NADD Bulletin Volume IV Number 4 Article 1

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Behavioral Phenotypes: A Glimpse into the Neuropsychiatry of Genes (Part II): Analysis of Behavioral Phenotypes—Social Anxiety in Fragile-X Syndrome and Autism

Jarrett Barnhill, MD

The clinical study of behavioral phenotypes focuses on the relationship between genes and behavior. Although the genes for many inherited disorders have been identified, the search for candidate genes responsible for psychiatric disorders is hampered by their clinical heterogeneity. As a result, genetic models of psychiatric disorders have relied on studies of family pedigrees, twins, and linkage studies with known biological markers. The Human Genome Project will eventually alter this scientific landscape, but geneticists will still struggle with the presence of secondary forms of most neuropsychiatric disorders (phenocopies). These phenocopies suggest that a final common pathway may be responsible, and that poor maternal nutrition, obstetrical complications or intrauterine insults, gestational exposure to environmental toxins, or other developmental insults will continue to complicate psychogenetics (Harris, 1995).

Most clinicians are baffled by the intricacies of molecular genetics, and focus instead on differential diagnosis and target behaviors. In clinical practice, the process of differential diagnosis involves a progression from symptoms or target behaviors to a psychiatric syndrome. Unfortunately, many clients with severe intellectual deficiencies (S/PMR) are difficult to categorize with the current DSM-IV criteria. Schizophrenia provides a good example. Rather than an unambiguous phenomenological diagnosis, the clinician trying to diagnose schizophrenia often struggles with a high degree of uncertainty. Frequently the process is abandoned in the jungle of “Psychosis NOS,” as the clinician is forced to infer symptoms and diagnose based on incomplete information. Aggressive behaviors provide another example. Aggression is best understood in terms of a multilevel assessment that begins with context (ecology), precipitants, and consequences—the ABCs of behavioral analysis. A second level of analysis includes an evaluation of associated level of affective arousal, intensity of the aggressive response, degree of planning (impulsiveness), targets of aggressive behavior, and complexity of the behavior. A third level incorporates associated symptoms of brain dysfunction, intoxication, mood disorder, or psychosis. The last step is frequently the most difficult. Aggression as a target behavior can be more precisely defined by including associated affective state (rage) or psychological distress (autonomic arousal), level of impulse control, explosiveness (predatory v. impulsive), neurovegetative signs of a mood disorder, and mood congruent hallucinations. With level of analysis, treatment can then be directed at a particular syndrome, a Major Depression Disorder with psychotic features.

This model of differential diagnosis progresses from a global typology (e.g. hallucination or aggression) to more specific subtypes. Each step in this process narrows the search field by judging the symptom or target behavior by the “company that it keeps.” The entire process is analogous to cladistic analysis in paleontology. Cladistic analysis is used to distinguish fossils based on nodal or distinguishing anatomical features. For example, there are two features that help to distinguish Cretaceous tyrannosoids (T. rex) from earlier Jurassic meat eaters (Allosaurus)—arm length and the number of claws on the forelimb. A newly discovered long forelimb with three claws is not likely to be from T. rex. The final conclusion is determined by applying more specific analytic tools. When applied to clinical settings, this model of cladistic analysis allows the clinician to define more homogeneous subtypes and be a valuable tool in pharmacological treatment planning as well as genetic studies (Barnhill, 2000). This paper applies a modified form of cladistic analysis to differentiate anxiety as a target symptom in clients with social phobia, autism, and Fragile X syndrome.

Anxiety

Anxiety is a common affective state that includes behavioral inhibition, withdrawal from novel events; threshold for and intensity of the fear responses; fear conditioning; and avoidance behavior. Neurophysiologically, anxiety is the result of an activation of limbic and subcortical structures, autonomic activation (flight or fight reactions), and the regions of the right hemisphere. This neurobiological system is sensitive to potential danger signals and initiates behaviors that are crucial to survival. The capacity to modulate these responses is also essential to exploratory behavior, adaptation, and other forms of learning. The capacity to recognize the termination of a threat, attune to “safety signals” and override conditioned fear responses requires a constant comparison between the current environment, memory of past experiences, anticipation of potential danger, and an ongoing revision of past learning experience with the current environment (Black, 1993).

Fragile X Syndrome (Fraxa)

Fragile X syndrome is the most common cause of X-linked mental retardation in males (Bailey & Nelson, 1995). The syndrome is associated with a trinucleotide repeating segments (DNA studies), breakage points on the X chromosome (Chromosome study), and a marked reduction in the FMR1 protein. Males with severe intellectual disabilities and FRAXA have more fragile chromosome sites, longer segments of repeating trinucleotides (greater than 200 kb), and little or no FMR1 protein. For females the pathophysiology is far more complex. (Abrams & Reiss, 1995; Lachiewicz, 1995). Unaffected (premutational) females have shorter repeating segments in their DNA. Although not mentally retarded, premutational females display an increased risk for language based learning disabilities, executive dysfunction, schizotypal and avoidant personalities, as well as social phobias (Franke, LeBoyer, & Ganiscke, 1998). Recognition of these partially affected (“carrier”) females is important, since their DNA repeating segments tend to elongate during meiosis (expansion). As a result of this expansion, female carriers may pass these expanded segments on to their male offspring who may express the full FRAXA syndrome (Lachiewicz, 1995).

Marked reduction or absence of the FMR1 protein is the biological expression of the molecular genetic abnormality in FRAXA—the levels of intellectual disability and dysmorphia appear to be inversely related to the levels of this protein. In normal brain development, the FMR1 protein is involved in neuronal migration, nerve cell differentiation and synaptic connections in the developing brain (Aronson & Dreyfus, 1998). The FMR protein is concentrated in the caudate, hippocampus, and cerebellum. In adulthood, the FMR protein may protect mature neurons. Neurons lacking the FMR1 protein appear more vulnerable to disruptions in synaptic connections and loss of synapses and neurons in the superior temporal gyrus and hippocampus. These regions are most vulnerable to aging in FRAXA and may result in declines in some cognitive abilities during adolescence (Abrams & Reiss, 1995; Bailey & Nelson, 1995).

The disruption in neuronal development ultimately results in mental retardation, as well as contributing to social avoidance and gaze aversion, hyperactivity and attention deficits, sequential memory deficits, and peculiarities in speech and language production. In addition to cognitive deficits, proneness to affective overarousal and social anxiety may be associated with self-stimulation and low intensity SIB (hand biting) (Cohen, 1995). These cognitive deficits and high levels of social anxiety disrupt interpersonal interactions and contribute to an association with some features of autistic spectrum disorders (Feinstein & Reiss, 1998).

Autistic Spectrum Disorders

Autistic spectrum disorders involve pervasive disruptions in social relatedness, communication systems, patterns of repetitive and ritualistic behaviors, perseveration, behavioral inflexibility, and compromised adaptive skills (Menshaw & Goldstein, 1998). Using these broad criteria there is a considerable range of variability based on age and level of cognitive impairment. Symptoms associated with infantile autism are more prominent in persons with severe or profound mental retardation. Low functioning autistic persons are more likely to present with higher degrees of social aloofness, communication deficits, need for sameness and predictability, stereotypies, SIB, and unusual sensory preoccupation (Lewis & Bodfish, 1998). Persons with high functioning autistic (HFA) and Asperger syndrome lack severe intellectual disability but display more subtle deficits in social communication, cognitive flexibility and adaptability (Smalley, McCracken, & Tanguay, 1995). In spite of intellectual abilities that fall within or above the range of normal, these persons lack adaptive behaviors to match their cognitive abilities. Undiagnosed people with HFA/AS are frequently referred to psychiatric centers for evaluation because of atypical clinical symptoms, resistance to or intolerance of standard psychiatric treatments, and/or as diagnostic enigmas.

Neuropsychiatric and neuropsychological evaluations of persons with HFA/AS reveal deficits in hierarchically organized cognitive functions- social communication (Travis & Sigman, 1998), affect perception and recognition (Menshaw and Goldstein, 1998), capacity to abstract or integrate increasingly complex social or informational cues, and social relatedness (Mundy & Markus, 1997). Deficits in language pragmatics and executive functions also implicate deficits in higher order processing and integration. HFA is also associated with significant deficits in the capacity to infer affective expression (Serra, Jackson, vanGreet, & Mindeerva, 1998); shared attention (Travis & Sigman, 1998); and intuit nuances of prosody and nonverbal communication (Buitelaar & van der Wees, 1997; Mundy & Markus, 1997). Persons with HFA have difficulty using this social information to anticipate, adjust, or predict ongoing social behavior. These deficits suggest a disconnection between the social perception, affective attunement, and socially pragmatic use of language, and result in a significant deficit in the intuitive understanding the intent of others. Impairments in empathy and attunement with the mindset of others contribute to a dysfunctional “theory of the mind” (Menshaw & Goldstein, 1998).

Social Phobia- Anxiety Disorders

Clinical anxiety disorders represent a dysfunctional system of affect and threat perception that impedes daily living. This imbalance is manifest in problems with novelty approach/avoidance, threat perception, or threshold for escape behaviors. The imbalance is further complicated in individuals with developmental disabilities. Impaired adaptability, diminished problem solving skills, and compromised communication skills may exaggerate the neurophysiological or temperamental components of anxiety and increase the likelihood that anxiety will approach clinically significant levels (Black, 1993; Stein, 1998). Social phobia is a subtype of anxiety disorder characterized by sympathetic overarousal in interpersonal or performance settings. The intensity of this reaction can range from a vague sense of threat to panic-fear reactions and need for escape (flight or fight reactions). Higher functioning people with social phobia are able to describe feelings of discomfort in unfamiliar social settings, as well as the need to avoid social activities in order to limit anxiety (Beidel & Morris, 1993).

Among persons with severe intellectual deficiency, distinguishing social phobia from other anxiety disorders (panic disorder and PTSD) is frequently a Herculean task. These clients may display intense arousal in response to a range of novel stimuli or environments, and changes in routine. Severe discomfort and sympathetic arousal often evokes a range of self-soothing behaviors such as stereotypies and compulsions/rituals. Left unmodified, continued arousal can result in increased levels of agitation, aggression and SIB. These severely disruptive behaviors may result in escape from the offending situation. In this context, the disruptive or destructive behavior is negatively reinforced as avoidance behavior. Left unabated, these behaviors may also contribute to increasing social isolation and further impede habilitation programming. Individuals with social phobia seem less able to habituate their autonomic responses to repeated exposure, but appear more readily conditioned to avoidance or escape behaviors. Cognitive disabilities and slow habituation tend to further complicate the treatment, especially exposure therapies (Beidel & Morris, 1993; Stein, 1998).

Cladistic Analysis

Cladistic analysis of anxiety in FRAXA, autism and social phobia involves a hierarchical, stepwise review of anxiety-related behaviors, ecological factors, level of physiological arousal, degree of social attachments, and communication, as well as comorbid psychiatric disorders:

1. Gender Differences:

Gender provides a useful starting point in differentiating anxiety in persons with and the behavioral phenotype of FRAXA, autism and social anxiety disorder. With the exception of obsessive compulsive disorder in males under 10, anxiety disorders tend to occur more frequently in post-pubertal females (Black, 1996; Alsobrook, 1999). The preponderance of males in early onset OCD is associated with an increased risk for later onset tic disorders. In addition, the typology of symptoms in young onset males may differ, with fewer obsessions or cognitive precursors and a higher incidence of touching, arranging, need for symmetry and impulse control disorders (Piacenetti & Grae, 1997). In persons with autism, the gender ratio is closer to 4-5 males: one female. The ratio may be even more exaggerated in HFA/AS (Szartmari, Jones, Zwaigenbaum, & MacLean, 1998). In FRAXA, males tend to display moderate to severe MR, and characteristic dysmorphic features (e.g. enlarged testicles). Premutational females may be intellectually intact but show high rates of learning disabilities and social anxiety disorder (Franke, LeBoyer, & Ganiscke, 1998).

2. Assessment of Adaptive and Intellectual Deficits:

Many people with autism have greater impairments of adaptive behaviors, and higher rates of stereotypies and SIB than anticipated from IQ scores (Lewis & Bodfish, 1998). In contrast, nonautistic persons with severe/profound mental retardation may share some autistic traits, but express a higher level of adaptive behaviors than anticipated from intellectual testing. Males with FRAXA and severe mental retardation display gaze aversion, impaired language, stereotypic behaviors, SIB and limited tolerance to environmental change. Stereotypies and hand biting SIB may also result from overarousal in novel social settings, disruption of routines, or excessive demands (Abrams & Reiss, 1995). In spite of these autistic behaviors, males with full syndrome FRAXA possess a higher level of adaptive skills than predicted from intelligence testing (Bailey & Nelson, 1993).

In persons with autism, repetitive and disruptive behaviors may result from exposure to a variety of novel or unexpected events and experiences (Feinstein & Reiss, 1998). Anxiety in social settings is also a prominent feature (Smalley, McCracken, & Tanguay, 1995), but on closer inspection several differences emerge. Controlling for level of intellectual disability, nonautistic people with FRAXA display less severe communication impairment, and a greater diversity of social attachments, and levels of affective attunement (Smalley, McCracken, & Tanguay, 1995; Abbeduto & Hagerman, 1997; Feinstein & Riess, 1998). People with social phobia present with increased anxiety in unfamiliar social settings, but may be quite comfortable and sociable in familiar settings with preferred staff. As a rule, persons with social phobia tend to show a greater range of social interests and higher levels of emotional attachment behaviors across settings (Cohen, 1995).

At this level of analysis, the clinician may have to rely on baseline attachment behaviors, increased attachment behaviors in novel settings, or general levels of social relatedness.

3. Comorbid psychiatric diagnoses:

Anxiety is a frequent symptom and anxiety disorders are often comorbid conditions with many psychiatric disorders. Anxiety disorders in persons with intellectual disabilities may be underrecognized because of the intensity of disruptive behaviors or problems with their environment. As a result, the etiopathogenic anxiety disorder is made during the referral assessment. For some individuals, the referral is triggered by anxiety. The developmental disorder is diagnosed during the psychiatric assessment. For example, anxiety with or without comorbid depression is the most common referral complaint among persons with mild intellectual disabilities. Fragile X or HFA may have been unrecognized. In clinical practice, people with HFA are often referred for treatment resistant ADHD, obsessive-compulsive disorder (OCD), atypical anxiety disorders, intermittent explosive disorder, and occasionally for unspecified psychosis (Lewis & Bodfish, 1998). People with FRAXA are frequently referred for hyperactivity, learning disabilities, autistic behaviors, stereotypies, SIB, and anxiety, affective and schizophrenic spectrum disorders (Bailey & Nelson, 1997; Lachiewicz, 1995). Individuals with social phobia are referred for panic attacks, separation anxiety disorders, elective mutism, as well as comorbid mood disorders (Black, 1993; Black & Uhde, 1995).

Although frequently confusing in clinical practice, a thoughtful investigation of psychiatric comorbidity may also be helpful. A family history of panic disorder or social anxiety is frequently enlightening. The use of family history to establish genetic risk has several pitfalls. The most obvious would be a history of abuse and neglect. Another complication involves the presence of increased social anxiety among many first-degree relatives of autistic probands—the presence of social anxiety in the broader phenotype for autism (Bailey, Palferman, Heavy, & Conteur, 1998; Piven & Palmer, 1999). A similar problem emerges in FRAXA, where premutational females share social anxiety as a part of their behavioral phenotype (Lachiewicz, 1995; Abbeduto & Hagerman, 1997). Given these factors, the presence of dysfunctional attachment, disturbed affective relatedness, behavioral inflexibility, and social communication are still the most useful nodal points for differentiating autism from FRAXA and primary anxiety disorders (Mazzocco et al., 1998)

4. General appearance, genes and physical evaluation:

 As a rule, persons with social phobia do not present with facial and dysmorphological stigmata of FRAXA (Abrams & Reiss, 1995). Although people with autism have higher rates of minor physical anomalies, the lack of facial dysmorphia and testicular enlargement helps differentiate FRAXA from most cases of autism. People with social phobias usually lack these distinguishing physical anomalies (Black, 1993). DNA and metabolic studies offer the most effective method of distinguishing FRAXA from social phobia or autism.

5. Physiological Overarousal and Behavioral Responses:

In individuals with social phobia, unfamiliar social settings or performance stimuli trigger hyperarousal. This reaction is related to beta-adrenergic, autonomic overactivity, and increases in cortisol release and other stress hormones (Black, 1993). At a clinical level, social phobia is also accompanied by behavioral inhibition, high levels of anxiety, and avoidance behaviors (Black & Uhde, 1995). When compared to persons with autism and FRAXA, people with social phobia tend to display more behavioral flexibility, a higher threshold for stereotypic or repetitive behaviors, and more effective language and communicative skills. People with FRAXA display a pattern of hyperarousal, and anxiety in response to novel stimuli or environments (Cohen, 1995; Abrams & Reiss, 1997). When compared with social phobia and FRAXA, people with autism also differ at other nodal points. Persons with autism may react to a wider range of stimuli, including unpredictable events, changes in schedules, or disruption in routine (Mazzocco et al., 1998). Language and social communication deficits are characteristic of autism and include dysprosody, echolalia or repetitive speech, and impaired language pragmatics or skills for expressing internal affective states (Abbeduto & Hagerman, 1997; Mundy & Markus, 1997). Persons with autism tend to display greater impairment in behavioral and cognitive flexibility, range of adaptive behaviors, and in dysfunctional repetitive behaviors. These behaviors may resemble obsessive compulsive disorder, but clinically differ in terms of overt anxiety, desire to inhibit the compulsion or ritual, and/or insight into the unusual nature of the repetitive behaviors (Cohen, 1995; Lewis & Bodfish, 1998).

It is apparent from this level of analysis that autism is the result of fundamental deficits in the functional integration of multiple brain systems. The level of impairment in FRAXA is more subtler and less crucial to affective and social integration. These differences are expressed qualitatively in the types of trigger stimuli or extend of disruption of adaptive behavior. The typology and intensity of anxiety are influenced by syndromal diagnosis as well as intellectual deficiencies and brain dysfunction.

6. Brain circuitry:

The presence of shared clinical symptomatology suggests a common neurobiological substrate. The most likely suspects involve the mediation of social communication and behavioral flexibility. Thus far, the suspects include the cerebellum, striatum (basal ganglia), thalamus, limbic system, and prefrontal neocortex—the fronto-striatal-pallidial-thalamo-frontal systems. This network is responsible for integrating complex behaviors, dealing with temporal discontinuities, retaining relevant information for problem solving (working memory), inhibiting responses to irrelevant stimuli, recruiting other brain regions to process and resolving novel or complex events (coherence), and modifying ongoing behavior to suit current internal and external conditions (Ozonoff & Jensen, 1999). This sort of multimodal processing requires intact sensory perception, grasp of the social ecology of the situation, inhibition of inappropriate responses, and set maintenance for specific tasks, as well as switching or shifting focus when needed. Dealing with novel or learning new adaptive skills also depends on the integrity of these networks (Russell, Jarrold, & Hood, 1999).

Males with FRAXA, premutational females, and people with schizophrenia and high functioning autism have deficits on neuropsychological measures of executive function and cognitive flexibility (Franke, LeBoyer, & Ganiscke, 1998). People with social phobias appear to lack these overarching deficits, and possess an intact capacity to integrate social communication and affective perception (Black, 1993). Persons with severe/profound mental retardation and social phobia share deficits in prefrontal functions, but retain the capacity for psychological attachment, social relatedness and affective attunement consistent with their developmental level (Feinstein & Reiss, 1998).

7. Differential Treatment Response

Anxiety disorders have a wide range of effective treatments. This mixed bag of treatment approaches creates several problems (Albert, Rapoport, & Swedo, 1993). One confound is the differences between “state” and “trait” phenomena. In some individuals, high levels of trait anxiety reflect temperamental differences. This temperamental trait may contribute to personality styles and vulnerability to anxiety disorders. Aside from generalized anxiety, most anxiety disorders appear to represent state-related phenomena, occurring at specific times or situations. Panic attacks and flashbacks in PTSD are state phenomena with characteristic patterns of CNS activity. As state phenomena, panic disorder and PTSD differ phenomenologically from social or anticipatory anxiety, separation anxiety, avoidance, and obsessive compulsive spectrum disorders. In clinical practice, this distinction is often blurred. Another confound involves the frequent comorbidity of anxiety disorders with other psychiatric disorders (especially mood disorders) (Stein, 1998). Although types of anxiety differ phenomenologically and neurobiologically, persons with anxiety disorders respond to the same pharmacotherapies. In general SSRIs, TCAs, MAO inhibitors, benzodiazepines, and buspirone are affective for most anxiety disorders (Black, 1993). This pattern of response suggests that, although the substrates may differ, the level of interaction and integration are critical limiting factors to any simplistic, neurochemical dissection.

There are no specific treatments for FRAXA or autism. SSRIs and chlorpramine have been helpful in comorbid anxiety and affective disorders as well as palliative for target symptoms such as social isolation and avoidance, irritability, impulse control and aggressive behaviors, SIB, and compulsive/ritualistic behaviors. This wide range of effects supports the multiple roles played by serotonin in the CNS (Bregman, 1996; Banford, 1998). In the cacophony of SSRI effects, several pieces of information may be helpful. Autistic persons tend to be quite sensitive to these antianxiety agents. As a result smaller doses are effective—subtherapeutic for conventional treatment of anxiety disorders. Anxious or compulsive people with autism also tend to respond more rapidly to treatment than do most people with OCD and other anxiety disorders. When compared to individuals with social phobia, people with autism appear to be more sensitive to adverse side effects or unusual drug reactions (McDonnell, Price, & Volkmar, 1994). People with FRAXA share some of these sensitivities to SSRIs, but may be responsive to the antianxiety effects of 5-HT2 antagonists—trazadone, nefazadone, and mitirzapine are currently available (Banford, 1998).

Avoidance behaviors, hyperkinetic movement disorders, aggression, SIB, and stereotypies/repetitive behaviors are responsive to dopamine antagonists. The antipsychotics of the past posed a significant risk for behavioral regression and dysphoria (akathisia), EPS, and tardive dyskinesia. The introduction of the atypical or second-generation antipsychotics (risperidone, olanzapine, quetiapine, and clozapine) has altered the risk landscape. The “atypical” antipsychotic drugs have been quite effective for psychosis, severe disruptive behaviors, aggression and SIB, with fewer untoward side effects (Zuddas, Ledda, Fratta, Muglia, & Cianchetti, 1996; Jinson & Tandon, 1998; Malek-Ahmadi & Simmonds, 1998). Although not effective in social phobias, the antipsychotic drugs have been used extensively to reduce the disorganizing effects of overarousal, and conditioned avoidance responses. In persons with autism, the atypical neuroleptics raise the threshold for disruptive, repetitive or escape behaviors. Persons with autism seem to respond at subtherapeutic doses for schizophrenia or mania (McDougle, Price, & Volkmar, 1994), and appear more vulnerable to EPS and akathisia. Akathisia can be confused with a worsening of anxiety (Barnhill, 2000).

Alpha-adrenergic agonists (clonidine and guanfacine) are useful in the treatment of hyperactivity, impulsivity, and explosive behaviors, but of limited value in SIB. Beta-blockers may be more helpful in explosive aggressive behaviors, SIB, stereotypies, and social phobia or performance anxiety (Reudrich, Grush, & Wilson, 1990). Buspirone, a 5-HT1a agonist, is occasionally helpful in primary treatment for nonspecific behaviors in autism, but of limited value in social phobia (Hilldebrand & Scott, 1995). Benzodiazepines are helpful in generalized anxiety, panic attacks, and anticipatory anxiety (Stein, 1998), but are frequently avoided in people with developmental disabilities because of concerns about disinhibition and paradoxical rage (Bregamn, 1996). The concerns may be overstated, but more research is needed. Anticonvulsant mood stabilizers play an increasing role in treatment-resistant anxiety disorders, disruptive/aggressive behaviors, and SIB. Neurontin has emerged as a treatment for social phobia and some compulsive behaviors (Stein, 1998). Buspirone and benzodiazepines are effective anti-anxiety agents, and in some instances are helpful in social anxiety in persons with FRAXA and HFA (Bregman, 1996).

To date, our knowledge of the neurochemistry of anxiety disorders is superior to what we know about FRAXA and most pervasive developmental disorders. This level of ignorance relates to the complexity of the hierarchical disorganization germane to developmental disorders. Social phobia may reflect a hard wiring sensitivity to social cues in a relatively intact brain (Black, 1993). Autism and FRAXA may reflect deficits at earlier stages of perception, cognitive integration of sensory experience, as well as deficits in social perception and communication that markedly reduce the client’s capacity to adapt behavior to this information (Ozonoff & Jensen, 1999). These core deficits confound the diagnosis of anxiety disorders in persons with autistic spectrum disorders (Smalley, McCracken, & Tanguay, 1995; Lewis & Bodfish, 1998). Even if social anxiety disorder is recognized and treated, the central features of autism remain. In FRAXA, overarousal can be attenuated, and social adjustment enhanced, but executive deficits remain. The lack of pharmacological specificity and inability to correct basic core neurobiological defects limits the use of pharmacological profiling. Apparently the dose response curve, sensitivity (pharmacodynamics), and adverse side effects may remain the best clinical tools for differentiating subtypes of anxiety in social phobia, autism, and the behavioral phenotype of FRAXA.

Conclusion:

The neurobiology of anxiety involves fear response and conditioning, behavioral inhibition, thresholds for threat and safety perception, and avoidance behaviors. Extinction and habituation play key roles. Both forms of learning occur at cortical and subcortical levels and play a role in adaptive responses and the clinical expression of anxiety. Learning creates a form of top-down regulation that is orchestrated by the frontal cortex—the “chief executive.” Anxiety disorders result from the experience of anxiety, as well as core deficits in cortical regulatory mechanisms, overpowering levels of subcortical activation, or a combination of both. These core deficits limit social adjustment. The cannulation of anxiety through vulnerable final pathways appears to determine the typology of anxiety and related psychiatric disorders (Black, 1993; Stein, 1998).

Social phobia, distress to social or performance failure cues, seems to represent intense arousal to intraspecific social cues, perhaps related to social dominance hierarchy, or the unpredictability of “strangers.” These ethnological premises may be applicable to recognizing social phobia in nonverbal persons with severe intellectual disabilities (Barnhill, 2000).

The behavioral phenotype for Fragile X includes social anxiety, gaze aversion, stereotypic behaviors, speech abnormalities, and hyperactivity. Even though anxiety is clearly related to high levels of autonomic arousal to novelty, the executive deficits and intellectual deficiency put limits on successful coping. Males with FRAXA are frequently labeled as autistic, but there are clinically relevant differences in adaptability, flexibility, and social-emotional attachment behaviors (Bailey et al., 1998).

Autism is also a collection of developmental disorders with core abnormalities in social attachment, affective attunement, communication and language, and adaptability. Within autism, there is a large range of variability in symptoms and etiologies. Among persons with severe intellectual deficiency and autism, anxiety is inferred from the presence of specific triggers as well as high levels of disruptive or self-soothing behaviors. Among persons with HFA, social anxieties and awareness of social deficits can be discussed in painful terms—the anxiety and loneliness engendered by deficits in social/emotional intuition and reciprocity, and maladaptive interpersonal interactions. Anxiety is accompanied by a defect in the “theory of mind” and difficulty predicting the social behavior of others. This deficit seems to be qualitatively different than anxiety in FRAXA (Mazzocco et al., 1998) or social phobia (Smalley et al., 1995).

This paper has compared anxiety in persons with intellectual disability with social phobia, FRAXA, and autism. The model of investigation has incorporated typology of anxiety, ecological analysis, impairment in the integration or communication, level of mental retardation and adaptive behavior, associated neurological disorders, and genetic vulnerability to anxiety disorders. The process begins with a psychiatric symptom (anxiety in social settings) and proceeds through a differential diagnosis by a systematic application of multiple clinical features and measurements. It is painfully obvious that any model (cladistic analysis in this case) is not a surgical procedure and that the complexity of the human brain-behavior relationships has doomed this project from the beginning. Continued attempts to understand and dissect anxiety as it occurs in primary anxiety disorders, behavioral phenotype of FRAXA, and a complex neurodevelopmental disorders like autism will remain both a challenging and humbling experience.

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For further information:

Jarrett Barnhill, M.D.
Director, Developmental Neuropharmacology Clinic
University of North Carolina School of Medicine, CB #7160
Chapel Hill, NC 27599-7160
e-mail: jbarnhill@css.unc.edu