What Is an Anxiety Disorder?

Diagnosis is based on the self-report of symptoms, whether provided solely by the patient or with the aid of a clinician's appraisal. In this section, we explore the structure of symptom self-report data, to evaluate the degree to which symptom reports share features in common across the anxiety disorders, making them distinct from mood disorders, and whether features of symptom self-report distinguish fear disorders from anxious-misery disorders. Later, we address the behavioral, physiological, cognitive, and neural correlates of symptom reports and diagnoses.

We begin with conceptualizing the terms “fear” and “anxiety,” since these constructs underlie the symptoms of anxiety disorders. Then, we consider whether self-reported fear and anxiety distinctly differ from each other and from depression. Finally, the relationship between symptoms of fear, anxiety and depression and existing diagnostic categories of anxiety and mood disorder is reported.

The definition of fear and anxiety varies greatly [for a review, see Reference (5)]. In this review, we use Barlow's (5) concepts, in which; anxiety is a future-oriented mood state associated with preparation for possible, upcoming negative events; and fear is an alarm response to present or imminent danger (real or perceived). This view of human fear and anxiety is comparable to the animal predatory imminence continuum (6). That is, anxiety corresponds to an animal's state during a potential predatory attack and fear corresponds to an animal's state during predator contact or imminent contact.

Lang (7) classified the symptoms of fear and anxiety into a system of three-responses: verbal-subjective, overt motor acts, and somato-visceral activity. In this system, and in accordance with the definitions of anxiety and fear, the symptoms of anxiety include worry (verbal-subjective), avoidance (overt motor acts), and muscle tension (somato-visceral activity). Fear symptoms include thoughts of imminent threat (verbal-subjective), escape (overt motor), and a strong autonomic surge resulting in physical symptoms such as sweating, trembling, heart palpitations, and nausea (somato-visceral) (Table 1). Importantly, these descriptions represent prototypes of fear and anxiety that lie at different places upon a continuum of responding. Along such a continuum, symptoms of fear vs. anxiety are likely to diverge and converge to varying degrees. Zinbarg (8) proposed a similar hierarchical model, with anxiety and fear as higher-order constructs that have effects on lower-order, partially-distinct response systems (i.e., verbal-subjective, overt motor actions, and somato-visceral activity).

There is evidence to support the distinction between self-reported somato-visceral symptoms that are likely influenced by fear and self-reported subjective symptoms that are likely influenced by anxiety. For example, across four different samples of undergraduates, air force academy cadets, and psychiatric outpatients, a two-factor model was a better fit to the data than a one-factor model: the two factors represented physiological arousal (e.g., heart racing) and subjective anxiety (e.g., unable to relax and nervous) (9). Similar findings have been demonstrated with other large community and undergraduate samples (10) and with psychiatric out-patients, (11) and in child and adolescent samples (e.g., (12)). The factors are distinct but highly correlated. These data highlight a distinction between self-report of fear-linked physiological arousal and anxiety-linked subjective distress, but their linkages to the constructs of fear and anxiety, respectively, are only implied.

The large literature testing the tripartite model of fear, anxiety, and depression (13) provides additional evidence for a distinction between self-reported somato-visceral symptoms of fear and verbal-subjective symptoms of anxiety. The tripartite model proposes that there are symptoms shared across “anxiety” and depression as well as symptoms unique to each. Shared symptoms typically are represented by a negative affect (NA) or general distress factor. Symptoms of anhedonia and the absence of positive affect are specific to depression whereas symptoms of physiological hyper-arousal are specific to “anxiety.”

Using the present terminology, the physiological hyperarousal items would be described as somato-visceral symptoms of fear. The subjective anxiety symptoms often are key markers of general distress. For example, when averaging factor loadings across five different samples (three student samples, an adult sample, and a patient sample), the item “worried a lot about things” had the second largest loading of any item on the general distress factor, (14) and the same was true in a sample of child and adolescent psychiatric inpatients (15).

Tests of the tripartite model demonstrate that somato-visceral symptoms of fear, symptoms of depression, and subjective symptoms of anxiety (along with other general distress symptoms) can be distinguished from each other. Such a distinction has been demonstrated in many samples, clinical and nonclinical, adult and child (e.g., (14–19)). As mentioned, although these factors can be distinguished from one another, they typically are moderately to highly correlated, albeit with some exceptions (e.g., (15)).

Some studies have identified two rather than three factors (e.g., (20)). The two-factor findings have been interpreted as symptoms of “anxiety” vs. symptoms of depression, without distinguishing fear from anxiety symptoms. However, these studies tend to rely on an insufficient number of items for independent measurement of fear and anxiety.

Only a handful of studies have examined whether different disorders load differentially on symptoms of fear and anxiety. One study with adult outpatients showed with zero-order correlations that autonomic arousal (somato-visceral symptoms of fear) was positively associated with constructs representing PD, GAD, SOP, obsessive-compulsive disorder (OCD), and MD, and that the correlation was significantly stronger with PD (0.89) than the other constructs (18). Others also report greater correlations between somato-visceral symptoms of fear with PD than with GAD (9, 21) or with MD (9). Thus, whereas somato-visceral symptoms of fear seem to be associated with anxiety disorders in general, they may be of particular relevance to PD. In further support of this premise, when Brown et al. (18) examined unique associations using all disorder constructs and negative affect as covariates, the PD construct was the only one to retain a significant, positive association with autonomic arousal. Also, the unique relationship between GAD and autonomic arousal was significant, but in the negative direction, suggesting a possible division between PD and GAD.

A similar specificity has been found between positive affect and both MD and SOP. That is, when structural models including multiple disorders and symptom constructs are considered, positive affect only displays significant associations with MD and SOP (9, 18). Notably, the similarity between MD and SOP in this regard is at odds with the separation of SOP as a fear disorder from depression as an anxious-misery disorder.

Furthermore, in clinically referred children and adolescents, after controlling for the variance in physiological hyperarousal associated with negative affect, the somato-visceral symptoms of fear were significantly associated with clinical severity ratings for PD only and no other disorders of anxiety or depression (22). Positive affect showed significant, negative associations with MD and SOP, whereas negative affect demonstrated significant, positive relations with PD, GAD, and OCD.

The psychometric distinction between symptoms of fear and anxiety is potentially confounded by the measurement of different response systems, since most studies assess only somato-visceral symptoms of fear and only subjective symptoms of anxiety. For example, studies of SP stimuli typically measure how much fear is expected if a specific stimulus was encountered in the coming week, without any indicators of anxiety about the stimulus (e.g., worry about encountering, or avoidance of situations involving the stimulus). Thus, it is unclear whether symptoms load on different factors because they represent differences between symptoms of fear and anxiety or because they represent differences among response systems (i.e., verbal-subjective, overt motor, and somato-visceral).

Another limitation is that most studies employ nonstimulus-specific items. For example, physiological hyperarousal (e.g., heart pounding) items usually refer to the frequency or intensity of symptoms over a specified period (past week or two), without reference to an eliciting stimulus. Individuals who experience fear symptoms in the presence of circumscribed stimuli (e.g., air travel) may not encounter such stimuli over the specified period of time, and thus would score low on fear items. Similarly, even though they may worry about particular circumscribed stimuli as they become more probable (e.g., days before air travel), such individuals may not typically worry about those stimuli and hence would score low on symptoms of anxiety. In contrast, individuals with PD would be more likely to score high on items of fear, as would individuals with GAD be more likely to score high on items of anxiety, because they experience fear and anxiety, respectively, more frequently. In other words, nonstimulus-specific measures appear to represent frequency of fear and anxiety. However, frequency does not take into account the magnitude of response in the presence of specific stimuli or the frequency of exposure to specific triggering stimuli.

Hence, non-stimulus-specific items (as a measure of frequency) may be best complemented by stimulus-specific symptom items (as a measure of magnitude). For example, social anxiety symptom items might include: “I avoid parties” (overt motor acts), “when alone I worry about meeting new people” (verbal-subjective), and “I get tense and irritable from worrying about social situations” (somato-visceral). Social fear items could include: “I try to leave social situations as soon as possible” (overt motor acts), “when speaking in public, I think I look like a fool” (verbal-subjective), and “my palms get sweaty when eating in front of others” (somato-visceral). Patterns of covariation among such items would reveal whether or not a future-oriented social anxiety factor, indicated by avoidance of and worry about potential social situations, was separable from a present-focused social fear factor, indicated by escape from social situations as well as fearful thoughts and physiological arousal during social situations. With this kind of measurement, the extent to which each disorder is marked by symptoms of fear vs. symptoms of anxiety could be determined.

The existing literature reveals that self-reported somato-visceral symptoms of fear (e.g., breathlessness) are separable from, yet related to, verbal-subjective symptoms of anxiety (e.g., worry a lot). Although verbal-subjective symptoms of anxiety are not always separable from other general distress symptoms, anxiety symptoms and fear symptoms generally are separable from, yet related to, symptoms representing anhedonia or the absence of positive affect (i.e., depression). The extent of the relationship between factors of fear, anxiety, and depression tends to be moderate-to-large, but can be quite modest depending on item content. While there is some evidence to indicate that several anxiety disorders are significantly, positively related to somato-visceral symptoms of fear, the relationship of these symptoms to PD seems to be stronger than with GAD. These findings lend support to a distinction between fear-based disorders and anxious-misery disorders. Symptoms of anhedonia are especially linked to both MD and SOP, thereby at odds with the proposed categorization of SOP as a fear disorder vs. anxious-misery disorder.

However, as noted, the limitations to existing self-report methodologies weaken the implications for DSM. That is, most studies are limited by the measurement of different response systems to assess fear (i.e., somato-visceral) vs. anxiety (i.e., verbal-subjective) symptoms as well as by restriction to nonstimulus-specific symptoms of fear and anxiety. Even when studies employ stimulus-specific items, they tend to address either fear or anxiety symptoms, but not both. Therefore, it is recommended that self-report items are developed that would better assess fear and anxiety symptoms across all three response modalities as well as in response to a range of stimuli.

This section reviews aversive conditioning, stress reactivity, and information processing (attention, memory, and appraisal) paradigms to evaluate commonalities and differences in behavioral, psychophysiological, and cognitive responding to aversive stimuli across anxiety and mood disorders. Symptom self-report (reviewed in the earlier section) entails retrospective estimation of how one has responded in the past or prediction of how one might respond in the future. In contrast, in this section we evaluate features of verbal-subjective, overt motor acts, and somato-visceral activity responding as they occur in the presence of specific stimuli. Discordances often exist between symptom self-report on the one hand and online measurement of behaviors and physiology on the other hand.² As before, our goal is to evaluate the extent to which these indices of on-line responding are shared across anxiety disorders and differ from mood disorders.

Pavlovian fear conditioning has long been applied as an etiological model for anxiety disorders (23). In a typical Pavlovian fear conditioning paradigm, a neutral stimulus is paired with an innately aversive stimulus (unconditional stimulus, US, such as a painful shock) a sufficient number of times for the neutral stimulus to become a reliable predictor of the aversive, and therefore capable of eliciting a conditional response (CR) in the absence of the US. The CR typically is measured by an increase in arousal (e.g., galvanic skin conductance response) and an increase in negative valence (e.g., startle blink reflex). The CR is even acquired to a CS that is masked to prevent conscious awareness (i.e., subliminal), at least with stimuli judged to be “fear-relevant.”³ Pavlovian conditioning also occurs through observation, as when observing others react fearfully in the presence of a given stimulus. Olsson and Phelps (24) found that observational conditioning in humans was measurable even to subliminal presentations of the CS. Furthermore, verbal instructions to expect a shock without actual shock delivery have been shown to elicit similar CRs, although only to supraliminal presentations of the CS (e.g., (24)). Thus, the Pavlovian conditioning model posits that fears are acquired through associations with aversive events, experienced directly, vicariously, or through informational transmission.

Developments in the basic science of fear conditioning have converged on a distinction between two types of learning, explicit threat cue vs. context learning. Explicit threat cues refer to the specific CSs that predict the US, whereas context refers to the location within which the US is presented. Like the CS, the context becomes predictive of the US and capable of eliciting a CR. Explicit threat cues are presumed to elicit phasic fear responses to certain or imminent threat, whereas contextual cues are presumed to elicit a more sustained anxious response to less certain threat (since the context is a reminder of threat but does not signal the precise timing of its occurrence). In this way, explicit threat cue vs. context learning map onto different defensive responses tied to proximal vs. distal threat on the predator imminence continuum, (6) for a related discussion also see Reference (25) and parallel the distinctions between self-reported fear and anxiety. Davis and colleagues (26) have demonstrated that two distinct neural substrates underlie these responses: phasic fear response to imminent threat (explicit threat cue) is mediated by the amygdala; and anxiety response to uncertain threat (context) is mediated by the bed nucleus of the stria terminalis, BNST (extended amygdala) (Table 2). Another body of research has established the role of the hippocampus in context conditioning relative to cue conditioning, (27) and perhaps more so for complex vs. simple contextual information (28).

In humans, the context may be the screen on which the CS and US are presented, ambient lighting, or the room itself. Several studies have investigated context conditioning in humans via the presentation of unpredictable USs.⁴ Greater context conditioning is observed following unpredictable than predictable shocks in healthy controls, as measured by startle reflexes during baseline conditions (conditions of anticipation prior to the delivery of an experimental procedure) and during intertrial intervals. In one study, (29) the effect of unpredictable shocks was tied to an elevated expectancy for the US, perhaps akin to the state of vigilance and preparation for threat that is believed to be characteristic of anxiety (5). In another study, (30) participants were less likely to subsequently explore the unpredictable vs. the predictable context for monetary reward; lack of exploration was interpreted as an index of anxious avoidance and further evidence of context conditioning.

In summary, the findings with nonclinical human samples (albeit small in number) are remarkably consistent with the findings from nonprimate samples, in differentiating explicit threat cue learning from contextual learning. In addition, human research has identified the role of the amygdala in cued fear conditioning (e.g., (31)) and initial findings indicate the role of the right anterior hippocampus and bilateral amygdala in context conditioning (32, 33). The next question is how well these features of explicit threat cue fear learning and contextual anxiety learning map onto the anxiety disorders vs. mood disorders.

Another extensive body of research measures psy-chophysiological response to a variety of different aversive stimuli, without testing the learning of an association with neutral stimuli. Such “stress reactivity” measurement illuminates differences between anxious groups and controls, and between anxiety disorders. Anticipatory baseline responding in studies of “stress reactivity” can be viewed as an index of contextual anxiety. The acute response measured during actual delivery of stressors can be viewed as an UR (when using generic stressors, such as shock), or a response to personally relevant stimuli (when using disorder-specific stressors, such as trauma reminders for PTSD). Stress reactivity paradigms typically measure skin conductance, heart rate, respiration, muscle tension, or startle reflex to index the somato-visceral response component of fear and anxiety. The most thorough evaluation would entail assessment of generic stressors and disorder-specific stressors across different anxiety disorders and mood disorders. However, instead, almost every study pertains to a single anxiety disorder vs. healthy controls, and usually tests either generic or disorder-specific stressors. Results are summarized in Table 5. Notably, this review does not cover pharmacological probes that exert central nervous system effects, such as meta-chlorophenylpiperazine or yohimbine, but rather is restricted to assessment of reactivity to inherently aversive stimuli that may occur in the natural environment.

Combining the psycho-physiological results from the studies of individual anxiety disorders and the few studies that address more than one anxiety disorder (Table 5), it may be concluded that PTSD and PD show elevations in baseline anticipation of generic stressors, (58, 59) and perhaps more so in PTSD than PD, (60) but do not show elevations in acute response to generic stressors relative to controls (58, 59). Also, individuals with PD show a stronger baseline response (e.g., (61)) but not a stronger physiological acute response to disorder-specific stressors (e.g., (62, 63)), although there are occasional exceptions (e.g., (64)). The disorder-specific stressors for PD have consisted mostly of carbon dioxide inhalation paradigms.^10,11 The majority of PTSD individuals additionally exhibit stronger acute physiological response to trauma reminders compared to controls (e.g., (69)] although not always (e.g., (70, 71)). SOP (nongeneralized) and SP may possess stronger baseline and acute physiological response to disorder-specific stimuli compared to healthy controls (e.g., (72–75)), although baseline and acute response have not been evaluated to highly aversive generic stressors such as shock, and the findings remain tentative. Evidence pertaining to GAD and OCD also is limited by insufficiently aversive generic stressors. Available evidence provides an inconsistent picture regarding baseline differences between GAD and healthy controls (76, 77) and for non-anxious individuals to sometimes have stronger autonomic responses to acute generic stressors than individuals with GAD (e.g., (77)), which may be due to tonic inhibitory effects in GAD (e.g., (78)). Individuals with OCD did not differ from controls during baseline recordings (79) although this may be due to the use of mild stressors; they show an elevated autonomic acute response when confronted with relevant stimuli, such as contaminated objects, relative to baseline conditions, although comparisons have not been made with controls (e.g., (80)).

Information processing refers to cognitive processes of attention, memory, and appraisal. An extensive body of research has evaluated these processes in relation to anxiety and depression. In this section, we evaluate the extent to which indices of information processing are shared across anxiety disorders and differ from mood disorders.

This section reviews pertinent neural circuitry with an emphasis on information gleaned from neuroimaging research. The brain basis of anxiety disorders and the potential neural underpinnings for the clinical, cognitive, and behavioral phenomena reviewed in prior sections are addressed. To the extent that neurobiology has been posed as one of the key validators for DSM-V, it is germane to explore a common circuitry-based pathophysiology that might serve to define the anxiety disorders as a category, as well as features that might distinguish among disorders. While pathophysiology may emanate from dysfunction at the level of molecules, cells, nodes, and/or networks, contemporary imaging has tended to characterize differences at the level of nodes or specific brain regions; we appreciate that while this represents an oversimplification, it provides for a relatively accessible approach. Where appropriate, we will draw upon recent reviews to enable a more concise treatment of these issues here (e.g., (47, 130, 131, 132)).

A constellation of brain regions has been implicated in mediating the normal functions pertinent to anxiety disorders. First, a network involving the amygdala, ventromedial prefrontal cortex (vmPFC), and the hippocampus has been a focal point for contemporary models of anxiety disorders (47, 130). The amygdala plays a critical role in threat assessment, in forming associations regarding danger in the environment (e.g., conditioned fear acquisition; see earlier section), and in mediating response to threat or potential threat via descending projections to regions that mediate autonomic responses (e.g., heart rate, blood pressure, respiration, sweating, etc.) (133). The vmPFC and hippocampus provide top-down governance over the amygdala, capable of inhibiting fear responding; for instance, the vmPFC mediates extinction recall via inhibition of the amygdala response to learned threat cues (see earlier section), and the hippocampus provides information that is permissive of extinction recall by providing information regarding safe vs. dangerous contexts (47) for review, see Reference (134). Importantly, the hippocampus also mediates contextual conditioning (30, 31, 135, 136) (see earlier section). Of note, the extended amygdala, including the BNST, is purported to play an important role in anxiety per se, as opposed to fear (26, 43) (see earlier section). However, given the challenges in resolving the extended amygdala vs. the amygdala proper, it is important to appreciate that most imaging studies to date that report amygdala findings have not sought to make this distinction. Although, the imminence continuum from anxiety to fear as a function of proximity to threat (see initial section) has been substantiated at the neural level as a shift from vmPFC to periaqueductal gray (137).

Second, the orbitofrontal cortex (OFC) is divisible into medial (mOFC) and lateral (IOFC) subterritories (138). To the extent that OFC plays an important role in computing, assigning, or weighing value, in the service of decision making and guiding behavior, the mOFC principally mediates positive valuations (e.g., of reward and safety) whereas the IOFC principally mediates negative valuations (e.g., of punishment) (e.g., (139)). In this context, mOFC (highly overlapping with vmPFC) plays a role in suppression of fear and anxiety, such as through mediating extinction recall (see earlier section), whereas IOFC with extension in ventrolateral PFC more generally, appears to mediate negative cognitions, obsessions and worry (see first section and earlier section).

Third, the insular cortex mediates interoception, and hence plays a critical role in individuals' awareness of and sensitivity to visceral activity (140) (see earlier section). In this context, the insula is implicated in anxiety sensitivity, something which is purported to enhance Pavlovian conditioning, since stronger perceived (as well as actual) physiological responses to aversive stimuli generally elicit stronger conditioning (129).

Fourth, the anterior cingulate cortex (ACC) is functionally heterogeneous, with distinct dorsal (dACC), pregenual (pgACC), and subgenual (sgACC) subdivisions (e.g., (141)). The dACC has been termed the cognitive division, and has been implicated in a host of functions including error detection, conflict monitoring, and attention (see earlier section). The pgACC has been termed the affective division; both the dACC and pgACC play a role in suppressing attention and response to specific input channels. To elaborate, the pgACC mediates the capacity to suppress attention and response to affective stimuli, whereas the dACC is implicated in suppressing attention and response to cognitive stimuli (see earlier sections). Of note, recent findings suggest that a subterritory of dACC may represent the human homologue of prelimbic cortex, in augmenting amygdala responses to conditioned fear cues (142, 143) (see earlier sections). The sgACC has been termed the visceromotor division, and is contiguous with vmPFC and mOFC; this territory has been implicated in depression (144).

Building on knowledge of normal functional anatomy, one can pose a variety of hypotheses seeking to link the observed clinical and behavioral phenomena of anxiety disorders and their neural substrates. For instance, exaggerated responsivity or sensitivity of the amygdala could mediate abnormal threat assessment (see earlier section), exaggerated fear responses including exaggerated autonomic output (see earlier section), or abnormalities in learning about danger in the environment (see earlier section). Further, in addition to vulnerabilities to anxiety conferred by intrinsic abnormality in amygdala function, abnormal amygdala responses could be secondary to insufficient vmPFC function, leading to inability to recall extinction information (see earlier section); or, secondary to abnormal hippocampal function, undermining the capacity to distinguish between safe and dangerous contexts (see earlier section). Cognitive manifestations such as worrying and obsessing are likely mediated by excessive activity in IOFC (and related regions). Interestingly, conditions characterized by globally excessive OFC activity may involve both complaints of such cognitive symptoms (mediated by IOFC) and paradoxically relatively reduced amygdala as well as autonomic responsivity (due to suppression by mOFC), perhaps characteristic of GAD (see earlier section).

Elevated insula activity would be expected as a consequence of normal interoceptive function in the face of elevated autonomic responses (such as secondary to exaggerated amygdala responses) in anxiety disorders. Interestingly however, aberrant insula activity, due to intrinsic dysfunction or hypersensitivity, could also be seen as a correlate of anxiety sensitivity (i.e., interoceptive hypersensitivity) (earlier section), in the absence of elevated autonomic measures or elevated amygdala output, as has been observed in relation to carbon dioxide inhalations and PD (e.g., (63)) (earlier section). Aberrant error detection (i.e., false alarms) leading to pathological doubting, as seen in OCD, could be mediated by dACC dysfunction. It is also possible that elevated activity in this region could exacerbate conditioned fear expression as seen with prelimbic cortical stimulation in rodents (142). In contrast, deficiency in pgACC may mediate attention biases to disorder-relevant cues in the anxiety disorders (earlier sections).

The above series of hypotheses hints at the range of possibilities as well as the potential heterogeneity of pathophysiological roots for the anxiety disorders. While numerous brain imaging studies have been performed in an effort to elucidate the brain basis of anxiety disorders, to date the aggregate data provide initial support for heuristic models as opposed to conclusive evidence of distinct pathophysiology by diagnosis. In fact, few of the above hypotheses have been investigated systematically across the anxiety disorders. We propose that it would be illuminating to take such a systematic approach, including comparisons with other conditions beyond the anxiety disorders, to test for the specificity of findings.

Here we present three examples for illustrative purposes. The first example pertains to amygdala function. Using a range of symptom provocation and cognitive paradigms, investigators have probed amygdala responses to generic (e.g., emotional faces¹²) and disorder-specific stimuli (Table 7). In this context, there is evidence that exaggerated response to disorder-specific stimuli is a shared feature of those anxiety disorders tested to date, whereas amygdala responses to generic threat-related stimuli may distinguish among the anxiety disorders (e.g., (145)). Consistent with the psychophysiology data from stress reactivity studies (see earlier section), there is preliminary evidence for PTSD and PD to be associated with elevated responses to generic stressors to a greater degree than SOP or SP. Of note, MD is also characterized by exaggerated amygdala responses to emotional faces (146) weighing against this being a unique feature for the anxiety disorders. However, there may be other aspects of amygdala function that distinguish between anxiety disorders and depression. For instance, with regard to laterality, there is some suggestion that anxiety disorders may be preferentially characterized by right-lateralized amygdala findings, (147) whereas depression is characterized by left-sided amygdala findings; this may reflect lateralized aspects of normal amygdala function in humans (148). Further, elevated resting/baseline metabolism within the amygdala has been consistently found in depression, but not in anxiety disorders (149).

Second, using a range of symptom provocation and cognitive paradigms, reduced mOFC function has been consistently found in association with anxiety disorders (131). Interestingly, increased activation within IOFC has been less consistent across anxiety disorders, but may be a hallmark of OCD, and GAD and other disorders characterized by cognitive anxiety (i.e., worry, obsessions, etc.).

Third, again, based upon data from a range of experimental paradigms, elevated insular signal may be a common finding across anxiety disorders (132).

Finally, it must be noted that there are limited data with regard to normal function as well as pathophysiology of anxiety disorders across development. There are some initial intriguing findings suggesting exaggerated amygdala response as a potential neural correlate of the behaviorally inhibited phenotype that engenders increased risk for developing anxiety disorders (e.g., (150)), as well as evidence for elevated amygdala and insular responses in individuals with anxiety-prone traits. (151) Moreover, early pioneering studies of anxiety disorders in children implicate potential amygdala dysfunction (e.g., (152, 153)). But more research in this area is especially sorely needed.

In summary, advances in neuroimaging and translational research of the past ≈20 years have helped to focus the field on neural circuitry implicated in the pathophysiology of anxiety disorders as well as relevant normal functions. While this research has yielded useful heuristic models, much work remains in order to definitively establish the brain basis of anxiety disorders. At this point, measures of amygdala, vmPFC/ OFC, and insula function stand as leading candidates for usefully defining anxiety disorders in future.