anxious children. Two other studies have found some support for the hypothesis that anxiety disorders are associated with strong inhibition (Oosterlaan & Sergeant, 1998; Pliszka et al., 1997). Oosterlaan & Sergeant (1998) used a modification of the stop task that exerts particularly high demands on the inhibitory process (De Jong, Coles & Logan, 1995; Logan & Burkell, 1986). Four small groups of children were compared: 11 anxious

children (six boys), 10 ADHD children (all boys), 11 disruptive children (nine boys), and 21 normal control children (15 boys). Subjects were in the age range 8 to 12 years. The anxious group consisted of children who obtained scores at or above the 95th percentile on at least two questionnaire measures of anxiety administered to the parent, the teacher and the child. It was found that anxious children showed better inhibition than normal children, but the two groups did not differ in their speed of the inhibitory process. However, ratings of anxiety, and ratings of ADHD and CD, differed in their association with the speed of the inhibitory process. Ratings of ADHD and CD correlated positively with the speed of the inhibitory process. In contrast, ratings of anxiety correlated negatively with the speed of the inhibitory process. That is, the higher the ratings of anxiety, the faster the inhibitory process. Pliszka et al. (1997) used a stop task to examine the impact of co-existing overanxious disorder on inhibitory control in a predominantly male sample of 6- to 10-year-old children with ADHD. Interestingly, the presence of concurrent anxiety disorder was found to attenuate the inhibition deficit in children with ADHD. Children with ADHD and co-existing overanxious disorder had better inhibition functions and faster inhibitory processes than children with only ADHD. These results support indirectly the hypothesis that anxiety disorders are associated with enhanced inhibition. A similar result has been obtained by Pliszka (1992). In this study, a task was used in which children had to react to different coloured shapes on a computer screen. However, when a blue square appeared on the screen, children had to inhibit their response. Three groups were studied: 58 children with ADHD, 34 children with ADHD and co-existing anxiety (child-reported overanxious disorder symptoms), and 12 normal control children. The majority of children in the three groups were boys (54, 29 and 9, respectively). Subjects were in the age range 612 years old. ADHD children were found to show inhibition deficits in comparison with normal controls. However, children with ADHD and co-existing anxiety did not differ from their normal peers. Interestingly, failures to inhibit correlated negatively with self-reported and parent-reported anxiety. Further support for enhanced levels of inhibition in anxiety disordered children was obtained in a study by Werry, Elkind & Reeves (1987). In this study, 21 anxious children (nine boys), 39 ADHD children (32 boys) and 35 children with comorbid ADHD+CD (31 boys) were compared with matched normal control children. Subjects were in the age range 5 to 13 years. When asked to draw a line as slowly as possible, anxious children showed longer latencies than normal controls. Children with ADHD and children with comorbid ADHD+CD did not differ from their normal peers. To summarize, the above studies yield some evidence for enhanced inhibition in children with anxiety disorders and children with high levels of anxiety, thereby supporting the overactive BIS hypothesis. Another prediction that could be derived from the hypothesis of increased BIS functioning in children with anxiety disorders is that these children would show increased sensitivity to aversive stimuli compared with their normal peers. This prediction was tested in a study by Daugherty & Quay (1991). Daugherty & Quay compared five small groups of children for their sensitivity to punishment and reward: nine anxious children, nine ADHD children, 10 CD children, 10 children with comorbid CD+ADHD, and 15 normal control children (7, 2, 5, 5 and 7 boys, respectively). These children were selected from

regular classes using teacher ratings. Children were in the age range of 8 to 12 years. Given their hypothetically overactive BAS, children with CD were predicted to show increased sensitivity to appetitive stimuli. Children were tested with a task in which credits could be earned and lost, simply by opening doors that were displayed on a computer screen. In this task, the probability of winning a credit decreased by 10% with each succeeding set of 10 trials (from 90 to 0%), whereas there was a complementary increase in the probability of losing credits. Children with CD (both the CD and the comorbid CD+ADHD group opened more doors than anxious and normal control children. Moreover, the majority of children with CD kept responding even when the odds were turning and more credits were lost than earned. In contrast, the majority of anxious children quit the task too early. That is, anxious children stopped responding even though more credits were earned than lost. These findings support the hypothesis of increased sensitivity for reward in children with CD as well as the hypothesis of increased sensitivity for punishment in children with anxiety disorders (Quay, 1988a,b, 1993, 1997). From the hypothesis that children with CD are characterized by both an overactive BAS and an underfunctioning of the BIS, it could be predicted that children with CD and co-existing anxiety disorder would be less impaired in their BIS functioning since anxiety is associated with overactivity in the BIS. This prediction was tested by McBurnett et al. (1991). Subjects were boys aged 8 to 13 years classified into four groups based on the presence or absence of CD and anxiety disorder (either separation anxiety disorder or overanxious disorder): 21 children with anxiety disorder, seven children with CD, 11 children with comorbid CD+anxiety disorder, and 28 children free from both CD and anxiety disorder. In this study, salivary cortisol was used as a measure of BIS functioning. Consistent with the hypothesis, children with both CD and co-existing anxiety disorder had higher levels of cortisol than children with CD alone. However, in the absence of CD, anxiety disorder was not clearly associated with higher levels of cortisol. To summarize, studies investigating diverse correlates of BIS functioning generally support the overfunctioning BIS hypothesis for anxiety disorders. However, research is scarce and findings await replication. Inhibition in childhood anxiety disorders: concluding remarks This chapter began with a discussion of the research that has been conducted on the temperamental quality of inhibition in children. Temperamental inhibition was described as a fairly stable and heritable trait to react consistently to novelty and unfamiliarity with initial restraint and avoidance. For this trait, specific physiological correlates have been found, including increased sympathetic reactivity. Next, three areas of research were discussed that bear on the suggestion that inhibition may be a predisposing factor in the development of childhood anxiety disorders. First, both cross-sectional and prospective studies showed that temperamental inhibition predicts anxiety disorders. The risk for anxiety disorders seems to be most pronounced in children who remain consistently inhibited over time, and in children who have parents with anxiety disorders. Second, there seems to be one brain system that mediates the behaviours associated with temperamental

inhibition, anxiety, as well as pathological anxiety: the BIS. An overactive BIS was put forward as a plausible neuropsychological substrate for the predictive link between temperamental inhibition and anxiety disorders. The core neurological structure that appears to discharge the functions of the BIS is the septohippocampal system. Third, studies of BIS correlates in anxiety-disordered children have supported the view that an overactive BIS is implicated in childhood anxiety disorders. All in all, there seems to be coherent evidence for a relation between inhibition and anxiety disorders in children. However, research is scarce and findings await replication. Little is known about how temperamental inhibition may lead to the development of childhood anxiety disorders. Turner et al. (1996) have suggested four different pathways. One hypothesis is that inhibition is a genetically transmitted trait that, by interaction with environmental factors, may culminate in the development of maladaptive anxiety. A second possibility is that inhibition is an inherited predisposition that makes a child particularly prone to respond intensely to anxiety producing events. This may ultimately result in the development of maladaptive anxiety. Third, inhibition may be a manifestation of a more comprehensive personality or behavioural disposition that predisposes to anxiety disorders, such as trait anxiety, neuroticism, negative affect and introversion. Finally, Turner et al. (1996) have suggested an overfunctioning BIS as a pathway by which inhibition may lead to childhood anxiety disorders. In this chapter the latter possibility is elaborated upon (see Figure 3.1). There is enough empirical evidence for the claim that some children have an inherited predisposition to react consistently with inhibition to situations of novelty and unfamiliarity. It is suggested that an overactive BIS is a plausible neuropsychological basis for this predisposition: the BIS produces, amongst others, inhibition in response to novelty, i.e. the behaviours that characterize temperamental inhibition. For some children, the overactivity in the BIS may lead to the development of pathological anxiety. Specifically, it is suggested that the undue activity in the BIS causes increased sensitivity to novelty, as well as sensitivity to cues signalling punishment and nonreward. This, in turn, may initiate a process of conditioning that generates avoidant behaviours and the development of anxious behaviour. Ultimately this may lead to the development of pathological anxiety. Indeed, activity in the BIS is associated with anxiety, and chronic overactivity in this brain system is linked with pathological anxiety. The BIS thereby provides a plausible neuropsychological basis for the predictive association between temperamental inhibition and childhood anxiety disorders. Evidence supports the idea of an overfunctioning BIS in children with pathological anxiety. It is clear that the association between temperamental inhibition and childhood anxiety disorders is not deterministic. Not all inhibited children develop anxiety disorders, and children with an anxiety disorder may not have a history of inhibition. Some uninhibited children may even develop anxiety disorders (Biederman et al., 1990, 1993; Hirshfeld et al., 1992). Inhibition may be seen as one factor that predisposes to the development of anxiety disorders, or if we assume that an overactive BIS underlies the temperamental trait of inhibition as an indicator of

an overfunctioning BIS which brings along an enhanced risk for the development of anxiety disorders. A variety of psychosocial influences may ultimately determine whether temperamental inhibition is followed by the onset of an anxiety disorder. For example, environmental influences may strengthen or counteract the over activity in the BIS. To illustrate, frequent experiences of being ignored (nonreward) or rejected (punishment) by peers may initiate a process of conditioning to these stimuli. This, in turn, may trigger BIS activity and lead to a vicious cycle with increasing levels of inhibition in situations with peers. Temperamentally inhibited children may be particularly prone to such a process of conditioning given their reluctance to engage in social interactions. Consistent with this reasoning, Asendorpf (1990) has reported a positive correlation between failed social interactions and inhibition. However, environmental influences may also counteract inhibition. Broberg (1993), for example, demonstrated that inhibited children in day-care facilities became less inhibited than children raised at home. It is important to note, however, that genetic factors seem to be much more powerful than environmental influences (Emde et al., 1992; Robinson et al., 1992). In addition to environmental influences, cognitive influences may be important. For example, cognitive factors may distort the perception of stimuli that activate the BIS (e.g. going to school may be perceived as threatening by a child with separation anxiety disorder, whereas it may be perceived as fun by a normal developing child). Extreme and persistent temperamental inhibition in childhood may indicate that a child is at risk for later anxiety disorders and thus may help identify children for preventive interventions. Longitudinal research is needed to study the transformation from temperamental inhibition to anxiety disorders. This kind of research would permit the study of factors that may protect against or further the development of anxiety disorders. In addition, more attention should be devoted to the study of the specificity of the relationship between temperamental inhibition and childhood anxiety disorders. First, little is known about whether inhibition is linked with particular kinds of childhood anxiety disorders. Second, future research should address the issue of whether inhibition is specifically related to anxiety disorders or a risk factor for the broader class of internalizing disorders. Third, research on inhibition has largely ignored the possible association between uninhibited behaviour and the development of externalizing psychopathology. Finally, more research is needed to test the validity of the overactive BIS hypothesis for temperamental inhibition as well as for anxiety disorders.

REFERENCES Asendorpf, J. B. (1990). Development of inhibition during childhood: Evidence for situational specificity and a two-factor model. Developmental Psychology, 26, 72130. Biederman, J., Rosenbaum, J. F., Bolduc-Murphy, E. A., et al. (1993). A 3-year follow-up of children with and without behavioral inhibition. Journal of the American Academy of Child and Adolescent Psychiatry, 32, 81421. Biederman, J., Rosenbaum, J. F., Chaloff, J. & Kagan, J. (1995). Behavioral inhibition as a risk factor for anxiety disorders. In Anxiety Disorders in Children and Adolescents, ed. J. S. March, pp. 6181. New York: Guilford Press. Biederman, J., Rosenbaum, J. F., Hirshfeld, D. R., et al. (1990). Psychiatric correlates of behavioral inhibition in young children of parents with and without psychiatric disorders. Archives of General Psychiatry, 47, 216. Broberg, A. (1993). Inhibition and childrens experiences of out-of-home care. In Social Withdrawal, Inhibition, and Shyness in Childhood, ed. K. H. Rubin & J. B. Asendorpf, pp. 15176. Hillsdale, NJ: Lawrence Erlbaum Associates. Broberg, A., Lamb, M. E. & Hwang, P. (1990). Inhibition: Its stability and correlates in sixteen-to forty-month-old children. Child Development, 61, 115363. Caspi, A., Moffitt, T. E., Newman, D. L. & Silva, P. A. (1996). Behavioral observations at age 3 years predict adult psychiatric disorders. Archives of General Psychiatry, 53, 10339. Daugherty, T. K. & Quay, H. C. (1991). Response perseveration and delayed responding in childhood behavior disorders. Journal of Child Psychology and Psychiatry, 32, 45361. Daugherty, T. K., Quay, H. C. & Ramos, L. (1993). Response perseveration, inhibitory control, and central dopaminergic activity in childhood behaviour disorders. Journal of Genetic Psychology, 154, 17788.

De Jong, R., Coles, M. G. H. & Logan, G. D. (1995). Strategies and mechanisms in nonselective and selective inhibitory motor control. Journal of Experimental Psychology, 21, 498511. DiLalla, L. F., Kagan, J. & Reznick, J. S. (1994). Genetic etiology of behavioral inhibition among 2-year-old children. Infant Behavior and Development, 17, 40512. Emde, R. N., Plomin, R., Robinson, J., et al. (1992). Temperament, emotion, and cognition at 14 months: The MacArthur longitudinal twin study. Child Development, 63, 143755. Gersten, M. (1989). Behavioral inhibition in the classroom. In Perspectives on Behavioral Inhibition, ed. J. S. Reznick, pp. 7191. Chicago, IL: University of Chicago Press. Gray, J. A. (1987). The Psychology of Fear and Stress (2nd edn). Cambridge, England: Cambridge University Press. Gray, J. A. (1988). The neuropsychological basis of anxiety. In Handbook of Anxiety Disorders, ed. C. Last & M. Hersen, pp. 1037. Elmsford, NY: Pergamon Press. Gray, J. A. (1991). The neuropsychology of temperament. In Explorations in Temperament: International Perspectives on Theory and Measurement, ed. J. Strelau & A. Angleitner, pp. 10528. London: Plenum Press. Hirshfeld, D. R., Rosenbaum, J. F., Biederman, J., et al. (1992). Stable behavioral inhibition and its association with anxiety disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 31, 10311. 68 J. Oosterlaan Kagan, J. (1989a). The concept of behavioral inhibition to the unfamiliar. In Perspectives on Behavioral Inhibition, ed. J. S. Reznick, pp. 123. Chicago, IL: University of Chicago Press. Kagan, J. (1989b). Temperamental contributions to social behavior. American Psychologist, 44, 66874. Kagan, J. (1997). Temperament and the reactions to unfamiliarity. Child Development, 68, 13943.

Kagan, J., Reznick, J. S. & Gibbons, A. (1989). Inhibited and uninhibited types of children. Child Development, 60, 83845. Kagan, J., Reznick, J. S. & Snidman, N. (1987). The physiology and psychology of behavioral inhibition in children. Child Development, 58, 145973. Kagan, J., Reznick, J. S. & Snidman, N. (1988). Biological bases of childhood shyness. Science, 240, 16771. Kagan, J. & Snidman, N. (1991a). Infant predictors uninhibited profiles. Psychological Science, 2, 404. of inhibited and

Kagan, J. & Snidman, N. (1991b). Temperamental factors in human development. American Psychologist, 46, 85662. Kagan, J., Snidman, N. & Arcus, D. M. (1992). Initial reactions unfamiliarity. Current Directions in Psychological Science, 1, 1714. to

Logan, G. D. & Burkell, J. (1986). Dependence and independence in responding to double stimulation: A comparison of stop, change, and dual-task paradigms. Journal of Experimental Psychology, 12, 54963. Logan, G. D. & Cowan, W. B. (1984). On the ability to inhibit thought and action: A theory of an act of control. Psychological Review, 91, 295327. Logan, G. D., Cowan, W. B. &Davis, K. A. (1984). On the ability to inhibit thought and action: A model and a method. Journal of Experimental Psychology, 10, 27691. Matheny, A. P. (1989). Childrens behavioral inhibition over age and across situations: Genetic similarity for a trait during change. Journal of Personality, 57, 25135. McBurnett, K., Lahey, B. B., Frick, P. J., et al. (1991). Anxiety, inhibition, and conduct disorder in children. II. Relation to salivary cortisol. Journal of the American Academy of Child and Adolescent Psychiatry, 30, 1926. Mullen, M., Snidman, N. & Kagan, J. (1993). Free-play behavior in inhibited and uninhibited children. Infant Behavior and Development, 16, 3839.

Oosterlaan, J., Logan, G. D. & Sergeant, J. A. (1998). Response inhibition in ADHD, CD, comorbid ADHD+CD, anxious and normal children: A meta-analysis of studies with the stop task. Journal of Child Psychology and Psychiatry, 39, 411 25. Oosterlaan, J. & Sergeant, J. A. (1996). Inhibition in ADHD, aggressive, and anxious children: A biologically based model of child psychopathology. Journal of Abnormal Child Psychology, 24, 1936. Oosterlaan, J. & Sergeant, J. A. (1998). Response inhibition and response reengagement in ADHD, disruptive, anxious and normal children. Behavioural Brain Research, 94, 3343. Pliszka, S. R. (1992). Comorbidity of attention-deficit hyperactivity disorder and overanxious disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 31, 197203. Pliszka, S. R., Borcherding, S. H., Spratley, K., Leon, S. & Irick, S. (1997). Measuring inhibitory control in children. Developmental and Behavioral Pediatrics, 18, 2549. Pollock, R. A., Rosenbaum, J. F., Marrs, A., Miller, B. S. &Biederman, J. (1995). Anxiety disorders of childhood: Implications for adult psychopathology. Psychiatric Clinics of North America, 18, 74566. Quay, H. C. (1988a). Attention deficit disorder and the behavioral inhibition system: The relevance of the neuropsychological theory of Jeffrey A. Gray. In Attention Deficit Disorder: Criteria, Cognition, Intervention, ed. L. M. Bloomingdale & J. A. Sergeant, pp. 11725. Oxford: Pergamon Press. Quay, H. C. (1988b). The behavioral reward and inhibition system in childhood behavior disorder. In Attention Deficit Disorder: New Research in Attention, Treatment, and Psychopharmacology, ed. L. M. Bloomingdale, pp. 17685. Oxford: Pergamon Press. Quay. H. C. (1993). The psychology of undersocialized aggressive conduct disorder: A theoretical perspective. Development and Psychopathology, 5, 165 80. Quay, H. C. (1997). Inhibition and attention deficit hyperactivity disorder. Journal of Abnormal Child Psychology, 25, 713.

Reznick, J. S., Gibbons, J. L., Johnson, M. O. & McDonough, P. M. (1989). Behavioral inhibition in a normative sample. In Perspectives on Behavioral Inhibition, ed. J. S. Reznick, pp. 2549. Chicago, IL: University of Chicago Press. Reznick, J. S., Hegeman, I. M., Kaufman, E. R., Woods, S. W. & Jacobs, M. (1992). Retrospective and concurrent self-report of behavioral inhibition and their relation to adult mental health. Development and Psychopathology, 4, 30121. Robinson, J. L., Kagan, J., Reznick, J. S. & Corley, R. (1992). The heritability of inhibited and uninhibited behavior: A twin study. Developmental Psychology, 28, 10307. Rosenbaum, J. F., Biederman, J., Bolduc-Murphy, E. A., et al. (1993). Behavioral inhibition in childhood: A risk factor for anxiety disorders. Harvard Review of Psychiatry, 1, 216. Rosenbaum, J. F., Biederman, J., Bolduc, E. A., Hirshfeld, D. R., Faraone, S. V.&Kagan, J. (1992). Comorbidity of parental anxiety disorders as risk for childhood-onset anxiety in inhibited children. American Journal of Psychiatry, 149, 47581. Rosenbaum, J. F., Biederman, J., Gersten, M., et al. (1988). Behavioral inhibition in children of parents with panic disorder and agoraphobia: A controlled study. Archives of General Psychiatry, 45, 46370. Rosenbaum, J. F., Biederman, J., Hirshfeld, D. R., et al. (1991). Further evidence of an association between behavioral inhibition and anxiety disorders: Results from a family study of children from a non-clinical sample. Journal of Psychiatric Research, 25, 4965. Rothbart, M. K. & Mauro, J. A. (1990). Temperament, behavioral inhibition, and shyness in childhood. In Handbook of Social and Evaluation Anxiety, ed. H. Leitenberg, pp. 13960. New York: Plenum Press. Scarpa, A., Raine, A., Venables, P. H. & Menick, S. A. (1995). The stability of inhibited/ uninhibited temperament from ages 3 to 11 years in Mauritian children. Journal of Abnormal Child Psychology, 23, 60718.

Schwartz, C. E., Snidman, N. & Kagan, J. (1996). Early childhood temperament as a determinant of externalizing behavior in adolescence. Development and Psychopathology, 8, 52737. Snidman, N., Kagan, J., Riordan, L. & Shannon, D. (1995). Cardiac function and behavioral reactivity in infancy. Psychophysiology, 31, 199207. 70 J. Oosterlaan Turner, S. M., Beidel, D. C. & Wolff, P. L. (1996). Is behavioural inhibition related to anxiety disorders? Clinical Psychology Review, 16, 15772. Werry, J. S., Elkind, G. S. & Reeves, J. C. (1987). Attention deficit, conduct, oppositional, and anxiety disorders in children. III. Laboratory differences. Journal of Abnormal Child Psychology, 3, 40928.