Gerry A. Stefanatos

Etiologic Subtypes of Attention-Deficit/Hyperactivity Disorder: Brain Imaging, Molecular Genetic and Environmental Factors and the Dopamine Hypothesis

Multiple theories of Attention-Deficit/Hyper- activity Disorder (ADHD) have been proposed, but one that has stood the test of time is the dopamine deficit theory. We review the narrow literature from recent brain imaging and molecular genetic studies that has improved our understanding of the role of dopamine in manifestation of symptoms of ADHD, performance deficits on neuropsychological tasks, and response to stimulant medication that constitutes the most common treatment of this disorder. First, we consider evidence of the presence of dopamine deficits based on the recent literature that (1) confirms abnormalities in dopamine-modulated frontal-striatal circuits, reflected by size (smaller-than-average components) and function (hypoactivation); (2) clarifies the agonist effects of stimulant medication on dopaminergic mechanisms at the synaptic and circuit level of analysis; and (3) challenges the most-widely accepted ADHD-related neural abnormality in the dopamine system (higher-than-normal dopamine transporter [DAT] density). Second, we discuss possible genetic etiologies of dopamine deficits based on recent molecular genetic literature, including (1) multiple replications that confirm the association of ADHD with candidate genes related to the dopamine receptor D4 (DRD4) and the DAT; (2) replication of differences in performance of neuropsychological tasks as a function of the DRD4 genotype; and (3) multiple genome-wide linkage scans that demonstrate the limitations of this method when applied to complex disorders but implicate additional genes that may contribute to the genetic basis of ADHD. Third, we review possible environmental etiologies of dopamine deficits based on recent studies of (1) toxic substances that may affect the dopamine system in early development and contribute substantially to the etiology of ADHD; (2) fetal adaptations in dopamine systems in response to stress that may alter early development with lasting effects, as proposed by the developmental origins of health and disease hypothesis; and (3) gene-environment interactions that may moderate selective damage or adaptation of dopamine neurons. Based on these reviews, we identify critical issues about etiologic subtypes of ADHD that may involve dopamine, discuss methods that could be used to address these issues, and review old and new theories that may direct research in this area in the future.

Cognitive and motor development during childhood in boys with Klinefelter syndrome.

The goal of this study was to expand the description of the cognitive development phenotype in boys with Klinefelter syndrome (47,XXY). We tested neuropsychological measures of memory, attention, visual‐spatial abilities, visual‐motor skills, and language. We examined the influence of age, handedness, genetic aspects (parental origin of the extra X chromosome, CAGn repeat length, and pattern of X inactivation), and previous testosterone treatment on cognition. We studied 50 boys with KS (4.1–17.8 years). There was a significant increase in left‐handedness (P = 0.002). Specific language, academic, attentional, and motor abilities tended to be impaired. In the language domain, there was relative sparing of vocabulary and meaningful language understanding abilities but impairment of higher level linguistic competence. KS boys demonstrated an array of motor difficulties, especially in strength and running speed. Deficits in the ability to sustain attention without impulsivity were present in the younger boys. Neither genetic factors examined nor previous testosterone treatment accounted for variation in the cognitive phenotype in KS. The cognitive results from this large KS cohort may be related to atypical brain lateralization and have important diagnostic and psychoeducational implications. The difficulty in complex language processing, impaired attention and motor function in boys with KS may be missed. It is critical that boys with KS are provided with appropriate educational support that targets their learning challenges in school in addition to modifications that address their particular learning style. These findings would also be an important component of counseling clinicians and families about this disorder.

Transition to young adulthood in Ullrich-Turner syndrome: Neurodevelopmental changes

Studies describing the neurocognitive profile of Ullrich-Turner syndrome (UTS) have focused primarily on neurodevelopmental changes in childhood and adolescence or in adults with UTS. The objective of the present study was to describe neurodevelopmental changes that occur in UTS females during the transition from adolescence to young-adulthood. The subjects included 99 females with UTS and 89 normal female controls matched for age and socioeconomic status. Subjects were between the ages of 13 and 21 years. All subjects received a battery of neurocognitive tests designed to assess general cognitive ability, academic achievement, memory, language, executive function, visual-spatial/perceptual and motor skills, affect recognition, attention, and motor skills. Results from our study indicated that females with UTS performed significantly less well than controls on measures of spatial/perceptual skills, visual-motor integration, affect recognition, visual memory, attentional abilities, and executive function, consistent with previous reports of cognitive abilities in adolescent UTS females. Moreover, our results indicate that decreased performance in some of these areas persists through late adolescence and into early adulthood while improvement occurs in other areas. It is possible that catch-up in certain cognitive deficiencies in UTS females represents a maturational/developmental lag. Alternatively, the neurodevelopmental changes that were observed in UTS females may result from the cumulative effects of estrogen replacement therapy during adolescence. Therapeutic interventions specific to the demands of young-adulthood are also discussed.

Attention-Deficit/Hyperactivity Disorder: A Neuropsychological Perspective Towards DSM-V

Neuropsychological methods and techniques have much to offer in the evaluation of the individual suspected as having Attention-Deficit/Hyperactivity Disorder (ADHD). After a review of the historical evolution of the ADHD concept, incidence and prevalence, and DSM-IV criteria for diagnosis, especially as regards omission related to gender differences, and other associated cultural, familial, socioenvironmental, and subject influences, this paper describes a number of dilemmas and obstacles encountered in clinical practice. Included are the confounds associated with the wide range of possible comorbidities, the insufficiency of current DSM-IV criteria, the emergence of subtype differentiation and its impact on diagnosis and treatment. The complex relationship between neuropsychological constructs and ADHD, and obstacles to valid assessment are also addressed. The complexities associated with a thorough ADHD evaluation are viewed within an impressive and expansive existing scientific framework and recommendations are made for future directions.

Regression in Autistic Spectrum Disorders

A significant proportion of children diagnosed with Autistic Spectrum Disorder experience a developmental regression characterized by a loss of previously-acquired skills. This may involve a loss of speech or social responsitivity, but often entails both. This paper critically reviews the phenomena of regression in autistic spectrum disorders, highlighting the characteristics of regression, age of onset, temporal course, and long-term outcome. Important considerations for diagnosis are discussed and multiple etiological factors currently hypothesized to underlie the phenomenon are reviewed. It is argued that regressive autistic spectrum disorders can be conceptualized on a spectrum with other regressive disorders that may share common pathophysiological features. The implications of this viewpoint are discussed.

Attention Deficit/Hyperactivity Disorder as a Right Hemisphere Syndrome

Abstract: Recent studies of ADHD implicate well‐defined neuroanatomical networks and neurochemical pathways in its pathophysiological basis. Considerable attention has focused on the role of anterior and superior frontal regions and portions of the basal ganglia, including the caudate nucleus and globus pallidus. This paper reviews a growing literature suggesting differential involvement of right hemisphere mechanisms specialized for behavioral regulation and attention. Supportive data are drawn from neuropsychology, neuroanatomy, and neurochemistry. In addition, three cases are presented that illustrate the complex role of right hemisphere dysfunction in adult manifestations of ADHD. We suggest that the pleomorphic presentations of ADHD can be understood in terms of a spectrum of disturbances in overlapping neural regions, especially involving frontal and parietal areas of the right hemisphere and their connections to subcortical structures (including the striatum, limbic system and diencephalic nuclei).

Persistent cognitive deficits in adult women with Turner syndrome

Background: Turner syndrome (TS) has a characteristic neurocognitive profile. Verbal abilities are, in general, normal; however, women with TS, as a group, have specific deficits in visual-spatial abilities, visual-perceptual abilities, motor function, nonverbal memory, executive function, and attentional abilities. Observed deficits could be caused by genetic or endocrine factors. Objective: To evaluate the specific cognitive deficits that appear to persist in adulthood, are not estrogen-responsive, and may be genetically determined. Methods: The cognitive performance of adult women with TS (n = 71) who were estrogen repleted was compared with verbal IQ– and socioeconomic status–matched female controls (n = 50). Sixty-one women with TS had ovarian failure and received estrogen replacement and 10 had preserved endogenous ovarian function and were not receiving estrogen replacement at the time of evaluation. Results: Similar to children and adolescents with TS, adults with TS have normal verbal IQ but have relative difficulty on measures of spatial/perceptual skills, visual-motor integration, affect recognition, visual memory, attention, and executive function despite estrogen replacement. These deficits are apparent in women with TS despite apparently adequate estrogen effect, either endogenous or by hormone replacement. Conclusion: The cognitive phenotypes of adults with TS, with or without ovarian failure, are similar, indicating that estrogen replacement does not have a major impact on the cognitive deficits of adults with TS.

Case Study: Corticosteroid Treatment of Language Regression in Pervasive Developmental Disorder

The authors describe a child whose language and behavior regressed at 22 months and in whom pervasive developmental disorder was later diagnosed. At 6 years, he displayed a profound receptive-expressive aphasia accompanied by behavioral disturbances characterized by hyperactivity, impaired social interactions, tantrums, gestural stereotypies, and echolalia. A single-photon emission computed tomography scan and steady-state auditory evoked potentials suggested bitemporal and left frontal pathophysiology. The overall profile resembled Landau-Kleffner syndrome, but no electroencephalographic disturbance was evident. Corticosteroid treatment resulted in amelioration of language abilities and behavior. These findings suggest that the factors underlying language regression in pervasive developmental disorder can, in special circumstances, be amenable to pharmacological treatment.

Mental rotation under head tilt: Factors influencing the location of the subjective reference frame

We report five experiments on the effect of head tilt on the mental rotation of patterns to the “upright.” In Experiment 1, subjects rotated alphanumeric characters, displayed within a circular surround. Experiment 2 was similar except that the character was an unfamiliar letter-like symbol. In Experiment 3, subjects again rotated alphanumeric characters, but they were displayed within a rectangular frame tilted 60° to the right. Experiment 4 was similar, except that the subjects were instructed to rotate the characters to the “upright” defined by the tilted frame. In all four experiments, the subjects performed the task with their heads either upright or tilted 60°. In Experiment 5, subjects had their heads and bodies tilted 90°, and rotated alphanumeric characters displayed within a circular surround. In all except Experiment 4, analysis of response latencies revealed that the subjective vertical lay closer to the gravitational than to the retinal vertical, although it was somewhat displaced in the direction of the head tilt—more so in Experiments 2 and 3 than in Experiment 1, and more so still in Experiment 5. In Experiment 4, instructions to adopt the axes of the frame land thus of the retina) succeeded in bringing the subjective vertical closer to the retinal than to the gravitational vertical, although the subjective vertical was still some 20° on average from the gravitational vertical. The results show that the subjective reference frame is distinct from both gravitational and the retinal frames, and that the gravitational frame exerts the stronger influence. They also argue against the primacy of a “retinal factor” in the perception of orientation.

A turner syndrome neurocognitive phenotype maps to Xp22.3

BackgroundTurner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities. We previously reported evidence that this phenotype results from haploinsufficiency of one or more genes on distal Xp. This inference was based on genotype/phenotype comparisons of individual girls and women with partial Xp deletions, with the neurocognitive phenotype considered a dichotomous trait. We sought to confirm our findings in a large cohort (n = 47) of adult women with partial deletions of Xp or Xq, enriched for subjects with distal Xp deletions.MethodsSubjects were recruited from North American genetics and endocrinology clinics. Phenotype assessment included measures of stature, ovarian function, and detailed neurocognitive testing. The neurocognitive phenotype was measured as a quantitative trait, the Turner Syndrome Cognitive Summary (TSCS) score, derived from discriminant function analysis. Genetic analysis included karyotyping, X inactivation studies, fluorescent in situ hybridization, microsatellite marker genotyping, and array comparative genomic hybridization.ResultsWe report statistical evidence that deletion of Xp22.3, an interval containing 31 annotated genes, is sufficient to cause the neurocognitive phenotype described by the TSCS score. Two other cardinal TS features, ovarian failure and short stature, as well as X chromosome inactivation pattern and subjects age, were unrelated to the TSCS score.ConclusionDetailed mapping suggests that haploinsufficiency of one or more genes in Xp22.3, the distal 8.3 megabases (Mb) of the X chromosome, is responsible for a TS neurocognitive phenotype. This interval includes the 2.6 Mb Xp-Yp pseudoautosomal region (PAR1). Haploinsufficiency of the short stature gene SHOX in PAR1 probably does not cause this TS neurocognitive phenotype. Two genes proximal to PAR1 within the 8.3 Mb critical region, STS and NLGN4X, are attractive candidates for this neurocognitive phenotype.