9 Defining Anxiety Disorders

Before discussing the anxiety disorders, it is important to consider the concept of anxiety and its heterogeneity. Anxiety refers to multiple mental and physiological phenomena, including a person’s conscious state of worry over a future unwanted event, or fear of an actual situation. Anxiety and fear are closely related. Some scholars view anxiety as a uniquely human emotion and fear as common to nonhuman species. Another distinction commonly made between fear and anxiety is that fear is an adaptive response to realistic threat, whereas anxiety is a diffuse emotion, sometimes an unreasonable or excessive reaction to current or future perceived threat.

Defining the boundaries between extremes of normal behavior and psychopathology is a dilemma that pervades all psychiatry. For some extreme conditions, such as Down syndrome, diagnostic decisions are straightforward. Milder forms, by contrast, present problems when one attempts to define the point at which “caseness” begins. A few symptoms escape this definitional conundrum by virtue of their being deviant, regardless of their severity. This applies to symptoms such as delusional beliefs or hallucinations. In the case of anxiety, however, it is especially problematic to distinguish between normal behavior and pathology. Anxiety plays an adaptive role in human development, signaling that self-protective action is required to ensure safety. Because anxiety can be rated on a continuum, some investigators suggest that extreme anxiety represents only a severe expression of the trait, rather than a distinct or pathological state. Distributions may consist of distinct entities, however. For example, some cases of mental retardation, as caused by neurological injury, represent a qualitative departure from factors influencing normal variations in intelligence. By analogy, the fact that anxiety falls on a continuum of severity does not preclude the presence of qualitatively distinct disorders at any point in the distribution (Klein & Pine, 2001).

Anxiety may become symptomatic at any age when it prevents or limits developmentally appropriate adaptive behavior (Klein & Pine, 2001). However, anxiety about certain circumstances may arise at different developmental stages, based on the typical age-related experiences that occur during a stage. For example, anxiety about separation is a normal aspect of development experienced by many young children. Similarly, in adolescence, questions arise concerning anxiety about social situations, given changes in the social milieu that many adolescents find stressful. A useful rule of thumb for determining the diagnostic threshold is the person’s ability to recover from anxiety and to remain anxiety-free when the provoking situation is absent. For example, it is not necessarily deviant for adolescents to respond with acute shyness when meeting an attractive peer. Such reactions reach clinical levels, however, when adolescents are unable to recover from the anxiety (as manifested by recurrent doubts or ruminations about how they behave) or when they avoid such encounters on a consistent basis. Similarly, clinical anxiety could manifest as persistent worry about future meetings with unfamiliar peers or even avoidance of activities that might require peer interactions. Therefore, an adolescent’s lack of flexibility in affective adaptation is an important pathological indicator. In addition, the degree of distress and impairment influences diagnostic decisions; these vary with developmental stage as well as with cultural and familial standards. When anxiety symptoms are developmentally inappropriate, subjective distress is relatively more informative. For example, separation anxiety is developmentally more congruent with early childhood than with adolescence. In brief, three clinical features figure in the definition of pathological anxiety. Two features (distress and impairment) vary in importance as a function of developmental stage, whereas the third (symptomatic inflexibility) is diagnostically relevant regardless of age.

The ability to draw firm conclusions regarding the ideal criteria for disorders will remain limited so long as signs and symptoms are the exclusive basis for establishing the presence of psychiatric disorders. Longitudinal research can provide some answers by identifying specific symptom patterns and thresholds that have long-term significance. In practice, however, such evidence has proved to be informative but rarely conclusive.

The past three decades have witnessed a great expansion in the study of anxiety disorders. An earlier emphasis on rating scales or interviews assessing multitudes of unrelated fears and worries has yielded to an emphasis on the study of diagnostic groups characterized by explicit clinical criteria. Scale ratings can be grouped to generate overall scores of anxiety, or what have come to be called “internalizing” symptoms, such as in the widely used Child Behavior Checklist (Achenbach, 1991), but as the evidence shows, scale ratings correspond poorly to clinical entities.

Difficulties separating “normal” from “pathological” anxiety are especially apparent in results from epidemiologic studies, in which the prevalence of anxiety disorders changes markedly with relatively minor changes in the definition of impairment (reviewed by Klein & Pine, 2001). However, adolescents with anxiety disorders who seek treatment typically suffer from markedly impairing anxiety, and there is little ambiguity about determining whether they have “normal” or abnormal levels of anxiety.

This challenge poses both practical and conceptual problems. The practical problem concerns the timing of treatment. Two mistakes are possible: an adolescent who needs treatment may fail to receive it if the threshold for diagnosing the disorder is set too high (“a false negative”), and an adolescent whose anxiety reflects a reasonable response to adverse circumstances may receive unnecessary treatment (“a false positive”). The decision to treat versus not treat is linked to costs and benefits that inform decisions about each adolescent.

The conceptual problem concerns the need to provide a principled basis for distinguishing disorder from nondisorder beyond the current imperfect clinically based principles. Ideally, these principles would be based on understandings of pathophysiology. Consistent with this perspective, some philosophers of medicine have attempted to provide objective, biological criteria for demarcating disorder (e.g., major depression) from distressing states that fall within the bounds of normal unhappiness (e.g., grief). Others have claimed that all ascriptions of disorder reflect nothing more than socially determined value judgments about undesirable states and behavior.

Merging these polarized views, Wakefield (1992) proposed a harmful dysfunction account of disorder, holding that disorder is a hybrid concept comprising a factual component and an evaluative component. The factual component specifies what is dysfunctional (a derangement in a psychobiological function) and the value component specifies the resultant harm (usually emotional suffering, social maladjustment, or both). Therefore, ascription of disorder requires that two interrelated criteria be met: a psychobiological mechanism is malfunctioning, and this underlying dysfunction results in suffering, maladaptation, or both.

Wakefield’s criteria imply that a person may be characterized by internal dysfunction but not qualify as having a disorder because no resultant harm occurs. For example, some youngsters characterized by extreme shyness or behavioral inhibition may find niches for themselves that enable them to flourish without marked distress. Even though the dysfunction requirement is met, these children would not be considered disordered because their dysfunction does not result in suffering or maladaptation. Conversely, some youngsters who are bullied by larger children may experience chronic anxiety at school, but because their suffering does not arise from dysfunction in the psychobiological mechanisms for estimating threat, Wakefield’s criteria would prohibit their diagnosis as disordered. Mechanisms for detecting threat work precisely as they are “designed” to work: the bullied youngsters experience chronic anxiety because they are continually under threat, not because they have a mental disorder. It is important to note that this is only one definition of mental disorder.

Wakefield’s (1992) framework is not without its limitations (McNally, 2011, pp. 69–96). Attempts to elucidate a value-free perspective on function—especially when cast within an evolutionary framework—raise yet another set of thorny problems. Nevertheless, the harmful dysfunction provides a useful model for posing questions regarding the distinction between normal psychological distress and its pathological variants.

In the following sections, we describe each of the anxiety disorders listed in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association, 2013). DSM-5 no longer classifies posttraumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD) as anxiety disorders. Conversely, separation anxiety disorder, selective mutism, substance/medication-induced anxiety disorder, and anxiety disorder due to another medical condition have been included among the anxiety disorders in DSM-5. As these latter two conditions are attributable to other causes rather than truly counting as independent syndromes, we do not discuss them here. Finally, reverting to the DSM-III scheme, DSM-5 conceptualizes agoraphobia as a disorder in its own right rather than as a complication of panic disorder.

For each anxiety disorder, DSM-5 stipulates that fear or anxiety must persist for at least 6 months, must be out of proportion to any genuine threat or danger, must produce significant distress or impairment in social, occupational, or other areas of functioning (e.g., school), and must not be attributable to another medical condition or explainable by another mental disorder. For an accompanying list of signs and symptoms, see Table 9.1.

A specific phobia is an intense fear or anxiety about a specific object or situation (e.g., animals, heights, flying in airplanes, receiving injections, seeing blood) that far exceeds any genuine danger. Phobic individuals usually experience anxiety when they anticipate encountering the dreaded object or situation, and they experience sudden, intense fear when they encounter it. They avoid their feared situations or endure them with intense distress. A diagnosis of specific phobia requires that the person experience extreme distress and impairment in normal functioning for at least 6 months. Although phobic disorders can begin at an early age, they often occur in childhood. Most children fear the same limited range of objects or events. Encounters with feared objects incite increases in physiological arousal (e.g., heart rate), with one notable exception: people who fear viewing blood (or receiving injections) exhibit a distinct biphasic cardiac response. After a brief, minor increase in heart rate, their blood pressure and heart rate plummet, often resulting in a faint.

The onset of separation anxiety disorder, defined by unrealistic worry accompanying separation from home or caretaker that interferes with appropriate behavior, usually occurs in late childhood but before adolescence. Because separation anxiety disorder is accompanied by a reluctance to engage in activities that require separation from a caretaker, it can take the form of fear of school attendance. Although some adolescents develop separation anxiety disorder, school refusal among adolescents can occur because of social anxiety rather than anxiety over separation.

People with social anxiety disorder have intense fear or anxiety about situations where they might encounter scrutiny by others. They worry that they will exhibit anxiety symptoms or otherwise act in ways that provoke ridicule or rejection by those observing them. Their dread of embarrassment, humiliation, and negative evaluation leads to them to avoid social situations or to endure them with marked distress. Although socially anxious children avoid these situations, some are unable to articulate their concerns and simply feel uncomfortable in unfamiliar social settings. To receive the diagnosis, children must be anxious among their peers, not merely in the presence of adults. Some people with this disorder experience anxiety only while performing in front of others (e.g., speaking in public, taking tests), whereas others experience distress in diverse social settings (e.g., attending parties, meeting new people, eating in public).

Selective mutism refers to a persistent failure to speak in certain social situations, such as school, despite doing so in other situations, such as at home. The failure to speak persists for at least 1 month (not limited to the first month of school), and it interferes with educational achievement. The problem does not arise from a communication disorder, another mental disorder (e.g., autism), or unfamiliarity with the spoken language.

A diagnosis of generalized anxiety disorder (GAD) is given to adolescents who worry about a variety of events or life circumstances—usually schoolwork, appearance, money, or their future. The age of onset of GAD is usually later than for most other disorders, although many patients report having been anxious for many years. Further, GAD is likely to be comorbid with other symptoms, but the primary symptom is a chronic state of worry rather than chronically avoidant behavior.

People with panic disorder experience sudden, unexpected surges of terror that peak within minutes and can occur without any obvious precipitants. Panic attacks are characterized by at least four of 13 symptoms, such as racing heart, sweating, trembling, smothering sensations, and fears of dying, losing control, or “going crazy.” The diagnosis requires a period of least 1 month of worry about further attacks or maladaptive behavior designed to prevent them (e.g., avoidance).

Panic disorder usually begins in late adolescence or early adulthood. Many young people develop the full-blown disorder only after experiencing occasional, sporadic attacks that culminate into persistent worry and maladaptive behavior to forestall their occurrence (Pine, Cohen, Gurlet, Brook, & Ma, 1998). Although young, prepubertal children can have occasional intense distress reactions, it is unclear whether these attacks are accompanied by thoughts of impending danger. Moreover, it is extremely rare for children to experience such episodes in the absence of a trigger. The apparent absence of spontaneous, unexpected panic attacks renders the diagnosis controversial in preadolescent children. If this disorder does occur in children, it is relatively infrequent. Some investigators believe that the essential missing component in early childhood is the unprovoked change in bodily sensations, whereas others believe that it is the inability to impose a catastrophic interpretation on these sensations.

Agoraphobia is intense fear and avoidance of a wide range of situations such as shopping malls, bridges, theaters, crowds, enclosed spaces, public transportation, or being away from home alone. The motivation for avoidance rests on fears that panic attacks or panic-like episodes (e.g., dizziness) may occur in places where escape or assistance from others would be difficult. Agoraphobia is not a fear of open or public places per se; rather, it constitutes fear of sudden, alarming bodily dysregulation in settings where such episodes would be problematic. A minimum of two situations is necessary for the diagnosis, and the fear must persist for at least 6 months and be out of proportion to any real danger. For example, fear of walking alone in a crime-ridden neighborhood would not qualify, whereas fear of walking alone for fear of having a sudden panic attack would.

Beginning with DSM-III-R, agoraphobia was classified not as a separate syndrome, but as a subtype of panic disorder. Indeed, dread of panic attacks or subsyndromal panic episodes falling short of the minimum of four symptoms required for a panic attack, motivates the hallmark avoidance behavior of people with agoraphobia. Agoraphobia’s reappearance as a distinct syndrome in DSM-5 does not signify a major discovery in psychopathology; it merely denotes the realization that some people can develop agoraphobia after experiencing insufficiently frequent panic attacks to qualify for panic disorder, attacks with fewer than four panic symptoms, and other, sudden physical problems (e.g., loss of bowel control, migraine headaches).

Accurate estimates of the prevalence of DSM anxiety disorders are only available for children older than 8 years of age. Studies on younger children have lacked population-based samples, explicit diagnostic criteria, or both. The best estimates of the prevalence of anxiety disorders in preschool children, based on a primary care clinic sample (Lavigne et al., 1996, 1998, 2001), were very low. The following sections summarize prevalence data based on samples from the general population and studies published over the past decade (Costello, Egger, & Angold, 2004). The prevalence of any anxiety disorder increases with the duration of time over which the symptom’s presence is counted. Thus, 3-month estimates range from 2.2% to 8.6%, 6-month estimates from 5.5% to 17.7%, 12-month estimates from 8.6% to 20.9%, and lifetime estimates from 8.3% to 27% (for more information see Kessler, Chiu, Demler, & Walters, 2005).

The relation between the diagnosis and everyday functioning remains a focus of controversy. Health maintenance organizations, insurance companies, and governmental agencies question whether children diagnosed with anxiety disorders require treatment (Costello, Burns, Angold, & Leaf, 1993). One perspective requires that impairment or disability attributable to the problem be apparent before a child receives a diagnosis. Clinicians could rate a child’s psychological functioning but fail to make a clinical diagnosis (Hodges, Doucette-Gates, & Liao, 1999; Shaffer et al., 1983).

The prevalence of anxiety disorders varies according to whether disability is a diagnostic requirement. If a child must meet the criteria for a diagnostically relevant symptom as well as impairment in everyday functioning, the prevalence of a diagnosis drops by 67%. Further, requiring both specific impairment and severe scores on the Children’s Global Assessment Scale (Shaffer, Fisher, Dulcan, & Davies, 1996), reduced the prevalence of disorder by almost 90%. This occurred most dramatically for specific phobia: requiring impairment in daily functioning lowered the prevalence from 21.6% to only 0.7%. Thus, all estimates of the frequency of the anxiety disorders depend in a serious way on the source of evidence and the criteria adopted. There is no “correct” prevalence in the sense that there is a correct height, in meters, for the Empire State Building.

Most investigators report that girls are more likely than boys are to have an anxiety disorder. For example, more girls than boys between ages 9 and 16 years had an anxiety disorder in the Great Smoky Mountains Study (12.1% vs. 7.7%; Costello et al., 2004). Three studies revealed more phobias in girls, two reported more panic disorder and agoraphobia in girls, and only one study found more separation anxiety disorder and overanxious disorder (OAD) in girls than in boys. In one of the few studies that examined the potential confounding factors linked to gender, the excess of anxiety disorder in girls remained even after the researchers controlled for 15 possible confounding variables (Lewinsohn, Gotlib, Lewinsohn, Seeley, & Allen, 1998). One confound was the frequent correlation between a child’s age and the timeframe for assessing symptoms. Investigators who used 3-month prevalence rates reported the lowest prevalence but studied the youngest subjects. By contrast, investigators using 12-month estimates had the highest prevalence but worked with the oldest children. In the Great Smoky Mountains Study, the prevalence of separation anxiety decreased with age, whereas social phobia, agoraphobia, and panic disorder increased with age. It is difficult to draw conclusions about gender differences in the fears, worries, and anxieties of clinic-referred samples given the modest amount of extant research. Further research in this area is of critical importance (see Silverman & Carter, in press).

On any day, between 3% and 5% of children and adolescents suffer from an anxiety disorder. Rates of GAD and specific phobia remain constant across childhood and adolescence. Although girls are more likely than boys are to have an anxiety disorder, the gender difference is less prominent in the general population than it is in the clinical population, perhaps because boys are less likely to receive referral for treatment than girls are. Numerous studies have demonstrated that girls who mature earlier than their peers exhibit higher rates of anxiety symptoms and disorders (e.g., Caspi & Moffitt, 1991); such findings have not been obtained with boys.

Marked comorbidity among the anxiety disorders has been a problem for nosology, epidemiology, diagnosis, and treatment. It occurs in the community as well as in the clinic (Brady & Kendall, 1992; Kendall & Clarkin, 1992; Kendall, Kortlander, Chansky, & Brady, 1992; Table 9.2). A review by Costello et al. (2004) yielded equivocal results because not all diagnoses were present in every study, there was a lack of consensus regarding controls for comorbidity, and concurrent comorbidity and sequential comorbidity were not always distinguished.

Beginning with DSM-IV, children who once received a diagnosis of OAD now receive one of GAD. Permissively conceptualized, the latter diagnosis was assignable if the child had only one of six symptoms (restlessness, fatigue, difficulty concentrating, irritability, muscle tension, or sleep disturbance), and these criteria differ from defining OAD (worry about the past or future, concern about one’s competence, need for reassurance, somatic symptoms, excessive self-consciousness, and muscle tension). Further, the newer criteria for GAD resemble those used to diagnose major depressive episodes; examination of the overlap between OAD and GAD should take into account the possibility of a correlation with depression.

The Great Smoky Mountains Study, involving 1,420 children, which examined comorbidity among OAD, GAD, and depression (Costello, Mustillo, Erklani, Keeler, & Angold, 2003), found that among children who were comorbid (5.4% of the entire sample, or 47% of those with any of the three diagnoses), more than half had all three disorders. Only 12 children (16% of those with GAD or OAD) had both disorders but no signs of depression.

There is no significant concurrent comorbidity between panic disorder and separation anxiety, but this does not preclude possible sequential comorbidity. Early appearance of separation anxiety appears to predict panic disorder (Black, 1994; Klein, 1995; Silove, Manicavasagar, Curtis, & Blaszczynski, 1996), but no community studies have tested this hypothesis adequately. A meta-analysis of 25 studies (prospective, retrospective, and case-control) revealed that a childhood diagnosis of separation anxiety disorder significantly increased the risk for subsequent anxiety disorders (Kossowsky et al., 2013). Although the effect size was largest for panic disorder with or without agoraphobia, it was not significantly greater than that for anxiety disorders in general. After correcting for publication bias, the authors found that separation anxiety did not increase the risk for depression or substance use disorders.

Comorbidity between any one anxiety disorder on the one hand, and attention-deficit/hyperactivity disorder (ADHD), conduct disorder, depression, or substance abuse disorder on the other, reveals the highest level of comorbidity with depression. The median odds ratio is 8.2 (95% confidence interval [CI], 5.8–12; Costello, Egger, et al., 2004).

There is also a sequential link between early anxiety and later depression (Costello et al., 2003; Orvaschel, Lewinsohn, & Seeley, 1995). It is unclear whether depression or anxiety increases the subsequent risk for the complementary disorder or whether the natural sequence is from an initial anxiety disorder to subsequent depression.

The odds ratio for the comorbidity of anxiety with risk for conduct disorder/oppositional disorder is 3.1 (95% CI, 2.2–4.6), and with ADHD it is 3.0 (95% CI, 2.1–4.3). These CIs imply a significant degree of comorbidity. Although the bivariate odds ratios that involve substance use or abuse were significant in some studies, an association between anxiety and substance abuse disappeared when comorbidity between anxiety and other psychiatric disorders was controlled for (Costello et al., 2004).

Although there is little concurrent comorbidity for anxiety and substance abuse (Weissman et al., 1999), childhood onset of an anxiety disorder might predict either lower or higher rates of substance abuse in adolescence. Kaplow, Curran, Angold, and Costello (2001) reported that children with separation anxiety were less likely than others were to begin drinking alcohol, and if they did, they began at a later age than that of most youth. But children with GAD were more likely to begin drinking and abuse alcohol earlier in adolescence.

Using a large British twin registry, behavior geneticists found more support for environmental than genetic sources of comorbidity among specific phobia and both social phobia and separation anxiety in school-age children (Eley, Rijsdijk, Perrin, O’Connor, & Bolton, 2008). In contrast to such studies on adults, shared environment accounted for significant variance, implying anxiogenic parental childrearing practices for all children within families or other sources of similarity among siblings (e.g., exposed to the same bullies at school).

The evidence does not permit a confident reply to the question of whether anxiety disorders in preschool children are precursors of similar disorders in adolescents. Invariably fallible retrospective data indicate that adolescents with anxiety disorders recalled their first onset at about 7 years of age (Costello, Erkanli, Federman, & Angold, 1999; Orvaschel et al., 1995). The Great Smoky Mountains Study revealed that specific phobias, GAD, separation anxiety, and social phobia all appeared around the time the child began school, whereas agoraphobia and OAD appeared several years later, usually at 9 to 11 years of age (Costello et al., 2003).

Although early anxiety disorder forecasts later depression (Alloy, Kelly, Mineka, & Clements, 1990; Breslau, Schultz, & Peterson, 1995; Kendler, Neale, Kessler, Heath, & Eaves, 1992; Lewinsohn, Zinbarg, Seeley, Lewinsohn, & Sack, 1997; Silberg, Rutter, & Eaves, 2001a, 2001b; Silberg, Rutter, Neale, & Eaves, 2001), we do not know the influence of anxiety on the timing or occurrence of other psychiatric disorders, with one exception: early separation anxiety and GAD have different predictive consequences for the later abuse of alcohol (Kaplow, Curran, Angold, & Costello, 2001).

Separation anxiety and phobic disorders occur in early childhood but are rare in adolescence. Panic disorder and agoraphobia have the opposite developmental profile: they are rare in childhood and increase in adolescence. We do not yet know whether some adolescent disorders are later manifestations of a syndrome that appeared earlier or whether they represent new forms of psychiatric illness. An answer to this question requires longitudinal research.

Early behavioral models for the treatment of anxiety rested on two primary suppositions. First, fears and phobias are acquired through classical conditioning—that is, through the formation of an association between a neutral stimulus and an aversive stimulus such that the former acquires the aversive properties of the latter. The aversive unconditioned stimulus (US) converts the formerly neutral one into a conditioned stimulus (CS) possessing the capacity to evoke the conditioned response (CR) of fear. Second, the acquired fears can be unlearned through extinction—that is, through presentation of the CS in the absence of the US. This conceptualization gave rise to exposure therapy, in which patients are taught systematically to confront their feared situations, objects, responses (e.g., tachycardia), or memories under safe circumstances with the goal of extinguishing their phobic fear.

However, merely because exposure therapy can reduce fears does not mean that they originated in classical conditioning. Indeed, many phobias of animals, heights, and so forth emerge in childhood without any apparent conditioning events involving a painful US (e.g., dog bites, falls from high places) whatsoever. Such findings motivated the nonassociative theory of phobias, which holds that the key question is explaining why many apparently innate fears fail to extinguish, not to explain why these fears emerge in the first place (Poulton & Menzies, 2002).

Although the original classical conditioning theory of fear acquisition that inspired exposure therapy encountered difficulties explaining the etiology of phobias (e.g., Rachman, 1977), 21st-century conditioning theory has evolved markedly in ways promising to provide a nuanced account of the etiology of anxiety disorders (e.g., Field, 2006). Rather than viewing conditioning as solely the acquisition of associations between physically realizable CSs and biologically significant USs, contemporary views conceptualize it as a form of predictive, causal learning embodied in cognitive representations of events occurring in context. Likewise, in contrast to early views that viewed verbal transmission of threat information and vicarious acquisition of fear as pathways to phobia distinct from conditioning (cf. Rachman, 1977), contemporary views emphasize the procedural similarities among the three pathways as exemplifying causal learning about the world (Field, 2006). The upshot is that developments in human associative learning may prove more theoretically fruitful in accounting for etiology than was the original classical conditioning model. Debates about the mechanisms mediating exposure therapy notwithstanding, considerable research documents its therapeutic benefits (cf., Barlow, 2001; Ollendick & March, 2004).

Discontent with the original, noncognitive accounts of the acquisition and extinction of pathological anxiety led to the development of theories that posited a pivotal role for cognitive factors in anxiety (e.g., Beck, Emery, & Greenberg, 1985). The assumption here is that it is not the events themselves but rather their threat “meaning” that is responsible for the evocation of anxiety. Meaning is represented in language. Accordingly, in cognitive therapy for anxiety disorders, verbal discourse provides the basis for challenging the patient’s threat interpretations of events in order to help replace them with more realistic ones, especially so with adolescents. The focus on the meaning of events paralleled the reconceptualization of conditioning in learning theories. For example, as Rescorla observed, “conditioning depends not on the contiguity between the CS and US but rather in the information that the CS provides about the US” (Rescorla, 1988, p. 153). Hence, the “organism is better seen as an information seeker using logical and perceptual relations among events along with its own pre-conception to form a sophisticated representation of its world” (Rescorla, 1988, p. 154). In the same vein, when discussing the phenomenon of extinction, Bouton (1994, 2000) stated that “in the Pavlovian conditioning situation, the signal winds up with two available ‘meanings’” (Bouton, 2000, p. 58).

Advances in information-processing theories of conditioning and of pathological anxiety (e.g., Lang, 1977) inspired similar views of anxiety disorders and their treatment. For example, in their emotional processing theory, Foa and Kozak (1986) conceptualized fear as a cognitive structure in memory that serves as a blueprint for escaping or avoiding danger that contains information about the feared stimuli, fear responses, and the meaning of these stimuli and responses. When a person is faced with a realistically threatening situation (e.g., an accelerating car in one’s path, or the approach of a fierce dog), the fear structure supports adaptive behavior (e.g., swerving away, running away). A fear structure becomes pathological when the associations among stimulus, response, and meaning representations do not accurately reflect reality; in this instance, harmless stimuli or responses assume threat meaning. In emotional processing theory, meaning is embedded in associations among stimuli, responses, and consequences (as in Rescorla, 1988), as well as in language, especially in the form of thoughts, beliefs, and evaluations (as in Beck, 1976).

According to emotional processing theory, anxiety disorders reflect the operation of specific pathological fear structures (Foa & Kozak, 1985). For example, the fear structure of individuals with panic disorder is characterized by erroneous interpretations of physiological responses associated with their panic symptoms (e.g., tachycardia, difficulty breathing) as dangerous (e.g., leading to a heart attack). Such misinterpretations motivate avoidance of situations and bodily sensations where these individuals anticipate panic attacks. Accordingly, the core pathology in panic disorder lies in the erroneous meaning of physiological responses. The supposition that inaccurate negative cognitions underlie the anxiety disorders has also been at the heart of theories posed by cognitive therapists (e.g., Clark, 1986; Rapee & Heimberg, 1997; Salkovskis, 1985).

If fear reflects the activation of an underlying cognitive fear structure, then changes in the fear structure should result in corresponding changes in emotions and behavior. Indeed, Foa and Kozak (1986) proposed that psychological interventions known to reduce fear, such as exposure therapy, achieve their effects through modifying the fear structure. According to emotional processing theory, two conditions are necessary for therapeutic fear reduction to occur. First, the fear structure must activate; second, information incompatible with the pathological aspects of the fear structure must be available and incorporated into the structure. Thus, within this framework, exposure therapy corrects the erroneous cognitions that underlie the specific disorder (e.g., tachycardia = heart attack). This is also the presumptive mechanism mediating the anxiolytic effects of cognitive therapy. Accordingly, exposure therapy and cognitive therapy work through overlapping mechanisms. Moreover, some cognitive therapists explicitly posit that fear activation is necessary to refute the patient’s false interpretations, and cognitive therapy programs routinely include an exposure component in the form of “behavioral experiments.” The evidence for cognitive change as the central mechanism in fear reduction remains incomplete. Accordingly, we need additional work on the mediators or mechanisms of change in both the cognitive and behavior therapies, especially in children and adolescents, for whom the role of cognition remains understudied (Prins & Ollendick, 2003).

The cognitive approach to anxiety disorders comprises two research traditions (McNally, 2001). In one tradition, researchers assume that introspective self-reports of anxious individuals can reveal aberrant cognition mediating symptom expression. These scholars administer questionnaires and conduct interviews to ascertain, for example, the intensity, frequency, and content of the worries and fears of children and adolescents. One such study revealed that school-age children worry most about school, health, and personal harm, especially the latter (Silverman, La Greca, & Wasserstein, 1995). Another indicated that children and adolescents with anxiety disorders report the same kinds of worries as those of their healthy counterparts, but that the intensity (not the number) of worries distinguished youngsters with anxiety disorders from those without anxiety disorders (Weems, Silverman, & La Greca, 2000). Researchers in this tradition have also studied the fear of anxiety symptoms (i.e., anxiety sensitivity; Reiss & McNally, 1985). Silverman and colleagues have developed the Childhood Anxiety Sensitivity Index (CASI; Silverman, Fleisig, Rabian, & Peterson, 1991; Silverman & Weems, 1999) to investigate this phenomenon.

In the second tradition, researchers eschew self-report as insufficiently sensitive to measure abnormalities in cognitive mechanisms that often operate rapidly, outside of awareness. These scientists apply the methods of experimental cognitive psychology to elucidate biases favoring processing of threat-related information in patients with anxiety disorders (McNally, 1996; Williams, Watts, MacLeod, & Mathews, 1997). In this section, we review experiments on information-processing biases in anxious children and adolescents (see also Vasey, Dalgleish, & Silverman, 2003; Vasey & MacLeod, 2001).

Because attentional capacity is limited, people can attend only to certain stimuli at a given time, and any bias for selectively attending to threat-related stimuli should increase a person’s likelihood of experiencing anxiety. Two experimental tasks have indicated that adults with anxiety disorders often exhibit an attentional bias for processing information about threat. In the emotional Stroop task (Williams, Mathews, & MacLeod, 1996), subjects view words of varying emotional significance, quickly naming the colors in which they appear while ignoring the meanings of the words. Delays in color naming (“Stroop Interference”) occur when the meaning of the word captures the subject’s attention despite the subject’s effort to attend to the color in which the word is printed. Most studies have shown that patients with anxiety disorders take longer to name the colors of words related to their threat-related concerns than to name the colors of other emotional or neutral words, and take longer to name the colors of threat words than do healthy subjects. It is debatable whether this task provides a pure measure of attentional bias; for example, an emotional response to threatening words might delay color naming.

Studies on the emotional Stroop in children have yielded mixed results. Relative to control subjects, spider-fearful children take longer to name the colors of spider words (Martin, Horder, & Jones, 1992) and colors of line drawings of spiders (Martin & Jones, 1995). However, not all Stroop studies have confirmed an anxiety-linked attentional bias for threat cues in youngsters. For example, nonanxious as well as anxious children have exhibited delayed color naming of threat words (Kindt, Bierman, & Brosschot, 1997; Kindt, Brosschot, & Everaerd, 1997). A pictorial version of the spider Stroop (naming colors of background against which spider pictures appeared) did not reveal a fear-related effect in children (ages 8–11; Kindt, van den Hout, de Jong, & Hoekzema, 2000).

A second paradigm provides a less controversial measure of attentional bias. In the dot probe attentional deployment task (MacLeod, Mathews, & Tata, 1986), subjects view two words on a computer screen, one appearing above the other. On some trials, one word is threat related, whereas the other is not. After the words disappear, a small dot appears in the location of one of the words. Subjects press a button as soon as they detect the dot. Relative to healthy control subjects, patients with anxiety disorders are faster to respond when the dot replaces a threat word than when it replaces a neutral word. Because threat cues capture attention in anxious patients, these individuals are especially quick to respond to the neutral dot that follows a threat cue.

Using this task, Vasey, Daleiden, Williams, and Brown (1995) found that children (ages 9–14 years) with anxiety disorders exhibited an attentional bias for threat, whereas control children did not. The attentional bias increased with age and with reading ability. Relative to their nonanxious counterparts, test-anxious schoolchildren (ages 11–14 years) exhibited an attentional bias for threat words (both socially and physically threatening; Vasey, El-Hag, & Daleiden, 1996). Patients with GAD (ages 9–18 years) exhibited an attentional bias for threat words, whereas patients with mixed anxiety and depression or healthy control subjects did not (Taghavi, Neshat-Doost, Moradi, Yule, & Dalgleish, 1999). The GAD patients did not show an attentional bias for depression-related words, and the attentional bias for threat words was unrelated to the age of the subject.

Anxious children tend to interpret ambiguous information in a threatening fashion. In one study, children (ages 7–9 years) heard homophones (e.g., whipping) that could be interpreted in either a threatening or a nonthreatening fashion (Hadwin, Frost, French, & Richards, 1997). The higher a child’s trait anxiety, the more likely the child selected threatening pictures (e.g., rope) over nonthreatening pictures (e.g., cream) that made the homophones (e.g., whipping) unambiguous. In another study, GAD patients (ages 8–17 years) and healthy control children were shown homographs (e.g., hang), each possessing a threatening and a nonthreatening meaning (Taghavi, Moradi, Neshat-Doost, Yule, & Dalgleish, 2000). They were asked to construct a sentence including the homograph. Relative to the sentences constructed by control children, the anxious children more often constructed sentences incorporating the threatening interpretation of the homograph, implying that they had interpreted the ambiguous word in terms of its threatening meaning. This interpretive bias was unrelated to the age of the subjects.

Bell-Dolan (1995) asked anxious and nonanxious children to provide interpretations of ambiguous scenarios. Anxious fourth- and fifth-graders were more likely than were their nonanxious peers to interpret nonhostile scenarios in a threatening fashion, whereas both groups interpreted ambiguous scenarios in a hostile fashion. Patients with anxiety disorders (ages 9–13 years) exhibited a bias for interpreting ambiguous scenarios in a threatening manner, and this effect was strongly predicted by level of trait-anxiety (Chorpita, Albano, & Barlow, 1996). Relative to healthy control children, patients ranging in age from 7 to 14 years who had OAD, separation anxiety, social phobia, or specific phobia exhibited a bias for interpreting ambiguous scenarios in a threatening fashion (Barrett, Rapee, Dadds, & Ryan, 1996). This bias was even more pronounced in patients with oppositional-defiant disorder.

Anxious children and adolescents exhibit threat-related attentional and interpretive biases that resemble those exhibited by anxious adults. Moreover, within most studies, the extent of bias did not vary as a function of the child’s age. Yet questions remain. In one study, the responses of anxious children to two measures of attentional bias (dot probe and emotional Stroop) were uncorrelated, indicating that these tasks tap distinct processes (Dalgleish et al., 2003). Further, researchers have yet to test whether these biases disappear following successful psychological or pharmacological treatment. A more detailed critique of information processing in adolescent psychopathology is available elsewhere (Vasey et al., 2003).

Human adolescence is both a biological and a social construction, defined as the period in life between puberty (a biological event) and achievement of independence (a socially determined event). Although the exact timing of puberty is not easy to specify, at its core puberty involves changes in the hormonal milieu, albeit ones shaped by the cultural setting. The end of adolescence, when independence is achieved, is more heavily shaped by culture. Some cultures, like our own, delay the assumption of adult roles; others require a clear transition, with or without a rite-of-passage ceremony (Schlegel & Barry, 1991). Nonetheless, across cultures, a period does exist between the ages of 12 and 18 years that is seen as unique. This period involves changes in hormones, brain structure, and behavior. These properties may have been conserved over evolution to promote autonomy and to foster dispersal of some individuals from the natal territory to another in order to avoid inbreeding (Schlegel & Barry, 1991; Spear, 2000). This is the period of adolescence.

Adolescence is marked by a reactivation of the hypothalamic–pituitary–gonadal axis, development of secondary sexual characteristics, and the onset of reproductive capacity, even though the increased circulation of sex hormones does not account for much of the variance in the behavior of adolescents (Brooks-Gunn, Graber, & Paikoff, 1994). The timing of pubertal signs is influenced by gender and environment; onset of puberty may be influenced more strongly by environmental stressors in girls than in boys (Moffitt, Caspi, Belsky, & Silva, 1992).

The brain undergoes changes throughout life (Eriksson et al., 1998), with intervals of modest change punctuated by periods of more rapid transformation (Spear, 2000). Periods of more dramatic change include not only prenatal and early postnatal eras but also adolescence (Spear, 2000). Rakic, Bourgeois, and Goldman-Rakic (1994) estimate that up to 30,000 cortical synapses are lost every second during portions of the pubertal period in nonhuman primates, resulting in a decline of nearly 50% in the average number of synaptic contacts per neuron, compared with the number prior to puberty. There is a similar loss of synapses in the human brain between 7 and 16 years of age (Huttenlocher, 1979), but the scarcity of human postmortem tissue prevents a more detailed description of this phenomenon. Although the functions of pruning are not fully understood, scientists do agree that pruning reflects an aspect of normal brain maturation. Pruning may lead to changes in functional capacities, facilitated by appropriately arranged neurons, given that some forms of mental retardation are associated with an unusually high density of synapses (Goldman-Rakic, Isseroff, Schwartz, & Bugbee, 1983).

The elimination of synapses that are presumed to be excitatory, accompanied by a reduction in brain energy utilization, is thought to transform the adolescent brain into one that is more efficient and less energy consuming (Chugani, 1996; Rakic et al., 1994). These changes could permit more selective reactions to stimuli that in younger children activate broader cortical regions (Casey, Geidd, & Thomas, 2000). Considerable research has accumulated on changes in the structures of the brain from childhood through adolescence. This research used refinements in magnetic resonance imaging (MRI), which has allowed for longitudinal studies. Despite inconsistencies across studies, a few areas of consensus have emerged. First, the immature state of the adolescent brain has been repeatedly demonstrated. That is, adolescence involves marked changes in the relative volumes, levels of activity, and connections among brain regions. For example, there is an increase in cortical white matter density, which is thought to reflect changes in the brain’s myelination and connections among regions, as well as a corresponding decrease in gray matter (Giedd et al., 1999; Sowell et al., 1999a, 1999b). Complex changes also occur in subcortical structures, including the hippocampus and the amygdala (Giedd et al., 1997; Yurgelun-Todd, Killgrove, & Cintron, 2003). Second, consensus has emerged on the broad pattern of changes in these regions. That is, phylogenically older regions, such as primary sensory and motor cortices, mature earlier than the older regions of association cortex. Finally, consensus has emerged on a few areas of brain development during adolescence as involving relative changes in the brain’s circuitry, as reflected in connections among regions.

Conversely, areas of disagreement persist. One area of disagreement concerns the precise nature of changes among the various regions. Thus, some models suggest that adolescence involves a relative imbalance between late-maturing prefrontal regions and earlier-maturing subcortical structures, such as the amygdala and striatum (Casey, Duhoux, et al., 2010; Casey, Jones, et al., 2010; Ernst, Pine, et al., 2006). Other models suggest that adolescence involves more complex, nonlinear changes (Crone & Dahl, 2012). Another area of disagreement concerns the precise timing of maturity for individual brain regions. This reflects differences in the methods among studies reporting different findings. Whereas older studies relied largely on cross-sectional data, newer studies use longitudinal methods and increasingly sophisticated data collection techniques (Giedd, Raznahan, et al., 2012; Raznahan, Lee, et al., 2010; Raznahan, Lerch, et al., 2011; Raznahan, Shaw, et al., 2014).

Studies in rodents and nonhuman primates use more invasive methods than can be employed in humans. Such invasive studies provide more fine-grained analysis of particular connections among brain regions. This research finds developmental shifts in patterns of innervation, including the circuits involved in the recognition and expression of fear, anxiety, and other emotions (Charney & Deutsch, 1996). This work also shows that the responsiveness of the cortical gamma-amino butyric acid (GABA)–benzodiazepine receptor complex to challenge increases as animals approach puberty (Kellogg, 1998); it also delineates changing function in the hippocampus involving GABA transmission (Benes, 1989; Wolfer & Lipp, 1995; Nurse & Lacaille, 1999) and changes in neurogenesis. Further, pubescent animals show lower utilization rates of serotonin in the nucleus accumbens than younger or older animals (Teicher & Andersen, 1999).

Studies in laboratory animals specifically demonstrate developmental increases in amygdala–prefrontal cortex (PFC) connectivity (Cunningham, Bhattacharyya, & Benes, 2002), along with alterations in amygdala activation (Terasawa & Timiras, 1968). This may explain the unique effects of amygdala lesions in immature and mature primates (Prather et al., 2001). Findings from functional MRI research in human adolescents provide some parallels with these data in laboratory animals. However, findings on aspects of normal adolescent development in functional MRI remain less consistent than in structural MRI (Casey, Jones, et al., 2008, 2010; Casey, Pattwell, et al., 2013; Crone & Dahl, 2012).

Maturational changes in the cerebellum, and the circuitry connecting the cerebellum to the prefrontal cortex, continue through adolescence. Lesions of the adult cerebellum disrupt the regulation of emotion and interfere with performance on tasks requiring executive functions (Schmahmann & Sherman, 1998), although this is less apparent in those younger than 16 years (Levisohn, Cronin-Golomb, & Schmahmann, 2000).

One consequence of this restructuring of the brain during adolescence is that early developmental compromises might be exposed. That is, brain regions vulnerable to dysfunction, due either to genetics or to adverse early experience, might be unmasked by the combination of brain restructuring and stressful life experiences (Goldman-Rakic et al., 1983; Hughes & Sparber, 1978).

There is great interest in detecting the biological variables that might distinguish anxious from nonanxious patients. Many, but not all, of these biological measures are influenced directly or indirectly by a brain circuit that connects a series of regions. This includes inferior aspects of the frontal cortex, the hippocampus, the amygdala, bed nucleus, and their projections to the brain stem, autonomic nervous system, endocrine targets, cortex, and central gray matter (Blackford & Pine, 2012; Pine, 1999, 2001, 2002; Pine, Cohen, & Brook, 2001; Pine, Fyer, et al., 2001; Pine, Grun, et al., 2001). It is relevant that connectivity between the amygdala and prefrontal cortex, along with level of amygdalar activation, increases during adolescence (Cunningham, Bhattacharyya, & Benes, 2002; Terasawa & Timiras, 1968).

As neuroscience research over the past decade repeatedly demonstrates the complexity of the human brain, questions have arisen regarding the degree to which one or another neural circuit mediates a relatively specific series of functions. Thus, as noted above, considerable research does implicate a collection of brain regions in the response to threats. This circuit encompasses ventral PFC, amygdala, hippocampus, and interconnected structures (Davis, Walker, et al., 2010; Davis & Whalen, 2001; LeDoux, 2012, 2013). However, neural circuits are now understood to serve many different functions (Bilder, Howe, et al., 2013). As a result, this circuit is engaged in many scenarios besides those involving threat. Moreover, fear is now understood to be a heterogeneous construct, with different forms of fear varying based on the contexts of the situation, the nature of the particular threat, and the types of cognitive processes engaged (Davis, Walker, et al., 2010; LeDoux, 2012, 2014). This complicates attempts to define a particular set of brain structures that regulates humans’ response to threat. Of course, because these same structures continue to evolve with adolescent maturation, it is even more difficult to define a particular circuit that relates to aspects of fear or threat responding in adolescence.

This broader debate concerning the nature of a so-called fear circuit encompasses a number of related issues. For example, some questions persist regarding the functions of particular structures. Hence, there is debate over whether the amygdala is activated primarily by events that are potentially harmful or events that are unexpected or discrepant (Davis 1992, 1998; LeDoux 1996, 1998, 2000). Clearly, because the amygdala responds to discrepant and unexpected events that are harmless as well as to positive events, the amygdala is not merely a fear-related structure. Select neurons in the amygdala, as well as in the bed nucleus, hippocampus, and brain stem sites, reliably respond to unexpected or discrepant events, regardless of whether they are threatening or harmful (Wilson & Rolls, 1993). And the reactivity of amygdalar neurons to unexpected or discrepant events habituates, often rapidly, as the event becomes expected and loses its surprise value (La Bar, Gatenby, Gore, Le Doux, & Phelps, 1998).

Other questions relate specifically to development. Some aspects of fear responding reflect the developmental experiences of the organism. The behavioral reactions of monkeys, chimpanzees, and human infants to a snake are no different from their reactions to discrepant events that are harmless (e.g., a tortoise or seaweed). Only 30% of monkeys born and reared in the laboratory showed more prolonged withdrawal to a live snake than to blue masking tape (Nelson, Shelton, & Kalin, 2003). If snakes were a biologically potent incentive for fear, a majority of monkeys should have shown an immediate withdrawal reaction.

A final set of questions relates to individual differences in fear- and anxiety-related behaviors. Do these relate to differences in particular brain structures or interactions among a series of regions? Moreover, do individual differences in fear-related behaviors reflect ontogeny, as appears to be the case for other aspects of individual differences (Giedd, Raznahan, et al., 2012)? This final set of questions has been addressed most completely through research on anxiety disorders in adolescence.

Advances in genetics, imaging, and cognitive neuroscience provide the opportunity to combine discoveries in neuroscience with insights from clinical psychobiology. Current views of adolescent anxiety disorders are influenced by two limiting facts. The first is that the research on adolescents has been modeled on investigations of adults; the second is that all current anxiety disorders are heterogeneous in their origin. This second fact means that investigators would profit from using biological variables to distinguish between patients with transient symptoms and those with more persistent disorders (Merikangas, Avenevoli, Dierker, & Grillon, 1999; Pine, Wasserman, & Workman, 1999).

Many, but not all, adults with anxiety disorders show abnormalities of autonomic regulation, especially lability of the cardiovascular system. This feature is most common among adults with panic disorder, social anxiety, and GAD (Gorman & Sloan, 2000). These abnormalities occur in both the sympathetic and parasympathetic systems and probably contribute to the association between anxiety disorder and cardiovascular mortality (Gorman & Sloan, 2000). Although children at risk for one or more anxiety disorders, because of a temperamental bias, show high sympathetic tone in the cardiovascular system (Kagan, Snidman, McManis, & Woodward, 2001), this relation is not robust, and children with different disorders often display similar autonomic profiles (Pine et al., 1998). One mechanism that ties autonomic regulation to psychology is the result of peripheral feedback from the cardiovascular system to the brain. If this somatic activity pierces consciousness, the person might conclude that a threat is imminent (Moss & Damasio, 2001).

Despite a consistent interest in autonomic correlates of anxiety over three decades, findings in this area remain relatively inconsistent. Such inconsistency manifests across particular autonomic measures, such as heart rate, skin conductance, and fear-potentiated startle (Craske, Waters, et al., 2008; Craske et al., 2012; Grillon, Dierker, et al., 1998). Such inconsistencies manifest based on the degree to which state- or trait-related anxiety is assessed (Craske, Waters, et al., 2008; Grillon, Dierker, et al., 1998). Finally, such inconsistencies vary with the nature of the paradigm employed (Britton, Grillon, et al., 2013; Britton, Lissek, et al., 2011; Davis, Walker, et al., 2010; Waters, Craske, et al., 2008).

Assessment of respiratory function represents one area where findings have appeared relatively consistent. Thus, perturbations in respiratory function are characteristic of panic disorder (Pine, 1999) and lead panic patients to experience a heightened feeling of anxiety (Coryell, Fyer, Pine, Martinez, & Arndt, 2001; Pine et al., 2000). Such perturbations are thought to occur in a relatively select set of anxiety patients, including patients with either panic disorder or separation anxiety disorder but not social anxiety disorder. The specificity of such findings generally has been replicated across studies performed over the past decade (Battaglia, Pesenti-Gritti, et al., 2009; Roberson-Nay, Klein, et al., 2010).

Patients with an anxiety disorder often show perturbations in the hypothalamic–pituitary–adrenal (HPA) axis. Further, both rodents and nonhuman primates show changes in the HPA axis during acute stress, as well as after a stress experienced early in life (Essex, Klein, Cho, & Kalin, 2002; Kaufman, Plotsky, Nemeroff, & Charney, 2000; Meaney, 2001; Monk, Pine, & Charney, 2002). The strongest association between activation in the HPA axis and anxiety disorder is seen in PTSD (Bremner, 1999; Bremner et al., 1999; Yehuda, 2002). Although enhanced feedback sensitivity in the HPA axis is often associated with an anxiety disorder, some children with an anxiety disorder exhibit the opposite pattern of reduced feedback sensitivity (Coplan et al., 2002; De Bellis, 2001; Heim & Nemeroff, 2002).

Brain chemistry can affect the excitability of a particular brain region in diverse ways. Neurochemical regulation in adult anxiety disorders is studied most often with pharmacological challenges, positron emission tomography, or measurement of peripheral neurochemical metabolites. Because the first two techniques are invasive, data on adolescents are restricted primarily to peripheral measures.

Adults with anxiety often show enhanced activity in the neurons of the locus ceruleus (Coplan et al., 1997; Sullivan, Coplan, & Gorman, 1998; Sullivan, Coplan, Kent, & Gorman, 1999). For example, adults with panic disorder and children with separation anxiety disorder show an abnormal response to the administration of yohimbine (Sallee, Sethuraman, Sine, & Liu, 2000). However, children and adults with a diagnosis of OCD show an abnormal, neurohormonal response to clonidine (Sallee et al., 1998). There is also an association between environmental stress and a prolactin response to serotonergic probes (Heim & Nemeroff, 2002), and adults with anxiety disorders show abnormalities in serotonergic regulation.

A dramatic indication of a relation between immunology and anxiety disorder comes from studies of children with OCD. Earlier work had found a specific association between OCD and neurological conditions affecting the basal ganglia, including pediatric Sydenham’s chorea. This discovery led to the recognition of a specific form of OCD called pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS; Swedo, 2002), marked by anxiety, OCD, and motor tics that emerge following infection with group A ß-hemolytic streptococcus. This syndrome is thought to occur when an immunological reaction disrupts fronto-striatal-thalamo-cortical-circuitry. It may be relevant that the offspring of adults with panic disorder show selected allergic disorders reflecting anomalies in the immune system (Kagan et al., 2001; Slattery et al., 2002). Of note, controversy has continued to surround research in this area over the past two decades. This controversy relates primarily to the range of conditions that have been tied to similar immunological perturbations. Thus, OCD may in fact relate to streptococcal infection, but this finding may reflect a broader association between a range of immunological insults and a range of emotional disorders that occur in adolescence (Leckman, King, et al., 2011). Work by Storch et al. (2006, 2011) highlights the importance of proper identification of the “sawtooth pattern” of infection, symptom increase, treatment of infection, and symptom alleviation, followed by at least one additional symptom increase associated with re-infection; moreover, biological treatments such as high-dose antibiotics may be brought to bear to treat the infection itself, but cognitive-behavioral therapy and selective serotonin reuptake inhibitors also play an important role in reducing symptoms both acutely and in the long term. More recently, Swedo et al. (2015) and Murphy et al. (2014) have described clinical presentation of pediatric acute-onset neuropsychiatric syndrome (PANS), which implicates more than just the streptococcal virus in the development of acute-onset OCD and related symptoms.

A variety of techniques have been used to study anxiety disorders. These include MRI, functional MRI, and electrophysiology. Findings from brain imaging studies in adolescent anxiety disorders using these varied methods generally conform to findings in adults. Moreover, at both ages, the data generally suggest that anxiety disorders can be divided into three large groups, comprising OCD and related disorders, PTSD and related disorders, and the remaining anxiety disorders, including social anxiety disorder and GAD. This broad grouping also is reflected in DSM-5 and conforms to the pattern of findings from longitudinal research.

Morphometric MRI evidence, which provides information on brain structure, reveals that OCD adults have abnormalities in the circuit involving the PFC, basal ganglia, and thalamus (Rauch, Savage, Alpert, Fischman, & Jenicke, 1997). Some of these abnormalities have been observed in children and adolescents with OCD (Blackford & Pine 2012; Rosenberg & Hanna, 2000; Rosenberg, MacMillan, & Moore, 2001). Adults with PTSD have reduced volume in the hippocampus, but children with PTSD do not show these specific reductions, even though they have a smaller brain volume (De Bellis et al., 1999; De Bellis, Spratt, et al., 2011). Children with GAD show increased volume of the amygdala and superior temporal gyrus of the right hemisphere (De Bellis et al., 2002).

Functional MRI quantifies brain activity. Despite its advantages, it relies on measures of blood flow and therefore is an indirect index of neuronal events. Moreover, it measures not the absolute amount of blood flow but rather differences in changes in blood flow during an experimental task compared with a control task.

Despite these caveats, available functional MRI studies do generally differentiate patterns of responding in anxious and nonanxious individuals. Thus, adolescents and adults with a range of anxiety disorders show enhanced amygdalar activation (Blackford & Pine, 2012; Rauch et al., 2000; Thomas et al., 2001a, 2001b). Other research suggests that patterns of responding might differ among OCD, PTSD, and other anxiety disorders when activation is examined in various regions outside of the amygdala, including the striatum and PFC (Blackford & Pine, 2012; Carrion, Garrett, et al., 2008; De Bellis, Spratt, et al., 2011). However, these conclusions remain tentative, since most available studies are small, and few individual studies directly contrast activation across groups of adolescents with anxiety disorders. Rather, conclusions on specificity arise by comparing patterns across different studies targeting different groups of anxiety disorder patients.

The electroencephalogram (EEG) represents the synchronized activity of large numbers of cortical pyramidal neurons that, at any moment, have a dominant frequency of oscillation at particular sites. A state of mental and physical relaxation is usually but not always associated with more power in the alpha frequency band (8–13 Hz) in frontal areas. A state of psychological arousal is associated with greater power in the higher-frequency beta band (14–30 Hz). The change to higher frequencies could be the result of more intense volleys from the amygdala to the cortex.

In addition, there are usually small hemispheric differences in the amount of alpha power on the right, compared with the left, at frontal and parietal sites. Because alpha frequencies are associated with a relaxed psychological state, the less alpha power at a particular site, the more likely that site is neuronally active. The technical term for loss of alpha power is desynchronized, and investigators assume that desynchronization of alpha frequencies is a sign that the individual has moved to a more aroused state.

Subjects reporting higher anxiety tend to have greater activation in the right frontal area than the left, whereas normal controls show more activation in the left frontal area. A preference for display of right versus left frontal activation could reflect either a stable trait or a transient state. It appears that a stable preference for right or left frontal activation can be influenced by an individual’s temperament and, therefore, could reflect a stable property (Fox, Henderson, Rabin, Caikins, & Schmidt, 2001). McManis, Kagan, Snidman, and Woodward (2002) have found that 11-year-old children who had been highly reactive infants and fearful toddlers were likely to show right frontal activation under resting conditions. However, an asymmetry of activation can also reflect a transient state. Infants watching the approach of a stranger showed greater right frontal activation during that brief period of time (Fox & Bell, 1990). Hagemann et al., who gathered EEG data on four separate occasions on a sample of 59 adults, concluded that 60% of the variance in asymmetry of activation reflected a stable trait while 40% was attributable to the specific occasion of testing (Hagemann, Naumann, Thayer, & Bartussek, 2002).

The event-related potential is a time-locked, postsynaptic potential generated by large numbers of cortical pyramidal neurons to a specific stimulus. The first waveform that represents the detection of a discrepancy is called N2 because it usually peaks at about 200 msec to an unexpected event. The two most frequently studied waveforms, P3 and N4, appear a bit later, with peak voltages at about 400 msec, and are prominent at frontal sites when the subject is passive and has no task to perform. Kagan et al. have unpublished data indicating that 11-year-old children who had been highly reactive infants and fearful toddlers showed a larger negative waveform at 400 msec to nonthreatening discrepant scenes. Interest also has focused on an earlier-appearing potential, the error-related negativity (ERN), which typically manifests in the first 100 msec after a research participant makes an errant motor response. Various forms of anxiety disorder have been linked to an enhancement of the ERN (Hajcak, MacNamara, et al., 2010; McDermott, Perez-Edgar, et al., 2009).

Years of work have affirmed that genetic factors influence the risk for anxiety disorders. One study of adults found modest heritability for GAD for both men (15%) and women (20%) and no effect of shared environment (Hettema, Prescott, & Kendler, 2001; Table 9.3). Other research affirms the heritability of panic disorder (Crowe, 1985; Gorwood, Feingold, et al., 1999; Marks, 1986; Skre, Onstad, Torgersen, Lygren, & Kringlen, 1993). Merikangas and Risch (2003) suggested heritability estimates of 50% to 60% for adult panic disorder, with risk ratios ranging from 3 to 8 for first-degree relatives of adult probands with panic disorder. A meta-analysis by Hettema, Neale, and Kendler (2001) uncovered a modest genetic contribution to four anxiety categories and little or no effect of shared environment. One of the most extensive explorations of the contribution of genes to anxiety disorders is the Virginia Twin Study of Adolescent Behavioral Development (Eaves et al., 1997). This corpus, which relies primarily on self-report data, discovered strong additive genetic effects for OAD in both boys and girls (37%), with little effect of shared environment (Topolski et al., 1997). Silberg, Rutter, Neale, and Eaves (2001) reported that 12% to 14% of the variance in OAD in girls was attributable to genes, and most of the remaining variance was due to nonshared environment.

The Virginia Study indicated a smaller genetic contribution to separation anxiety (only 4%) but large nonshared environmental effects (40% and 56%). The data for girls revealed minimal genetic effects on separation anxiety and a greater contribution of shared environment (11% for children 8–12 years old, 23% for children 14–17 years old; Silberg, Rutter, Neale, et al., 2001). However, parent-report checklists from an Australian national twin registry found a higher genetic loading for separation anxiety symptoms in girls (50%) and a much lower one for boys (14%) (Feigon, Waldman, Irwin, Levy, & Hay, 2001).

The Virginia Study indicated that about 9% to 10% of the variance in phobic symptoms was genetic in girls; the remainder was attributable to nonshared environment (Topolski et al., 1997). However, a Swedish study found that shared environmental factors explained considerably more of the variance for fears of animals, unfamiliar situations, and mutilations than nonshared environment (Lichtenstein & Annas, 2000). Thus, it is important to appreciate that conclusions based on twin studies can vary markedly as a function of the site of the laboratory, as well as the informant supplying the relevant information. When mothers reported on separation anxiety disorder in a population-based sample of female twins living in Missouri, heritability estimates were high (62%) and there was only a modest effect of shared environment.

Weissman (1988) argued that high rates of separation anxiety in children of parents who were comorbid for panic and depression disorder implied an association between separation anxiety disorder in childhood and the later development of panic disorder. There was a fairly specific association between separation anxiety in children who had been brought to clinics and separation anxiety in the parents when they were children years earlier (Manicavasagar, Silove, Rapee, Waters, & Momartin, 2001).

In addition, there is evidence for genetic contributions to personality traits such as neuroticism and introversion (Eaves, Eysenck, & Martin, 1989), shyness (Daniels & Plomin, 1985), and behavioral inhibition (DiLalla, Kagan, & Reznick, 1994; Kagan, 1994). A group of very shy 7-year-old Israeli children were more likely than others to inherit the long form of the allele for the serotonin transporter promoter region polymorphism (Arbelle et al., 2003); however, not all studies have found this association.

Some research has focused on aspects of genetics that might vary in anxiety disorders, expressed at particular ages. Thus, twin studies on depression suggest that different genetic factors might shape risk before and after puberty (Silberg, Rutter, et al., 2001). Data suggest that similar developmental variation may occur for anxiety (Kendler, Gardner, et al., 2008). Relatively few studies focus on differences among the particular forms of pathological anxiety. In fact, limited research targets any specific disorder, tending to focus more on patterns for symptom ratings or temperament. Sufficient research does exist on separation anxiety disorder, where 18 cohorts provide data to demonstrate high heritability (Scaini, Ogliari, et al., 2012). However, insufficient research exists to draw similar conclusions regarding any other adolescent anxiety disorder.

Despite these findings, many studies fail to meet the highest research standards, which include the following:

These standards are occasionally met in studies with adults, but rarely in studies with children and adolescents.

Genes are only expressed within a certain envelope of environments, and individuals both shape and select their environments (Rutter, Silberg, O’Connor, & Siminoff, 1999a, 1999b). Finally, it should be appreciated that the attribution of a genetic risk to an individual should not invite fatalism (Rutter et al., 1990). Some heritable conditions can be treated, and a few can be controlled. The classic example is phenylketonuria, for which the cognitive impairment is caused by an inherited metabolic defect that can be controlled by restricting the child’s diet.

By developing personalized treatment plans, the revolution in molecular genetics promises to transform the identification and treatment of anxiety disorders across the lifespan. Two complementary approaches are described. Pharmacogenomic studies use genomic technologies to identify chromosomal areas of interest and, hence, potential drug targets (see, e.g., Arbelle et al., 2003; Smoller et al., 2003). Pharmacogenetic studies identify candidate genes that moderate drug response (see, e.g., Basile, Masellis, Potkin, & Kennedy, 2002) or adverse event profile (see, e.g., Murphy, Kremer, Rodrigues, & Schatzberg, 2003). Identified difference may interact with age, gender, race, and ethnicity (Lin, 2001).

In the adult literature on genetic factors, the most robust findings involve polymorphisms in the serotonin transporter (Weizman & Weizman, 2000). In comparison to progress in ADHD (Rohde, Roman, & Hutz, 2003), however, little is known about pharmacogenetic or pharmacogenomic approaches to anxiety disorders in the pediatric population. Shyness (Arbelle et al., 2003) and behavioral inhibition (Smoller et al., 2003) but not internalizing symptoms (Young, Smolen, Stallings, Corley, & Hewitt, 2003) all have been linked to candidate gene variation, illustrating how lack of consistency in phenotypic identification, among other factors, limits progress despite clear evidence from statistical genetic methods regarding the importance of genetic factors (Stein, Chavira, & Jang, 2001).

Future progress will depend on an improved understanding of the nature and identification of disease states and their natural course, which in turn will allow the development of more specific treatments, better risk prediction, and the implementation of preventive strategies based in pharmacogenomic and pharmacogenetic approaches (Gottesman & Gould, 2003; Pickar, 2003).

The research of the past few decades has expanded our understanding of the phenomena linked to the concepts of anxiety and anxiety disorder. A comparison of contemporary reports with those of the last half-century provides reason for optimism, for we have learned several important facts.

First, the state we call anxiety in humans is not unitary in origin or consequence and can be the result of living with realistic threat, past history, conditioning, or a temperamental bias for unexpected somatic sensations that are interpreted as meaning one is anxious. Second, epidemiological and genetic data imply distinct biological profiles for the varied anxiety disorders, many of which implicate neurochemical processes. Finally, clinicians and investigators now have an initial set of cognitive and biological procedures that promise to aid differential diagnosis of individuals who report anxiety. Major advances will occur when investigators and clinicians add these procedures to their interview data. The results of this work will permit the parsing of individuals who have a particular diagnosis into subgroups with more homogeneous biological and psychological features. This knowledge should lead to a more fruitful set of psychiatric classifications.