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Early Childhood Neurobehavioral Assessment for the Differential Diagnosis of Fetal Alcohol Syndrome and Alcohol-Related Neurological Disorders
March 8-10, 2000
Differential Diagnosis of Fetal Alcohol Syndrome
and Alcohol-Related Neurodevelopmental Disorder
Bethesda Marriott Hotel
March 8–10, 2000
The Interagency Coordinating Committee on Fetal Alcohol Syndrome
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
Enoch Gordis, M.D., National Institute of Alcohol Abuse and Alcoholism
Faye Calhoun, D.P.A., National Institute of Alcohol Abuse and Alcoholism
Jan Harlow, Ed.D., U.S. Department of Education
Karen Stern, Ph.D., U.S. Department of Justice
Sandra Jacobson, Ph.D., Wayne State University
SESSION I – DEVELOPING A NEUROBEHAVIORAL PROFILE
The use of nonbehavioral symptoms in understanding neurodevelopmental disorders
Kenneth Warren, Ph.D., National Institute of Alcohol Abuse and Alcoholism, Chair
Patricia M. Rodier, Ph.D., University of Rochester
The use of event-related potentials as a tool for studying early neurobehavioral development
Charles A. Nelson, Ph.D., University of Minnesota
An overview of current models of executive function and working memory in autism and other neurodevelopmental disorders
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
Shelly Tanable, Office of Senator Tom Daschle
An overview of the state of the art in diagnosing and profiling fas/fae from animal to human research
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
Executive control functioning in children exposed to alcohol prenatally: a cross-cultural perspective
Piyadasa Kodituwakku, Ph.D., University of New Mexico
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., 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
What can we learn from comparing alcohol-affected children to those with adhd?
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
Dr. Sandra Jacobson
SESSION III – USING ANIMAL MODEL STUDIES TO IDENTIFY DEVELOPMENTAL NEUROBEHAVIORAL PROFILES OF THE ALCOHOL-DAMAGED BRAIN
Prenatal alcohol and maternal-fetal endocrine balance: contributions of animal studies to understanding neurobehavioral deficits in fas/arnd
Laurie Foudin, Ph.D., National Institute of Alcohol Abuse and Alcoholism
Joanne Weinberg, Ph.D., University of British Columbia
Neural substrates of classical eyeblink conditioning in human and nonhuman animals
Joseph E. Steinmetz, Ph.D., Indiana University
Developmental studies of eyeblink conditioning in human infants and an animal model
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
Does lead intoxication have a behavioral signature? examples from epidemiologic and case studies
Kim N. Dietrich, Ph.D., University of Cincinnati
Attention deficit disorder (add): clinical research, diagnostic issues, and assessment tools
Lisa Freund, Ph.D., National Institute of Child Health and Human Development
Polychlorinated biphenyls and methylmercury
Joseph Jacobson, Ph.D., Wayne State University
Does prenatal cocaine exposure provide a roadmap to outcome? what we have learned from neonates and young infants
Marylou Behnke, M.D., University of Florida
Postneonatal outcomes following prenatal cocaine exposure: methodologic complexities in multiple developmental dimensions
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
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
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
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.
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.
Associate Director for Collaborative Research, NIAAA
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.
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
Program Manager, Office of Juvenile Justice and Delinquency Prevention
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.
Professor of Psychology, Department of Psychiatry and Behavioral Neurosciences
School of Medicine
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.
Director, Office of Scientific Affairs
Patricia M. Rodier, Ph.D.
Professor of Obstetrics and Gynecology
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.
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.
Distinguished McKnight University Professor, Child Psychology, Neuroscience, and Pediatrics
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."
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.
Assistant Professor, Clinical and Social Sciences in Psychology
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.
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.
Senior Scientist, Brain and Behavior Program
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.
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."
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
Senior Staff Member
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.
Department of Psychology, Center for Behavioral Teratology
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.
Associate Director, Center for Behavioral Teratology
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.
Dr. Mattson reported that the brains of children with PEA also show corpus callosum displacement. Specifically, the isthmus or posterior region of the corpus callosum is much smaller in children with PEA. Furthermore, the extent of corpus callosum displacement is correlated with the extent of externalizing behavior in these children. Therefore, the brain abnormalities observed in children with PEA are related to behaviors that have real-life implications.
Executive Control Functioning in Children Exposed to Alcohol Prenatally: A Cross-Cultural Perspective
Piyadasa Kodituwakku, Ph.D.
Neuropsychologist, Center on Alcoholism, Substance Abuse, and Addictions (Albuquerque)
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.
School of Medicine
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.
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.
Professor, Fetal Alcohol and Drug Unit
Department of Psychiatry and Behavioral Sciences
School of Medicine
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.
Associate Professor, Department of Psychiatry and Behavioral Sciences
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 without disability status.
Because of these diagnostic confounds, Dr. Coles’ laboratory has examined whether individuals with FAS perform similarly to those with ADHD on neuropsychological tests. The sample consisted of African-American children with low socioeconomic status. Four groups of children were compared: (1) children with no alcohol exposure; (2) children with dysmorphic FAS facial features; (3) children with alcohol exposure, but no dysmorphic features; and (4) children with ADHD, but no alcohol exposure. The investigators assessed the children’s mothers for addiction severity, drug and alcohol use, demographic profile, and IQ. The investigators administered many standardized tests to the children, including subscales from general aptitude tests, the VMI (Beery Developmental Test of Visual/Motor Integration), paired associate test, a test of sustained attention, the ZOO test (a paired associate test developed by Swanson and Kinsborne), the WCST, and parent-teacher behavioral checklists.
Cognitive assessments revealed that the alcohol-exposed and ADHD groups had statistically equivalent IQ levels. The ADHD group demonstrated significantly different behavioral outcomes from the other groups, but the FAS group did not differ from other groups on behavioral measures. Neurocognitive tests revealed some differences among the groups. Children with ADHD but not FAS demonstrated sustained attention deficits. This finding is corroborated by longitudinal studies indicating no hyperactivity or impulsivity in children with FAS. Individuals with both FAS and ADHD have unique profiles with respect to their ability to focus, encode, shift attention, and sustain attention. Dr. Coles concluded that not all children exposed to alcohol have ADHD.
The implications of Dr. Coles’ findings are as follows: (1) similar global behaviors may have very different etiologies; (2) ADHD is overdiagnosed and a comprehensive examination of these patients is rare; (3) research design, especially of clinical studies, must be sensitive to confounding factors such as socioeconomic status, race, and family dysfunction; (4) specific behaviors associated with prenatal alcohol exposure can be identified, but researchers must triangulate alcohol-related behavior patterns using appropriate methodologies; and (5) with the right research design, comparisons with other clinical groups can be helpful in revealing a neurobehavioral profile of FAS — specifically, appropriate contrast groups can help determine whether behavioral effects are due to alcohol or environmental confounders.
Revising The Diagnostic and Statistical Manual of Mental Disorders: Relevance to Arnd
Michael First, M.D.
New York Psychiatric Institute
American Psychiatric Association
Dr. Michael First is chair of the American Psychiatric Association (APA) committee responsible for revising the Diagnostic and Statistical Manual for Mental Disorders (Fourth Edition)
( DSM-IV). FAS is not represented as a specific mental disorder in the current DSM-IV. In order to raise clinical awareness of FAS as well as to facilitate communication among clinicians and among researchers, it might be advantageous for FAS to be included in future editions of the DSM.
Dr. First explained that the first edition of DSM was published in 1952. At that time, DSM was a brief pamphlet and was not very helpful to clinicians. In 1968, the APA published the DSM-II as a larger pamphlet that contained a list of mental disorders and a brief description of each.
DSM-III, published in 1980, was substantially different from previous editions. In addition to the list of disorders and brief descriptions, the volume provided diagnostic criteria for each disorder, based on lists of symptoms (i.e., syndromes) and the number of symptoms from each list that must be displayed by the patient to qualify for the disorder. Therefore, diagnoses were defined by clusters of symptoms rather than etiology. In addition, DSM-III specified patterns and durations of symptoms, provided criteria to distinguish among different disorders, and also listed features that exclude the presence of the disorder.
DSM-III was very successful, and the use of diagnostic criteria was particularly popular. Another well-received feature of DSM-III was its textbook-like information on each disorder. This edition was also successful because it avoided speculative causal inferences concerning the etiology of mental disorders, although it did describe causal factors for specific disorders whose etiology is known. This atheoretical approach was intentional and made DSM-III useful to mental health professionals from all theoretical perspectives.
Since 1980, the APA has revised DSM twice, although the basic characteristics of DSM-III have not altered. With the advent of DSM-III-R in 1987 and DSM-IV in 1994, many professionals believed that the pace of revision was too rapid. Some were particularly concerned about whether the revisions were consistent with the current research. As a result, the APA has decided to delay publication of DSM-V until 2007 or even later. However, some experts were concerned that in the interim, DSM-IV’s text might become outdated. The APA will therefore release
DSM-TR (text revisions) in June 2000, which will contain updated text but no changes in diagnostic categories.
DSM-IV ’s categories are intertwined with the diagnostic codes of the World Health Organization’s International Classification of Diseases ( ICD-9), which is the official international system for all medical diagnoses. (A clinical modification of ICD-9, called IDC-9-CM, is the official coding system for use in the United States.) Although the tenth edition of this book is already used throughout the world, the United States still uses ICD-9-CM, but is expected to start using ICD-10 within the next 5 years. While ICD-9-CM includes diagnostic categories for all medical conditions, DSM includes only mental disorders. ICD-9-CM contains a category for "noxious influences affecting the fetus via the placenta or breast milk" (760.7), and FAS is a subcategory (760.71) of this. Other noxious influences in this category include exposure to other drugs and toxins. Dr. First emphasized that ICD-9-CM provides only diagnostic categories, rather than clinical definitions.
Dr. First commented that there is a window of opportunity for new diagnostic criteria to be included in DSM-V. Including a disorder in DSM produces increased attention to it and helps educate professionals in the field about the disorder.
Dr. First listed several ways in which FAS could be incorporated into the current DSM system. The first option is for the APA to add a "behavioral disorders due to prenatal exposure" category to DSM-V. This would mean that FAS would not be a viable psychiatric diagnosis until 2007. Because ICD-9 contains FAS, coordination of a new DSM diagnostic category with ICD-9 would not be difficult.
A second option is to obtain a diagnosis based on existing DSM-IV categories. For individuals with adaptation deficits who have IQs of less than 70, a diagnosis of mental retardation would apply. This category does not refer to the etiology of the mental retardation, although the text for this disorder does mention prenatal exposure as a possible cause. In this diagnostic category, clinicians frequently code etiology on Axis III (physical disorders relevant to the case). Dr. First acknowledged that there are manifestations of FAS other than low IQ. Specific relevant childhood disorders already included in DSM could be noted as the primary diagnosis. For example, reading, mathematics, learning, written expression, or communication disorders could be listed as the main diagnostic disorder with prenatal alcohol exposure noted under Axis III.
A third option is to include FAS under alcohol-induced disorders, which would imply that there is a causal link between the behavior observed in individuals with FAS and the direct physiological consequences of alcohol exposure. Typically, this diagnostic category is used to describe reversible changes in the behavior of adults under the influence of alcohol (with the exception of alcohol persisting dementia and alcohol persisting amnestic disorder). For most disorders under this diagnostic category, DSM-IV implies that the symptoms are resolved once alcohol leaves the body, and the alcohol chapter clearly implies that individuals in this category must have actually consumed alcohol. Although prenatal exposure has not traditionally been included in alcohol-induced disorders, DSM-IV includes toxin exposure as a clear example of a substance-related disorder, so the diagnostic system might have some flexibility to include FAS.
Dr. Betsy Lozoff commented that adding a disorder to DSM can unintentionally affect the type of care that patients receive. For example, pediatricians and neurologists may not be reimbursed for treating children with FAS if the disorder is included in DSM. Dr. First remarked that the APA has traditionally ignored reimbursement issues when revising DSM because reimbursement policies vary among insurers. In some cases, nonpsychiatrists who treat disorders listed in DSM can be reimbursed, and this may be the case for FAS treatment.
Mrs. DeVries commented that, from the family’s perspective, including FAS in DSM is very important and requested that the APA collaborate with the FAS Family Resource Center to include FAS in DSM.
OF GOALS FOR THE SECOND DAY
Dr. Sandra Jacobson
Dr. Jacobson suggested that participants focus on identifying the core deficits observed in individuals prenatally exposed to alcohol rather than on developing a behavioral profile. In many cases, the child’s behavior is influenced by prenatal exposure to multiple substances that affect several neural pathways.
Dr. Jacobson also announced that the agenda had been changed to include two breakout sessions, rather than three.
Using Animal Model Studies To Identify Developmental Neurobehavioral Profiles of the Alcohol-Damaged Brain
Prenatal Alcohol and Maternal-Fetal Endocrine Balance: Contributions of Animal Studies to Understanding Neurobehavioral Deficits in FAS/ARND
Chair: Laurie Foudin, Ph.D.
Division of Basic Research, NIAAA
Joanne Weinberg, Ph.D.
Professor, Department of Anatomy
University of British Columbia
Dr. Joanne Weinberg remarked that the endocrine system is critical to the normal physiological and behavioral functioning of the adult female and the fetus. Research has established that alcohol can alter the activity or function of the endocrine system. Dr. Weinberg’s laboratory has examined whether alcohol-induced changes in endocrine balance contribute to FAS/FAE, and how these effects might occur.
Dr. Weinberg explained that because the hormonal systems of the mother and fetus are linked by the placenta, and because the placenta itself produces hormones, the balance between maternal, fetal, and placental endocrine systems is critical. The placenta provides a communication link between mother and fetus through which gases and nutrients are exchanged and wastes are removed. The placenta also acts as a partial barrier that separates the genetic and immune systems of the mother and the fetus.
During pregnancy, the fetus is exposed to hormonal secretions originating from the placenta, the mother, and its own endocrine glands, which are active by 12 weeks of gestation. The placenta does not have all of the enzymes that are necessary to synthesize the full complement of hormones, so precursors for placental steroidogesis are produced by both the maternal and fetal adrenal glands.
Pregnancy maintenance depends largely on progesterone, which the placenta secretes into the maternal circulation from early in pregnancy. However, the placenta also secretes estrogen, which opposes the actions of progesterone. Investigators have recently discovered that the shift from progesterone to estrogen dominance that triggers birth is due to corticotropin-releasing hormone (CRH). Stress and alcohol are two factors that increase CRH levels, and an induced increase in CRH can stimulate preterm birth.
Dr. Weinberg briefly described the effects of glucocorticoid hormones (such as cortisol in humans and corticosterone in rodents) on maternal and fetal physiology. Generally, glucocorticoid hormones influence metabolism as well as nervous system, muscle, and immune system function. These hormones, which are released in response to stress, activate bodily systems that meet stress challenges. However, chronic elevation of glucocorticoid hormones can produce a variety of stress-related disorders.
The maternal hypothalamic-pituitary-adrenal (HPA) axis, which is involved in the normal response to stress, increases its activity during pregnancy, and alcohol increases this activity further. High levels of glucocorticoids can produce negative outcomes, such as congenital anomalies, spontaneous abortion, and preterm birth. Furthermore, fetal exposure to high levels of alcohol may produce hormonal hyper-responsiveness to stressors. In humans, chronic exposure to alcohol has been shown to increase fetal cortisol levels, and researchers have demonstrated that these increases persist until the infant is 13 months old.
Exposure to prolonged stress and stress hormones is reliably associated with many pathological conditions, including depression. Prolonged exposure to stress hormones may mediate some of the behavioral characteristics observed in children with FAS such as hyperactivity and deficits in attention and response inhibition.
The maternal hypothalamic-pituitary-gonadal (HPG) axis ultimately produces estrogen and progesterone, two hormones that have substantial physiological effects on the mother and fetus. Prenatally, estrogen, progesterone and androgens play important roles in fetal sexual differentiation, including differentiation of the central nervous system. The sex hormones also influence events at puberty, such as the growth and development of sex organs, secondary sex characteristics, metabolic functions, and other physical effects.
Alcohol consumption by nonpregnant women is associated with several reproductive function disorders. Females frequently experience menstrual problems, ovarian pathology, and possible premature menopause. These effects could be due to inhibition of pituitary responsiveness to releasing hormones and subsequent increases in the levels of estradiol and CRH, which may suppress the HPG axis and progesterone. During pregnancy, such alcohol-induced hormonal alterations could result in spontaneous abortion, premature labor, or fetal malformations.
Animal studies of the effects of alcohol exposure on the fetus have demonstrated that the fetal reproductive system is significantly altered in response to alcohol exposure. The feminization of male or masculinization of female alcohol-exposed fetuses affects sex organs, hormone levels, central nervous system regulation of the HPG axis, sexual and nonsexual behaviors, and the timing of menopause. Female children with FAS do mature sexually and can become pregnant, but they sometimes have altered fertility and menstrual cycles.
Dr. Weinberg explained that the hypothalamic-pituitary-thyroid (HPT) axis is critical to the normal growth and development of almost all organ systems. Specifically, the HPT axis regulates fetal metabolism, tissue oxygen consumption, metabolism of macronutrients, immune system development, and other critical aspects of fetal growth. Alcohol consumption in women negatively affects thyroid function, especially responsiveness to thyroid challenges. The fetal thyroid becomes functional around the 11 th week of pregnancy, but thyroid hormones from the mother circulate prior to that. Altered thyroid function due to alcohol can have major effects on the entire developmental cascade, especially if the alcohol exposure occurs during critical periods. Children with FAS frequently demonstrate hypothyroidism, which has profound effects on growth, activity level, and developmental delays.
Dr. Weinberg concluded that alcohol has significant effects on maternal, fetal, and placental endocrine function. Alcohol can affect overall maternal health and the ability to maintain a successful pregnancy, and can alter fetal development through both direct and indirect mechanisms. Neuroendocrine dysregulation early in fetal development can influence the entire developmental cascade. Assessing neuroendocrine functions may facilitate the diagnosis of alcohol exposure, and examining endocrine alterations may increase our understanding of the neurobehavioral deficits observed in children exposed to alcohol.
Supported by a grant from National Institute on Alcohol Abuse and Alcoholism AA07789 "Alcohol and Stress: Interactive Effects."
Neural Substrates of Classical Eyeblink Conditioning in Human and Nonhuman Animals
Joseph E. Steinmetz, Ph.D.
Eleanor Cox Riggs Professor and Chair, Department of Psychology
Dr. Joseph Steinmetz described the classically conditioned eyeblink response in animals and humans as a simple neurobehavioral system about which a great deal is known. This response can therefore be used to examine the impact of prenatal alcohol exposure and to inform clinical research. For example, Dr. Steinmetz’s laboratory has examined parallels between classical eyeblink response in animals and humans, the neural correlates in alcohol-preferring rats (a genetic model of alcoholism), and the effects of prenatal alcohol exposure in an animal model.
Because the eyeblink response involves simple conditioning, it is a type of nondeclarative/ procedural/implicit learning. Classical eyeblink conditioning in animals and humans can be studied using the same procedure of pairing a tone with a puff of air into the eye, which naturally elicits a blink. With many paired presentations, the subject associates the tone and air puff. After the association is established, the tone alone (conditioned stimulus: CS) elicits an eyeblink (conditioned response: CR). In eyeblink conditioning, subjects also learn to respond when the air puff should be presented (CR timing). Investigators have a rich set of data about this behavior, which permit the identification of the underlying neurobiological circuitry.
Dr. Steinmetz briefly described the brain pathway involved in the classical eyeblink response. The interpositus nucleus of the cerebellum is critical to eyeblink response learning, and animals with lesions in this area of the brain are unable to learn the eyeblink response. Destroying this area of the brain permanently abolishes an established response. Unit recording shows interpositus nucleus activity before the eyeblink response is executed. When combined, these observations provide compelling evidence that the interpositus nucleus of the cerebellum is an underlying neural substrate for the eyeblink response.
The neural pathways for learning and performing the conditioned eyeblink response are limited to only a small number of areas of the brain. The tone is processed through the basilar pontine nuclei, which sends converging input to the cerebellar cortex and the deep cerebellar nuclei. The air puff is processed through the inferior olive in the lower brain stem and this structure sends information to areas in the cerebellar cortex and the deep cerebellar nuclei.
Investigations of human eyeblink responses have generally found the same results as investigations of animal responses. Humans with cerebellar lesions cannot learn the response. Because individuals with autism have cerebellar deficits, including deficits in the cerebellar cortex, investigators had expected that these individuals would be unable to learn the eyeblink response. However, autistic individuals demonstrated facilitated learning of the conditioned eyeblink response, and their conditioned responses were mis-timed, indicating a general hyper-excitability condition.
Dr. Steinmetz’s laboratory has also investigated eyeblink responses in individuals with obsessive-compulsive disorder (OCD). Researchers expected that those with OCD would show facilitated learning of the eyeblink response and that, once established, the response would be resistant to extinction. Their studies confirmed both hypotheses and Dr. Steinmetz stressed that the conditioned eyeblink response paradigm could be used to test the behavior of other clinical populations.
Studies involving an FAS animal model have shown eyeblink conditioning deficits in adult rats exposed to binge levels of alcohol on the first few postnatal day of life. Cerebellar abnormalities have been shown in these animals. Dr. Steinmetz explained that future research in his laboratory will further examine the activity of the neurons in the brain circuit that has been shown to underlie learning and performance of the classically conditioned eyeblink response in the FAS model animals.
Supported by grants from National Institute on Alcohol Abuse and Alcoholism AA11945 "Alcohol and Development: Effects on Cerebellar Systems," AA10120 "Disinhibition and Risk for Alcohol Abuse," and AA7611 "Indiana University School of Medicine Alcohol Research Center."
Developmental Studies of Eyeblink Conditioning in Human Infants and an Animal Model
Mark E. Stanton, Ph.D.
Psychobiologist, Environmental Research Center, Neurotoxicology Division
U.S. Environmental Protection Agency
Dr. Mark Stanton explained that the eyeblink conditioning paradigm has known behavioral properties and neurobiological mechanisms, has been compared across species and across the lifespan, and has relevance to clinical disorders. These are all critical characteristics for a model of normal and abnormal behavior. Simple behavioral manipulations in the eyeblink conditioning paradigm permit the examination of different components of the underlying brain circuits. Furthermore, the brain circuits involved in the eyeblink response, particularly the hippocampus and cerebellum, are abnormal in clinical conditions such as autism, Down’s syndrome, mental retardation, schizophrenia, hypothyroidism, and FAS.
Dr. Stanton described studies in his laboratory on developing rats using the freely moving rat eyeblink conditioning procedure. Rats as young as 24 days old demonstrate a precisely timed, conditioned eyeblink response. Investigators have observed that there is an increase in learning with age that is not related to differences in performance. According to Dr. Stanton, the study indicates that eyeblink response is developed in the late postnatal period and the developmental timing of eyeblink response is consistent with cerebellar involvement, since the cerebellum develops approximately 20 days postnatally. Trace conditioning, which is sensitive to hippocampal damage, develops approximately 30 days postnatally.
Neonatal damage to the cerebellum impairs the postnatal development of the conditioned eyeblink response but not the unconditioned reflex. Neonatal rats exposed to alcohol also demonstrate deficits in the conditioned eyeblink response but not reflexive response. These animals show some learning with extended training, but their performance reaches asymptote at a lower level than that of unexposed control rats.
Dr. Stanton’s laboratory has investigated eyeblink conditioning in animal models of autism and hypothyroidism. The autistic rat model shows significantly increased eyeblink response amplitudes that resemble those observed in autistic individuals. Rats with induced developmental hypothyroidism demonstrate impaired eyeblink response learning only with an increased interstimulus interval, suggesting that the cerebellar cortex, rather than deep nuclei in the cerebellum, is preferentially targeted in this condition. Developmental hypothyroidism also produces deficits in conditioned response timing.
To study the eyeblink conditioning procedure in human infants, the infant sits in the mother’s lap and wears a headband fitted with an apparatus to deliver a puff to the eye. Eyeblink conditioning is apparent at about age 4 or 5 months. This finding, together with other studies in the literature, suggest that eyeblink conditioning develops postnatally in humans. Dr. Stanton concluded that eyeblink conditioning is suitable for studies of learning in rodents and human infants. The eyeblink conditioning paradigm can be used to probe the functional development of brain areas, such as the cerebellum and hippocampus, which are frequently damaged by numerous developmental insults.
This work was supported by the Office of Research and Development, U.S. EPA, and by the following pre-and postdoctoral fellowships: National Institute of Child Health and Human Development 1AG1-Y02-HD-0-V279-00 "Eyeblink Conditioning in the Human Infant," and National Research Service Awards 1-F31-MH10366-01 to John H. Freeman "Developmental Psychobiology of Eyeblink Conditioning," 1-F31-MH11292-01 to Christy S. Carter "Neurobiology of Cognitive Development: Latent Inhibition" and 1-F32-MH/HD11729-01 to Dragana Ivkovich "Ontogeny of Trace Conditioning in Animals and Humans. "
Bidirectional Hypothesis Testing between Animal Models and Humans
Charles R. Goodlett, Ph.D.
Professor, Department of Psychology
Indiana University–Purdue University, Indianapolis
Dr. Charles Goodlett emphasized that alcohol abuse is not equivalent to an environmental toxin because it is self-administered, allowing the individual to control the dose, timing, and pattern of his or her exposure. In most cases of FAS, the mother has a long history of alcohol abuse. Alcohol exposure and withdrawal from alcohol affect the fetus, placental function, and maternal physiology. Prevention of FAS requires behavior change, making it complicated to remove the toxin.
According to Dr. Goodlett, the following characteristics of FAS make causal inferences uncertain in the neurobehavioral profiling process:
- There are many secondary factors in alcohol exposure.
- Alcohol exposure is not precisely known.
- Alcohol exposure is identified ex post facto.
- The population with FAS is heterogeneous.
These variables can affect neurobiology and neuroendocrine status, which may alter the pattern of behavior and cognitive problems observed in individuals with FAS.
Animal studies on the effects of prenatal alcohol exposure can experimentally control all of these factors, making it possible to derive causal inferences about the source of behavior. Dr. Goodlett stressed that there is excellent correspondence between the neurobiological outcomes observed in humans and animals prenatally exposed to alcohol. The neurobehavioral profile of prenatal alcohol exposure may involve subtypes or clusters of covarying symptoms. The pattern of drinking during pregnancy may influence the neurobehavioral subtype. Such factors as the number of drinking episodes, the amount of alcohol per episode, the frequency of episodes, the developmental timing of episodes, the duration of drinking in pregnancy, and the presence of alcohol withdrawal may contribute to the neurobehavioral profile observed.
In such a complex issue as FAS, it is critical to study a simple system first. A thorough investigation of eyeblink conditioning, for example, provides a functional analysis of learning and performance, sensory-motor associative learning, and higher-order learning. Once the neurobiological basis of learning deficits is defined, simple paradigms can be used to screen for targeted interventions or early identification.
Dr. Goodlett described the effects of exposure to alcohol binges during the third trimester as being equivalent in an animal model of FAS. The binge pattern of alcohol exposure late in gestation reduces the number of cells in the cerebellar cortex and inferior olivary nucleus. Purkinje cell loss, in particular, demonstrates a dose-response relationship. Even one binge alcohol exposure can have effects if it occurs during a critical developmental period. Cerebellar damage and eyeblink conditioning deficits are most likely to occur when the fetus is exposed to heavy alcohol use in weeks 24 to 32.
Other scientists have demonstrated the detrimental effects of a single, heavy alcohol exposure on other areas of brain, such as the parietal and cingulate cortex and thalamus. Exposure to a heavy dose of alcohol in late pregnancy affects the medial hypothalamus and parts of the thalamus. Therefore, dose and timing have a critical influence on the pattern of brain damage.
The duration of alcohol exposure affects cell loss in the brain. Investigators found that daily binge exposure resulted in significant cell loss in the hippocampus only when drinking occurred during the third trimester equivalent in rats. Hippocampal damage produced persistent deficits in spatial learning, but cerebellar loss was produced by a different exposure pattern.
Dr. Goodlett concluded with a brief description of his research on rehabilitative training. Given the permanent alcohol-induced cell loss in the cerebellum, it is important to develop treatments to improve functional outcomes. The normal adult brain retains a significant capacity for experience-dependent plasticity; that is, brain development can be stimulated in adults based on therapeutic behavioral experience. Dr. Goodlett’s laboratory recently investigated whether acrobatic training affected the brains of alcohol-exposed and normal rats. Alcohol-exposed rats that received rehabilitative training performed better on motor tasks than alcohol-exposed rats that were not trained. Autopsies revealed that the rats that received rehabilitative training had increased brain cell connections in the cerebellum and motor cortex.
Lessons Learned from the Study of Neurodevelopmental Disabilities Caused by Teratogens and Congenital Disorders
Environmental Teratogens: Lessons from Lead and Other Toxins
Chair: Dr. Claire D. Coles
Herbert L. Needleman, M.D.
Professor, Department of Psychiatry
University of Pittsburgh
Dr. Herbert Needleman stated that lead is the longest recognized and best studied neurotoxin. He briefly reviewed the history of lead as a model neurotoxin to illuminate the scientific understanding of other neurotoxic substances. The effects of lead on the mind have been recognized since ancient times. In 1943, Byers demonstrated that exposure to lead during childhood produces long-term effects. Even low levels of lead exposure produce effects. Thirty studies have demonstrated that lead has neurotoxic effects, even in the absence of overt symptoms. In 1991, the Public Health Service established a strategic plan to eliminate lead poisoning. In 1993, the third National Academy of Sciences report on lead asserted that blood levels of 10 micrograms per deciliter are neurotoxic.
The blood level of lead reflects only short-term exposure. Dr. Needleman has developed an assay for long-term lead exposure using teeth. High levels of lead in teeth are associated with significant deficits in performance on various neurocognitive assessments, including IQ tests, the Seashore rhythm test, the token test, and the sentence repetition task. Children exposed to lead respond slowly, have difficulty inhibiting distraction, and show attention deficits. Teachers who are unaware of a child’s lead exposure level report that such children demonstrate attention problems in school. Investigators in Britain and other countries have reported similar findings, demonstrating that the number of children affected by lead exposure is substantial. Longitudinal studies of children exposed to lead have found poor academic outcomes, such as increased risk of high school failure, poor reading scores, and lower IQ scores.
Childhood lead exposure is also related to delinquent behavior. Individuals classified by early onset and persistent delinquent behavior demonstrate a high prevalence of neurological dysfunction. While such individuals represent only 6 percent of the U.S. population, they account for 50 percent of the crimes committed. Dr. Needleman presented data showing the ratings of teachers, parents, and subjects showed increased rates of aggression, attention dysfunction, and delinquency in relation to bone lead levels. Arrested and adjudicated delinquents had higher bone lead levels than controls. Dr. Needleman encouraged changes in public health policy to reduce lead exposure. For example, removing lead from gasoline is related to the decrease found in blood lead levels in recent years.
Dr. Deborah Frank asked whether the effects attributed to lead could be due to alcohol, given that there are confounds among lead, socioeconomic status, and the possibility of alcohol use during pregnancy. Dr. Needleman responded that he does not have the data needed to address this issue, but added that animal research has shown that rats who are given lead prefer alcohol to water.
Ms. Ann Waller asked how Dr. Needleman derived the conclusion that teacher checklist reports on child behavior are more accurate than parent reports. Dr. Needleman replied that teachers do not have the same vested interest as parents, are with children for a larger portion of the day, and can compare a child’s behavior with that of other children. All of these factors make teachers more accurate judges of a child’s behavior. Ms. Waller remarked that the differences in the home and classroom environment must be considered. Dr. Needleman agreed that it is important to consider different behavioral contexts, but argued that the best predictor of ADHD is peer ratings since children interact constantly. Ms. Waller noted that other factors, such as the copying of misbehavior among peers, should be considered before drawing conclusions about the accuracy of parent reports.
Does Lead Intoxication Have a Behavioral Signature? Examples from Epidemiologic and Case Studies
Kim N. Dietrich, Ph.D.
Professor of Environmental Health, Department of Environmental Health Sciences
College of Medicine
University of Cincinnati
After stressing that the neurobehavioral effects of lead are still not a fully understood, Dr. Kim Dietrich described the neurobehavioral manifestations of low to moderate levels of lead exposure and reported the evidence from epidemiological studies and a prospective case analysis.
Investigators have concluded that the effects of environmental lead exposure depend on the interaction of a number of factors, such as the individual’s social characteristics and the period of development at which the peak level of exposure occurs. Recent international prospective studies of lead and child development have found consistent effects. However, it is difficult to determine the relationship between lead exposure and critical developmental periods because postnatal exposure is confounded with age. Blood lead profiles for children peak at a time when they typically have high levels of hand-to-mouth contact. This period is also characterized by rapid central nervous system development. Dr. Dietrich remarked that even though the field does not have a behavioral endpoint that can be used as a screen for neurocognitive damage, the behavior of children exposed to lead is generally consistent across studies and demographic strata.
Several neuropsychological domains are affected by lead exposure, and these have been demonstrated in international prospective studies. Visual-motor, visual-spatial, fine motor coordination, postural stability, attention, and executive functions are impaired in individuals with higher lifetime blood lead levels. Social behavioral outcomes, such as self-reported, parent-reported, and teacher-reported acts of delinquency, increase as lifetime lead exposure increases. Even low levels of lead exposure are related to significant deficits in reading ability.
Dr. Dietrich described a prospective case analysis of a child who presented with symptomatic lead exposure. A wealth of data exists on this patien t because she participated in a clinical trial through which she underwent frequent and detailed neurobehavioral assessment. The child was enrolled in the study when she was 14 months old and had a very high blood lead concentration (142 µg/dl). Her exposure to lead was related to the collapse of the ceiling in her apartment. The child had the symptoms of lead poisoning and after her successful treatment, she was transferred to lead-safe housing. She had a negative heredity medical and social background for adverse factors, but her IQ test performance was lower than would be expected from her mother’s IQ. She also had low scores on tests of attention and executive function, poor fine motor and sensory-motor skills, and oppositional and hyperactive social behavior. Like many children exposed to toxic substances, the child demonstrated severe balance problems, which are sensitive indicators of exposures to a number of neurotoxic substances (other than methylmercury).
While ascribing a specific "behavioral signature" to lead neurotoxicity is still difficult, the following interrelated functional domains appear to be particularly affected:
- Visual-motor and visual-spatial skills
- Attention and executive functions
- Neuromotor and postural coordination
- Social conduct
- Reading disabilities
Support in part by grants and contracts from the National Institute of Environmental Health Sciences R01-ES08158 "Early Exposure to Lead and Adolescent Development," 1u01-ES309720 "Treatment of Lead-Exposed Children Multicenter Clinical Trial," and R01-ES08659 "Prevention of Neuromotor Deficits in Lead-Exposed Children."
Dr. Weinberg commented that there seem to be final common pathways for neurobiological damage. The domains of function affected by lead are also critical in FAS and in children born at low gestational age. Researchers may not be able to develop unique neurobehavioral profiles, but they may be able to identify core deficits that will facilitate diagnosis.
Dr. Coles remarked that there are common neurocognitive deficit areas among the elderly and those who suffer brain injury.
Dr. Kieran O’Malley asked whether lead has an effect on cyclic adenosine monophosphate (cAMP) and other cellular functions. Dr. Needleman replied that lead alters protein and enzyme function in animals.
Attention Deficit Disorder (Add): Clinical Research, Diagnostic Issues, And Assessment Tools
Lisa Freund, Ph.D.
Program Director, NICHD
Dr. Lisa Freund remarked that the clinical research, diagnostic issues, and assessment tools in the ADD field are relevant to FAS because the behaviors associated with ADD and FAS overlap. The development of the behavioral symptoms used in the diagnostic schema for ADD may be a useful model for the development of a diagnostic screen for FAS.
ADD is characterized by inattention, hyperactivity, and impulsivity associated with a developmental pathogenesis. Initially, this disorder was called "minimal brain dysfunction" and its diagnosis was based on neurodevelopmental lag, electrophysiological measures, and evidence of adaptive dysfunction. However, this diagnostic profile lacked specificity and did not establish the number of behavioral symptoms required for the diagnosis.
Dr. Freund explained that as DSM evolved, so did the diagnostic profile for ADD. DSM-II renamed the disorder "hyperkinetic reaction of childhood" and based its diagnosis on three symptom dimensions: motor activity, impulsivity, and attention deficit. But this diagnostic profile emphasized the hyperactivity component, which concerned experts because many individuals with ADD are not hyperactive, although they do display impulsivity and attention deficit. DSM-III retained the inattention, impulsivity, and hyperactivity symptom dimensions, but required that a certain number of symptoms within each dimension be demonstrated for an ADD diagnosis. DSM-III also included the diagnostic subtypes of ADD/WH (with hyperactivity) and ADD/WO (without hyperactivity).
DSM-III-R established ADHD as a unidimensional disorder with no subtypes. Eight of 14 behavioral items were now required for a single diagnostic profile that incorporated inattention, impulsivity, and hyperactivity. The earlier requirement for the distribution of symptoms across the three dimensions was removed due to the lack of supporting evidence. DSM-IV contains two dimensions — inattention and hyperactivity-impulsivity — because factor analysis reveals that hyperactivity and impulsivity are part of this underlying construct. The diagnostic criteria listed in DSM-IV include the following:
- Has difficulty sustaining attention
- Does not seem to listen
- Does not follow through on instructions
- Loses things
- Is easily distracted by extraneous stimuli
- Has difficulty organizing tasks and activities
- Fails to attend to details
- Is forgetful
- Cannot stay seated
- Runs or climbs excessively
- Has difficulty playing quietly
- Talks excessively
Dr. Freund explained that field research and factor analysis on the DSM-IV diagnostic profile distinguishes three ADHD subtypes: inattentive, hyperactive/impulsive, and combined. These subtypes differ by type and degree of impairment, age, sex ratio, and developmental course. Girls display the inattentive subtype more frequently than boys, and individuals with this subtype experience more learning difficulties. Inattentive symptoms tend to decline with age more than hyperactive/impulsive symptoms. Individuals with the combined subtype (who have symptoms from both dimensions) tend to be more severely impaired in adaptive functioning and comorbidity. Estimates of ADHD prevalence are approximately 16 percent (8.8 percent inattentive, 2.6 percent hyperactive/impulsive, and 4.7 percent combined) if individuals without significant impairment are included.
Behavior rating scales specific to the ADHD Conners Rating Scales and the SNAP-IV are quite sensitive and can distinguish the three subtypes. "Broad-band" behavioral checklists are not as sensitive or specific to ADHD diagnosis. The neurocognitive/neurobehavioral symptoms underlying the ADHD diagnostic dimensions include the following deficits:
- Poor working memory
- Internalization of self-directed speech
- Poor control of emotion, arousal, and motivation
- Alerting deficits, particularly deficits in maintaining vigilance, readiness to react, and temporal accuracy of responses
- Poor performance on motor inhibition tasks
Dr. Freund suggested that disinhibition and the behavioral symptoms of ADHD are secondary to the EF deficits. The brain areas related to EF are abnormal in individuals with ADHD in that they demonstrate volumetric abnormalities in the frontal lobe, basal ganglia, caudate nucleus, parietal lobes, and frontal and striatal areas. These volumetric abnormalities reflect smaller brain structures. Functional brain imaging reveals reduced brain activity in the prefrontal and parietal cerebral lobes and the caudate nucleus. Functional MRI brain scans of individuals with ADHD during motor control tasks demonstrate subnormal activation of the prefrontal system.
Research supports the two-dimensional scheme for ADHD, and studies of twins show that the inattentive, hyperactive/impulsive, and combined subtypes all contain a larger proportion of monozygotic twins of the same subtype. The genetic basis of ADHD subtype must be further examined.
Dr. Freund emphasized that the following issues in the ADHD field still need to be studied:
- There is no consensus on the core neuropsychological and neurophysiological deficits in ADHD.
- Most neurobiological studies have examined the combined subtype; more studies must focus on the inattentive and hyperactive/impulsive subtypes.
- Neurobiological studies have predominantly investigated males, but sex differences in ADHD may exist.
- Long-term outcome studies are needed.
- Researchers need a better understanding of normal and disordered brain development.
- Anatomic and functional imaging phenotypes must be developed and incorporated into state-of-the-art cognitive neuroscience programs.
Polychlorinated Biphenyls and Methylmercury
Joseph Jacobson, Ph.D.
Professor of Psychology, Department of Psychology
Wayne State University
Dr. Joseph Jacobson noted that there are fewer data on the neurobehavioral effects of PCBs and methylmercury (MeHg) than for lead and alcohol, even though PCBs and MeHg are toxic and widely distributed. PCBs are in the family of synthetic chemicals that were commonly used from the 1930’s until they were banned in 1975. PCBs were designed not to biodegrade and, therefore, persist in the environment. Because they are lipophilic, PCBs are stored in animal fat and move up the food chain. Humans are exposed to PCBs by eating fatty foods, such as sport fish, pork, beef, and cheese.
Mercury is a naturally occurring element, but its industrial use in utility plants and waste incinerators has made it a pollutant that accumulates in lakes and oceans. Humans are exposed to MeHg by eating fish from polluted bodies of water. The toxicity of MeHg was recognized in the 1950’s, when the children of women who had consumed fish from the highly polluted Minamata Bay in Japan were born mentally retarded with severe and persistent seizure disorders.
Dr. Jacobson described two prospective longitudinal studies of prenatal MeHg exposure, one in the Faroe Islands in the North Sea, and another in the Seychelles Islands in the Indian Ocean. The Faroe study found neuromotor deficits, difficulties with sustained attention, and poor verbal learning in individuals exposed prenatally to MeHg. However, the Seychelles study did not find these deficits in exposed individuals. The contrasting results are difficult to reconcile, which makes policy judgments regarding requiring expensive banning and cleanup of MeHg in lakes and oceans difficult to make.
Several differences in study methodology might account for the discrepant results. First, MeHg was measured differently: The Faroe study measured cord blood levels of MeHg, while the Seychelles study measured maternal hair levels. However, when the Faroe study investigators reanalyzed their data using maternal hair levels of MeHg, they obtained the same results as they had obtained with cord blood levels. Thus, the method of measuring MeHg cannot account for the disparity between the results. The two studies also differ with respect to the subjects’ ages at testing and the types of neuropsychological tests used, which might account for the discrepant results. A third study conducted in New Zealand with very similar methods and exposure patterns to the Seychelles study found effects similar to those of the Faroe study: deficits in full-scale IQ and performance IQ.
Dr. Jacobson remarked that prenatal PCB exposure negatively affects full-scale IQ scores, spatial reasoning, and reading ability, but does not affect EFs. In contrast, data from his 7-year follow-up study did not demonstrate an effect of prenatal alcohol exposure on full-scale IQ, but did reveal more specific adverse effects in executive function.
Dr. Jacobson stressed that investigators must examine the moderating variables that make individuals more susceptible to FAS. Animal studies and imaging techniques should also inform neurobehavioral profiles.
Supported by grant CR80852010 from the U.S. Environmental Protection Agency, and grants R01-ES03246 and R01-ES05843 from the National Institute of Environmental Health Sciences.
Does Prenatal Cocaine Exposure Provide a Roadmap to Outcome?
What We Have Learned from Neonates and Young Infants
Marylou Behnke, M.D.
Professor of Pediatrics/Division of Neonatology
College of Medicine
University of Florida
Dr. Marylou Behnke explained that research on prenatal cocaine exposure began with the epidemic use of crack cocaine in the 1980’s. Because crack cocaine was inexpensive, readily available, potent, and addictive, it quickly became a drug of abuse. A large number of women used crack cocaine during pregnancy, and teachers subsequently reported being overwhelmed by the behavioral problems of cocaine-exposed children. The media paid a great deal of attention to this issue and scientists recognized the need for well-designed outcome studies of children exposed to cocaine prenatally.
Prenatal cocaine exposure has both direct and indirect effects on fetal development. It directly affects the fetal monoaminergic neurochemical system, and both structural and functional brain development. Prenatal cocaine exposure indirectly affects the fetus through maternal vasoconstriction, which impairs placental blood flow and produces maternal hypertension, fetal vasoconstriction, and fetal hypoxia. All of these indirect effects can potentially influence the infant’s physical development, especially the development of its neurological system.
Dr. Behnke commented that well-designed studies are essential to investigate the neurobehavioral outcomes of prenatal cocaine exposure. Well-designed studies incorporate the following methodological elements:
- Prospective participant enrollment
- Inclusion of diverse populations
- Unbiased participant selection
- Adequate sample size
- Control of confounding variables
- Assessments by blinded evaluators
- Nonselective subject loss
In the study by Dr. Behnke and her colleague, Dr. Gyler, of children exposed prenatally to cocaine, the children and their mothers were drawn from a Southern, rural population with minimal access to drug treatment. To enroll a prospective, matched cohort of women, research staff approached mothers when they appeared for prenatal care. Women were excluded from the study if they used illicit drugs other than marijuana. The investigators identified 154 women who used cocaine to various degrees while pregnant, and about 6 percent of these women received drug treatment during pregnancy. Prenatal cocaine use was measured by assessing the amount of money spent on the drug per week.
The investigators compared the women who used cocaine to controls matched for psychosocial issues and pregnancy-related medical outcomes. Compared to controls, women who used cocaine during pregnancy used other drugs more and began to use drugs at earlier ages. They were also older and had experienced a greater impact from life events. Psychologically, cocaine-using mothers had lower self-esteem, a more external locus of control, and more symptoms of depression, and did not feel positively about their parenting skills. Women who used cocaine also had higher obstetrical risk, and began prenatal care later, but did not experience significantly more fetal deaths than nonusers. Moreover, when other drug use was controlled for, the gestational age, birth weight, and length of the infants of cocaine-using women did not differ from those of the infants of the controls. There was, however, an interaction effect of cocaine and tobacco use. After controlling for prenatal alcohol and marijuana use, cocaine users who also smoked tobacco had infants with smaller chest and head circumferences. Finally, the infants of women who had high levels of cocaine use during the third trimester of pregnancy tended to be shorter and have smaller head circumferences.
The investigators administered blinded neurobehavioral assessments to the infants of study participants and, after controlling for other drug use, found a significantly lower score only on the Brazelton Qualifier Score of Alert Responsiveness in the exposed infants. Other prospective, controlled studies have identified negative effects related to cocaine exposure, including poor state and autonomic regulation, irritability, decreased alertness and orientation, abnormal reflexes, and decreased habituation. However, about a third of more recent behavioral studies have reported no statistically significant effects of prenatal cocaine exposure.
Dr. Behnke remarked that in their study, the prevalence of abnormal cranial ultrasound results in infants born to cocaine-using mothers was lower than had previously been reported and was not significantly different from the results of the control group. The identified lesions observed through ultrasound were less severe than had been previously reported, and abnormal ultrasound findings were not related to cocaine exposure, although they were related to other prenatal risk factors. Furthermore, ultrasound findings were not associated with abnormal neurobehavioral outcomes at birth.
Also noted in their study was that a small proportion of infants prenatally exposed to cocaine had clinically significant congenital anomalies, the most common of which was microcephaly. However, there was no clear pattern of anomalies in cocaine-exposed infants and there was not an increased number of anomalies when compared to the non-exposed infants.
Other investigators have reported that neonates who had been prenatally exposed to cocaine demonstrated behavioral alterations, such as sleep disturbances, alterations in acoustic cry measures, lack of attention modulation relative to their level of arousal, and poor behavioral scores, most often regulation of state.
Other behavioral problems noted throughout the first 12 months of life have included:
- Early hypertonia and movement difficulties
- Problems with visual expectancy, recognition memory, and information processing
- Less arousal and responsiveness in learning tasks
- Less positive face-to-face interaction
- Less secure attachment
- Problems in unstructured play
- Poor performance on the Bayley Scales
Supported by NIDA grant DA 05854 and CRC grant RR00082.
Postneonatal Outcomes Following Prenatal Cocaine Exposure: Methodologic Complexities in Multiple Developmental Dimensions
Deborah A. Frank, M.D.
Director, Growth and Development, Boston Medical Center
Associate Professor of Pediatrics, Boston University School of Medicine
Dr. Deborah Frank remarked that few data exist on children beyond the first grade who have been exposed to cocaine. She commented that many studies in the literature have not been rigorously conducted and then described the appropriate methodology for investigating the neurobehavioral outcomes of prenatal cocaine exposure.
Dr. Frank had recently reviewed approximately 60 studies of prenatal cocaine exposure and postneonatal outcomes. Approximately half of these studies generated at least partially credible data. In the course of her review, Dr. Frank established criteria for a credible investigation of prenatal cocaine effects. She argued that studies must have a control group and masked examiners, who are especially important, because knowledge of cocaine exposure affects observer ratings. To avoid confounding factors, the sample should not contain a large number of HIV-positive mothers or mothers who are users of other potent illicit substances such as amphetamines or opiates. Prospective recruitment before or immediately after birth is critical to avoid recall and selection bias, which produces an overestimation of adverse outcome risk. Investigators should also examine their data for and take steps to avoid differential attrition and overaggregation of confounding variables. Too often, questionnaires administered to mothers do not measure the levels of important covariates, such as amount of cigarette and alcohol use and severity of violence exposure. Simply coding these variables as "yes or no" is not sufficient. The dose–response to prenatal cocaine exposure is critical and investigators must recognize that the relationship is not linear, which may alter the estimated relationship magnitude. Determination of prenatal cocaine use is imprecise and researchers must consider the implications of this when they draw conclusions.
Dr. Frank recommended that researchers identify and quantify the risk and protective factors present in the lives of children prenatally exposed to cocaine. For example, children exposed to cocaine tend to experience other factors that affect their development, such as depressed caregivers, stigma, and family instability.
A review of the outcomes of apical tests, such as the Bayley Scales or Stanford-Binet tests, on children over 1 year of age who had been exposed prenatally to cocaine, these tests showed no unique effects due to cocaine use when cigarette, alcohol, and marijuana use was controlled for.
Studies by other researchers have found language deficits in cocaine-exposed children. But Dr. Frank questioned these results because the studies did not control for maternal tobacco use during pregnancy. These studies also have other methodological difficulties, such as nonmasked observers, retrospective samples, and a lack of proper comparison groups.
Dr. Frank noted that most masked, prospective studies have not found statistically significant effects of prenatal cocaine exposure on toddler play, problem-solving ability, CBCL scores, or the Vineland and Conners tests. One investigation of the physiological responses of children exposed to cocaine have found lower basal cortisol levels but no differences in cortisol levels in response to a stressor. Preliminary results showed that arousal regulation is diminished in children prenatally exposed to cocaine. Sustained attention was also found to be impaired on a continuous performance task in one study. These findings regarding possible cocaine effects on the HPA axis and on regulation of attention and affect are found in sophisticated laboratory paradigms that require further replication and assessment of their "real world" clinical impact.
Dr. Frank identified the biological and social risk factors associated with prenatal cocaine exposure. Biological risk factors include shortened gestation and depressed head circumference at birth, as well as inadequate prenatal care and exposure to cigarettes, alcohol, and other psychoactive substances. Effects of gender vary by outcome and sample with some investigators showing no difference, whereas others note increased vulnerability in one gender or the other. Social risk factors include maternal psychological distress, welfare status or unemployment, low maternal education or IQ, and violence exposure. These factors may increase the risk of negative outcome following heavy prenatal cocaine exposure. It is unclear whether the status of the child’s caregiver as a relative or nonrelative is a risk factor, compared to the child’s biologic mother. Some protective factors improve outcomes for cocaine-exposed children, including better home environments, early intervention programs, and preschool attendance in enrichment programs. Preliminary data indicate that home visits from social workers, higher maternal IQ, a drug-free environment, and case intervention may also be protective factors.
There are some indications that cocaine exposure makes infants more sensitive to experience, both good and bad. An investigation of cocaine-exposed infants and a special therapeutic intervention showed that children with higher cocaine exposure who received the intervention performed better than did children with lower exposure. This paradoxical result led Dr. Frank to focus on identifying the environmental conditions under which different patterns of cocaine exposure produce measurable impairments, and the ages, endpoints, and populations in which these impairments occur.
Dr. Frank emphasized that while children exposed to cocaine may not show effects as a group, individual children may still be affected, and these effects may be seen in later life. In conclusion, Dr. Frank expressed her concern about the stigma associated with diagnoses related to prenatal drug exposure. Even though a diagnosis may assist with the purchase of services, the stigma remains. Dr. Frank stressed that clinicians should treat children, rather than the origins of their disorders.
Supported by grant 06532, National Institute on Drug Abuse, and grant M01 RR00533, National Institutes of Health, National Center for Research Resources.
Dr. O’Malley asked about the presence of cocaine withdrawal in newborns prenatally exposed to cocaine. Dr. Frank responded that her group had not found evidence of withdrawal or acute toxicity in newborns.
Dr. West asked whether newborns were screened for cocaethylene. Dr. Frank responded that her group did not screen for cocaethylene in the urine of newborns exposed to cocaine, but that this should be done. Cocaethylene is more potent and its effects last longer than cocaine alone.
Dr. Frank stated that the possibility that cocaine lowers the threshold for FAS warrants further investigation.
Dr. Astley supported Dr. Frank’s remark that access to services should be driven by the level of dysfunction rather than the etiologic event. Dr. Clarren stated that individuals in the FAS field must recognize brain damage and treat it. They must also acknowledge that many people with FAS have spent years consulting with doctors without obtaining a diagnosis. While the diagnosis of FAS is primarily based on psychological assessments, diagnosticians do not usually have these data, but those who collect neuropsychological data may not be available or may not be reimbursed by insurance companies for their services.
Dr. Adamson stressed that individuals in the field are trying to help children, not label them. However, treatment requires resources, and children must be identified as having a recognized disorder before costs will be reimbursed. Dr. Frank replied that this is a problem with billing, not with science. Dr. Coles agreed that insurance coverage is a policy issue, not a science issue, and suggested that mixing science and policy issues can be problematic.
Mrs. DeVries noted that labeling is not a problem from the parent’s perspective. Parents need a diagnosis to help them cope with their child’s condition.
Iron Deficiency and Infant Development
Betsy Lozoff, M.D.
Director, Center for Human Growth and Development
University of Michigan
Dr. Betsy Lozoff explained that because a subnormal iron level is a nutritional deficiency, it cannot cause brain "damage." However, iron deficiency does influence infant development and its physical and neurobehavioral effects may inform those in the FAS field.
Dr. Lozoff stated that iron deficiency is the most common nutrient disorder in the world. Anemia, which results from iron deficiency, is an especially pervasive problem for women and children. Poor dietary sources of iron and rapid growth make anemia a major concern in infant health. Iron deficiency results from:
- Impaired placental iron transport caused by multiple disorders
- Diabetes during pregnancy
- Prenatal alcohol exposure
- Intrauterine growth retardation
- Nutritional iron deficiency
- Maternal stress (as demonstrated by a study of primates)
Dr. Lozoff described the effects of early iron deficiency on the developing brain from research on an animal model. An iron deficiency can be corrected, but the effects of a previous deficiency are permanent because iron is essential to normal neurological development. Iron deficiency in the developing individual affects the following:
- Cognitive functions related to the hippocampus, such as recognition memory
- Myelination and slower nerve conduction
- The development of the dopamine neurotransmitter system
Studies of iron-deficient children have found poor neurocognitive outcomes and a distinct behavioral pattern. Iron-deficient children perform poorly on mental and motor tests. Corrective treatment with a full course of iron does not bring scores back to average level and at 4 to 8 years of age, many of these children continue to score at lower levels on mental and motor tests. Investigators have shown other detrimental effects of iron deficiency, including deficits in visual integration, quantitative concepts, gross and fine motor control, and performance IQ, but
Dr. Lozoff stressed that these results have not been replicated. Longitudinal studies of iron-deficient children have shown that by 12 years of age, the IQ scores of formerly iron-deficient children are not significantly different from average. However, these children still demonstrate problems with arithmetic, reading, motor abilities, selective recall, and spatial memory. Dr. Lozoff commented that deficits in spatial memory may be related to the effect of iron deficiency on hippocampal development.
Dr. Lozoff described iron-deficient infants as hesitant, tense, and easily tired. Activity analysis of 10-year-old children who were formerly iron-deficient infants reveals that their spontaneous activity level is lower than that of control children. Clinical descriptions indicate that formerly iron-deficient children tend to be more withdrawn and easily fatigued. Longitudinal studies of formerly iron-deficient 12-year-old children demonstrate that they exhibit more anxiety, depression, attention problems, and social problems, according to parents and teachers.
The concept of functional isolation may be useful to understanding this behavioral pattern. Iron deficiency may produce some change in affect or activity that leads the infant to seek or receive less stimulation from the physical or social environment. Over time, this pattern of functional isolation may affect the child’s behavioral and cognitive acquisition. Therefore, there is an indirect path from the brain to behavior through the stimulation that children receive.
Dr. West requested clarification on whether iron deficiency contributes to brain damage. If the treatment of anemia does not lead to recovery of function, this may indicate the presence of brain damage. Dr. Lozoff replied that nutritional deficiencies produce developmental delays and investigators are conducting longitudinal studies to determine whether neurocognitive performance levels eventually return to normal. Dr. West stressed that lack of recovery indicates brain damage, but Dr. Lozoff was reluctant to use the term "brain damage."
Dr. Coles added that "damage versus delay" is an issue in developmental disabilities.
Dr. Clarren commented that those in the FAS field focus on brain damage as a source of neurobehavioral deficits. However, their perspective on brain damage is out of context with the views of many neuroscientists.
Dr. Goodlett asked whether Dr. Lozoff would consider brain damage to include subtle brain changes related to nerve conduction measures. Dr. Lozoff replied that prenatal exposure to toxins is different because iron deficiency is, for the most part, a postnatal phenomenon. Therefore, iron deficiency leads to more subtle effects. She declined a discussion on brain damage due to iron deficiency until she had more opportunity to consider the issue.
Dr. Anderson asked whether hypoxia is an issue in iron deficiency since iron is important in oxygen transport. Dr. Lozoff replied that individuals with iron deficiencies severe enough to cause hypoxia were not included in her studies.
Dr. Weinberg noted that the functional alterations observed in iron deficiency are similar to endocrine functional alterations. Even when the peripheral deficits are corrected, functional alterations may persist. Dr. Lozoff agreed and commented that she had observed blunted prolactin responses in 12-year-old children in the longitudinal study.
Dr. Coles remarked that alternations in development have a cascade of effects, and not all of these may be repairable. Researchers must be careful to consider factors that have not been investigated or measured.
Review of Goals for Breakout Session and Charge to Participants
Overview of Breakout Session
Chair: James R. West, Ph.D.
Department of Human Anatomy and Medical Neurobiology
College of Medicine
Texas A&M University
Prior to the breakout session, Dr. James West briefly summarized the history of research in the FAS field, explained the charge of the sessions, and made suggestions to guide participant discussion.
During the 1970's and early 1980's, which Dr. West described as the "phenomenological stage" of the FAS field, researchers examined the systems and measures of interest to them. Animal researchers investigated whether alcohol was teratogenic or if the effects seen were due to polydrug use and malnutrition. By the mid-1980's, the field was mostly driven by animal research and the investigation of specific mechanisms. However, at this time human studies began to define symptoms more clearly and investigate more specific questions. In the 1990's, a larger cohort of children with FAS was available for study participation and researchers focused on noninvasive brain imaging. Dr. West suggested that with the current emphasis on brain imaging, human studies are driving animal research on the underlying mechanisms of alcohol teratogenesis. He expressed the hope that the current workshop could begin to address the urgent needs of children prenatally exposed to alcohol.
Dr. West read aloud the charge of the breakout session:
To match developmental tasks with age of onset and the methods of diagnosis. If known, to add the affected brain regions that result in altered function and whether the research was conducted in animal or human subjects.
Participants received a copy of the specific aims for the workshop and the Discriminating Neuro-Assessment Tools Chart to guide their discussion. Dr. West explained that participants should discuss the following:
- Relevant animal research
- The needs for research as indicated by "gaps" in understanding
- Current information relating chronological age to the effects of prenatal alcohol exposure
- Matching the method used to detect neurocognitive dysfunction to particular brain regions with altered function
Dr. West advised FAS researchers to avoid investigating easy or familiar areas and focus on the most appropriate questions in the field. Furthermore, researchers should investigate the possibility that several teratogens act through a common pathway, even though such investigations are complicated. Dr. West also stressed the importance of specifying the neuronal circuitry involved in learning, social behavior, and emotional responsiveness, and the practical problems faced by alcohol-exposed children and their families.
Group I Chair: Nancy Day, Ph.D.
University of Pittsburgh
Group I Rapporteur: Vivian Faden, Ph.D.
Group II Chair: Laurie Foudin, Ph.D.
Group II Rapporteur: Dr. Joseph Jacobson
Participants divided into two groups to focus on sharpening the diagnosis of prenatal alcohol effects by comparison with other teratogenic and neurodevelopmental disorders. Rapporteurs were to summarize the work of both breakout groups for all participants, while the larger group was to describe the primary characteristics of prenatal alcohol exposure. Experts on teratogenic exposures and neurodevelopmental disorders would then summarize the neurobehavioral characteristics of these conditions, because the identification of commonalities and differences is critical to understanding the effects of prenatal alcohol exposure.
To avoid redundancy, the major issues discussed by both groups are listed below. The report combines the comments of both groups under each topic discussed, and provides details on the discussion of one particular group only when relevant.
The Long-Term Goal for the Workshop
Dr. Calhoun called participants’ attention to Evidence Report/Technology Assessment Number 11: Treatment of Attention-Deficit/Hyperactivity Disorder (Agency for Healthcare Research and Quality, Publication Number 00-E005). This book provides a meta-analysis of research on the treatment of ADHD. A long-term goal for the fetal alcohol field could be to produce a similar document that summarizes the scientific knowledge on prenatal alcohol exposure.
Goals of the Breakout Session
Dr. Nancy Day noted that in previous sessions, participant discussion had not identified which of the three possible goals of the workshop their comments addressed, which could be confusing. She asked participants of Group I to clearly identify which of the following goals their comments addressed:
- Identification of core characteristics unique to prenatal alcohol exposure and definition of diagnostic criteria
- Identification of clinically relevant characteristics and opportunities for intervention and treatment development
- Identification of general research ideas, particularly research questions, areas of disagreement, and determining the field’s future direction
Group II discussed the following possible goals of the breakout session:
- To redefine ARND because the current definition is too diffuse for diagnostic purposes
- To identify and describe a specific set of features that are uniquely associated with prenatal alcohol exposure
- To determine the extent to which behavioral deficits seen in individuals prenatally exposed to alcohol overlap with those seen in individuals who have experienced other teratogenic insults
- To determine whether prenatal alcohol exposure produces subtypes of effects (behavioral phenotypes or sets of core deficits) and whether the subtypes should be defined behaviorally or in terms of brain functions
Dr. Jacobson reported that Group II discussed the purpose of the breakout session at length. The group did not reach a consensus about the delineation of neurobehavioral characteristics for ARND, and some felt that it may be premature to develop a diagnostic category for ARND.
Importance of Communication between Animal and Human Researchers
Bidirectional communication between clinical and animal research has yielded knowledge about prenatal alcohol exposure. Both types of research have increased their level of specificity and have shared information as they progressed. As researchers move toward differential diagnoses of FAS and ARND, the communication between animal and human researchers should increase. Animal models provide an opportunity to investigate possible intervention strategies, and the measurement tools used in these studies could be improved based on the clinical knowledge of primary behavioral deficits. Researchers should share the preliminary research on intervention in animals with those working with children prenatally exposed to alcohol.
Importance of Distinguishing Two Types of Children
Researchers must clearly distinguish children identified as having FAS due to prenatal exposure to alcohol from children identified as having FAS based on their behavioral and cognitive problems. The term "fetal alcohol effect" should be used to identify children with an FAS diagnosis due to prenatal alcohol exposure. When investigators describe neurobehavioral outcomes, they should identify the population studied.
Complexity and Levels of Profiling
It is possible to specify neuropsychological profiles by age. However, it is difficult to establish that the profile is specific to alcohol exposure alone. Neuropsychological profiling is critical and participants identified three levels on which it can be done:
- Neuropsychological test results
- Affected brain structures
- Behavioral symptoms (the method used in the Diagnostic and Statistical Manual for Mental Disorders [ DSM])
Suggestions from the Neuropsychology Perspective
Dr. Dennis noted that the different sources of information in the prenatal alcohol field are driven by different issues: Animal models are driven by structure-function hypotheses, parent observations by their everyday experiences, and neuropsychology by tradition. Multiple information sources and goals often characterize the state of the art when a behavioral phenotype is first characterized.
From the neuropsychology perspective, Dr. Dennis suggested that the prenatal alcohol field might benefit from the following actions:
- Link current neuropsychological measures of executive function more closely with parent observations
- Make measures of executive function more sensitive to behaviors reflecting social dysfunction:
- The Behavior Rating of Inattention and Executive Function (BRIEF) by Gerard A. Gioia is an example of a straightforward test that is sensitive to executive and social functions.
- The Test of Everyday Attention includes anterior and posterior attention tasks that are useful for diagnostic purposes, because anterior attention is impaired and posterior attention is preserved in individuals with FAS.
- Conduct human studies using the available tests of function for neural structures, such as the motor adaptation learning paradigm that tests cerebellar function
- Develop tests of function for more neural structures in conjunction with animal researchers
- Use currently available tools to describe the social cognitive dysfunction of individuals prenatally exposed to alcohol
Core Neurobehavioral Effects of Prenatal Alcohol Exposure in Infants
Participants identified the positive symptoms (characteristics that are present) and negative symptoms (characteristics that are absent) in those prenatally exposed to alcohol.
Dr. Joseph Jacobson reported that Group II participants described the range of effects produced by prenatal alcohol exposure on various systems in infants. Infants prenatally exposed to alcohol exhibit some developmental delays but generally, there is no evidence that these developmental delays predict long-term neurocognitive deficits.
- Abnormal brainstem auditory response (it is not clear whether this reflects hearing deficits or problems with brainstem functioning/processing)
- Difficulties maintaining balance (measured by a dynamic balance instrument)
- Weaker sucking (experimental research supports this, but it might not be seen clinically); sucking behavior involves multiple brain areas, and some affected infants have demonstrated feeding problems in later infancy
- Habituation to light and odor (robust but transient effects, reflecting a developmental delay)
Other sensory delays have not been studied in much detail.
Autonomic State Regulation
- Disruption of sleep–wake cycles (observed in maternal reports, clinical monitoring, and electroencephalograph monitoring)
- Sleep disruptions in adults with FAS also
- Difficulties on the Bayley Scales, although not after 18 months of age; older children may have motor function deficits, but tests may not be sensitive enough to detect these.
- Infants who have experienced heavy prenatal alcohol exposure may demonstrate motor deficits.
- Motor function can be measured by the Movement Assessment of Infants.
- Neonatal reflexes may exhibit reaction time delays.
- Humans prenatally exposed to alcohol demonstrate elevated cortisol levels in response to stress, but normal basal levels.
- Animal research has found elevated cortisol and thyroxin in response to alcohol exposure.
Attention and Learning
- Infants demonstrate slower reaction time in attention tests and slower processing speed compared to other children.
- Alcohol-exposed infants show poor ability to imitate on the Bayley Scales, which predict later verbal ability.
- Microcephaly (although infants with many types of neurological problems demonstrate this characteristic)
- Neurological deformations
- Specific dysfunction of the brainstem, cranial nerves, and cerebellum
- Failure to thrive, but for environmental and physical reasons
Infant Attachment to Caregivers and Temperament
- Researchers have not found any effects of prenatal alcohol exposure on infant attachment unless the infant experiences a break in caregiving.
- The research of Mary O’Connor has linked prenatal alcohol exposure to disorganized attachment, a risk factor for serious behavioral disorders in later life.
Cognition and Language
- Recognition memory deficits not observed
- Slower information processing
- Slower information processing in a novelty preference paradigm procedure
- Slower reaction time in an attention-orienting paradigm
Effects Categorized as Primary, Secondary, and Tertiary Processes
Dr. Vivian Faden reported that Group I participants separated the effects of prenatal alcohol exposure into one of three categories:
- Primary processes: biological changes within the organism, including alterations in the neural substrates
- Secondary processes: neuropsychological characteristics that reflect physical changes. These include altered behavioral and cognitive processes, some of which can be measured through neuropsychological assessment.
- Tertiary processes (global outcomes): the long-term effects of prenatal alcohol exposure on the life of the individual and those around them
The primary, secondary, and tertiary processes affected by prenatal alcohol exposure are described in Appendix B.
Linking Primary, Secondary, and Tertiary Processes
Dr. Stanton asked whether there is an empirical, analytic basis for connecting the three processes. Dr. Dietrich referred participants to the theoretical developmental models developed by Terrie Moffitt. Dr. Sandra Jacobson acknowledged that the field is not yet at the point where primary dysfunctions can be linked to secondary or tertiary outcomes. However, it might be useful to categorize the effects of prenatal alcohol exposure in this way. Dr. West recommended that participants describe primary and secondary effects according to their likelihood of occurring. Specifying the likelihood that an effect will occur might facilitate our understanding of the neurobehavioral variability observed as it relates to dose and timing differences.
Differential Diagnosis of FAS and ARND
To facilitate the differential diagnosis of disorders related to prenatal alcohol exposure, researchers should:
- Specifically document critical information, such as the timing and duration of neuropsychological measurements and the dose, timing, and pattern of prenatal alcohol exposure in humans.
- Develop tests that can be used in both animals and humans, because these will facilitate the identification of the specific structural and neurochemical alterations that result from prenatal exposure to alcohol.
- Identify factors that commonly covary with alcohol, define the specific role of the covariates, and determine how to control for them.
- Develop measures that can be used in differential diagnosis.
- Model data and identify what has been learned from the few models currently available.
- Identify the behavioral characteristics of prenatal alcohol exposure that might share neural substrates or neurotransmitters to inform the development of possible treatments.
- Specify neurobehavioral deficits in alcohol-exposed individuals and match these to neurological alterations and overall functioning.
Emphases for the Prenatal Alcohol Field
Dr. Faden described Group I’s recommendation that the prenatal alcohol field emphasize the following:
- Identifying commonalities and differences with other teratogens and other neurodevelopmental disorders is critical to understanding the effects of prenatal alcohol exposure.
- Those conducting research on FAS/ARND must address many measurement issues:
- Specifying the dose and timing of teratogenic exposure is particularly critical because these variables can be linked to the neural and physiological developmental course.
- Researchers should review global and specific neuropsychological measurements for appropriateness. Participants mentioned the BRIEF and Test of Everyday Attention as possibly appropriate assessment tools.
- More neuroimaging studies of alcohol-exposed individuals are needed.
- Animal and human studies must inform each another:
- Researchers must develop tests and paradigms that apply to both animals and humans.
- Research is needed to understand the causal pathways and mechanisms involved in FAS/ARND. Perhaps a more sophisticated analysis, such as structural equation modeling, is required:
- Research on the mechanisms involved in FAS/ARND should identify neural systems and capabilities that are not affected by prenatal alcohol exposure.
- Researchers should link the current knowledge base with implications for treatment.
Neurobehavioral Profiles and The Differentiation of Effects of Alcohol from Other Teratogenic Effects and Disorders: Presentations by Breakout Group Representatives
Chair: Dr. James West
Synthesis of Results: Brief Descriptions of Other Teratogenic Insults and Neurodevelopmental Disorders
Experts on several different teratogenic insults and neurodevelopmental disorders briefly summarized the neurobehavioral characteristics that distinguish these exposures and disorders. Dr. West commented on the importance of identifying the neurodevelopmental deficits, final common pathways, and abilities that are preserved in these conditions that are shared with alcohol exposure.
The Neurobehavioral Effects of Prenatal Exposure to Polychlorinated Biphenyls (PCBs)
Dr. Joseph Jacobson
Dr. Jacobson commented that developmental psychology has generally held that measures of infants do not predict well for childhood. However, this axiom may not be true for children exposed to teratogens, although the Bayley Scales predict well only for individuals with severe impairment.
Dr. Sandra Jacobson noted that her laboratory has found that specific aspects of the Bayley test are predictive of later performance on neuropsychological assessments.
Dr. Joseph Jacobson noted that researchers must consider the level and timing of exposure when identifying teratogenic effects and take into account that binge exposure might produce a different pattern of effects.
The findings Dr. Jacobson planned to discuss reflect studies on children with low-level, chronic prenatal exposure to PCB across the full period of pregnancy. He summarized the following effects of prenatal PCB exposure on neurocognitive development:
- Infants exposed to PCBs demonstrate visual recognition memory impairments on the Fagin test, which predicts later verbal IQ. It is striking that alcohol does not affect visual recognition memory.
- At the preschool and childhood stage, the most salient characteristics involve verbal IQ and verbal memory and learning deficits. Slower processing speed during this developmental period predicts lower performance IQ. Similarly, deficits in imitation play predict later verbal IQ. Imitation play is correlated with language ability, online motor planning, and, possibly, social planning.
Dr. Jacobson reported that the following abilities are not affected by prenatal exposure to PCB:
- Executive function (this is important because so many toxins affect this ability); PCBs seem to affect verbal memory, but not the organization and monitoring aspect of thought.
- Fine motor function; however, assessment of this function has not been exhaustive.
- In general, domain-specific tests do not reveal any damage of specific brain regions. However, mental rotation deficits indicate possible damage to the lower parietal cortical area.
Participants discussed whether recognition memory deficits reflect specific hippocampal damage or damage of the hippocampus and other memory systems.
The Neurobehavioral Effects of Prenatal Exposure to Methylmercury
Dr. Joseph Jacobson
Dr. Jacobson identified neurobehavioral deficits related to prenatal methylmercury exposure:
- Neuromotor function (suspected but not fully demonstrated)
- Verbal ability, specifically, vocabulary and verbal learning and memory (demonstrated by two studies)
- Performance IQ (demonstrated by two studies)
- Visual recognition memory (one animal study)
Dr. Jacobson reported that all of the neurocognitive domains studied to date show some effects of methylmercury. There is a paucity of data on the brain regions affected by prenatal methylmercury exposure.
The Neurobehavioral Effects of Lead Exposure
Dr. Kim Dietrich
Dr. Dietrich remarked that researchers have conducted many studies on postnatal lead exposure, but have not reached a consensus on the effects of lead exposure, in part because the effects of lead are multifocal. Lead exposure produces multiple effects on the fundamental developmental mechanisms of the central nervous system. Lead has pervasive effects on the body because it substitutes for calcium and has a stronger and longer lasting effect.
Animal studies demonstrate the fundamental effects of lead on the structure of the central nervous system. Specifically, exposure results in concentrations of lead in the cerebellum and hippocampus. Lead exposure also affects neurotransmitter metabolism and action, specifically, of catecholamines. Lead exposure disrupts the trophic factors that guide the development of the central nervous system, as lead exposure produces the promotion of disorderly apoptosis, programmed cell death, delayed conversion of neuronal cell adhesion molecule (NCAM) from the embryonic to the adult form, mistimed neuroglial development, and disruption of synaptic connections. Ultimately, the disruption of these fundamental processes affects the architecture of the brain. For example, the capillary integrity of the brain is compromised with high exposure levels. But at low exposure levels, animal models demonstrate altered synaptogenesis, myelination, and catecholamine metabolism. Picomolar concentrations of lead in the brain activate phosphokinase C, which increases neuronal responsivity and might alter higher-order cerebral architecture.
Dr. Dietrich stressed the following points about lead exposure research: (1) generalizing these findings to humans is uncertain, and (2) researchers have identified no single mechanism capable of integrating the effects of lead to associate brain structure abnormalities with functional outcomes.
Dr. Dietrich described the following effects of postnatal lead exposure on humans:
- Visual motor deficits
- Neuromotor deficits, especially in fine motor performance and difficulty with postural stability (the parameters of postural stability for children exposed to high levels of lead and those with FAS are similar)
- Visual spatial deficits
- Disruption of attention and executive function, which may result in reading and decoding deficits
- Antisocial behavior
- Slower performance on simple, distracted, and delayed reaction time tests
- Very small effects on growth and stature
- Slight suppression of immune system functioning, which might make children more prone to infection
- Global intellectual deficits and delays: specifically, performance IQ
Dr. Dietrich emphasized that intellectual deficits may be related to an interaction of many biopsychosocial factors. Lead exposure is usually confounded with lower socioeconomic status (SES), making it difficult to determine whether the lead or the psychosocial factors are responsible for the IQ deficits observed in many studies. Similarly, such characteristics as slow reaction time may influence performance on neuropsychological tests. The extent to which a researcher should control for SES covariates is a constant debate in the lead exposure field.
The neuropsychological batteries administered to individuals exposed to lead indicate widespread neurodevelopmental effects, but the overall pattern might reflect damage to the prefrontal and right cerebral areas. Currently, very few brain imaging studies have examined the neurological structure of lead-exposed individuals.
Dr. Dietrich briefly described the effects of prenatal lead exposure, which appear to be transient. Some studies have found lower birth weight and decreased gestational maturity in children prenatally exposed to lead, according to the Ballard of Dubowitz measures. Researchers have observed developmental delays in these individuals at up to 24 months of age, according to the Mental Development Index (MDI) and Psychomotor Development Index (PDI). Prenatal lead exposure affects some selected long-term outcomes, such as mild hearing loss and altered central auditory processing. However, prospective studies do not, when taken together, demonstrate long-term effects.
A participant asked if the lead exposure studies controlled for alcohol use during pregnancy. Dr. Dietrich responded that all of the prospective studies controlled for alcohol, but these studies could have documented alcohol exposure more specifically. Tobacco use is a confounding variable associated with outcome and exposure in Dr. Dietrich’s studies.
The Neurobehavioral Effects of Iron Deficiency
Dr. Betsy Lozoff
Dr. Lozoff emphasized that many different enzymes are iron dependent, and some of these affect central nervous system development. The degree of iron deficiency also affects the observed outcome. Iron deficiency is usually confounded with low SES and psychosocial factors, such as mother’s education level and IQ and the duration of breast feeding.
Dr. Lozoff summarized the following effects of iron deficiency:
- Animal studies indicate that severe iron deficiency definitely impairs growth, but minimal deficiency does not. Human studies of iron deficiency and growth impairments are equivocal.
- Iron deficiency affects basic immune system mechanisms, but whether it affects functional outcomes is not clear.
- Studies demonstrating the effects of iron deficiency on cognitive functions have not been replicated.
- Very few studies have investigated the effect of iron deficiency on sensory systems.
- Researchers have observed effects on visual spatial and visual motor function, but these diminish when covariates are excluded.
- Iron-deficient children have difficulty with arithmetic, according to one study.
- Iron-deficient adolescents have trouble with writing and reading; however, these effects are eliminated when social factors are taken into account.
- Some studies have observed gross and fine motor differences. These effects are pronounced in some studies, but absent in others.
- Iron-deficient infants tend to display a wary and unhappy affect. A longitudinal study has demonstrated that anxiety and depression may occur in previously iron-deficient individuals during the adolescent years. These effects have been replicated in four studies.
- Animal studies show that iron deficiency affects prolactin indirectly through dopaminergic mediation.
Current research indicates that iron deficiency does not produce any gross structural brain abnormalities. However, a few studies have shown hippocampal and striatal alterations. Recent studies indicate that neurotransmitter function, particularly the dopaminergic system, is disrupted by iron deficiency, which also disturbs normal myelination. Dr. Lozoff recommended that future research examine the effect of iron deficiency on the cerebellum. Neuroimaging studies might be useful, but there are still technical barriers to iron neuroimaging in humans.
The Neurobehavioral Effects of Prenatal Cocaine Exposure
Dr. Marylou Behnke
Dr. Deborah Frank
Dr. Behnke remarked that the study of prenatal cocaine exposure is not as well developed as some of the other fields represented at the workshop. The identification of the brain regions influenced by prenatal cocaine exposure is still speculative. Animal studies generally indicate that prenatal cocaine exposure influences the brain regions affected by the monoaminergic neurotransmitter system. Researchers hypothesize that the striatum, basal ganglia, and prefrontal areas might be affected, but currently no neuroimaging work or autopsy studies support these hypotheses. Indirect effects of prenatal cocaine exposure might also occur through hypoxia, but few neuroanatomical studies confirm this hypothesis.
Dr. Riley commented that many animal studies have shown very little brain damage after prenatal exposure to high doses of cocaine, but it is difficult for these studies to be published and recognized. Dr. West added that many cocaine users also use alcohol, and it is difficult to separate the neurobehavioral effects when there is polydrug use. Dr. Behnke remarked that her laboratory has found that the effects of prenatal cocaine exposure are diminished or eliminated when other drug exposures are taken into account.
Dr. Behnke reported that some studies consistently demonstrate growth restriction in infants who were prenatally exposed to cocaine. However, this effect is eliminated if other drug exposures are accounted for. Many of the growth parameters observed in Dr. Behnke’s studies have been correlated with prenatal alcohol exposure. Rats injected with cocaine during the early postnatal period demonstrate growth restriction; however, this effect is eliminated if the researcher ensures adequate nutrition for the rats.
Dr. Frank remarked that children prenatally exposed to cocaine initially demonstrate growth restriction, but eventually catch up to typically developing children. She noted that children exposed to alcohol prenatally do not make up for their earlier growth restriction to the same extent as cocaine-exposed children.
Dr. Frank added that cocaine constricts placental blood vessels, thus limiting nutrient and oxygen transport. Here, cocaine’s effects are similar to those of cigarettes.
Dr. Sokol commented that alcohol, smoking, and cocaine use during pregnancy are all associated with premature birth and restricted growth. These effects are additive, so that an individual exposed to all three substances has a much higher risk of growth restriction. Dr. Behnke noted that studies in her laboratory have found that the use of cocaine and other drugs during pregnancy results in a smaller head circumference.
Dr. Frank reported that several studies have demonstrated that prenatal care affects the outcomes of prenatal cocaine exposure. The infants of women who receive prenatal care have better outcomes than do those infants of women who do not receive prenatal care. This effect occurs even if the women do continue to use cocaine. Dr. Day stressed the importance of prenatal care and noted that the lack of prenatal care accounts for many of the outcomes observed in the cocaine studies. The effects of prenatal cocaine exposure are attenuated if researchers control for all of the factors associated with lack of prenatal care.
Dr. Sandra Jacobson noted that prenatal cocaine exposure does not produce the dysmorphology observed in alcohol-exposed individuals.
Dr. Frank pointed out that cocaine and nicotine appear to accelerate endogenous stress neurotransmitters in certain areas, while alcohol seems to impede brain development. Visual responsiveness is more rapid in cocaine-exposed children, who may mature more quickly, which may lead to better survival in some premature infants. Dr. Frank agreed with a participant that faster is not better here, and uneven development might be problematic. Although researchers had expected that children prenatally exposed to cocaine would be very hyperactive, they found that these children’s emotional responses tended to be dampened. Dr. Lozoff remarked that the under-responsiveness of both iron-deficient and cocaine-exposed individuals may be related to alterations in the dopaminergic system. Perhaps these individuals experience ordinary stimuli as less inherently rewarding, resulting in a dampening of their interaction with the social and physical environment. Dr. Frank remarked that the field is in its early stages, but studies have shown that children prenatally exposed to cocaine are less expressive than other children.
Dr. Coles listed the following effects of prenatal cocaine exposure:
- Infants and young children demonstrate some motor effects.
- Researchers have observed increased irritability at birth, and at ages 8 weeks, 2 years, and 6 years. Older children have shown increased aggression.
- Investigators have observed restricted growth at birth, but this effect is diminished by 8 weeks.
- Prenatal cocaine exposure does not result in dysmorphology.
- Researchers have found differences in social attention at 8 weeks and 2 years.
Dr. Coles noted that her studies have found a very large interaction between cocaine exposure and caregiving.
Dr. Sokol and colleagues have demonstrated the following effects of prenatal cocaine exposure:
- Language effects
- Externalizing behaviors through midchildhood
Dr. Frank noted that researchers have studied school-aged children who were prenatally exposed to cocaine, but their results are not yet ready for publication.
The Neurodevelopmental Effects of Spina Bifida and Hydrocephalus
Dr. Maureen Dennis
Brain imaging of individuals with spina bifida and hydrocephalus reveals the following brain dysmorphologies:
- Reduced volume of the cerebellar hemispheres and a small posterior fossa
- Significant displacement of the vermis, which produces breaking of the tectum in about 70 percent of patients
- Two abnormalities of the corpus callosum: (1) primary agenesis, especially in the splenium, in about 65 percent of patients; and (2) secondary hypoplasia
- Front/back asymmetry in cortical volume (the posterior is thinner than the anterior cortex)
Dr. Dennis explained that research to specify the volume loss is ongoing. Research must carry out three-dimensional warping and should further characterize the brain abnormalities related to spina bifida and hydrocephalus. Three-dimensional warping techniques will distinguish brains that are smaller in volume but correctly proportioned from brains that are structurally abnormal.
Since hydrocephalus and spina bifida occur together, it is difficult to distinguish their unique effects, although hypoplasia is probably related to hydrocephalus. Similarly, researchers have not yet fully distinguished the effects due to altered neurogenesis from those of mechanical origin. However, neurogenic effects result in absent structures. An examination of the corpus callosum should illuminate this issue.
Dr. Dennis summarized the following neurocognitive characteristics observed in individuals with spina bifida and hydrocephalus. These individuals tend to:
- Recall mathematical facts, but have difficulties with the procedural aspects of mathematics. Many studies demonstrate that children with hydrocephalus do poorly in mathematics.
- Experience difficulty with procedural learning in several domains.
- Have a word level understanding similar to that of other children but their text level understanding is deficient and their oral and reading comprehension is poor.
- Have appropriate referential language but deficits in inferential language.
- Have deficient inferential processes across multiple domains (space, developing mental models, and language).
- Have adequate visual perception and object recognition.
- Exhibit problems with eye-hand coordination and spatial orientation.
- Have fluent and verbose spoken language (use more words to deliver content).
- Display subtle ataxic dysarthria, including phonation problems, intact resonance, and other articulatory issues.
- Demonstrate problems with bimanual coordination, which reflect corpus callosum dysmorphology.
- In social interactions, tend to use stereotic comments (a canned social repertoire); are often socially inappropriate; and are not proficient with online social interactions (understanding how to approach someone in a new situation).
Dr. Streissguth commented that she has observed similar social interactions in individuals with FAS, especially those raised in an enriched environment. Dr. Clarren remarked that the social pattern of children with FAS is broader and more subtle than that of children with spina bifida. Neurobehavioral descriptors among the various disorders occur along a continuum.
Dr. Sandra Jacobson asked Dr. Dennis to compare the social repertoire of children with spina bifida and Williams Syndrome. Dr. Dennis responded that she and some colleagues are investigating this issue.
Future research in this area must determine how the amount of brain damage is related to the extent of cognitive deficits.
Dr. Dennis remarked that the expression of neurocognitive deficits varies. Identified variables that tend to increase the degree of neurocognitive problems in individuals with spina bifida and hydrocephalus include:
- A high spinal lesion
- Shunt infections
- Number of shunt revisions (lifetime number of shunt revisions predicts adulthood cognitive problems)
- Seizure (other than a neonatal seizure)
Other medical history factors probably affect neurocognitive outcome, but have not been documented in the literature.
Dr. Clarren encouraged participants to consider the postnatal comorbid conditions experienced by children prenatally exposed to alcohol. The postnatal conditions are remediable and it is worthwhile to investigate the factors (early interventions) that improve outcomes for these children. Dr. Clarren asked Dr. Dennis about early intervention for children with spina bifida and hydrocephalus. Dr. Dennis knew of case studies, but no group studies, that described interventions. Dr. Dennis and colleagues are identifying children with spina bifida and hydrocephalus at birth and following them prospectively.
The Neurodevelopmental Effects of Autism
Dr. Loisa Bennetto
Dr. Bennetto described the neurocognitive deficits of individuals with autism:
- Executive function (prefrontal cortex)
- Consistent evidence of poor cognitive flexibility (possibly dorsal lateral cortex)
- Equivocal evidence of working memory deficits (dorsal lateral cortex)
- Poor strategy and planning ability
- Adequate performance on simple inhibition tasks
- Difficulty with reversal tasks, which might be related to orbital frontal cortex
- Excessive focus on small details so that the global picture is lost
- Language deficits, especially functional language skills:
- Grammatical aspects (little research)
- Motor skills:
- Fine and gross motor skills
- Difficulty with imitation (not due to problems with social relatedness or encoding visual spatial information)
- Planned motor movements (frontal lobes), especially kinesthetic information (parietal lobes)
- Balance and gait abnormalities similar to those of individuals with frontal lobe damage (cerebellum)
- Sensory deficits (preliminary evidence)
- Social skill deficits, which may be due to underlying deficits in social relatedness:
- Difficulty understanding irony and idioms; possibly because these individuals tend to interpret the concrete meaning of language or have difficulty integrating what is said with the context of the conversation in working memory
- One neuroimaging study suggests that the orbital frontal cortex might integrate social and emotional information.
Individuals with autism often demonstrate a scattering of abilities in their neurocognitive profiles. The test scores of some autistic individuals are quite high, while their scores on other tests are very low. Other neurodevelopmental disorders also show a scattering of abilities.
The following neurocognitive abilities are generally preserved in individuals with autism:
- Rote memory
- Recognition memory
- Semantic information encoding (but individuals with autism have difficulty using semantic information to help organize memory)
- Reading and decoding is adequate in higher functioning individuals with autism. Often, these individuals are hyperlexic (they read better than their IQ scores predict).
- Spatial skills are relatively strong in individuals with autism, which distinguishes them from individuals prenatally exposed to alcohol and those with Asberger’s Syndrome. Often, individuals with autism are superior at block design.
Dr. Bennetto listed brain function characteristics associated with autism:
- Lower metabolism in the frontal lobes
- Abnormal frontal lobe functioning (neuroimaging studies, inconsistent evidence)
- Abnormalities in the hippocampus (histological studies)
- Monkeys with lesions of the amygdala and limbic system demonstrate some "autistic-like" characteristics.
Final Discussion of Differential Diagnosis of FAS and ARND
Participants discussed key issues in the differential diagnosis of FAS and ARND, identified primary neurobehavioral deficits unique to FAS, and proposed areas of future research.
Dr. West noted that since its inception, the fetal alcohol research field has been criticized for not being "hypothesis driven." The outcome of prenatal alcohol exposure varies due to timing, dose, and pattern of alcohol exposure; genetic factors; polydrug use; socioeconomic factors; and other characteristics. Hypothesis-driven research may clarify discrepancies in the literature.
The Core Deficit Construct
In Dr. Clarren’s view, developing a list of core deficits is counterproductive. Such a list might encourage researchers to examine only the core deficits, leading them to miss other important features of exposure. Dr. Day added that it is difficult to identify core deficits because abilities vary depending on cofactors, exposure, and individual differences. Dr. Frank noted that investigators must consider the experimental system in which they are conducting research. For example, investigators who study populations in the lower socioeconomic strata may not observe deficits due to the basement effect, while investigators who work with a broader social class range might observe these effects. Population differences might explain some of the inconsistent results in the fetal alcohol literature.
Dr. Astley remarked that the usefulness of identifying core deficits depends on the ultimate purpose. Identifying core deficits may be useful for targeting and connecting laboratory research projects but is probably not as useful for clinical and diagnostic purposes. Dr. Sandra Jacobson suggested that investigators use core deficits as a model for directing research. They could use other levels of analysis, such as modal profiles, for diagnosis and clinical work. Dr. Sokol commented that diagnosis and research are seldom exclusive purposes. Diagnostic definitions change, but it is still useful to summarize the findings about prenatal alcohol exposure.
Dr. Weinberg added that a neurobehavioral profile sets the parameters, which are needed to formulate research questions. These questions are needed to find the mechanisms underlying the effects, and the mechanisms might lead to the development of interventions.
A Classification System for Prenatal Alcohol Exposure
Dr. Clarren suggested selecting a menu of characteristics from different categories to define prenatal alcohol exposure. Researchers need to develop a battery of tests that correspond to a menu of dysfunctions, which will vary by individual but themes will probably emerge. Dr. Coles remarked that the test battery in this area should not be too restrictive because the field is not sufficiently advanced for this.
Dr. Coles suggested that researchers and clinicians in the FAS field follow the model used by the World Health Organization (WHO) with respect to disability. In its development of the International Classification of Diseases 10, WHO traces a functional disability from its etiology through multiple stages to a tertiary outcome. This model is used for other disabilities and would be appropriate for prenatal alcohol exposure. Dr. Schacht added that functional and etiological terminologies together predict outcomes better than either does separately. The WHO system allows environmental factors, such as nutrition and the influence of caregivers, to be taken into account.
Dr. Clarren described organic brain syndrome, a term that had been used previously to describe a condition of brain dysfunction that is not captured by IQ score and makes individuals very disabled. The scores on adaptive scales of many individuals prenatally exposed to alcohol, drugs, and other teratogens are much lower than their IQ scores. These individuals often do not receive the social services they need because their brain damage is not recognized by diagnostic manuals. Dr. Clarren speculated that the DSM system
would lend itself to a global statement of organic brain damage with subcategories, patterns of specific dysfunction and patterns of causation... [and] ...that kind of addition to the DSM system would be absolutely phenomenally important.
Dr. Clarren noted that a large number of disabled individuals do not qualify for the services of, or go unrecognized by, the social service system because the identification of disability and identification of the need for social services are not coordinated. In addition, the summation of many concurrent, subtle problems can produce a disability that is frequently unrecognized.
Dr. Streissguth remarked that over 90 percent of the 400 individuals with FAS studied by her research team had sought the help of mental health practitioners. Unfortunately, many of the practitioners were not aware of FAS or ARND. Therefore, the field must address the need to educate mental health providers about FAS/ARND. Dr. Sandra Jacobson pointed out that clinicians need to distinguish between those who have behavioral problems due to alcohol exposure and those whose behavioral problems are related to other causes. This has been a problem with other disorders, such as ADHD, but may be a particular concern with fetal alcohol exposure since many children who present with behavioral problems are adopted and their parents may not know the extent of their alcohol exposure. Dr. O’Malley added that prenatal exposure to alcohol results in a chronic neuropsychiatric condition that affects the individual throughout the lifespan. Participants recognized that the process of differential diagnosis of FAS/ARND must continue beyond the workshop.
Primary Deficits of FAS
Participants identified the following as the primary neurobehavioral deficits of FAS:
- Executive function:
- Visual working memory (even after controlling for IQ)
- Verbal working memory
- Mental flexibility and shifting, although this ability is less affected in individuals with FAS than those with ADHD.
- Verbal fluency (although this deficit may diminish if IQ is controlled for):
- Category fluency (generating words from a semantic category) is preserved.
- Letter fluency is selectively impaired.
- Attention (the literature is inconsistent):
- Sustained attention (deficits in sustained attention are different in individuals with FAS from those of individuals with ADHD).
- Impulsivity and activity level
- Tests to measure attention:
- Seashore Rhythm Test (for younger children)
- Stroop task
- Taloned letter cancellation test (test of motor attention)
- Visual CPT
- Auditory CPT
- Physical growth deficits
- Morphological abnormalities (especially craniofacial dysmorphology, which is the hallmark of FAS; these are due to the timing and dose of alcohol exposure, and occur during a brief window in the first trimester)
- Disruption of fetal brain development can occur at almost any stage. The effects may vary according to timing, dose, and pattern of alcohol exposure.
- Poor arithmetic ability (although this is a global ability and is comprised of component skills)
- Working memory deficits, but no simple encoding deficits
- The Stepping Stone Maze, a spatial problem-solving task, can be used as a spatial memory test
- Researchers have studied language deficits, but have not demonstrated such deficits in individuals prenatally exposed to alcohol.
- Fine motor deficits (across the lifespan):
- Hand steadiness
- Neurological coordination
- Gross motor deficits
- Balance problems (at ages 4 and 21 years)
- Lower IQ:
- Some researchers have demonstrated lower IQ (global, verbal, performance) in individuals with FAS. Some studies have demonstrated that individuals prenatally exposed to alcohol have a significantly lower (12–15 point difference) verbal IQ than performance IQ, but these findings are inconsistent. Dr. Joseph Jacobson noted that individuals prenatally exposed to alcohol might have "a verbal IQ attention discrepancy, but not a verbal performance discrepancy."
- Individuals with moderate-to-heavy prenatal alcohol exposure may not show reduced IQ scores. Therefore, reduced IQ may not be a core deficit of prenatal alcohol exposure.
Dr. Mattson remarked that the discrepancy between verbal and performance IQ in individuals prenatally exposed to alcohol is very inconsistent. The discrepancy could be due to individual variability.
Dr. Streissguth noted that other standardized measures used in individuals with FAS demonstrate large individual variation that is not accounted for by IQ.
Participants agreed that specific cognitive deficits not highly correlated with IQ are especially critical for profiling the neurobehavioral characteristics of prenatal alcohol exposure.
Dr. Clarren noted that while there may be core deficits, children prenatally exposed to alcohol vary tremendously. He remarked that "they are not linked by a specific pattern. They are linked by the complexity of their individual disability."
Differences between Children Diagnosed with FAS and ARND
Children diagnosed with FAS and ARND demonstrate differences in craniofacial dysmorphology. Dr. Clarren commented that the facial dysmorphology could be superficially linked to a corpus callosum anomaly. This might explain why facial dysmorphology is linked to a pattern of brain damage. The face may be a marker for brain damage, but brain damage can certainly occur over a longer exposure. Dr. Sandra Jacobson noted that researchers need to be specific about how they determine whether an individual has dysmorphic features.
Areas for Future Research
Participants identified studies of the following as future research priorities:
- The relationship of the corpus callosum to neurocognitive deficits and underlying information processing
- Differentiation and comparison of individuals prenatally exposed to alcohol, individuals with neurodevelopmental disorders, and individuals prenatally exposed to other teratogens
- Functional imaging studies of individuals prenatally exposed to alcohol, especially adults; use of this technology to connect brain structure and function
- Socioemotional outcomes in individuals prenatally exposed to alcohol:
- Empathy and the ability to take the perspective of another, using measures from the autism field
- The physiological responses to emotionally arousing stimuli (social cognition)
- The relationship of structural alterations in the amygdala to difficulties in making emotional inferences
- The moral development of individuals prenatally exposed to alcohol, especially the inability to understand cause and effect
- Emotional volatility
- Determining whether cognitive problems in early childhood are associated with socioemotional difficulties in adolescence
- Disruption of sleep-wake cycles in individuals prenatally exposed to alcohol
- The relationship of infant temperament and attachment styles and later behavioral outcomes in alcohol-exposed individuals
- The effects of a new teratogenic exposure, toluene. Sniffing toluene, a solvent, has become popular and produces effects similar to those seen in individuals prenatally exposed to alcohol. Some have called these effects "fetal solvent syndrome" and researchers will need to differentiate the effects of prenatal alcohol from those of prenatal toluene exposure.
- Whether polydrug use during pregnancy and multiple exposures have summative or synergistic effects
- The degree to which FAS subgroup phenotypes of cognitive behavioral profiles (subtypes) might exist within the set of all alcohol-exposed individuals, profiles that might help target laboratory research and assist in the design of intervention studies
- Clear communication that subtypes may not be specific to alcohol
- Relating the size of the corpus callosum to subtype differentiation
- Differentiating deficits that result directly from brain damage (core or primary deficits) from effects that result from environmental influences
- Comparing children of alcoholics who have been prenatally exposed to alcohol with those who have not
- Developing the knowledge base regarding the experiential component of developmental psychopathology
- Developing the knowledge base regarding the effects of postnatal experience on brain development
- Comparisons of individuals prenatally exposed to alcohol to those prenatally exposed to cocaine (although essentially the same populations, they experience very different neurobehavioral outcomes)
- Comparing conduct disorders in children prenatally exposed to alcohol with conduct disorders in children not prenatally exposed to alcohol
- Development of possible interventions, including drugs, to counteract the effects of alcohol in pregnant women and to affect the injured neurotransmitter systems of individuals prenatally exposed to alcohol. The intervention should be based on a multimodal, individualized assessment and the treatments must be multimodal.
- Developing performance-enhancing behavioral therapies for individuals prenatally exposed to alcohol and focusing remediation efforts on disabilities that affect quality of life and everyday functioning
Dr. Kenneth Warren thanked Dr. West for serving as chair for the final session and all participants for their contributions to the workshop. He recognized the workshop organizers,
Drs. Sandra and Joseph Jacobson and Dr. Megan Adamson. He commented that the workshop, especially the final session, provided future direction for the field.
Dr. Sandra Jacobson thanked all participants and expressed her appreciation to those working in areas outside alcohol research. The comparative approach adopted for the workshop was very timely and worthwhile.
The meeting for The Early Childhood Neurobehavioral Assessment for the Differential Diagnosis of Fetal Alcohol Syndrome and Alcohol-Related Neurodevelopmental Disorder held on March 8–9, 2000, was charged with developing a neurobehavioral profile for ARND. A basic goal was to come up with a core and maybe secondary features, but also to be able to rank them. That is, if one holds constant as many variables as possible, are there certain deficits that are present most of the time? Can they be ranked in terms of prevalence? Several important points (some of which were surprising) came out of the meeting: (1) There was no consensus as to defining a neurobehavioral profile for ARND. Furthermore, there is a primary reason for this. Several clinicians had different agendas and perspectives. (2) In an important way, significant progress in human FAS research has reached an impasse. This opinion may be surprising to many researchers in the field, because there are an increasing number of studies being published in the area. We already know what has traditionally been the hard part in teratology research; we know that alcohol is causing FAS and ARND, but that does not solve the problem. However, in spite of the apparent progress, the majority of the human studies to date have been descriptive. A large number of patients of varying ages with fetal alcohol damage have been identified. This has not resolved the problem because no affective treatment regimens have been established, nor has there been a significant decrease in the incidence of FAS and ARND. Before additional progress can be made, clinical research must progress to a different level. In order to make the transition, it is essential to do a much better job at defining research and clinical objectives and generate experiments that are hypothesis driven. This is especially true for human research related to ARND and for developing appropriate intervention strategies.
Several fundamental issues have limited the progress of both human and animal research to date. First, surprisingly, not very much was known about either the development of cognitive function in humans or the development of complex learning in animals. Second, both human and animal researchers had difficulty in differentiating long-lasting deficits from cases of developmental delay. This occurred because of two factors. In humans, development continues over many years and it is difficult and time-consuming to follow the same cohort over a broad time period. In animals the problem is a practical one. It is expensive maintaining animals for many months and many researchers felt pressure to publish findings when they were found in developing animals rather than hold the animals for later studies and risk having any deficits resolved with maturity. Unfortunately, tasks that challenged very young subjects were usually trivial to more mature subjects. This is true in both humans and animals. Therefore, a problem of developmental delay might pose a serious risk, since subsequent, or downstream, developmental events often depend on the timing of a previous, or upstream, maturation process. A delay early on could prevent other key developmental events from occurring later. This, however, is difficult to demonstrate and prove. Third, while there has been substantial agreement between animal and human studies, until recently there were really no tasks that had been identified that could be studied in both humans and animals. Fortunately, today there is a realization that such tasks are extremely important to identify. One of these, the conditioned eyeblink, which was discussed in detail at the meeting, can be used in both animals and humans and, importantly, can be evaluated over the life span of the subject.
Several other model systems such as autism, spina bifida, lead exposure, PCBs, and cocaine were examined with the hope of generating fresh approaches to fetal alcohol research. It is important to realize that examining other systems can prove helpful, but there are also several disadvantages. Most of the other model systems of neuroteratology are much less advanced than the fetal alcohol field in recognizing and trying to incorporate crucial variables such as the dose and timing of the exposure. With that caveat, it is with the creative use of neuropsychological testing that some of the other fields might be the most helpful.
Brain Damage Assessments in Humans
Much of what we know about brain damage associated with fetal alcohol exposure we have learned from animal studies. Since FAS is not generally fatal, few cases have come to autopsy. Recently, however, powerful noninvasive techniques, including MRI, fMRI, PET, and ERPs, are being utilized to determine which brain regions and processes appear to be particularly vulnerable or modified by fetal alcohol exposure. Currently, we can only approximate the brain problems. The neuroimaging can give us only gross answers. Animal studies can tell more about what is associated with specific exposure. Taken together, these methods can reveal more about structure/function relationships and fetal alcohol-induced brain damage.
We know that alcohol can disrupt brain development at practically any stage of fetal development and that the effects can vary. In this regard, in addition to looking to research on other developmental disorders, perhaps we can also learn from our colleagues involved in assessing the brain damage that chronic alcohol exposure produces in adults.
Neurobehavioral Profile of ARND
The goal of establishing a well-defined neurobehavioral profile of ARND is a good one. Just as in every other area of medicine and psychology, it is a distinct advantage to be able to identify and treat a patient based on a set of criteria. For example, in the case of autism, having a neurobehavioral profile has been extremely useful in establishing a very stable diagnosis.
A number of good questions were raised related to establishing a neurobehavioral profile for ARND. For any particular deficit, when did the exposure occur and how did the timing impact on the deficits seen later? To what extent is the pattern of neurobehavioral deficits associated with the exposure sufficiently specific to aid in a diagnosis when an affected child presents with certain deficits? Given the number of variables or risk factors, including dose, timing of exposure, polydrug use, individual differences (genetics), and the postnatal environment, neurobehavioral subtypes are likely quite variable.
Any attempt at establishing a neurobehavioral profile for ARND must take into consideration at least six stages of life, including infancy, preschool, childhood, adolescence, adulthood, and old age. One of the most important points made repeatedly at the workshop was that identified deficits change with age.
Part of the meeting was directed toward trying to compare ARND with the effects of other substances, exposures, and disorders. It is important to look at things that are shared across different teratogens because there is some indication that there are a few common pathways. However, we cannot just look at their respective behavioral repertoires and subtract the things that they have in common with kids exposed to other teratogens and say that what is different is due to alcohol. We know there is a broad spectrum of effects at different ages. Can we at least examine the comparisons in terms of statistical distributions? When we control for known confounds and age of testing, what do these kids have in common? Are there similarities in deficits produced by alcohol and other teratogens during development? Obviously there are differences or FAS would not have been identified. Are certain parts of the brain especially vulnerable to lots of agents? Toluene produces similar effects as FAS, even down to the facial dysmorphology. The answers to these questions are key to establishing a neurobehavioral profile for ARND.
A goal should be to identify some of the most salient features of ARND that might distinguish it from other disorders. Also, it will be important to ask how FAS looks different from the moderately alcohol-exposed child.
To date, we do not have a neurobehavioral profile for ARND. Furthermore, the workshop was not able to produce one, so it is reasonable to ask whether it is feasible to try to develop one. It does seem clear from the discussion there cannot be a single neurobehavioral profile, not only for the reasons of variability, but also because different problems will emerge at different stages of development. Testing at 5 or 7 years may give us little information about whether something might show up at puberty. Anticipatory neurobehavioral profiles of child development after fetal exposure to alcohol of various doses and timing of doses are what are needed.
Purposely not setting limits to the definition of the FAS or ARND diagnoses might help to prevent the exclusion of some children from receiving social services, but it certainly will make it more difficult to establish neurobehavioral profiles and perhaps, most importantly, effective treatment strategies for alcohol-exposed children. Not specifically defining these diagnoses may help some children who might have slipped through the cracks, but it will not help less experienced clinicians to recognize ARND, nor will it help basic science research find effective therapeutic intervention.
There is a reluctance by some clinical researchers and care providers to define ARND, and a preference to describe ARND as broadly as possible without specific boundaries, for fear that patients who need help from social services would be denied because they do not fit a specific set of criteria.
Two problems contributed to the lack of success at establishing a neurobehavioral profile of ARND. First, there was some confusion over what was the goal of the workshop. Second, there was a lack of consensus over whether it was appropriate to attempt to establish even general restrictions of what to exclude in the description of the neurobehavioral phenotype.
The suggestion of refinement of the diagnosis of ARND turned out to be especially contentious among the participants; there was no consensus to even discuss diagnosis. Moreover, there arose discussion of the usefulness of the core deficit construct. One clinician voiced the opinion it is highly counterproductive to even try to define whether there are core deficits. His concern is that if we make a list, the next five years will be filled with research papers examining those core deficits, instead of looking ever more broadly at what is wrong with those brains.
Clearly, there were different, and sometimes competing goals at the meeting. On the one hand, some clinicians do not want core limits that would exclude patients. On the other hand, animal researchers want precise definitions so they can model them. On the one hand, there are a lot of different deficits because of key biological and environmental variables. On the other hand, there are a finite number of ways that brain development can play out, e.g., different teratogens can disrupt the same developmental cascades. Rather than reaching definitive conclusions about core deficits and so forth, the workshop functioned as a starting point for a refocus of the optimal approach. Perhaps the workshop helped us to see that we have not been focusing in the right direction — just as someone swimming underwater needs to surface occasionally to re-orient.
Participants could not agree on what or even whether there are core deficits, yet there was a strong belief that alcohol exposure has effects across a multitude of domains, effects that are unusual and different from other exposures. This should not be surprising if it is. There are likely many things that are common among different teratogens due to common developmental cascades. In fact, a cautionary word is needed concerning the evaluation of FAS and ARND with other teratogens. For example, toluene produces effects similar to FAS, even including the facial dysmorphology (which lends more credence to the need of defined neurobehavioral profiles, for the benefit of diagnosis and more closely matched therapies).
On the other hand, trying to focus too much on how alcohol is like other teratogens may lead to problems. Keeping in mind the caveat that some or much of the variability that we see is a function of variables such as dose and timing of exposure, we must insist that the same criteria be used when evaluating these other situations, as is used when evaluating effects of alcohol exposure. Otherwise, we are really evaluating apples and oranges.
Is ARND simply a function of not drinking during the day or two during first trimester when the facial dysmorphology associated with FAS is produced, or is it something significantly less? In other words, are there fundamental differences in children diagnosed with FAS and ARND other than a different face? If so, what are these differences? The women who drink heavily enough during first trimester to produce an FAS face are likely to be the ones who are also drinking the most during the third trimester. Can you get just as severe effects if the mother abstains for just that short period of exposure needed to produce the FAS face? Is it just a matter of timing that you don’t get the face but you get the problem?
Clearly, there needs to be some work directed toward hypothesis testing to determine why there are discrepancies among studies; e.g., does a certain deficit show up only in some of the cases because other variables mask or modify it? Part of this problem may be that we tend to think of a behavioral deficit in terms of variety and severity (analog), but the dysmorphic face in terms of "if it is there or not" (digital).
The repertoire of behavioral deficits associated with ARND and FAS is broad. It is quite likely that the alcohol is not responsible for all of the behavioral problems exhibited by children whose mothers abused alcohol during pregnancy. Therefore, wanting to include all behavioral problems may be extremely counterproductive. To try to include everything is really not doing a service to the children with FAS and ARND, nor is it a help to other clinicians in their diagnosis. It also greatly complicates the chances of coming up with a rational and effective intervention strategy.
One of the clearest messages that came from the workshop was the need for a better approach or effort in identifying, and especially, in evaluating patients damaged by alcohol. However, another problem is that if a parent, caseworker, clinician, or other healthcare provider identifies a child with behavioral problems, and they find out that the mother abused alcohol during pregnancy, there can be a rush to label that child as damaged by alcohol in order to get government services for that individual. Just as it can be damaging to categorize or stereotype someone, it is also dangerous to label someone as ARND when that might be inaccurate. The one thing agreed on was that diagnostic and evaluative testing can be improved.
The lack of agreement in testing results is troubling. Some studies have found attention deficits, but others did not find attention to be impaired. Why are there such discrepancies in the literature? These differences must be compared to find out why they exist. Are the differences due to differences in the children or is it a function of the testing? How sure are we that children from different FAS research groups are evaluated in the same way? In evaluating children with suspected or known fetal alcohol exposure, it is important to determine both what kinds of problems (deficits) the majority of them share and what kinds of things they do well.
Based on what we now know, what are the best tests, not only for current assessments, but as predictors of what kinds of problems that we can anticipate later? There are some things that may not show up until later. For instance, adolescents have a different set of problems. We need to identify specific neurobehavioral tests that are the most useful in detecting the neurobehavioral deficits at each stage of development.
Unfortunately, there is not much evidence that the deficits observed in infancy, with some exceptions, are predictive of long-term deficits. Perhaps other tests would be better for this. Are they available? Currently, we are not approaching these tests as predictive tools. Rather, they are simply being used as an "assessment now" approach. This is a key point. Some dysfunction may not manifest itself until later, e.g., adolescence. Therefore, do we have a changing, evolving phenotype? The answer must be yes. ARND patients show problems throughout the life span, but those problems can and do differ over time. It will be necessary to characterize these deficits over time while matching for age, IQ, and mental age.
Treatment and Intervention Strategies
At this point, simply knowing that someone who has a serious problem is fetal alcohol exposed does not tell us anything about how to treat him or her. Unfortunately, little is known about how to improve the function of brains that have been damaged by alcohol. Given the wide spectrum of deficits, some people advocate individual treatments. However, if core deficits can be identified, then perhaps treatment regimens can be developed. If we have unlimited profiles, then we have the need for unlimited intervention strategies. For instance, it makes little sense to work on motor skills if that is not a common problem. Intervention studies can give important information on subtypes. At least they can be designed that way. Identifying subgroup-type profiles would certainly help to target laboratory-type research. From the perspective of trying to come up with some kind of intervention therapy in the future, we need to know which deficits we are dealing with and which we are not.
In the late 70’s and 80’s both clinical and basic science researchers focused on trying to elucidate the spectrum of effects produced by alcohol exposure during development. This stage of research was almost exclusively descriptive. In the last decade, animal studies attempted to model factors more closely related to the human condition. While this has made it easier to extrapolate their results to humans, it was clearly better, whenever possible, to study cognitive functioning in children with FAS and ARND than to infer from animal studies what might be the situation in humans. Clinical researchers began to use ideas generated from animal studies to drive their own work. As this work progressed, several things became clearer. First, there were many aspects of child cognitive development that were unknown. Second, few researchers apparently had thought much about which battery of behavioral tests were the best for providing a thorough evaluation of brain function. Third, unlike what resulted with the identification of other environmental teratogens, simply discovering that alcohol abuse was teratogenic did not eliminate the problem; FAS was not going to go away simply by talking about it. Fourth, an increasing number of children from alcoholic mothers were identified who exhibited so-called "fetal alcohol effects," that is, expressing some of the symptoms of FAS but not the whole syndrome; little was known about the extent of their deficits. As it became clearer that an alcohol-related neurodevelopmental disorder could occur in the absence of the full FAS, questions arose concerning the prognosis and treatment of such disorders and even how affected children would qualify for social services.
Depending on the analysis, the workshop can be considered a success or a failure. It was a success in that it pointed out how far we still need to go in terms of establishing hypothesis-driven research in FAS. It was a failure in that we were not successful in reaching a consensus on core deficits. A major problem was that participants kept forgetting the main goals of the workshop. This is understandable given the variety of backgrounds and perspectives of the participants, the complexity of the issues, and the fact that the goals really were not that well defined in the beginning. Adding considerably to that difficulty was that due to the different perspectives and agendas represented, it became clear that not all of the participants were eager to achieve those goals. This last comment is not meant to be a criticism of any participant, but rather to identify the single biggest obstacle to achieving the basic goal of the workshop; not everyone felt that developing a neurobehavioral profile of ARND was a good thing and were concerned that it might actually interfere with some children receiving help in the future.
Several issues surfaced when it was time to attempt to establish even broad parameters for defining a neurobehavioral phenotype for ARND. It was obvious that differences in testing make it very difficult to compare across studies. Such variables as age of testing and type of test are obvious factors, but so are problems of trying to group patients who may have significant differences in the timing and dose of their alcohol exposures.
While it is wrong-thinking to criticize anyone for doing everything possible to help insure that all children damaged in any way by prenatal exposure to alcohol are able to receive help, the zeal with which some people aspire try to do this can, paradoxically, hinder attempts to extend the ability of other health professionals to identify children with ARND. Even more importantly it can interfere with achieving the long-term goal of developing useful intervention strategies for helping those with FAS and ARND.
We must realize that defining core deficits should not limit or exclude children from receiving treatment, but rather it will increase the likelihood of a correct diagnosis. There is clearly the need for another workshop on this problem. Given the importance of this problem, it should be conducted sooner rather than later, but is should only be attempted once some more precise goals for the workshop are defined. However, if we cannot separate our concern for being able to effectively treat affected children from our concern that someone might get left out if we define anything, we are doomed to failure in terms of establishing a neurobehavioral profile of ARND. A next meeting would have to include a willingness of the participants to restrict agendas and agree to this approach.
Several issues that need to be addressed include the overall problem of a lack of hypothesis-driven clinical research. Other areas need to refocus. For instance, there was a discussion concerning a need for more imaging studies. However, MRI is certainly not the most sensitive measure, so what is the ultimate goal of this technique and what is anticipated or hoped to come from such information?
The most important question to be addressed at this time is why there are so many areas of major disagreement in the human literature? That is not the case with the animal literature.
What needs to be done to help these children with ARND beyond identifying them, sheltering them, and providing a better environment for them in which to develop? We need to look at future research in terms of how can we predict what future problems will be. That is, how can we determine what intervention strategies will be effective until we have a better understanding of changing neurobehavioral deficits across the life span?
In the fetal alcohol field, animal studies correlate remarkably well with human studies. The problem now is that if animal model systems are going to have value in helping to develop therapeutic interventions, there has to be agreement on what to model. For instance, it will be of little value for animal researchers to work on drug therapy for hyperactivity if hyperactivity is seldom or never a feature of ARND.
The greatest difficulty with failing or refusing to define characteristics (set parameters) related to ARND is that it makes it impossible for animal researchers to model the human condition. Since a major thrust for animal studies in the future is likely to involve issues related to intervention therapy, it will be essential to define in some agreed way what functions and conditions should be evaluated. Further, if there is no consensus as to the core components of ARND, it is unclear how treatment protocols will be developed or evaluated.
Clearly, the unsolved problem is understanding complex problems associated with brain development and its more vulnerable regions and processes and the structure/function relationships affected by fetal alcohol exposure. We need to unravel this complexity before developing successful intervention strategies to alleviate the behavioral problems. In this sense, perhaps the variability, complexity, and subtleties of the deficits associated with ARND patients may offer attractive challenges for more excellent neuropsychologists to enter the field and explore better tests.
It is crucial to realize that not every deficit exhibited by a child who was exposed to alcohol in utero is always a result of that alcohol exposure. To be reluctant to establish a neurobehavioral profile for ARND for fear of excluding anyone is harming the many children who have been identified with ARND by postponing the development of rational treatment.
The problem with arguing against any restrictions on a neurobehavioral profile for ARND is that at least some commonly occurring behavioral features or deficits in children exposed to alcohol are what attracts the attention of a clinician in the first place. This clinical approach strengthens the argument for establishing such a profile. On the other hand, if a label of ARND is attached to a dysfunctional child simply because it is known that he/she was exposed to alcohol, it has no worthwhile meaning other than helping to get services for that specific child. In the long run though, such an approach will delay the establishment of treatment options. The major participants in the field must resolve these complicated issues or it is very unlikely that substantive, qualitative advancements in the intervention and treatment will be made.