Neurodevelopmental Aspects of Childhood Anxiety Disorders:
Neurobiological Responses to Threat

Bruce D. Perry, M.D., Ph.D.

The ChildTrauma Academy
www.ChildTrauma.org

*This is an Academy version of a chapter originally published in the Textbook of Pediatric Neuropsychiatry.

Official citation:  Perry, BD Neurophysiological Aspects of Anxiety Disorders in Children. In: Textbook of Pediatric Neuropsychiatry (CE Coffey and RA Brumback, Eds.). American Psychiatric Press, Inc, Washington, DC. In press (1998)

ANXIETY: The apprehensive anticipation of future danger or misfortune accompanied by a feeling of dysphoria or somatic symptoms of tension. The focus of anticipated danger may be internal or external.

(DSM IV: Appendix C, Glossary of terms)

Anxiety, an emotion, is the subjective sensation that accompanies the body's response to real or perceived threat (Izard. 1991; Izard. 1977). All individuals experience some degree of real or perceived threat, and, therefore, we all have had the sensation of anxiety. For some individuals, however, the frequency, duration, intensity or context of anxiety is extreme and can interfere with normal development and functioning. These individuals are considered to have anxiety disorders.

Over the recent past, efforts at understanding abnormal anxiety symptoms resulted in clustering similar clinical presentations of anxiety symptoms into anxiety disorders. In DSM III-R there were two child-specific anxiety disorders: separation anxiety of childhood and overanxious disorder of childhood, and disorders present in children and adults: panic disorder, agoraphobia, specific phobias (e.g., social phobia), post-traumatic stress disorder and obsessive-compulsive disorder. While each of these disorders had distinguishing clinical phenomenology, profound anxiety was the core symptom common to all. With DSM IV, there has been a refinement of this phenomenology (see Table 1).

The specific clinical phenomenology of the evolving classifications of childhood anxiety disorders has been described in detail elsewhere (Wells & Vitulano. 1984; Strauss, Lease, Last, & Francis. 1988; Prince. 1968; Bernstein & Borchardt. 1991). This chapter will focus on neurobiological correlates of anxiety and the clinical implications of formulating anxiety as a subjective manifestation of the brain's fear-response systems.

While childhood anxiety problems are common mental disorders in the general population (Wells & Vitulano. 1984) and anxiety is a pervasive symptom in childhood neuropsychiatric disorders, very few studies have directly examined neurobiological or neurophysiological aspects of childhood anxiety disorders. This is due, in part, to the evolving difficulties with phenomenological classification of these disorders (see above). Despite this lack of direct neurobiological data regarding anxiety disorders, tremendous advances have been made in understanding the neurobiology of stress and the response to threat (Goldstein. 1995). Furthermore, it is becoming increasingly clear that the neurobiology of vigilance and 'fear' can give important clues to the neurobiological underpinnings of the subjective emotion of anxiety (Davis. 1992b). Whether 'fear' is due to an imagined threat, a neutral but 'mislabeled' cue now categorized as threat-related, or an actual external or internal (e.g., hypoxia) threat, the brain responds in a similar fashion. The threatened organism activates the central and peripheral nervous system in an attempt to mobilize appropriate responses to promote survival. In humans, the key emotion related to this total body mobilization is anxiety.

The present chapter will outline aspects of the human neurobiological responses to threat, the relationship between the neurophysiology of fear and the subjective state of anxiety, developmental issues in the response to threat and pathological processes which can result in abnormalities in the fear-response neurobiology which, in turn, may mediate childhood anxiety disorders.

OVERVIEW

The prime 'directive' of the human brain is to promote survival and procreation. All of the sensory, perceptual, storage and acting portions of the brain are 'over-determined' to sense, process, store, perceive and act on information from the external and internal environments to interpret the world, promote survival and facilitate mating. When potentially-threatening cues are present in these environments, the brain activates a complex set of neurophysiological, neuroendocrine, and neuroimmunilogical responses to optimize the survival of the individual (Murberg, McFall, & Veith. 1990; Giller, Perry, Southwick, & Mason. 1990; Cannon. 1929; Selye. 1936). In humans, as these threat-response systems are activated, the subjective perception of 'anxiety' or fear is present. A simple overview of this process provides a useful framework for more detailed examination of the known neurobiological correlates of anxiety.

Sensory information from the external environment (visual, auditory, tactile, olfactory, gustatory) and the internal environment (e.g., blood glucose, arterial pressure, CO2 levels) enters the central nervous system at the level of the brain stem and midbrain (for review see Goldstein. 1995). As this primary sensory input comes into the brain stem and midbrain, it is matched against a previously stored patterns of activation and if unknown, or if associated with previous threat, an initial alarm response begins (e.g., Aston-Jones, Ennis, Pieribone, Nickel, & Shipley. 1986). The alarm response begins a wave of neuronal activation in key brainstem and midbrain nuclei which contain neurons utilizing a variety of neurotransmitters (e.g., norepinephrine, dopamine, serotonin), neuromodulators and neuropeptides such as ACTH, corticotrophin releasing factor, vasopressin. Activation of these key systems results in patterns of neuronal activation which move from brainstem through midbrain, to thalamic, limbic and cortical areas. At the level of the brainstem and midbrain, there is little subjective perception. It is at the level of the thalmus and the limbic areas that specific patterns of neuronal activity result in the actual sensation of anxiety. At the sub-cortical and cortical level, more complex cognitive associations are made, allowing interpretation of that internal state of anxiety (Singer. 1995). Cortical, limbic, midbrain and brainstem-based neuronal activity, then, may be involved in various aspects of anxiety regulation or dysregulation (see Gorman, Liebowitz, Fyer, & Stein. 1989).

This overview describes the sensing and perceiving elements of the response to threat. At each level of the CNS, as the afferent input is 'interpreted' and matched against previous similar patterns of activation, an efferent arm is initiated. The CNS responds to the potential threat. The classic adult 'response' to the threatening cues involves activation of the autonomic nervous system. Originally described by Cannon (Cannon. 1929; Cannon. 1914) and coined the 'fight or flight' reaction, the physiological manifestations of alarm and arousal frequently co-occur with the emotion of anxiety (e.g., profuse sweating, tachycardia, rapid respirations). These physical symptoms are manifestations of activation of the autonomic nervous system and the hypothalamic-pituitary axis (HPA, Yehuda, Southwick, Perry and Giller, 1994). It is important to differentiate, however, between the subjective sensation of anxiety and these co-occuring neurophysiological activities. Someone may be anxious in the absence of intense autonomic nervous system arousal. Conversely, autonomic arousal, albeit different patterns of arousal, need not be accompanied by the subjective sensation of anxiety (e.g., exercise, excitement, anger).

Both the afferent and efferent wings of the threat response are involved in anxiety regulation. In a 'healthy' situation, anxiety would be proportional to the nature of the internal or external threat. The intensity and duration of the subjective state of anxiety can vary depending upon various factors including the nature of the threat, the 'sensitivity' of the individual's stress-response neurophysiology, and previous history of exposure to threat. In some cases the intensity is so great that the individual is sure that they are about to die -- this terror may be present in the face of true life threatening events or in the midst of an abnormal paroxysmal activation of the threat-response neurophysiological apparatus (e.g., panic attack). In other cases the intensity is less but a state of anxiety is pervasive even in the absence of any true internal or external threat.

The threat-response apparatus is so critical to survival that it makes complete teleological 'sense' that the neurobiological systems involved in sensing and responding to threat are redundant and involve diverse brain areas and systems. The subjective emotion of anxiety appears to be a common final 'pathway' symptom for many neuropsychiatric disorders. In order to systematically examine possible neurobiological correlates of primary anxiety disorders, then, it is important to review possible abnormal organization, regulation or development of neurobiological systems and sub-systems in the key systems within various brain regions (i.e., brainstem, midbrain, thalamus, limbic or cortical) which appear to be involved sensing, processing and responding to threat.

THREAT-RESPONSE NEUROBIOLOGY IN THE MATURE CNS

The network of ascending arousal-related neural systems in the brain consisting of locus coeruleus noradrenergic neurons, dorsal raphe serotonin neurons, cholinergic neurons from the lateral dorsal tegmentum, mesolimbic and mesocortical dopaminergic neurons, among others, form the reticular activating system (RAS). A great deal of the original research on arousal, fear, response to stress and threat was carried out using various lesion models of the RAS (Moore & Bloom. 1979). With the onset of more specific techniques in neuropharmacology allowing specific manipulation and lesioning of individual neurochemical systems, the concept of the RAS as a functional unit lost popularity. Recently, the RAS as a viable neurophysiological system involved in arousal, anxiety and modulation of limbic and cortical processing has re-emerged (Munk, Roelfsema, Konig, Engel, & Singer. 1996). These brainstem and midbrain monoamine systems, working together, provide the flexible and diverse functions necessary to modulate the variety of functions related to anxiety regulation.

Locus coeruleus: Regulation of arousal

A critical brain stem nuclei involved in initiating, maintaining, and mobilizing the total body response to threat is the locus coeruleus(LC) (Aston-Jones, Chiang, & Alexinsky. 1991; Murberg, McFall, & Veith. 1990; Aston-Jones, Valentino, Van Bockstaele, & Meyerson. 1996). This bilateral grouping of norepinephrine-containing neurons originates in the pons and sends diverse axonal projections to virtually all major brain regions, enabling its function as a general regulator of noradrenergic tone and activity (Aston-Jones, Ennis, Pieribone, Nickel, & Shipley. 1986; Foote, Bloom, & Aston-Jones. 1983). The LC plays a major role in determining the 'valence' or value of incoming sensory information, increasing in activity if the information is novel or potentially threatening (Abercrombie & Jacobs. 1987b; Abercrombie & Jacobs. 1987b). The ventral tegmental nucleus (VTN) also plays a part in regulating the sympathetic nuclei in the pons/medulla (Moore & Bloom. 1979). Acute stress results in an increase in LC and VTN activity and release of norepinephrine that influences the brain and the rest of the body. These brainstem catecholamine systems (LC and VTN) play a critical role in regulating arousal, vigilance, affect, behavioral irritability, locomotion, attention, the response to stress, sleep and the startle response (Morilak, Fornal, & Jacobs. 1988b; Morilak, Fornal, & Jacobs. 1988b; Morilak, Fornal, & Jacobs. 1988b; Levine, Litto, & Jacobs. 1990b).

Pharmacological manipulation of LC activity can alter 'sensitivity' to anxiety in various situations. Alpha-2 adrenergic receptors in the LC when stimulated by full (e.g., epinephrine) or partial agonists (e.g., clonidine) will decrease tonic and stimulated LC activity, resulting in behavioral changes suggesting less reactivity and sensitivity to anxiety-provoking stimuli. In contrast, yohimbine, a alpha2 adrenergic receptor antagonist, increase LC activity and can induce panic attacks, and increase anxiety in individuals with panic disorder or PTSD (for review see Giller, Perry, Southwick & Mason. 1990).

A number of other neurotransmitters and neuropeptides play a role in modulating LC activity, thereby influencing sensitivity of the threat-response systems. Serotonin (Adell, Garcia-Marquez, Armario, & Gelpi. 1988), enkephalins (Abercrombie & Jacobs. 1988), CRF (Butler, Weiss, Stout, & Nemeroff. 1990), and epinephrine (Perry, Stolk, Vantini, Gucchait, & U'Prichard. 1983; Vantini, Perry, Gucchait, U'Prichard, & Stolk. 1984) all can alter LC sensitivity.

Dopaminergic systems and sensitization

Dopaminergic systems play a critical role in the response to threat. In animal models, various stress paradigms have demonstrated alterations in dopamine metabolism, dopamine receptor densities and 'sensivity' (Kalivas, Duffy, Abhold, & et.al. 1990). Dopaminergic systems originating in the mesencephalon send projections to key limbic and cortical areas involved in the afferent and efferent wings of the threat response. These systems are very important in sensation, perception and interpretation of stress and threat-related cues.

Important clues to the neurophysiological mechanisms which may underlie the development of a sensitized anxiety response comes from studies of psychostimulant and stress-induced sensitiation of these dopaminergic systems (Kalivas, Duffy, Abhold, & et.al. 1990). Sensitization, an increased sensitivity to a constant stimulus, occurs following a specific patterns of activation of these dopaminergic systems (Post, Weiss, Uhde, Clark, & Rosen. 1993). In rats (Kleven, Perry, Woolverton, & Seiden. 1990), primates (Farfel, Perry, Kleven ) and humans (Post & Weiss, 1988), psychostimulants (e.g., methamphetamine, cocaine) administered in moderate doses can induce dramatic sensitization syndromes which include agitation, impulsivity, autonomic arousal, even seizures. Stress can induce similar sensitiztion in animal models (Kalivas & Duffy. 1989; Antelman, Eichler, Black, & Kocan. 1980; see case example).

CASE EXAMPLE: Psychostimulant induced panic attacks: S. is a 16 yo male admitted to the emergency room with diaphoresis, tachycardia, sense of impending doom and profound anxiety. He had no previous history of psychiatric disorder and denied previous anxiety or panic attacks. On history, he describes a four month history of cocaine use, characterized by binge nasal use. His last binge was five days prior to the admission. He described an escalating 'sensitivity' to stress, with increased irritability and difficulty sleeping over the five days prior to admission. Following extensive and neuropsychiatric medical, this was formulated to be a psychostimulant-induced panic disorder, related to 'sensitizing' pattern of cocaine use. Following discharge, he experienced more panic attacks (approximately two per week) and elected to follow through with recommended outpatient treatment. Successful drug rehabilitation accompanied by use of a benzodiazepine anxiolytic for six weeks resulted in disappearance of panic attacks.

Sensitization involves a cascade of cellular and molecular processes likely related to long-term potentiation (Madison, Malenka, & Nicoll. 1991; Brown, Chapman, Kairiss, & Keenan. 1988). It has been hypothesized that sensitization of the biogenic amines (NE, EPI, DA) in the reticular activating and related systems plays a key role in the development of seizure disorders (see Kalivas, Duffy, Abhold, & et.al. 1990), affective disorders (Post. 1992) , anxiety disorders (Post & Weiss. 1988) and post-traumatic stress disorders in adults (Perry, Southwick & Giller. 1990) and children (Perry. 1994).

The developing brain organizes in a use-dependent fashion, to hypervigilance, increased startle response, and, anxiety that is pervasive, out of context, and extreme in reactivity to neutral or minor threatening cues (Konarska, Stewart, & McCarty. 1989; Adell, Garcia-Marquez, Armario, & Gelpi. 1988). Therefore, many anxiety syndromes may represent a maladaptive generalized activation of the alarm response (i.e., a sensitization), with symptoms representing exaggerations of originally adaptive and appropriate functions: hypervigilance instead of appropriate prediction and early detection of future danger; avoidance and re-enactment rather than adaptation and survival (Perry & Pate. 1994; Perry. 1994). The sensitized monoamines send projections to limbic and cortical areas, where perception and interpretation of the threat takes place.

CASE EXAMPLE: Persisting 'fear' in a traumatized child: M. is a 10 yo female. She currently lives in foster care after being removed from her family due to chronic exposure to domestic battery and the severe physical assault of a sibling by her step father. She was seen in an outpatient setting for problems of sleep difficulties, increased startle response, difficulty concentration (hypervigilance), academic failure, and profound anxiety. Her resting heartrate was 120 bpm. Following extensive neuropsychiatric evaluation, she was diagnosed with post-traumatic stress disorder. Treatment included a) psychoeducation for the foster family and school regarding the impact of exposure to trauma on the emotional, behavioral and cognitive functioning of children, b) small group therapy with a focus on social skills and c) pharmacotherapy with clonidine. Dramatic improvement in sleep, impulsivity, anxiety and concentration were noted following the clonidine. Temporary discontinuation of the medication resulted in partial return of symptoms.

Sensory thalamic areas receive input from various afferent sensory systems and, at this level, feeling begins. Thalamic nuclei are important in the stress response yet these regions have been studies primarily as 'way-stations', transmitting key arousal information from the RAS neurons (e.g., LC noradrenergic neurons) to key limbic, subcortical and cortical areas involved in sensory integration and perception of threat-related information (Castro-Alamancos & Connors. 1996). Future studies may reveal a more central role of thalamic areas, particularily in regulation of the perception of anxiety -- analogous to the central role of thalamus in regulation of other core emotions such as pain.

The neuroendocrine, and likely neuroimmunological, afferent and efferent wings of the response to threat are mediated by hypothalamic and anatomically-linked nuclei (Loewy & Spyer,. 1990). Neural activation of these important nuclei involves dopaminergic, serotonergic and noradrenergic neurons, among others. The relationship between these brain areas and systems is not well understood. Indeed, despite well-documented correlations between HPA-axis and hypothalamic functioning exist for affective disorders, little is known about these areas in anxiety disorders. Animal studies have demonstrated important roles of various hypothalamic nuclei and hypothalamic neuropeptides in the stress response (e.g., Miaskowski, Ong, Lukic, & Haldar. 1988; Rosenbaum, Biederman, Gersten, & et al. 1988; Bartanusz, Jezova, Bertini, Tilders, Aubry, & Kiss. 1993; Young & Lightman. 1992).

The central role of sub-cortical network of brain structures in emotion was hypothesized by Papez (1937). In 1949, MacLean coined the term limbic system, integrating Papez' circuit (hypothalamus, anterior thalamus, cingulate gyrus and hippocampus) and other anatomically and functionally-related areas (amygdala, septum, orbito-frontal cortex). Over the years, various regions have been added or removed from this 'emotion' processing circuit.

Amygdala: Perception of threat and emotional memory

In the recent past, the amygdala has emerged as the key brain region in the processing, interpreting and integration of emotional functioning (Davis. 1992b). In the same fashion that the LC plays the central role in orchestrating arousal, the amydgala plays the central role in the CNS in processing afferent and efferent connections related to emotional functioning (Sapolsky, Krey, & McEwen. 1984; Phillips & LeDoux. 1992; Pavlides, Watanabe, & McEwen. 1993). The amygdala receives input directly from sensory thalamus, hippocampus (via multiple projections), entorhinal cortex, sensory association areas of cortex, polymodal sensory association areas of cortex, and from various midbrain and brainstem arousal systems via the RAS (Selden, Everitt, Jarrard, & Robbins. 1991). The amygdala processes and determines the emotional value of simple sensory input, complex multisensory perceptions and complex cognitive abstractions, even responding specifically to complex, socially relevant stimuli. In turn, the amygdala orchestrates the response to this emotional information by sending projections to brain areas involved in motor (behavioral), autonomic nervous system and neuroendocrine area of the CNS (Davis. 1992a; Davis. 1992a; LeDoux, Iwata, Cicchetti, & Reis. 1988a). In a series of landmark studies, LeDoux and colleagues have demonstrated the key role of amygdala in 'emotional' memory (LeDoux, Cicchetti, Xagoraris, & Romanski. 1990; LeDoux, Romanski, & Xagoraris. 1989). Animals, including humans, store information other than cognitive, and the storage of emotional information is critically important in normal and abnormal regulation of anxiety. The 'site' of perception of anxiety is likely to be the amygdala (Davis 1992a). It is in these limbic areas that the patterns of neuronal activity associated with threat, and mediated by the monoamine neurotransmitters systems of the reticular activating system, become an emotion.

Hippocampus: Association, generalization and storage of threat-related cues

A key neuroanatomical region in memory and learning is the hippocampus. This brain area is involved in the storage of various forms of sensory information and is very sensitive to 'stress' activation (Sapolsky, Krey, & McEwen. 1984; Phillips & LeDoux. 1992; Pavlides, Watanabe, & McEwen. 1993). It appears to be critical in the storage and recall of cognitive and emotional memory (Selden, Everitt, Jarrard, & Robbins. 1991). Therefore, in any emotional state related to arousal or threat, hippocampal functioning is altered, changing the efficiency and nature of hippocampal storage and retreival functions. The state-dependent learning and related phenomenon (critical in understanding various clinical aspects of childhood anxiety disorders) involve hippocampal 'tone'. Threat alters the ability of the hippocampus and connected cortical areas to 'store' certain types of cognitive information (e.g., verbal) while efficiently storing other types (e.g., non-verbal). Many of the important over-generalizations which appear to be related to the development of anxiety disorders (e.g., agoraphobia) involve hippocampal and cortical association areas.

Neuronal systems are remarkably capable of making strong associations between paired cues (e.g., the growl of a tiger and threat). Associations between patterns of neuronal activity and specific sensory stimuli takes place in all brain areas, yet complex associations involving the integration of multiple sensory modalities requires more complex brain areas (e.g., amygdala) and the most complex associations take place in cortical areas. Under ideal conditions, this threat response capacity for association is able to rapidly identify sensory information in the environment which is associated with threat, allowing the organism to act rapidly to promote long term survival. Yet the remarkable capacity of the brain to take a specific event and generalize, makes humans vulnerable to the development of 'false' associations and over-generalizations from specific threat situations to other non-threatening situations.

In anxiety disorders, associations between specific complex cues (e.g., snakes) may become linked to the limbic-mediated emotion (anxiety). Limbic activation may result from cortically-mediated images (e.g., interpretation of a specific event as potentially threatening, or imagining a specific fear-inducing object such as a snake). Once these limbic areas are activated, there may (or may not be) activation of lower midbrain and brainstem areas involved in the response to threat -- the efferent wing of the alarm response may or may not be activated, depending upon the sensitivity of the individual's stress-response system (see above).

The quality and intensity of any emotion, including anxiety, is dependent upon subjective interpretation or cognitive appraisal of the given situation (Maunsell. 1995; Singer. 1995). Most theories addressing the etiology of anxiety disorders discuss the process of 'mislabeling' of stimuli as being 'threat'-related, thereby inducing a fear-response and anxiety in situations where no true threat exists (Wells & Vitulano. 1984). How an individual cortically-'interprets' the limbic-mediated activity (i.e, their internal state) associated with arousal plays a major role in the subjective sense of anxiety (Gorman, Liebowitz, Fyer, & Stein. 1989). Kluver-Bucy syndrome, resulting from damage or surgical ablation of temporal lobes results in loss of fear for current and previously threatening cues (Kluver & Bucy. 1937). The general disinhibition of this syndrome suggests a loss of the capacity to recall cortically-stored information related to previous threat, or to efficiently store threat-related cues from new experience.

Other areas of the cortex play a role in threat, primary among these are the primary and multimodal association areas which have direct connection to the amygdala. Important neurotransmitters in cortical, as well as other regions involved in threat are GABA (Haefely. 1990) and glycine (Gittleman-Klein R. & Klein. 1988). The capacity of benzodiazepines to alter arousal and sensitivity to threat has long been known. Indeed in humans, primary pharmacological treatment for many anxiety disorderrs involves benzodiazepine treatment, targeting GABA receptor complexes. While the GABA binding sites are ubiquitous in the CNS, the specific primary region for the therapeutic effects of benzodiazepines is unknown. It is likely that therapeutic effects are the result of action in multiple areas of the brain, including the cortex.

CASE EXAMPLE: Anxiety following frontal lobe damage: X is an 8 yo boy presenting to clinic 8 months after a car accident in which he suffered a traumatic head injury. He sustained significant fronto-temporal injury with resulting loss of fluent speech, motor and complex integrated sensory processing capabilities. Further progress in his rehabilitation was being impeded by the appearance of profound anxiety, unwillingness to travel to the hospital for rehabilitiation services, a combative and 'frightened animal' -like reaction when he was forced to leave the house to go anywhere. All novel situations appeared to 'trigger' his fearful, regressed combative tantrums. Once an episode started, it was nearly impossible to stop and it took almost a whole day for him to 'calm down' and return to his baseline state. After extensive neuropsychiatric evaluation, these episodes were conceptualized as being 'fear'-equivalents complicated by, and related to, a) difficulty processing complex, novel stimuli and b) an inability for previously intact cortical modulatory mechanisms to contain his arousal and impulsivity once they were activated. Psychoeducation for the school, family and rehabilitation staff regarding the need for consistent, predictable and familiar cues and pharmacotherapy with beta-blockers resulted in significant improvement. Physical, speech and other rehabilitative services were resumed with continuing improvement in functioning in all domains over the next few years.

NEURODEVELOPMENT AND CHILDHOOD ANXIETY DISORDERS

To this point, the neurobiology of the response to threat and anxiety in the mature central nervous system has been described. As is the case for other areas of neuroscience, much more is known about the neurophysiology and neurobiology of the mature brain than of the developing brain. A great deal is known, however, about anxiety and the development of arousal states in infants and children that is relevant for understanding the neurobiology of anxiety disorders.

In the recent past systematic study of the temperament of infants has suggested that at birth certain properties of the sensitivity of the arousal system may be constitutional (Kagan, Reznick, & Snidman. 1989; Kagan, Reznick, & Snidman. 1987; Kagan, Reznick, & Snidman. 1987). The rudimentary organization and sensitivity of the arousal systems appear to be present at birth. Differential internal states of anxiety appear to be associated with differential behaviors such as initiation of social contact, exploration, and the capacity to form and maintain peer attachments (Ainsworth, Blehar, Waters, & Wall. 1978; Last, Phillips, & Statfeld. 1987; Waldron, Shrier, Stone, & Tobin. 1975).

There are thousandsof gene products which, if abnormal, could result in altered development or functioning of the many neurotransmitter and neuroanatomical regions involved in regulating anxiety. It should not be surprising that there are a number of studies suggesting a strong familial tendency for anxiety disorders(Turner, Beidel, & Costello. 1987; Harris, Noyes, Crowe, & Chaudery. 1983; Crowe, Noyes, Pauls, & et al. 1983; Cloninger, Martin, Clayton, & Guze. 1981; Berg. 1976). Within family heritability, however, need not translate into a common genetic vulnerability across families (Torgesen. 1983). Indeed, heritability need not even mean genetic. While promising, no clear genetic data exist to support specific genetic etiology of any of the childhood anxiety disorders.

At birth, infants are capable of exhibiting distress (anxiety ?) when exposed to loud noises, pain, heights and strangers (395, 397). While it is unwise to presume that they are feeling anxiety, it is certainly not unreasonable to hypothesize that they are having a subjective sensation of distress. Distress may be due to feeling cold, feeling low blood sugar, from hearing loud noises. Any simple set of sensory cues, internal or external, which threaten the integrity of the organism, have the capacity to activate the threat response apparatus in infants (Gunnar. 1986).

There are a variety of experiences in utero which may influence the sensitivity of the threat-response neurobiology in children. One of these is prenatal exposure to psychoactive drugs which may disrupt normal development of the brainstem catecholamines (Perry. 1988). In animal models, altered development of hippocampal organization and the HPA axis can result from perinatal and prenatal stress (Shors, Foy, Levine, & Thompson. 1990; Plotsky & Meaney. 1993).

Whether temperment is related to genetic or intrauterine factors is unknown. As with all complex human behavioral phenomena, temperment is likely due to a combination of genetic and intrauterine factors with significant individual variation as to the primary factors.

At birth, portions of the stress response apparatus, i.e., the treat response apparatus are intact (Gunnar. 1986). Brainstem and midbrain nuclei key in the reticular activating and threat response are intact at birth (see Perry, 1994) and continue to mature during the first three years of life. Yet even as these less complex regions are organized, thalamic, limbic and cortical areas are not. The human brain develops sequentially, organizing in a use-dependent fashion, altering neuronal migration, differentiation, synaptogenesis, apoptosis and other processes of neurophysiological organization in response to a host of external molecular cues (e.g., nerve growth factor, cellular adhesion molecules, pattern and quantity of neurotransmitter receptor stimulation (for review see Thoenen. 1995; Perry, 1994). Therefore, as the child matures, limbic (emotional) and cortical (cognitive) development is very experience sensitive (Brown. 1994). What is different in the young child, therefore, may not be the subjective emotion related to the threat, but the response of the central nervous system to the internal state of distress or anxiety (Perry, Pollard, Blakley, Baker, & Vigilante. 1995) and the capacity of the immature cortex to make complex interpretations of the associations between paired stimuli (Singer. 1995).

Response to threat

The developing threat response systems have developmentally-appropriate precursors of the mature response, but during development are quite sensitive to experience (Ainsworth, Blehar, Waters, & Wall. 1978). Because the brain develops in the "use-dependent way" (Perry, Pollard, Blakley, Baker, & Vigilante. 1995; Courchesne, Chisum, & Townsend. 1994), the presence and pattern of childhood threat will play a major role in determining the sensitivity and final organization of the individual child's threat response apparatus. Children that are exposed to traumatic experiences will develop anxiety regulation problems with remarkable consistency (Schwarz & Perry. 1994; Perry & Pate. 1994; Perry. 1994).

The classic adult response to impending threat is fight or flight (Cannon. 1914). Clearly infants are incapable of effectively fighting or fleeing. Therefore, for the same internal state of anxiety and sense of impending doom, an infant will have a different behavior set, they will cry and thrash as infants, and if this is unsuccessful, they will typically utilize a very primitive adaptive response, comparable to the defeat reaction in animals that are stressed in an inescapable fashion, the defeat reaction (Miczek, Thompson, & Tornatzky. 1990; Henry, Stephens, & Ely. 1986). Infants and young children when they are feeling extremely anxious typically freeze and may dissociate as opposed to fighting or feeling (Perry, Pollard, Baker, Sturges, Vigilante, & Blakley. 1995; Perry, Pollard, Blakley, Baker, & Vigilante. 1995). As children get older, while they may have the same subjective sensation of anxiety, they will begin to act and react differently, demonstrating a more 'adult'-like efferent wing of the threat response.

Use-dependent development

As the child develops, the stress response apparatus become more mature. Prior to devloping an internal stress-response capability, the infant has an external stress response apparatus -- the primary caregiver (Erickson, Sroufe, & Egeland. 1985; Bowlby. 1969). When feeling internal distress associated with hunger, cold, fear, the infant cries and the mother responds. If the caregiver responds, there is, overtime, the building in of the neurobiology which allows the infant to carry around or internalize what was once an external stress response capacity (Bowlby. 1969).

Abnormal stress response capabilities and anxiety will result when there are abnormalities of these early experiences (Lee & Bates. 1985; Carlson, Cicchetti, Barnett, & Braunwald. 1989). The abnormalities may be characterized by either inconsistent or absent external, soothing by a caretaker or when there is abnormal persistence of "overmothering." In the latter cases the child has never been allowed to explore and has always had a persisting infancy such that they have never had the opportunity to build in and organize (in a use dependent way) a healthy threat-response apparatus. Therefore, when they are chronologically of an age to go to school, they have the threat-response apparatus of a much younger child. This can lead to significant school-based anxiety.

As children get older, they develop fears to specific situations and objects (Abe & Masui. 1981). These fears are common, and some may be related to genetic 'fixed-action' patterns developed over eons of evolution (e.g., snakes, dogs). Yet most of these specific fears are related to the paired (or mis-paired) internalization of cues with anxiety from previous experience. During infancy and childhood, the child mirrors from caretakers and interprets internal states of pain, arousal, or anxiety (Bowlby. 1969; Ainsworth, Blehar, Waters, & Wall. 1978). The child that falls on the playground and hurts her knee will look over to the parent to see how to interpret that internal state. She can either get a calm reassuring look or an anxious, frightened, response. Over time, then, the child will label a host of external cues as potentially threatening and label internal sensations as 'fearful'. This process has been hypothesized as an etiology of specific phobias and generalized anxiety disorders in children (see Kendall & Ronan. 1990). Another illustration of these principles is seen in children of adults with PTSD who develop PTSD like symptoms, often in response to the same cues that trigger the adult's PTSD (Main & Hesse. 1990).

CLINICAL IMPLICATIONS: ANXIETY DISORDERS OF CHILDHOOD

Clearly, based upon the available data, diverse areas of brain appear to be involved in the response to threat. The subjective symptom of anxiety may result from a cortically-originated set of signals (e.g., a thought) or from brainstem-originated signals (e.g., tachycardia or hypoxia). Anxiety may result from a primary sensitization of the brainstem and midbrain 'stress'-response catecholamines. In each of these situations, a different primary pathophysiology can lead to the same subjective sense of anxiety. The specific phenomenology and treatment issues focusing on anxiety disorders and on anxiety symptoms in other neuropsychiatric disorders reflect this diversity. The current classifications of childhood anxiety disorders depend upon the phenotypic manifestations of emotional and behavioral functioning. Similar phenotypic manifestations, however, are likely to result from a variety of etiologies. The anxiety which manifests as the primary symptom in any given disorder may be related to dysregulation within any of the primary 'threat' response systems described above or any combination of these systems. In addition, the primary 'deficit' within any given system (e.g., locus coeruleus) may be due to dysfunction within any single or combination of primary neurobiological processes (e.g., altered adrenergic receptor/effector coupling, abnormal re-uptake or release, inefficiecies in membrane transduction). Clearly, complex neurobiology underlies anxiety regulation.

The clinical threshold for assignment of a disorder continues to evolve as descriptive phenomenology of these disorders improve. Debate about specific diagnostic categorization continues: elective mutism, for example, is now being re-conceptualized as an anxiety disorder (Black and Uhde, 1995) and the category of overanxious disorder of childhood has been subsumed by generalized anxiety disorders. This process of descriptive phenomenology is being informed by an evolving understanding of the developmental continuities (and discontinuities) between childhood and adult anxiety and affective disorders (e.g., Biederman, Faronane, Marrs, & et al. 1997). Recent epidemiological studies using DSM III-R diagnostic criterion demonstrated that between 15 to 23 % of all children may meet criteria for some anxiety disorder (Milne, Garrison, Addy, et al. 1995; King, Gullone, Tonge, & Ollendick. 1993; Kashani & Orvaschel. 1988). Estimates of population prevalence for the DSM IV anxiety disorders is illustrated in Table 1. Studies of high risk populations suggest that for some anxiety disorders even higher rates are present; for example in communities impacted by violence the prevalance of post-traumatic stress disorders is in excess of fifty percent (Singer. 1995).

Children with anxiety disorders have astounding co-morbidity with other childhood neuropsychiatric disorders (Leckman, Weissman, Merikangas, Pauls, & Prusoff. 1983; Last, Strauss, & Francis. 1987). ADHD co-occurs with anxiety disorders with high frequency (Beiderman et al. 1990). In some studies, over sixty percent of the children with affective disorders have an anxiety disorder, while seventy percent of children with school refusal had affective disorders (for review see Bernstein and Borchardt. 1991).

Anxiety disorders in childhood appear to be a risk factor for the development of affective and anxiety disorders in adolescence and adulthood (Reinherz, Stewart-Berghauer, Pakiz, Frost & et al.., 1989). In turn, depressive symptoms in childhood appear to play a role in vulnerability to anxiety disorders across the life cycle (Kovacs, Gatsonis, Paulauskas & Richards. 1989; Kovacs & Goldston. 1991).

The co-occurrence of multiple diagnoses with anxiety disorders and the inter-related vulnerability of the anxiety and affective disorders should not be surprising considering that the brainstem monoamines (e.g., NE, 5HT, DA) are common mediators of both arousal and affect. Abnormal regulation of these systems resulting in primary 'anxiety' symptoms would likely be accompanied by affective symptoms, and vice versa.

Other neuropsychiatric disorders where anxiety is a prominent symptom include psychotic disorders, mental retardation, post-traumatic head injury, developmental delay, profound neglect and physical abuse. The common thread in all of these disorders is a compromised capacity to effectively and efficiently interpret experience. Whether the cortical and sub-cortical impairments in these disorders impair the capacity to process, store or recall stored information, the effect is the same -- each experience is too 'new'. Any process which alters the capacity of the brain to efficiently make associations, store these and then generalize from that specific event to a future event means that each moment is novel. Novel cues are interpreted by the brain as threat-related until proven otherwise. Imagine the experience of a psychotic child where abnormal pairing of sensory information is taking place, and ever-changing from moment to moment.

Anxiety in all of these situations plays a major role in the clinical presentation of these disorders, yet no clear neuropathological process emerges that is common to a given diagnostic category or to individuals with specific anxiety-like symptoms. The widely-distributed and redundant threat-response systems in the human brain have many possible mechanisms and sites for becoming 'dysregulated'.

Treatment Aspects

Among the most effective treatments of childhood anxiety disorders are cognitive-behavioral interventions. A hallmark of these interventions is the progressive internalization of more appropriate cognitive interpretations during desensitization techniques (Kendall & Ronan. 1990; Graziano, DeGiovanni, & Garcia. 1979). These techniques activate the arousal systems, induce a low level of anxiety, and are paired with supportive and reassuring interactions with the therapist. Mislabeled cues (e.g., school, snakes,) can be re-labeled. Over time, a use-dependent internalization of new sets of arousal cues takes place. While these techniques support the critical role of amygdala, hippocampus and cortical areas in mediating anxiety, they provide no specific clues to the neurobiological mediators of anxiety in any given disorder -- or individual child.

Many of the most important clues to the neurobiology of anxiety disorders in adults come from the empirical results derived from effective pharmacotherapies for various conditions. Studies have demonstrated effective pharmacotherpy in adults suffering from post-traumatic stress disorders, panic disorder, agorophobia, obssessive compulsive disorder and for anxiety associated with various neuropsychiatric disorder (Erickson, Sroufe, & Egeland. 1985; Noyes, Chaudry, & Domingo. 1986; Liebowitz, Gorman, Fyer, & et al. 1988; Gaind, Suri, & Thompson. 1975; Frank, Kosten, Giller, & Dan. 1988).

In contrast, data supporting the efficacy of anxiolytic pharmacotherapy in children is scant, consisting of primarily case reports, case series and open trials (Allen, Leonard & Swedo. 1995). Gittlemen-Klein and Klein have demonstrated partial efficacy of imipramine in children with separation anxiety and in children with anxiety-induced school absenteeism (Gittleman-Klein R. & Klein. 1988). A case series of three has suggested efficacy of imipramine in panic disorder and agoraphobia (Ballenger, Carek, Steele, & Cornish-McTighe. 1989). Case reports with atypical antidpressants have suggested some efficacy in childhood anxiety disorders (for review see Allen, Leonard & Swedo, 1995). Buspirone, which alters serotonergic neurotransmission, has been reported to decrease anxiety in case studies (Kranzler. 1988). Serotonin-selective re-uptake inhibitors have been used in childhood anxiety disorders with moderate efficacy (Birmaher, Waterman, Ryan, et al. 1994; Black & Uhde. 1994). In children with trauma-related physiological hyperarousal, including anxiety, open trials with clonidine, an alpha2 partial agonist, has improved symptoms in 17 (Perry. 1994) and 65 (Perry, submitted) children. In sum, agents which act to modulate the brainstem catecholamine neurotransmitters of the RAS (i.e., NE, DA and 5-HT) appear to have limited to moderate efficacy in some children with anxiety disorders.

Benzodiazepines (e.g., clonazepam) and the triazolobenzodiazepine, alprazolam, appear to provide episodic relief from panic disorder and from procedure-associated anxiety in pediatric settings (Simeon & Ferguson. 1987; Pfefferbaum, Overall, Boren, & et al. 1987; Biederman. 1987). Overall, however, controlled studies of various psychotherapeutic agents in childhood anxiety disorders are lacking (Coffey. 1990).

FUTURE DIRECTIONS

Anxiety disorders of childhood may be related to abnormal regulation or development of any of the key neurotransmitter systems or brain areas involved in the threat response. As the threat response involves brainstem, midbrain, thalamic, limbic and cortical areas (and a host of neurons of using various neurotransmitters), diverse pathophysiology may be involved in the symptoms of anxiety within any given individual. The threat response has primitive and complex elements, any of which could be altered to result in sensitivity to internal or external threat. The core emotion of the response to novel and threatening stimuli is anxiety. Considering the prime-directive of the human brain -- to sense, process and act to keep us alive -- , it should not be surprising that disorders of anxiety are the most common in our current neuropsychiatric nosology.

There are few studies directly examining neurochemical aspects of anxiety in children. Future understanding of the neurobiology of childhood anxiety disorders will depend upon data. With advances in the descriptive phenomenology of childhood anxiety disorders and in various techniques in the neurosciences, researchers will be able to begin to more clearly understand the neurophysiological and neurodevelopmental correlates of childhood anxiety disorders. The future is likely to yield complex and varied neuropathologies underlying childhood anxiety disorders.

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norephinephrine (NE); serotonin (5-HT); gamma-aminobutyric acid (GABA); dopamine (DA); not available (N/A)