Early Childhood
Neurobehavioral Assessment
for the
Differential Diagnosis of Fetal Alcohol Syndrome
and Alcohol-Related Neurodevelopmental Disorder

Bethesda Marriott Hotel
Bethesda, Maryland

March 8–10, 2000

The Interagency Coordinating Committee on Fetal Alcohol Syndrome
and
The National Institutes of Health
National Institute on Alcohol Abuse and Alcoholism
National Institute of Child Health and Human Development
National Institute of Neurological Disorders and Stroke
National Institute of Environmental Health Sciences

Kenneth Warren, Ph.D., National Institute of Alcohol Abuse and Alcoholism, Chair

Patricia M. Rodier, Ph.D., University of Rochester

Charles A. Nelson, Ph.D., University of Minnesota

Loisa Bennetto, Ph.D., University of Rochester

What is involved in delineating a behavioral profile?

Maureen Dennis, Ph.D., The Hospital for Sick Children, Toronto

Attention and ef in children with arnd

Dr. Sandra Jacobson

SESSION II – ALCOHOL AS A TERATOGEN

Introduction

Shelly Tanable, Office of Senator Tom Daschle

Edward Riley, Ph.D., San Diego State University, Chair

Neurobehavioral function and imaging studies in children with fas

Sarah Mattson, Ph.D., San Diego State University

Piyadasa Kodituwakku, Ph.D., University of New Mexico

Sterling Clarren, M.D., University of Washington

Susan J. Astley, Ph.D., University of Washington

Brain, behavior, ef, and prenatal alcohol exposure

Ann Streissguth, Ph.D., University of Washington

Observations from the collective family experience

C. Jocie DeVries, FAS Family Resource Institute

Claire D. Coles, Ph.D., Emory University School of Medicine

SPECIAL SESSION – REVISING THE DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL DISORDERS: RELEVANCE TO ARND

Michael First, M.D., American Psychiatric Association

THURSDAY,  MARCH 9, 2001

REVIEW OF FIRST DAY AND RESTATEMENT OF GOALS FOR THE SECOND DAY

Dr. Sandra Jacobson

SESSION III– USING ANIMAL MODEL STUDIES TO IDENTIFY DEVELOPMENTAL NEUROBEHAVIORAL PROFILES OF THE ALCOHOL-DAMAGED BRAIN

Laurie Foudin, Ph.D., National Institute of Alcohol Abuse and Alcoholism

Joanne Weinberg, Ph.D., University of British Columbia

Joseph E. Steinmetz, Ph.D., Indiana University

Mark E. Stanton, Ph.D., U.S. Environmental Protection Agency

Bidirectional hypothesis testing between animal models and humans

Charles R. Goodlett, Ph.D., Indiana University–Purdue University, Indianapolis

SESSION IV – LESSONS LEARNED FROM THE STUDY OF NEURO-DEVELOPMENTAL DISABILITIES CAUSED BY TERATOGENS AND CONGENITAL DISORDERS

Environmental teratogens: lessons from lead and other toxins

Dr. Claire D. Coles, Chair

Herbert L. Needleman, M.D., University of Pittsburgh

Kim N. Dietrich, Ph.D., University of Cincinnati

Lisa Freund, Ph.D., National Institute of Child Health and Human Development

Polychlorinated biphenyls and methylmercury

Joseph Jacobson, Ph.D., Wayne State University

Marylou Behnke, M.D., University of Florida

Deborah A. Frank, M.D., Boston University School of Medicine

Iron deficiency and infant development

Betsy Lozoff, M.D., University of Michigan

SESSION V – REVIEW OF GOALS FOR BREAKOUT SESSION AND CHARGE TO PARTICIPANTS

Overview of breakout session

James R. West, Ph.D., Texas A&M University

Breakout session

Nancy Day, Ph.D., University of Pittsburgh, Chair–Group I

Vivian Faden, Ph.D., National Institute of Alcohol Abuse and Alcoholism, Rapporteur–Group I

Laurie Foudin, Ph.D., National Institute of Alcohol Abuse and Alcoholism, Chair–Group II

Dr. Joseph Jacobson, Rapporteur–Group II

SESSION VI – NEUROBEHAVIORAL PROFILES AND THE DIFFERENTIATION OF THE EFFECTS OF ALCOHOL FROM OTHER TERATOGENIC EFFECTS AND DISORDERS: PRESENTATIONS BY BREAKOUT GROUP REPRESENTATIVES

Dr. James West, Chair

Synthesis of results: brief descriptions of other teratogenic insults and neurodevelopmental disorders

The neurobehavioral effects of prenatal exposure to polychlorinated biphenyls (pcbs)

Dr. Joseph Jacobson

The neurobehavioral effects of prenatal exposure to methylmercury

Dr. Joseph Jacobson

The neurobehavioral effects of lead exposure

Dr. Kim Dietrich

The neurobehavioral effects of iron deficiency

Dr. Betsy Lozoff

The neurobehavioral effects of prenatal cocaine exposure

Dr. Marylou Behnke

Deborah Frank

The neurodevelopmental effects of spina bifida and hydrocephalus

Dr. Maureen Dennis

The neurodevelopmental effects of autism

Dr. Loisa Bennetto

Final discussion of differential diagnosis of fas and arnd

SUMMARY BY JAMES R. WEST, PH.D.

PREFACE

This report summarizes the discussions of the workshop on Early Childhood Neurobehavioral Assessment for the Differential Diagnosis of Fetal Alcohol Syndrome and Alcohol-Related Neurodevelopmental Disorder, which took place in Bethesda, Maryland, on March 8–10, 2000. This workshop examined the degree to which certain developmental disorders, exposure to certain toxic substances, and nutritional deficiencies are associated with distinct patterns of neurobehavioral deficits. Participants attempted to determine whether there is a distinct alcohol-related neurobehavioral profile and, if so, how it differs from that seen in response to other teratogens, to dietary deficiencies, and to certain syndromes which have similar neurobehavioral effects associated with them.

The neurobehavioral effects of heavy prenatal alcohol exposure, such as cognitive and attention deficits, were first identified in children with the unique facial features of fetal alcohol syndrome (FAS). While FAS is most frequently diagnosed in children whose mothers were alcohol dependent during pregnancy, recent research has shown that prenatal exposure to even moderate amounts of alcohol can produce neurocognitive difficulties and behavioral problems, although these problems are typically less severe than those seen in children exposed to greater amounts of alcohol. These alcohol-related neurobehavioral deficits can occur in the absence of the typical FAS craniofacial dysmorphology and are far more common than FAS.

The Institute of Medicine has recommended using the expression "alcohol-related neurobehavioral disorder" (ARND) to refer to alcohol-exposed children displaying neurobehavioral effects in the absence of facial dysmorphology. Unfortunately, the term "ARND" is so broad that it could apply to any child with a developmental problem who has been exposed to alcohol. The ARND diagnostic category would be more useful if it referred only to a specific pattern of neurobehavioral deficits consistently found to be related to prenatal alcohol exposure. To date, there has been no coordinated effort to determine whether a distinctive alcohol-related neurobehavioral response exists. If it does exist, then researchers must characterize how it differs from the neurobehavioral response associated with other teratogens or developmental disorders.

To address these issues, workshop participants focused on the following questions:

• Given a specific exposure, dietary deficiency, or developmental disorder, which neurobehavioral outcomes are affected and which are not?

• How consistent is the evidence across studies? Can we identify differences in studies that account for inconsistencies in results?

• For a particular exposure, dietary deficiency, or disorder, how does the profile of deficits vary by age (infancy, preschool, childhood, adolescence, adulthood, or old age)?

• Which neurobehavioral tests appear to be the most useful for detecting neurobehavioral deficits at each stage of development?

• Which brain regions and processes appear to be particularly vulnerable to or modified by the exposure or disorder? Which procedures are proving to be the most useful for investigating the brain-behavior relationship? How does the timing and dose of the exposure affect the deficits observed subsequently?

• To what extent is the pattern of neurobehavioral deficit associated with the exposure or disorder sufficiently specific to aid in a diagnosis when an affected child presents with certain attention or behavioral problems?

The workshop was cosponsored by the Interagency Coordinating Committee on Fetal Alcohol Syndrome (ICCFAS) and four Institutes within the National Institutes of Health (NIH): The National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Child Health and Human Development (NICHD), the National Institute of Neurological Disorders and Stroke (NINDS), and the National Institute of Environmental Health Sciences (NIEHS). Participants included experts on the neurobehavioral outcomes of FAS; other teratogenic exposures such as lead, methylmercury, polychlorinated biphenyls (PCBs), and cocaine; developmental disorders, such as attention deficit hyperactivity disorder (ADHD), autism, spina bifida, hydrocephalus; and the nutritional disorder, iron deficiency. Clinicians, family advocates, and government representatives also participated in the workshop.

Enoch Gordis, M.D.

Director, NIAAA

Dr. Enoch Gordis welcomed the participants and thanked Drs. Faye Calhoun, Megan Adamson, Kenneth Warren, Laurie Foudin, Vivian Faden, Ellen Witt, and, especially, Drs. Sandra and Joseph Jacobson for their contributions to the workshop. The goal of the workshop was to increase the specificity of diagnosis of alcohol-related disorders, beyond the well-known facial and physical malformations. This task is difficult because developmental disorders have so many causes; however, sharper diagnostic criteria could provide an important foundation for future research. Dr. Gordis asked participants to consider the efficiency and cost effectiveness of the diagnostic measures involved in differential diagnosis.

Faye Calhoun, D.P.A., M.S.

ICCFAS

Dr. Faye Calhoun recognized the 12 government organizations that cosponsored and assisted with the workshop, giving special thanks to NINDS, NIEHS, and NICHD, the three NIH Institutes that co-sponsored the workshop with NIAAA. The remaining co-sponsors belong to the ICCFAS.

The objectives of the ICCFAS are to facilitate the exchange of information and build collaborative partnerships to improve communication among the government agencies that are addressing FAS. The Committee strives to improve diagnosis, screening, prevention, education, and correctional interventions with children, and to foster basic research to identify the mechanisms of alcohol teratogenesis. Although the ICCFAS sponsors workshops on all of these issues, activities related to distinguishing the diagnosis of alcohol related neurological deficits from those of other disorders is one of the most critical concerns.

Dr. Calhoun hoped that meaningful action would result from this workshop because of its unique mix of researchers, clinicians, family advocates, and representatives of government agencies. The ICCFAS membership includes organizations that generate new knowledge and those that translate the research into practice in various professional settings. Therefore, the workshop will inform the programs of the U.S. Departments of Justice and Education. Representatives from these Departments addressed the audience briefly.

Jan Harlow, Ed.D.

Education Research Analyst, Office of Special Education Programs, U.S. Department of Education Chair, FAS Work Group (jointly administered by ICCFAS and the Federal Interagency Coordinating Council)

The Work Group comprises representatives of Federal agencies and parents who wish to promote early intervention and services for children with disabilities. Members collaborate to develop and disseminate materials on disabilities, especially educational interventions that are appropriate for children from birth to age 8.

Dr. Jan Harlow reported that the Work Group’s October 1999 meeting brought together parents, educational professionals, academics, the medical director of an FAS diagnostic network, representatives from the Head Start program, and government agencies concerned about FAS. The Work Group is establishing links with school psychologists to disseminate information about FAS and related disorders to the field.

The Work Group is creating an action plan to achieve the following goals:

• Develop a method for early diagnosis of children with FAS/fetal alcohol exposure (FAE)

• Clarify the ethical and confidentiality issues involved in screening and assessment in schools and early intervention settings

• Identify and refine appropriate intervention strategies to effectively serve children with FAS/ARND and their families and to prevent secondary disabilities

• Provide intensive, effective, and ongoing training and technical assistance to those in the field

Karen Stern, Ph.D.

U.S. Department of Justice

The Office of Juvenile Justice and Delinquency Prevention receives many inquiries from the field about screening and assessment. Among its responses is a project involving a review of current literature and practices on screening and assessment instruments and protocols, with an expert panel using the information to propose model approaches and future research. Juvenile and criminal justice professionals are interested in FAS/ARND because these disorders are known risk factors for juvenile delinquency and criminal behavior.

Dr. Karen Stern remarked that earlier diagnosis and identification would help individuals with FAS/ARND receive services in a more timely fashion, perhaps preventing or reducing the likelihood of future involvement with the justice system. Therefore, the workshop’s focus on early diagnosis has implications for the lives of many individuals affected by FAS/ARND.

Sandra Jacobson, Ph.D.

Wayne State University

As the scientific organizer of the workshop, Dr. Sandra Jacobson was pleased that the workshop organizers adopted the comparative approach as the focus of the workshop. Comparing the effects of teratogenic substances with those of developmental disorders will further researchers’ understanding of their specialty areas.

At the many FAS study meetings she has attended, Dr. Jacobson has observed that most participants are familiar with the distinguishing facial features of FAS. However, many children who do not have these features may also be affected by FAE. A method to identify children with atypical cases of FAS or ARND must therefore be developed. Improving identification methods would: (1) Enhance research on FAS and related disorders, including the development of pharmacological treatments; (2) assist parents who are seeking advice and treatment for their children; and (3) facilitate the development of a comprehensive, multilevel model.

Dr. Jacobson noted that it is important for researchers to identify the level of analysis that they plan to study. She presented Dr. Maureen Dennis’ work on neurobehavioral profiling and the following terms that Dr. Dennis has defined:

• Cognitive behavioral phenotype: the appearance of mental and behavioral skills

• Modal profile: the most typical set of cognitive strengths and weaknesses associated with a disorder

• Core deficit: a cognitive impairment defined in terms of the underlying processes that are robust across various levels of disorder severity and mental ability

• Cognitive phenocopies: cognitive behavioral phenotypes that are superficially similar but arise from fundamentally different cognitive processes

Dr. Jacobson displayed the Discriminating Neuro-Assessment Tools Chart, which was developed by individuals from NIAAA to help participants compare disorders and identify specific neurocognitive tasks that might distinguish among disorders.

Developing a Neurobehavioral Profile

The Use of Nonbehavioral Symptoms in Understanding Neurodevelopmental Disorders

Chair: Kenneth Warren, Ph.D.

NIAAA

Patricia M. Rodier, Ph.D.

University of Rochester

According to Dr. Patricia Rodier, autism is a neurodevelopmental disorder for which a behavior profile has been developed. This profile has been used successfully to achieve a stable diagnosis but, from a research perspective, has deficits. Dr. Rodier reviewed several areas that are important to autism profile development because they might be helpful to those attempting to develop a profile for FAS and ARND.

Establishing diagnostic criteria is critical to profile development. Dr. Rodier briefly listed the three diagnostic criteria for autism:

• Deviant social behavior, such as lack of comfort seeking and of joint attention

• Deviant communication, such as lack of gestures and eye contact, and absence of or odd language

• Restricted and repetitive interests or behaviors, such as head banging

Even though the criteria cannot currently be linked to specific brain structures or neural systems, they have been very helpful in the diagnostic process.

Dr. Rodier suggested that the diagnostic criteria could be improved by enhancing their specificity. Researchers need to identify the areas of brain damage and link them to alterations in particular functions that are present in individuals with the disorder. Researchers tend to focus on neurobehavioral criteria, and Dr. Rodier encouraged participants to expand their studies to symptoms and characteristics not included in the diagnostic criteria. For example, sensory alterations are not included in the diagnostic criteria for autism, yet they influence quality of life and may reveal distinct neurological deficits. Hyperacousis may be due to a problem with the auditory nerve, but autistic children also exhibit a lack of taste sensation or disturbed taste sensation.

But investigators must also take into consideration the disorder’s subtypes since neurobehavioral disorders are not typically due to a single gene or teratogen. Differentiation of disorder subtypes may illuminate the etiologies of the various subtypes. Researchers have found, for example, that several genes and teratogens are related to autism.

The identification of physical symptoms is also critical for profile development. Dr. Rodier suggested that FAS researchers carefully examine magnetic resonance imaging (MRI) data and other physical measurements because symptoms that have not yet been observed may distinguish the disorder. The understanding of autism was greatly enhanced by the overlap of physical symptoms between children exposed to thalidomide and those with autism. This observation helped investigators pinpoint the developmental stage in which individuals are affected.

Dr. Rodier noted that these physical features of autism have been reported, but received little attention until the discovery of their overlap with the effects of thalidomide.

Researchers now understand that clinicians may miss some features associated with autism in patients with a normal IQ. Autistic individuals with average intelligence may have strabismus, slight hypertelorism, ear malformations, oral hypotonia, and lack of innervation to the muscles controlling facial expression. Many of these features have now been linked to neurological abnormalities in specific areas. Autopsies reveal that the brain stems of autistic individuals are shortened and missing all the facial nuclei and the auditory relay nucleus. Additionally, the brain stems of individuals with autism display a shortened fifth rhombomere and other neuropathology similar to the HOXA-1+ knockout mouse. Experts in population genetics are attempting to identify a heterozygosity that signifies linkage to a disorder.

The identification of discriminating behaviors--characteristics present in autism that distinguish it from other disorders--was critical to the development of a neurobehavioral profile of autism. Susan Bryson identified a task that can discriminate autism from other disorders in infants as young as 4 months of age. Infants’ eye movements are measured during a simple attention task that requires them to visually follow a moving stimulus, then shift to a second stimulus. During disengagement trials, the first stimulus continues while the second one appears. Unlike non-autistic children, autistic children fail to disengage—do not move their eyes—from the first stimulus. Performance on this task is unaffected by IQ, so it can identify autism in individuals of various intelligence levels. Failure to disengage is not due to eye movement problems but, rather, reflects an orientation deficit. Dr. Rodier commented that all of the current evidence indicates that this task is a "perfect discriminator of autism."

The identification of behaviors applicable to animal studies was critical to the development of a neurobehavioral profile. Dr. Rodier commented that investigators in the FAS field have an advantage over autism researchers in this area. Animal models of neurobehavioral disorders permit crucial neuroanatomical studies and the development of drug treatments and behavioral interventions. Therefore, animal studies must test behaviors parallel to behaviors found in the human disorder before appropriate treatments and interventions can be investigated.

Discussion

Dr. Gordis remarked that having a sensory problem does not mean that the individual’s perceptual nerve is abnormal. Dr. Rodier agreed and cited the example of hyperacousis.

Dr. James West remarked that FAS researchers should not limit their attention to particular symptoms because in doing so, they may not notice other important factors. Dr. Rodier agreed and commented that FAS researchers took more than 20 years to identify the optic nerve problem because they were not seeking it.

The Use of Event-Related Potentials as a Tool for Studying Early Neurobehavioral Development

Charles A. Nelson, Ph.D.

University of Minnesota

Dr. Charles Nelson explained that there are a limited number of tools for studying the developing human brain, which has made it difficult to study the link between brain and behavior. However, event-related potentials (ERPs) permit the noninvasive examination of the neural correlates of many different cognitive functions across the lifespan. Recorded from electrodes placed on the scalp, ERPs measure the activity of large numbers of neurons activated in synchrony and, therefore, reflect unique cognitive/neural events. ERPs yield good temporal resolution, but their spatial resolution is not as good, although it is improving.

Work in Dr. Nelson’s laboratory has focused on normal and clinical populations. Following a seemingly obligatory attention response that takes the form of a Negative Component (NC), studies of nonclinical populations of children reveal a baseline ERP pattern of neural activity to familiar visual or auditory stimuli. In contrast, if the stimulus presented is only partially familiar, and requires memory updating, the NC response is followed by a slowly moving positive wave (Positive Slow Wave, or PSW).

One study examined the neural events underlying infant recognition of the mother’s face. Experimenters presented 6-month-old infants with the image of their mothers’ or a stranger’s face in a single frame on a computer. ERP patterns showed that infants paid greater attention to the mother’s face. For the stranger’s face, the positive, slow-wave pattern found indicated that the infant created a partial mental template of the stranger’s face that required memory updating, as reflected by the PSW; in contrast, the mother’s face elicited a baseline response, suggesting the infants were highly familiar with the mother. These responses were strongest from the right temporal scalp, which is over an area of the brain that appears to be responsible for face discrimination in adults. Therefore, the ability to recognize faces and the neural substrate responsible for face recognition are present in humans as young as 6 months of age.

Dr. Nelson’s laboratory has also examined performance of 8-month-old infants on the crossmodal recognition task. Researchers displayed a visual image of an object previously only known by touch and a novel object, and examined the infants’ ability to distinguish between the two objects. The ERP patterns demonstrated a baseline response to the familiar object and a positive slow wave for the novel object. This different neural response indicates that normal
8-month-old infants are able to distinguish between a familiar and a novel object.

Dr. Nelson’s laboratory is now studying the ERP pattern in normal newborn infants who are hearing brief clips of their mothers’ and a stranger’s voices. At this age, infants are known to quickly distinguish their mother’s voice from that of a female stranger. Preliminary data indicate that infants produce ERP patterns that reflect this ability. Further research in this area is expected to illuminate the normal development of the neural systems involved in auditory recognition and memory.

Dr. Nelson described his research with Patricia Bauer on longer-term memory in infants. In the deferred imitation paradigm, infants over 9 months of age viewed a series of objects that formed a story during which ERPs were recorded. One week later, the investigators presented images of the novel or previously seen object. One month later, the investigators presented to the infant the props displayed in the original sequence and recorded whether the child spontaneously reproduced the sequence. Approximately 50 percent of the infants demonstrated long-term memory by spontaneously reproducing the sequence. Differential ERP patterns in response to the familiar and novel objects 1 week after initial exposure predicted which infants were able to reproduce the sequence 1 month later.

ERPs can also be used to examine neural correlates of cognitive functions in clinical populations. Dr. Nelson described a study that examined the effects of oxygen deprivation on the developing brain. Four-month-old infants who had experienced various degrees of hypoxia were compared to infants who had not experienced hypoxia. The two groups demonstrated markedly different ERP patterns, indicating that ERPs might be sensitive to metabolic disturbances in the developing brain.

Rat models suggest that rats made iron-deficient and hypoxic demonstrate damage to the areas of the brain that are responsible for recognition memory, such as the hippocampus. In an extension of this model to the human infant, Dr. Nelson and colleagues have hypothesized that the probable combination of iron deficiency, hypoglycemia, and hypoxia in infants of diabetic mothers (IDMs) would show comparable neural injury and concomitant memory impairment. IDMs are asymptomatic, so clinicians do not usually identify any problems. The researchers found that 6-month-old IDMs, unlike infants with nondiabetic mothers, do not produce a differential ERP pattern in response to the mother’s and a stranger’s face. Therefore, they demonstrate no electrophysiological evidence of recognition memory. They also exhibit an inability to perform the crossmodal task, in contrast to non-IDMs.

Dr. Nelson cited the longitudinal work of other researchers on children who have suffered acute hypoxic episodes around the time of their birth. These children show bilateral hippocampal pathology and significant impairments in episodic memory, despite intact semantic memory. Episodic memory deficit is a major impairment, even though it may not severely affect school performance.

In combination, these results suggest that deficits in recognition memory are linked to damage in the hippocampal region of the brain. Dr. Nelson’s laboratory is conducting a longitudinal study and he expects that IDMs will display normal development by overt behavioral measures, but that such assessments may not detect subtle impairments. Dr. Nelson’s group will collect functional MRI and more ERP data on these children when they reach the age of 6.

The work on IDMs could serve as a model for investigating the impact of altered fetal environments on brain and behavioral development. ERPs could be used to examine the neural correlates of cognitive functions in children with FAS. Establishing differences in the ERP pattern of children with FAS may indicate regions of neural damage and demonstrate a specific link between brain circuits and cognitive functions. In addition, ERPs could be used to examine preserved and impaired functions and the effects of interventions in those with FAS.

The research in this presentation was funded through National Institute of Neurological Disorder and Stroke grants NS34458 "Neurophysiologic Assessment of At-Risk Newborns" and NS32976 "Neural Mechanisms of Early Memory Development."

Discussion

Dr. Ellen Witt inquired about the appropriate stage for intervention and asked if Dr. Nelson had intervened with IDMs and examined subsequent ERP changes. Dr. Nelson responded that his group has not intervened, but ERPs could be used as an evaluation technique for interventions. Dr. Nelson and his colleagues intend to conduct interventions after they have established an (approximately) appropriate stage for the interventions and obtained a larger sample size.

Dr. John Hannigan asked whether ERPs could be used to explore new dysfunctions. Dr. Nelson replied that ERPs could be used for this purpose and would allow researchers to investigate whether children with neurobehavioral disorders show compensatory brain development.

Ms. Susan Rich referred to a study demonstrating that iron potentiates alcohol’s teratogenic effects, suggesting that this could be a topic for later discussion.

An Overview of Current Models of Executive Function and Working Memory in Autism and Other Neurodevelopmental Disorders

Loisa Bennetto, Ph.D.

University of Rochester

Dr. Loisa Bennetto discussed executive function (EF) in autism and other neurodevelopmental disorders. EF deficits might explain the diagnostic characteristics and some of the functional problems of children with neurodevelopmental disorders. EF deficits translate well into supports and compensatory strategies for children with developmental disabilities. However, executive dysfunction may not be an appropriate candidate for a core deficit, because the EF model has weaknesses. But reviewing the lessons from EF in other neurodevelopmental disorders may be helpful to the FAS community.

"EF" is an umbrella term that describes goal-directed and future-oriented neurocognitive processes and behaviors. EF involves the ability to inhibit behavior, cognitive flexibility, attention control, monitoring, planning and organizing, and working memory. Dr. Bennetto emphasized the importance of working memory—the ability to hold information in memory while processing other information—as a major EF.

The EF model has weaknesses that have implications for diagnosis and research in neurodevelopmental conditions. EF deficits are present in a diverse set of disorders with different etiologies, including autism, ADHD, fragile X syndrome (FXS), schizophrenia, ARND, and early treated phenylketonuria. The presence of EF deficits in multiple disorders with different causes has raised questions about the discriminate validity of executive dysfunction as a core deficit.

In addition, some neurocognitive assessment tasks that measure EF lack sensitivity, which results in nondetection in some patients and incomplete detection of some EF deficits in others. Impairment in EF may differ by age. For example, in some studies EF deficits were not observed in very young children with autism. This issue is complicated by the lack of full EF development in typically developing children, perhaps showing that finding EF deficits depends on cortical maturity in both patient and control groups. Alternatively, EF tasks might measure different cognitive functions at different ages.

Impairment in EF may also differ by IQ level. Thus, group differences may vary depending on the IQ of the subject and control groups. These findings may be due to the high correlation between EF and fluid IQ subtests. Impairments in EF are an important functional deficit, so treatment models should address them even if they are not an appropriate core deficit for diagnostic purposes.

Dr. Bennetto explained the reasons for EF’s limitations as a core deficit. There are concerns related to EF’s definition and the identification of EF’s component processes. The organization of EF components is still not clear, as investigators have not determined whether the components are independent or hierarchical. Additionally, the relationship between EF components and neural structures is not clear. EF is thought to be related to the frontal lobes, but EF deficits do not necessarily indicate frontal lobe damage because the frontal lobes are interconnected with many brain regions.

Moreover, EF presents measurement challenges to researchers. It is difficult to theoretically dissociate EF components, and few tasks assess only a single EF component. It is also difficult to distinguish nonexecutive components during the performance of EF assessment tasks. EF tasks typically involve several nonexecutive processes, and differences in nonexecutive processes can affect performance on EF tasks and could change the pattern of performance across different groups. For example, a nonexecutive function, such as spatial processing, can influence performance on spatial working memory tasks that assess EF. Similarly, social skills may affect performance on the Wisconsin Card Sorting Test (WCST) when it is administered in person versus by computer. Thus, processes that are not related to EF also affect many tasks used to assess EF.

Dr. Bennetto added that many EF assessments do not display a normal statistical distribution and lack reliability and statistical consistency. Low levels of reliability imply that the assessment task might not discriminate among groups with neurocognitive deficits. Some groups of children with neurodevelopmental disorders demonstrate a ceiling effect, as the test does not discriminate individuals performing at the higher end of the scale. In addition, many children reach adult levels of performance on EF tasks by early adolescence, which further restricts the range of scores. Because many EF tasks involve responding to and using information from novel situations, they are also sensitive to practice effects in longitudinal studies. Therefore, the usefulness of EF assessments for discriminating among different neurodevelopmental disorders is uncertain.

Dr. Bennetto next reviewed several of the putative components of EF, and described some of the traditional and experimental tasks that are used to assess them. Flexibility and set-shifting involve switching from one idea, response, or context to another. Impairment in this component is often evident in perseverative behavior and concrete, rigid approaches to problem solving. Planning involves identifying a goal, organizing the steps needed to reach that goal, and anticipating and generating strategies to avoid future problems. Organization can also be measured in the present, by assessing how a subject encodes or organizes complex stimuli.

Dr. Bennetto discussed how poor organization might lead to later difficulties in recall. Working memory is an ability that is distinct from short-term memory, and involves online storage and processing of information. Finally, tasks of inhibition measure the ability to inhibit the processing of irrelevant details or to stop oneself from carrying out a well-practiced response when it is no longer adaptive.

Research on EF in autism has found:

• Impaired performance on tasks of cognitive flexibility and set shifting

• Impaired ability to plan and organize

• Impaired verbal working memory

• Generally intact ability on simple inhibition tasks

This pattern of executive processes may help explain some of the social and other deficits in autism. In addition, looking for patterns both within executive processes and between executive and nonexecutive processes might address the issue of discriminate validity.

Investigations that compare EF in different neurobehavioral disorders may improve the discriminate validity of EF tasks and help differentiate among disorders. Dr. Bennetto described a study comparing three groups with EF deficits: Children with autism, women with FXS, and children with ADHD. Age and IQ were matched for each group, and each had an appropriate control group. Investigators examined the performance of these women and children on the WCST, focusing specifically on perseverative errors. All three groups with a neurobehavioral disorder showed impaired performance relative to their own control groups. The investigators also examined two tasks that specifically assess verbal working memory and ability to inhibit a response. Individuals with autism and women with FXS displayed a significantly poorer performance on the working memory task than their control groups. In contrast, children with ADHD displayed poorer performance on the inhibition task compared to their control group.

Dr. Bennetto indicated that the autism research could provide important lessons to FAS investigators. Researchers should focus on assessment tasks that have within-subject manipulations of executive and nonexecutive components or, in other words, tasks that permit the researcher to control for the nonexecutive components of EF tasks. To overcome the limitations of EF as a core deficit, researchers should also focus on the subcomponents of EF, and identify tasks that permit predictions from EF to other domains to determine if there are consistent patterns in different neurobehavioral disorders. Finally, it is important that the EF deficits characterizing a particular neurobehavioral disorder be consistent across age and IQ. It is difficult to conduct valid longitudinal studies without tasks that measure the same function in different age groups, but such studies could make invaluable contributions to our understanding of neurobehavioral disorders.

Discussion

Dr. Vivian Faden commented that the concept of IQ matching is intuitively appealing, but IQ is affected by some neurobehavioral disorders. She suggested that investigators match for IQ, age, and mental age. Dr. Bennetto agreed that IQ matching is an important issue. For autism researchers, matching for verbal or performance IQ, depending on the specific task, is a critical decision.

What Is Involved in Delineating a Behavioral Profile?

Maureen Dennis, Ph.D.

The Hospital for Sick Children, Toronto

Dr. Maureen Dennis discussed the process of developing a behavioral profile for hydrocephalus and spina bifida, which may inform the process for other neurobehavioral disorders, such as FAS.

Delineating a behavioral profile for individuals with neurobehavioral disorders involves some assumptions, and it is useful to articulate these assumptions. Neurocognitive test scores are the final, common paths of a set of cognitive processes; of themselves, they do not directly represent brain processes. Neurocognitive test scores are "opaque"; that is, they do not immediately reveal the neurocognitive processes that generate them. Delineating a behavioral profile involves moving from test scores to processes. Identification of the processes underlying complex behaviors requires functional models, which can facilitate the development of hypotheses about neurocognitive processes.

Dr. Dennis described the approach used by investigators in her laboratory to study hydrocephalus and spina bifida. She began by defining some useful key terms. A modal profile is the most typical set of cognitive strengths and weaknesses identified on the basis of neurocognitive test scores. Variability around the modal profile is not error variance but may instead be related to variations in the medical or developmental features of the disorder. A core deficit is a cognitive deficit defined in terms of processes that is robust across medical severity and mental ability. In contrast, general deficits become more severe as IQ level increases and are typically linked to global mental ability. The challenge level of a task may be important in identifying the level of deficit, because some deficits do not emerge until the challenge level escalates. Phenocopies are cognitive phenotypes that look similar but arise from different processes. Researchers must conduct the same tests in individuals with different conditions to observe important differences across disorders and so distinguish phenocopies from distinct cognitive phenotypes.

Dr. Dennis described techniques from cognitive developmental psychology and developmental linguistics that can be used to observe deficits in neurocognitive function or "craters in landscapes of higher function." These techniques have been used to understand spina bifida, a birth defect resulting from failure of the neural tube to close. Spina bifida produces sensory motor deficits that are associated with brain malformation, and often leads to hydrocephalus, a condition characterized by large cerebral ventricles due to abnormality in production, absorption, or circulation of cerebrospinal fluid.

Investigators have identified the characteristic features of a behavioral test profile for spina bifida and hydrocephalus. Chief among these features is poor comprehension, so those children with these disorders often fail to understand what they hear or read. Comprehension deficits in individuals with spina bifida and hydrocephalus are more severe than would be expected on the basis of IQ alone or on the basis of facility in understanding and reading words. Therefore, children with these disorders show significantly impaired oral and written comprehension.

Dr. Dennis and her colleague, Dr. Marcia Barnes, have conducted a series of studies to investigate the source of comprehension deficits in children with spina bifida and hydrocephalus. These studies have involved analyses of comprehension for single words, for literal text, for non-literal language, and for inferential language.

In studies of word-level skills, Drs. Barnes and Dennis found that children with spina bifida and hydrocephalus were not impaired in relation to typically developing children in the ability to understand or read single words. They examined understanding of the literal text base, in studies that presented children with ambiguous English words. When an individual hears an ambiguous word, both meanings are activated, and then the meaning that is not relevant in that context is suppressed. Children with spina bifida and hydrocephalus performed similarly to children without these conditions on meaning activation and meaning suppression processes. Sentence comprehension also relies on the ability to use the context in which a word appears to select which of two ambiguous meanings is the appropriate one for the context. In studies of contextual enhancement, children with spina bifida and hydrocephalus were slower than typically developing children to select the appropriate meaning based on the context. Because the use of context is important for comprehension, lack of contextual enhancement significantly impairs these children’s ability to derive meaning from written and spoken language.

Subsequent studies have examined the ability to understand figurative language, such as idioms. Children with spina bifida and a low IQ showed poorer ability to understand idioms than do children without spina bifida. Children with spina bifida and average IQ performed as well as controls. Therefore, comprehension of familiar idioms is tied to general cognition rather than spina bifida per se. However, children with spina bifida had poorer comprehension of idioms embedded in text than controls, regardless of IQ. These results suggest that context-based processing of both literal and non-literal language is deficient in individuals with spina bifida.

Joelene Huber, a doctoral student in Dr. Dennis’ laboratory, is currently studying the comprehension of decomposable and non-decomposable idioms (those that cannot be changed without altering the meaning) in children with spina bifida. The study of idioms will help reveal whether the comprehension problems of children with spina bifida are based on the lack of contextual enhancement.

Understanding text depends on the ability to make inferences or go beyond the information given. Individuals who have difficulty generating meaning from context also have difficulty making inferences. But because inferencing is influenced by how much an individual knows about a subject (known as the knowledge base), context and inferencing must take an individual’s knowledge base into account.

In one study, Dr. Barnes and Dr. Dennis created an invented world, about which children were required to make inferences. Children with spina bifida and hydrocephalus made fewer inferences to make a story coherent or to elaborate its meaning. Although they could remember the knowledge needed for an inference, they were less able than controls to combine knowledge with appropriate text during story comprehension, even though they were capable of making inferences if they were provided with both relevant knowledge and text.

Differences in inferencing may arise from separate mechanisms in different special populations. For example, Dr. Barnes and Dr. Dennis showed that the comprehension deficits of children with head injury are distinct from those demonstrated by children with spina bifida and hydrocephalus.

Dr. Dennis hypothesized that the core deficits of spina bifida involve slow and inefficient access to context. Based on the deficits observed in spina bifida, researchers are investigating specific parts of the brain (in particular, the cerebellum) that could be responsible for contextual processing and synchronizing information in working memory.

Dr. Dennis stressed that a child’s poor performance on a neurocognitive test is merely one indicator. Several clinical groups may perform poorly on a particular neurocognitive task, which is the end result of many different processes. Therefore, researchers must consider the task used and the various processes that led to the poor test result.

The search for the nature of comprehension deficits in children with spina bifida is illustrative of more general principles involved in defining a cognitive phenotype. It is important to decompose the neurobehavioral disorder’s phenotype before formulating hypotheses about which brain structures are involved. Core deficits are more likely than more general impairments to be related to the distinct pattern of brain compromise in a neurodevelopmental disorder, so that a core deficit will demonstrate a dose-response relationship with brain damage such that the greater neurocognitive deficiency, the greater the brain damage. Many complex neurocognitive tasks recruit multiple brain areas, which complicates efforts to relate neurodevelopmental disorders to brain damage in a single brain area.

Dr. Dennis stressed that individuals involved in generating profiles for neurodevelopmental disorders should incorporate the work of developmentalists into their efforts. That is to say, researchers must understand normal cognitive and behavioral development if they are to conceptualize abnormal behavioral phenotypes in neurodevelopmental disorders.

Supported in part by NICHD Grant P01 HD 35946 "Spina Bifida: Cognitive and Neurobiological Variability" and by project grants from the Ontario Mental Health Foundation.

Discussion

Dr. Sterling Clarren was impressed by the number of confounding variables linked to core deficits in conditions with variable brain malformations and destructive processes. In conditions characterized by multiple problems, it can be difficult to determine the origin of neurobehavioral deficits. Dr. Clarren asked Dr. Dennis if she has started to separate the post- from the prenatal issues to determine the core deficit of spina bifida. Dr. Dennis replied that in the current NIH Project, primary brain dysmorphologies would be separated from secondary damage due to hydrocephalus.

Dr. Robert Sokol requested clarification of a factor that is modulated by another factor would not be considered a core deficit. Dr. Dennis responded that she did not intend to imply that processes are not interconnected and mutually modulated. Rather, her point was that researchers should identify core deficits and show how they are related to each other and to other, more general, cognitive function.

Attention and EF in Children With ARND

Dr. Sandra Jacobson

Dr. Jacobson discussed her laboratory’s investigation of the core deficits demonstrated for children with ARND and neurobehavioral deficits resulting from exposure to toxic substances.

Dr. Jacobson described a study comparing infant development in children exposed to PCBs. Investigators presented infants with familiar and novel pictures while measuring how much the infants looked at each picture. It is known that normal infants prefer to look at novel pictures and that looking at the novel and familiar pictures for equal durations indicates a deficit in recognition memory. Furthermore, the duration of looking is an indication of processing speed. Infants that look back and forth quickly perform well on other tests, and processing speed predicts later IQ scores.

Children exposed to high levels of PCBs looked at the novel picture for a shorter duration. A Taiwanese study of acute PCB exposure later confirmed these results and found that infants currently born to Yu-cheng mothers still demonstrated difficulties with recognition memory on the Fagan test but not on processing speed. This result surprised Dr. Jacobson and prompted her to consider test sensitivity.

Another study in Dr. Jacobson’s laboratory examined children exposed to low and moderate levels of alcohol. These children’s mothers drank in concentrated bursts (approximately seven drinks a week) during pregnancy but were not alcohol dependent. Children whose mothers used cocaine but not alcohol during pregnancy were also included in the study. Children with ARND did not demonstrate a distinctive facial dysmorphology, but they did show intellectual and behavioral deficits.

Dr. Jacobson described a cross-modal recognition task (also called the cross-modal transfer test) that was also administered to the sample of children exposed to alcohol. The results indicated that alcohol exposure negatively affects the duration of looking on the Fagan and the cross-modal transfer tests. Children exposed to as few as two drinks per day, on average, show poorer performance on this task. This study also examined children’s reaction time on the Haith Visual Expectancy Paradigm, a test that for the first time can be used to assess reaction time in infancy. The experimenter measured how long it took the child to move his or her eyes in response to an alternating stimulus. Children exposed to one drink per day, on average, demonstrated slower reaction times on this task. Dr. Jacobson stated that this is a sensitive and robust test of developing neurocognition.

Dr. Jacobson also described studies of elicited play or imitation in children exposed to different toxins. Imitation is an early indicator of language and symbolic development. Research in Dr. Jacobson’s laboratory found that prenatal alcohol exposure affects levels of imitation in children independent of their processing speed. Dr. Jacobson highly recommends level of imitation as a measure of neurocognitive development.

Dr. Jacobson’s laboratory also compared the effects of prenatal cocaine exposure on neurobehavioral tests. Children exposed to heavy prenatal cocaine use processed information more quickly than the children of abstainers and light cocaine users. However, these children performed more poorly on recognition memory, indicating that they look more quickly but are not processing as well as normal children.

In the three tests of infant neurocognition conducted by Dr. Jacobson’s laboratory on children exposed to various toxins, the infants demonstrated different patterns depending on whether they had been exposed to PCBs, alcohol, or cocaine. The infants’ cortisol levels—a physiological measure of stress—were also different depending on the type of exposure. Investigations of children’s postnatal exposure revealed no effects on neurocognitive outcomes.

Dr. Jacobson described the effects of low-level lead exposure and prenatal alcohol exposure on 7-year-old children. Prenatal alcohol exposure did not affect IQ but did influence "freedom from distractibility" (similar to working memory) and arithmetic ability. These effects are greater than would be expected based on the children’s verbal IQ deficits. In contrast, lead exposure negatively affected full-scale IQ and perceptual organization.

Dr. Jacobson’s laboratory has also examined attention deficits in children prenatally exposed to different toxic substances using Mirsky’s Model of Attention, which has four components: sustained attention, selective attention, EF, and working memory. Children prenatally exposed to alcohol show no effects on sustained attention, but they do demonstrate problems with selective attention. These problems are more severe for children exposed to alcohol during the last trimester, which indicates that time of exposure is an important variable for FAS researchers to consider. The results of EF tests, such as WCST and the Tower of London task, reveal that alcohol has effects on performance, but lead exposure does not. Therefore, children exposed to alcohol have EF deficits.

Dr. Jacobson described research on the behavioral effects of various exposures. These may be the most devastating problems in children and may indicate particular areas of brain damage. Behavioral effects are measured on the Teacher Report Form (TRF) of child behavior checklists. Prenatal maternal drinking was related to attention, aggression, delinquency, and social problems on the TRF, while postnatal alcohol use was not.

Dr. Jacobson reported findings on the relation between low-level lead exposure, inattention, and impulsivity. While prenatal alcohol exposure is related to both the inattention and impulsivity components of ADHD, lead exposure is related only to inattention. Such a difference may indicate separate neurobiological causes.

Teacher behavioral reports also indicate that children exposed to alcohol prenatally show problems with attention, aggression, and delinquency. Aggression persists even when attention is controlled for, which suggests that aggression is a primary deficit associated with alcohol exposure.

Teacher checklist scores on attention, aggression, and social functioning for children with moderate to heavy prenatal alcohol exposure are often in the clinical range. Dr. Jacobson emphasized that there is a large gender effect in these results. Girls with high levels of prenatal alcohol exposure do not show problems in these areas according to the teacher checklists. However, teachers rate boys with the same level of exposure as showing high levels of behavior problems. It is important to determine if girls show problems in other behavioral domains, and the gender effect should be further examined.

In summary, neurobehavioral disorders such as FAS, lead exposure, and ADHD are characterized by selective attention deficits and behavioral problems. Most findings are currently at the phenotypic level, so researchers must deconstruct complex neurocognitive functions such as arithmetic, EF, and aggression, and study the components. To improve research in this area, Dr. Jacobson suggested that neurocognitive measures should be made more specific, and that researchers increase their consideration of moderating variables and physiological measures.

The alcohol portions of the research presented were funded by grants R01-AA6966 "Prenatal Alcohol Exposure and Infant Cognition," R01-AA09524 "Prenatal Alcohol Exposure and School-Age Cognitive Function," and P50-AA07606 Fetal Alcohol Research Center from the National Institute on Alcohol Abuse and Alcoholism, with supplemental support from a Minority Access to Research Centers grant T34-GM08030 and a Minority Biomedical Research Support grant S06-RR088167 from the National Institutes of Health and from the Joseph Young, Sr., Fund of Michigan. The Michigan PCB studies were funded by grants from the U.S. Environmental Protection Agency "The Influence of Environmental Toxins of Infant Development" and the National Institute of Environmental Health Sciences R01-ES03246 "Pre- and Postnatal PCB and PBB Exposure: Effects at 4 Years," and R01-ES05843 "Human Exposure to PCBs: Cogeners and Development Effects." The Yu-cheng study was funded by a grant from the National Science Council, Taiwan," Prenatal Growth and Postnatal Neuropsychological Development of Yu-cheng Infants."

Discussion

Dr. Warren asked Dr. Jacobson to distinguish distractibility and freedom from distractibility.

Dr. Joseph Jacobson explained that freedom from distractibility is roughly equivalent to working memory.

Dr. Nancy Handmaker has observed differences in the child behavior reports of mothers and teachers. These differences might explain the gender effect. Specifically, teachers report high rates of behavioral problems in boys in general, and in African-American boys in particular.

Dr. Handmaker now controls for this factor in her data analysis. Dr. Jacobson agreed that this is an important consideration. Her group validates teacher reports with laboratory tests, but it would be wise to validate the mother’s reports as well, as these are influenced by psychological state.

Dr. Ann Streissguth reported that mother and teacher reports of attention deficits corroborate one another.

Alcohol As A Teratogen

Introduction

Shelly Tanable

Office of Senator Tom Daschle (Democrat, South Dakota)

According to Ms. Tanable, Senator Daschle is committed to FAS efforts, and has spoken with affected families and community leaders concerned about the high levels of FAS in South Dakota. Senator Daschle supports the efforts of NIAAA and ICCFAS and the legislation to establish the National Task Force for FAS. Ms. Tanable regarded it as critical to determine the direction of the FAS agenda and specific areas for future scientific work. To increase researcher involvement in FAS efforts, Senator Daschle’s office is attempting to obtain $25 million in funding for a competitive grant program to support the development of models for FAS.

Ms. Tanable encouraged participants to submit issues intended for the attention of Congress to Senator Daschle’s office.

An Overview of the State of the Art in Diagnosing and Profiling FAS/FAE from Animal to Human Research

Chair: Edward Riley, Ph.D.

San Diego State University

Dr. Edward Riley noted that alcohol has clearly been established as a teratogen. Investigators have observed a distinct pattern of anomalies, known as FAS, in the offspring of women who chronically consume alcohol during pregnancy. However, not all children prenatally exposed to alcohol have FAS.

In describing the characteristic FAS neurobehavioral phenotype, Dr. Riley explained that children with FAS demonstrate attention problems, learning deficits, memory problems, executive dysfunctions, motor dysfunctions, and other neurobehavioral deficits. He believes that researchers in the field must try to identify the core deficits of FAS.

The brain damage observed in individuals with FAS appears to be closely linked to behavioral problems. For example, the corpus callosum is abnormal in individuals with FAS, and it corresponds to the poor ability of those with FAS to process information between the two hemispheres of the brain. In addition, individuals with FAS have microcephaly and reduced size in some brain areas. However, the data describing the typical brain changes that occur with heavy prenatal alcohol exposure, and how these may vary as a function of facial characteristics, dose, and pattern of exposure, are in the process of being collected.

Dr. Riley indicated that there are reliable and valid animal models for studying prenatal alcohol exposure and these will be critical to the success of research in the field. The animal models demonstrate excellent concordance with the human condition with respect to distinctive facial characteristics, brain abnormalities, and behavioral similarities. The FAS animal models also indicate microcephaly, cerebellum changes, and smaller basal ganglia and corpus callosum. In addition, the models show variability in brain damage depending on the following factors:

• Alcohol dose

• Pattern of exposure (binge exposure may be more dangerous than chronic exposure)

• Gestational time of exposure

• Genetic differences (especially as they affect the ability to metabolize alcohol)

• Maternal age

• Synergistic reactions with other drugs

• Interaction with nutritional variables

Given the large number of factors that influence the outcome following prenatal alcohol exposure in the animal model, Dr. Riley regards it as remarkable that the behavior phenotype is at all uniform. He urged FAS researchers to use a multidisciplinary approach because the condition involves many interacting factors. Instead of identifying FAS by a single behavioral dimension, investigators should list the symptoms in various domains, such as neuroimaging results, behavioral characteristics, biomarkers of exposure, and maternal history of alcohol exposure. The determination of whether an individual has FAS or behavioral problems resulting from prenatal alcohol exposure could be based on the presence of a particular number of symptoms from each of a variety of domains.

Supported by National Institute on Alcohol Abuse and Alcoholism grants R01-AA10417 "Behavioral, EEG, and MRI Evaluation of Prenatal Alcohol" and R01-AA06902 "Behavioral Effects of Neonatal Alcohol Exposure."

Neurobehavioral Function and Imaging Studies in Children with FAS

Sarah Mattson, Ph.D.

San Diego State University

Dr. Sarah Mattson commented that the social and emotional problems of children with FAS/FAE have a great impact on their quality of life and that of their families. Parents frequently indicate that these problems are difficult to explain to teachers.

Dr. Mattson reviewed studies of socioemotional functioning and brain imaging of children with FAS, which are based on comprehensive assessments of children’s socioemotional skills using direct child measures and parent reports, such as the Child Behavior Check List (CBCL), the Personality Inventory for Children (PIC), the Affective Judgement Questionnaire (AJQ), and a structured psychiatric interview. The PIC is an inventory completed by parents that has 12 scales or behavioral categories, and is the child analog to the Minnesota Multiphasic Personality Inventory, which is widely used to diagnose mental and behavioral disorders.

Dr. Mattson’s laboratory has used the PIC to compare children with prenatal exposure to alcohol (PEA) (no dysmorphology, but maternal history of drinking during pregnancy), FAS, and a control group. The researchers found that the children exposed to alcohol prenatally and those with PEA or FAS were different from controls on every scale, except for the hyperactive scale. The achievement, intellectual screening, cognitive functioning, delinquency, and psychosis scale score differences from the controls were clinically significant for children with PEA. Indeed, the intellectual screening and delinquency scales differed by approximately three standard deviations from the average scores of the control children.

Children with PEA and FAS scored similarly on most PIC scales. However, children with PEA performed better than children with FAS on the cognitive scales. As a group, the children with PEA outscored the children with FAS on IQ tests by 20 points. Dr. Mattson emphasized that children with PEA frequently show socioemotional problems but not low IQ scores.

Investigators have recently used parent ratings of their child’s behavior to assess the socioemotional functioning of children with PEA. Even when children with PEA and control children were matched for IQ level, the children with PEA showed a greater number of behavior problems than the control children. Parents rated children with PEA as displaying externalizing behaviors and experiencing difficulty in solving social problems. Generally, children with PEA and FAS had very similar scores on this metric. Structured psychiatric interviews with children and parents corroborated the parent ratings of increased externalizing behaviors in children with PEA. An analysis of several externalizing disorders, such as ADHD, conduct disorder, disruptive disorder, and oppositional defiant disorder, revealed that children with PEA tend to meet the diagnostic criteria for ADHD only. As they study more children with PEA, investigators may find comorbidity with other externalizing disorders.

Dr. Mattson explained that in the AJQ, the investigator reads a story and shows a picture to the child, who must identify the feelings of the protagonist or make emotional inferences. Children with PEA find it difficult to make emotional inferences. They use only information provided in the story and are unable to make abstract inferences about the emotional state of the characters. However, children with PEA display a normal ability to label or produce faces with different emotions. The ability to make emotional inferences is critical in everyday functioning, because it affects peer interaction. A child who is unable to make emotional inferences may misinterpret the behavior of others, which may lead to fights with peers.

In addition, children with PEA demonstrate problem-solving deficits. In tower tasks, the child moves disks to match a model in as few moves as possible according to certain rules. Such tasks indicate the child’s level of executive functioning. Children with FAS and PEA have difficulty with these tasks, reflecting their deficits in planning and working memory. Children with PEA also violate more of the rules for these tasks and continue to break rules after they are informed of their violations. Therefore, children with PEA are aware of rule violations, but cannot inhibit their own behavior.

The California 20 Questions task is another test of executive functioning. In this test, the child is shown a group of items and must ask "yes or no" questions to identify a target object. This task determines four levels of question sophistication that reflect problem-solving ability. Most children do not tend to ask the most sophisticated level of questions. But children with PEA and control children ask different types of questions. Children with PEA or FAS ask more questions at the lowest level of sophistication than do control children. This level of questioning is similar to trial and error and reflects poor executive functioning. Dr. Mattson emphasized that problem-solving deficits are related to adaptive functioning and have real-life implications for social and behavioral outcomes.

Dr. Mattson’s laboratory has also studied brain imaging to examine the structural changes that result from teratogenic exposure. When investigators compared brain images of children with FAS and PEA, they found that the cortical lobes and subcortical areas, such as the basal ganglia, were smaller in children with FAS. Neither children with FAS nor those with PEA demonstrated reductions in the hippocampus, which was consistent with some animal studies. Brain imaging also revealed that nucleus accumbens size was reduced in children with PEA, who showed more than normal gray matter and less than normal white matter in comparison to control children. These differences were observed primarily in the left parietal cortex, and this finding is consistent with those of other laboratories.

Executive Control Functioning in Children Exposed to Alcohol Prenatally: A Cross-Cultural Perspective

Piyadasa Kodituwakku, Ph.D.

University of New Mexico

Dr. Piyadasa Kodituwakku commented that the neuropsychology of prenatal alcohol exposure is a very complex area. Researchers are attempting to understand the underlying neuropsychological processes that produce the behavioral deficits observed in children exposed to alcohol prenatally.

Dr. Kodituwakku’s laboratory has examined executive control functioning in children with FAS. Executive control functioning involves two primary processes, working memory and response inhibition, and two levels of action selection, cognitive and emotional. There is evidence that two distinct neural circuits subserve these two levels. Dr. Kodituwakku’s research has investigated both the cognitive and emotional aspects of action selection. While tests of planning probe the cognitive aspect of executive control functioning, those of response–reward association measure the emotional aspect.

Dr. Kodituwakku briefly described the neuropsychological tests used to assess planning. "Look-ahead puzzles," such as the Tower of Hanoi, Tower of London, and the Progressive Planning Test (PPT), involve moving beads according to rules in order to match a model. The PPT has three levels of difficulty and two levels of constraint: the "highly constrained condition," in which bead movement is restricted by two rules; and the "minimally constrained condition," in which bead movement is restricted by only one rule. The PPT is a valid test of planning, provides flexibility, and is a culture-fair test. In addition, the PPT is anchored, allowing the investigator to determine the failed processes according to the errors made by the child. Furthermore, researchers have determined the performance level of normally developing children on the PPT. Normal children older than 7 or 8 years show the emergence of competence to solve complex PPT problems in the highly constrained condition.

Dr. Kodituwakku described two studies that compared normal children with children exposed to alcohol prenatally on the PPT. The first study was conducted in an area of South Africa that has a high rate of FAS. The investigators compared the ability of children with FAS and controls matched for age, sex, and socioeconomic status to perform the easiest level of the PPT. In the minimally constrained condition, control children performed at the expected level, but children with FAS performed poorly. These results did not change when intellectual ability was controlled for in the data analysis. Studies of older children with FAS conducted in the United States also showed performance deficits on the moderate level of the PPT after controlling for other factors, such as sex, ethnicity, and age.

The poor performance pattern of children with FAS on the PPT is also seen in individuals with other neurobehavioral disorders. For example, investigators have demonstrated that children and adults with autism perform normally on the easiest PPT level, but do poorly on the moderately difficult PPT. These results indicate that poor performance on the PPT is related to difficulties in mentally manipulating information in working memory, and that these deficits are not unique to FAS.

Dr. Kodituwakku described a study involving a reversal learning task, in which two stimuli were presented. One stimulus was designated as "the winner" and was reinforced by awarding the child a point, while the other stimulus was "the loser" and caused the child to lose a point. The child was asked to discriminate between the two stimuli. After the child reached a learning criterion on this task, the reinforcement contingencies were reversed without warning at two different times. During extinction trials, children were punished for responding to either stimulus, so they were required to inhibit the previously learned contingencies. Children with FAS and FAE experienced great difficulty in reaching the learning criteria, even after large amounts of practice time. Generally, these children were able to learn the correct response in the extinction trials, but their performance variability was great.

Several variables predict the extent of behavioral problems in children with FAS, including the combination of specific performance measures such as perseverative errors on the WCST, variability on extinction trials, and omission errors in reversal learning. Dr. Kodituwakku closed by emphasizing that the measures of the emotional aspect of executive control functioning, not the measures of the cognitive aspect, can predict behavior and that, therefore, this finding should be further investigated.

Supported by National Institute on Alcohol Abuse and Alcoholism grants R01-AA09440 and R01-AA11685 and the National Institutes of Health Office on Minority Health Research (to P.A May).

The Washington State FAS Diagnostic and Prevention Network of Clinics: (A) Alcohol Exposure and Physical Findings as Markers of Wide-Ranging Central Nervous System Compromise, and
(B) Cognitive/Behavioral Profile of the First 1,000 Patients Diagnosed

Sterling Clarren, M.D., and Susan J. Astley, Ph.D.

University of Washington

Drs. Sterling Clarren and Susan Astley are Co-Directors of the Washington State FAS Diagnostic and Prevention Network (FAS DPN) of clinics.

Dr. Clarren explained that the different terms used to describe individuals exposed to alcohol prenatally are confusing to professionals working in education and the social services. These professionals typically use functional rather than etiological diagnoses, but the current terminology in the field does not support this approach.

Dr. Clarren noted that a very large number of children have been prenatally exposed to alcohol and a smaller number have sustained detectable brain damage. Dr. Clarren stressed that the brains of individuals with FAS/ARND/FAE are not very different from each other. All diagnostic groups demonstrate a gradation in impairment from severe to mild, and not all behavioral problems are due to brain dysfunction. The origin of the behavioral problem must be identified for diagnostic clarity and in order to implement effective interventions. Diagnostic procedures must distinguish between patients who are disabled from those who are not and define the degree of disability and approaches to habilitation.

Animal research clearly demonstrates that alcohol is a teratogen that produces widespread damage to many brain structures. Therefore, researchers should not regard the problem as an insult to only one part of brain. Alcohol-related brain damage frequently occurs in combination with many other factors--such as genetic problems, other teratogens, and a variety of postnatal circumstances--that cannot be clinically separated. Researchers should focus on helping individuals with brain damage rather than on clinically separating co-occurring etiologic factors.

Dr. Clarren explained that the diagnostic terminology currently used to describe the neurobehavioral results of prenatal alcohol exposure is inadequate. Using the term "FAS" leads to a substantial underestimate of the number of individuals affected by prenatal alcohol exposure. Additionally, the term is so vague that clinicians vary widely in their diagnoses. The other terms used to describe individuals exposed to alcohol prenatally that do not meet the diagnostic criteria for FAS, such as "FAE," alcohol-related birth defects, and "ARND," are not sufficiently specific. Furthermore, these labels may imply a causal relationship between alcohol and the neurobehavioral characteristics.

To overcome limitations in current diagnostic guidelines, the Washington State FAS DPN developed a more objective, case-defined approach to diagnosis called the 4-Digit Diagnostic Code. Dr. Astley reported that the 4-Digit Diagnostic Code system has worked exceptionally well in over 1,300 FAS DPN patients. The four digits reflect the magnitude of expression of four key diagnostic features, each ranked separately, in the following order: (1) growth deficiency, (2) the FAS facial phenotype, (3) evidence of organic brain damage, and (4) prenatal alcohol exposure. These scales document the full spectrum of outcome and exposure observed in this patient population.

The majority of studies on children affected by alcohol rely on circular definitions; that is, they depend on cognitive and behavioral problems to establish a diagnosis and use these characteristics to summarize the neurobehavioral profile of the patients. In contrast, the 4-Digit Code documents each of the four key diagnostic features (growth deficiency, facial features, and evidence of organic brain damage and alcohol exposure) independently, thus allowing for a profile to be developed that is not circular in nature.

Dr. Astley discussed the profile derived from the FAS DPN clinic population of the first 845 patients with confirmed prenatal alcohol exposure. She briefly provided the demographic profile of the population as follows:

• Approximately half are under 7 years of age.

• Females are 45 percent of the affected patients.

• Half are Caucasian, 12 percent are African American, and 25 percent are Native American.

• On average, maternal drinking occurred 5 days per week during pregnancy.

• Seventy-seven percent of women reportedly drank in the first trimester.

• Sixty percent of the women reportedly drank throughout the pregnancy.

• Over 70 percent of mothers also engaged in illicit drug and tobacco use.

• Most patients are referred by family or social services, or are self-referred.

Of the first 845 children with confirmed prenatal alcohol exposure seen in the FAS DPN, 7 percent received a 4-Digit diagnosis of FAS. An additional 32 percent had structural, neurological, and/or psychometric evidence of bran damage, but did not meet the full criteria for FAS. Dr. Astley briefly described the behavioral problems observed in these alcohol-exposed children based on caregiver reports using the CBCL and semi-structured interviews with caregivers. Twenty-nine to 73 percent of the children had t-scores in the clinical range across the syndrome, internalizing and externalizing scales of the CBCL. Key areas of concern were inattention, hyperactivity, poor judgement, poor memory, and impulsiveness. Dr. Astley’s group found no sex differences in caregiver reports on child behavior checklists. Because other investigators have found a sex difference in teacher reports, Dr. Astley suggested that it would be interesting to compare the results of teacher and caregiver checklists.

The psychometric profiles of these children are largely derived from standardized tests administered by schools. Not all patients present with the same battery of assessments. Of the 120 alcohol-exposed children who had completed standardized tests of intelligence, achievement, neuropsychology, and language, 27 percent performed normally across all four domains, 51 percent performed significantly below the norm across one or two of the domains, and 22 percent performed below the norm across three or all four of the domains. These results demonstrate the wide range of outcome typically observed in the patient population. The race, gender, IQ, and alcohol exposure levels of these 120 children were comparable to those of the remaining 725 alcohol-exposed children who did not present with this more complete battery of assessments; thus these results may be generalized to the FAS DPN population as a whole.

Since the 4-Digit Code documents growth, facial phenotype, brain damage, and alcohol exposure on separate scales, it offers the opportunity to assess correlations between these key diagnostic features. The proportion of patients with structural and/or neurological evidence of brain damage increased linearly with increasing magnitude of growth deficiency, the FAS facial phenotype, and prenatal alcohol exposure as measured on the 4-point Likert Scales of the 4-Digit Code. Significant linear associations were also identified between increasing magnitude of expression of the FAS facial phenotype and the proportion of patients with (1) structural and/or neurologic evidence of brain damage, (2) language deficiency, (3) developmental delay, and (4) reduction in IQ. These finding strongly support that the facial phenotype, when measured using the 4-Digit Code, correlates with brain structure and function and intermediate expressions of the facial phenotype are clinically meaningful.

Discussion

Dr. Sandra Jacobson asked whether certain FAS facial features are weighted more heavily than others. Dr. Astley replied that their published discriminate analysis of the FAS facial phenotype demonstrated that the key diagnostic features were palpebral fissures (less than two standard deviations below the norm), a smooth philtrum (Ranks 4 or 5 on the Lip-Philtrum pictorial guide), and a thin upper lip (Ranks 4 or 5 on the Lip-Philtrum pictorial guide).

Dr. Charles Goodlett inquired about the use of functional MRI to measure brain damage and how this tool would affect the diagnostic system. Dr. Clarren responded that the diagnostic categories would not change, but new diagnostic tools would shift the ranking definitions within the category. Dr. Astley added that magnetic resonance spectroscopy, which measures brain chemistry, is another important tool that should be incorporated into diagnosis.

Dr. Clarren stressed the importance of regarding FAS as a brain damage phenotype, rather than as a behavioral phenotype.

Supported by a grant from Division of Alcohol and Substance Abuse, Department of Social and Health Services, Washington State.

Brain, Behavior, EF, and Prenatal Alcohol Exposure

Ann Streissguth, Ph.D.

University of Washington

Dr. Ann Streissguth introduced her colleague, Helen Barr, who has tested children prenatally exposed to alcohol on standardized assessments such as the Wechsler IQ, the Wide Range Achievement Test, the Vineland Adaptive Behavior Scales, and Offenbach’s Child Behavior Checklist (teacher and self-reports). The observation that children with FAE have a higher mean IQ than children with FAS has been frequently reported in the literature. However, on a variety of neuropsychological tests, children with FAE perform at a lower level than do children with FAS. Furthermore, children with FAE perform at lower levels than predicted by their full-scale IQ scores on almost all standardized tests administered in this laboratory. On the Vineland Scales, ABC Socialization and Daily Living Skills, Offenbach Checklists, and measures of externalization, children with FAE or FAS score very poorly. Ms. Barr summarized these findings by explaining that IQ scores alone do not adequately reflect disability. She has strong reservations about the argument that FAS represents the most severe consequence of prenatal alcohol exposure.

Dr. Streissguth commented that the results of standardized tests demonstrate that more research must be conducted on the relationship between neuropsychological function and organic brain dysfunction. Even individuals exposed to alcohol who have high IQ scores have a disorder and may not receive the services they truly need.

Dr. Streissguth’s study included adult males with FAE, adult males with FAS, and age- and race-matched controls. Brain imaging revealed that the variability of corpus callosum shape in the alcohol-affected individuals was much higher than in the control group. There was a high correlation between corpus callosum shape and neuropsychological test results. A thin corpus callosum was associated with poor motor performance as measured by the Stepping Stone Maze, the Pursuit Rotor task, the hand steadiness task, the dynamic balance test, and other well-established assessment tools. A thick corpus callosum was associated with EF deficits as measured by the WCST and other assessment tools. Dr. Streissguth stressed that motor and EF deficits can be distinguished, which might indicate subtypes within the FAS neurobehavioral profile. These results have been replicated with adult females, and a similar study with adolescents is almost complete.

Another study conducted in Dr. Streissguth’s laboratory examined EF in the Seattle 500 birth cohort, a group of alcohol-affected individuals who have been longitudinally studied. Investigators examined members of this cohort at 21 years of age and gave them a battery of neurocognitive assessments, including EF and IQ tests. Because the investigators were concerned about the relationship between IQ and EF, they adjusted EF test scores for IQ. They found that the WCST is a more effective assessment than the IQ test to determine EF deficits. Other measures of EF deficits independent of IQ include the Stroop Task and Trails Scores. When full-scale IQ scores were adjusted by composite EF scores, alcohol-exposed individuals demonstrated more EF deficits than would be expected from their IQ level alone.

Dr. Streissguth reported that the neuropsychological assessment of the Seattle 500 birth cohort revealed a relationship between prenatal alcohol exposure and neurobehavioral effects at the ages of 7, 14, and 21. Specifically, prenatal alcohol exposure was related to neuromotor and multiple mental measures at age 7; attention and memory deficits at age 14; and memory, attention, and EF deficits at age 21.

Observations from the Collective Family Experience

C. Jocie DeVries

Executive Director, FAS Family Resource Institute

Mrs. Jocie DeVries discussed the collective family perspective on FAS, noting that parents have difficulty finding counselors and psychiatrists who can recognize individuals with FAS/ARND and normal IQs. Most professionals also cannot separate the co-occuring conditions that typically affect these children. In 1980, Mrs. DeVries and her husband unknowingly adopted two children who had experienced prenatal alcohol exposure and were very traumatized from domestic violence when they arrived in the home. At the age of 16, Mrs. DeVries’ son was finally diagnosed with FAS. The family found themselves alone, with no professionals, no support services, or even other parents to assist them. The FAS Family Resource Institute originated from Mrs. DeVries’ efforts to obtain resources and assistance for her son and others affected by FAS.

It can be difficult for parents of these children to communicate with professionals because FAS and ARND are currently not included in the mental health diagnostic manual, nor is ARND recognized as a medical diagnosis. In order to facilitate family communication with professionals and service providers, members of the FAS Family Resource Institute have developed several tools, including a developmental profile. This 4-Track Developmental Profile reflects the child’s history through documentation of major events and issues in four primary life domains:

• Physical: The physical domain is simple for most families to describe; it focuses on the child’s physical health, life experiences, the number of foster/adoptive placements, etc.

• Social: The social domain describes the child’s ability to make and keep friends.

• Educational: Families frequently have a great deal of written information and academic testing in this domain if the child has had difficulties in school. This is the ability to understand and remember factual information.

• Moral: The moral domain describes the child’s understanding of cause and effect learning and his/her ability to cooperate with rules and regulations in the family, community, and society.

Mrs. DeVries stressed that the inability to understand cause and effect spans all four life domains. In the physical domain, children with FAS/ARND frequently cannot associate bodily events with causal problems. The social domain of FAS children can be tumultuous due to their difficulty in perceiving cause and effect in reciprocal relationships. Most children exposed to alcohol are of normal intelligence, but their misperception of social relations can lead to negative peer relationships, mental distress, and even severe depression. Some children exposed to alcohol do not experience academic problems, but most cannot develop good study habits, are easily distracted (have ADHD), and have behavior problems in school. The collective family experience indicates that these children can learn, but they may not know how to use the information, i.e., gain the wisdom to apply the learning they have acquired in school. The inability to comprehend cause and effect affects the moral domain because children affected by alcohol do not understand the need for social cooperation and rules. This characteristic is frequently observed in children affected by alcohol and distinguishes them from other children. They can often repeat the rules and consequences but do not feel personally responsible to obey the rules. Children with FAS often do not remember or know how to apply their accepted family values to other situations. When combined with volatile emotions, especially during puberty, the deficits in the moral domain can lead to antisocial behavior and criminal charges in the legal system.

The common family experience with individuals who have FAS/ARND is that they truly do not understand right from wrong; but it is difficult for families to describe this characteristic without implying that their child is "bad." The FAS Family Resource Institute emphasizes that children with FAS/ARND are disabled in their ability to comprehend cause and effect, especially in the moral domain; but this does not mean they are morally deficient--they are just stuck on a very low level of conscience development (about 3-year-old equivalent). While many individuals with FAS/ARND have volatile or assertive outbursts, they do not typically have predatory intent. If they do seem to be predatory, a screening and/or evaluation for a co-occurring mental health disorder is recommended because medications have often been found effective in these situations.

Mrs. DeVries stressed that as researchers develop a behavioral profile of children with FAS/ARND, they also need to develop a way to measure the cause-and-effect comprehension deficits of these individuals in the moral domain. This factor is very important to the preservation of the family unit and has a significant widespread societal impact.

What Can We Learn from Comparing Alcohol-Affected Children to Those with ADHD?

Claire D. Coles, Ph.D.

Emory University School of Medicine

Dr. Claire Coles discussed the major theoretical and methodological distinctions between ADHD and FAS, based on her published studies. Dr. Coles emphasized that researchers must distinguish between two groups of children with FAS: (1) Those identified as a result of the mother’s alcohol use during pregnancy, and (2) those referred to clinics because they clearly have behavioral problems. It is important to study both of these groups longitudinally, but they are different and researchers should indicate the nature of the sample studied.

Children who have been referred from clinics and diagnosed with ADHD are frequently also diagnosed with FAS. The concern is that clinicians often assume that FAS is present in a child with ADHD and a dysfunctional family. Minority status, parental substance abuse, and poverty are associated with increased rates of FAS, ARND, and ADHD diagnoses, as well as placement in special education programs. Such factors represent confounding variables, rendering it difficult to determine whether the behavioral disorders are a function of socioeconomic factors or are true disabilities.

Several socioeconomic factors have an impact on diagnostic and neurobehavioral outcomes. For example, deficits in IQ scores are associated with social class. Individuals from a lower social class are more likely to be diagnosed with FAS or ARND than individuals from a higher social class. Individuals with disability status are more likely to have an ADHD diagnosis than individuals