High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a highly prevalent childhood psychiatric disorder characterized by impaired attention, excessive motor activity, and impulsivity. Despite extensive investigation of the neuropathophysiology of ADHD by a wide array of methodologies, the neurobiochemical substrate of this disorder is still unknown. Converging evidence, however, suggests a primary role of the dopaminergic system. METHOD: This study examined the integrity of presynaptic dopaminergic function in children with ADHD through use of positron emission tomography and the tracer [18F]fluorodopa ([18F]DOPA). Accumulation of [18F]DOPA in synaptic terminals, a measure of dopa decarboxylase activity, was quantified in regions rich in dopaminergic innervation, including caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). RESULTS: Accumulation of [18F]DOPA in the right midbrain was higher by 48% in 10 children with ADHD than in 10 normal children. Despite its magnitude, this difference would not have reached statistical significance if corrected by the Bonferroni test for multiple comparisons. However, [18F]DOPA in the right midbrain was correlated with symptom severity. No other dopamine-rich regions significantly differed between groups. CONCLUSIONS: These findings are suggestive of dopaminergic dysfunction at the level of the dopaminergic nuclei in children with ADHD. Abnormality in dopa decarboxylase activity may be primary or secondary to deficits in other functional units of the dopamine pathway (e.g., receptor, uptake transporter, vesicular transporter, degradation enzymes). Efforts toward defining the origin of this abnormality should help delineate mechanisms of midbrain control of attention and motor behavior important for the understanding of the causes and treatment of ADHD.

Adrenergic and noradrenergic plasma levels in Lesch-Nyhan disease.

Noradrenergic dysfunction and abnormality in monoamine oxidase (MAO) enzyme activity have been reported previously in Lesch-Nyhan (LN) disease. This study examines peripheral indices of adrenergic, noradrenergic, and MAO function in children and young adults with LN disease (n = 11), and healthy subjects (n = 9). Blood samples, collected in identical conditions prior to a positron emission tomography (PET) study, were assayed for concentrations of epinephrine (EPI), norepinephrine (NE), and 3-methoxy-4-hydroxyphenylglycol (DHPG) (which results from the degradation of NE by monoamine oxidase type A [MAO-A]). The LN subjects had significantly higher EPI levels by 245% (p < .00) and lower DHPG levels by 42% (p < .00) compared to the control group. No group differences were noted in NE plasma levels. Cognitive function (IQ tested by Stanford Binet Intelligence Scale) was associated with EPI in the LN group (r = 0.77, p = .009), but not in the control group. The abnormally high EPI plasma concentrations may indicate another biochemical dysfunction secondary to the absence of the HPRT enzyme in LN patients. Such a biochemical deficit is likely to originate from the adrenal medulla, which is the primary site of EPI synthesis. The adrenal medulla may be directly affected by the absence of hypoxanthine guanine phosphoribosyl transferase (HPRT) enzyme, or may receive inappropriately high descending activation input from the brain. The abnormally low DHPG levels, in the context of normal NE levels, indicates low MAO activity, either as a primary deficit, or as secondary adaptive changes to spare NE levels that would otherwise be too low for adequate noradrenergic function.

High presynaptic dopaminergic activity in children with Tourette's disorder.

OBJECTIVE: Tourette's disorder is characterized by chronic fluctuating motor and vocal tics. Despite extensive investigation of the neuropathophysiology of the disorder by a wide array of methodologies, its neurobiochemical substrate is still unclear. Converging evidence, however, suggests a primary role of the dopaminergic system, particularly within the basal ganglia. METHOD: This study examined the integrity of presynaptic dopaminergic function in children with Tourette's disorder, using positron emission tomography and the tracer [18F]fluorodopa (FDOPA). Accumulation of FDOPA in synaptic terminals, a measure of DOPA decarboxylase activity, was quantified in caudate nucleus, putamen, frontal cortex, and midbrain (i.e., substantia nigra and ventral tegmentum). RESULTS: Subjects with Tourette's disorder showed higher FDOPA accumulation than controls in the left caudate nucleus (by 25%; p = .03) and right midbrain (by 53%; p = .08). CONCLUSION: These findings provide evidence of dopaminergic dysfunction in children with Tourette's disorder which affects both cell nuclei and nerve terminals. Based on the known regulation of DOPA decarboxylase activity by post- and presynaptic receptors, and by extracellular dopamine concentration, abnormal activity in this enzyme may reflect deficits in a variety of functional elements of the dopamine system. The precise mechanism underlying an up-regulation of DOPA decarboxylase activity needs to be identified in future studies.

Are ADDH and ADHD the same or different?

To assess the relationship between the DSM-III criteria for attention deficit disorder with hyperactivity (ADDH) and the DSM-III-R criteria for attention-deficit hyperactivity disorder (ADHD), children from an inner city parochial school were evaluated using a 30-item teacher questionnaire consisting of the DMS-III and DSM-III-R criteria for these disorders, the revised Conners Parent and Teacher Questionnaires, and a continuous performance test. Diagnostic groups were established based on teacher ratings of the DSM items and evaluated in relation to the rating scale data and continuous performance test. While children who were identified by teachers as having ADDH almost always satisfied the criteria for ADHD, a new group of children who were hyperactive and impulsive but less clearly inattentive also met the criteria for ADHD. Implications of the change in diagnostic criteria are discussed.

Attentional capacities in children with autism: is there a general deficit in shifting focus?

Twenty-three children with autism and two control groups completed an attention battery comprising three versions of the continuous performance test (CPT), a digit cancellation task, the Wisconsin Card Sorting Test (WCST), and two novel, computerized tests of shifting attention (i.e., the Same-Different Computerized Task and the Computerized Matching Task). Children with autism could focus on a particular stimulus and sustain this focus as indicated by their performance on the digit cancellation task and the CPT. Their performance on the WCST suggested problems in some aspects of shifting attention (i.e., disengaging attention). The autism group performed as well as controls on the Same-Different Computerized Task, however, that required successive comparisons between stimuli. This implies that they could, in fact, shift their attention continuously. In addition, they did not differ from controls on the Computerized Matching Task, an analog of the WCST, suggesting that they do not have a general deficit in shifting attention.

Parent and teacher ratings of attention-deficit hyperactivity disorder symptoms: implications for case identification.

This study was designed to evaluate the relationship between the DSM-III criteria for attention-deficit deficit disorder with hyperactivity (ADDH) and the DSM-III-R criteria for attention-deficit hyperactivity disorder (ADHD). Seventy-two children from an inner-city elementary school were evaluated using parent and teacher ratings on a scale consisting of the symptoms of DSM-III-R ADHD and oppositional-defiant disorder and DSM-III ADDH. Each child was also assessed using a psychometric test battery designed to examine cognitive function, attention, and activity level. Teacher ratings identified more children as DSM-III-R ADHD than DSM-III ADDH. Among these ADHD children, those who also met the ADDH criteria missed more targets on a continuous performance test (CPT) and were rated more overactive than controls. They also had a greater likelihood of being rated ADHD by parents. Children rated as meeting criteria for DSM-III-R ADHD, but not DSM-III ADDH, were not substantially different from controls on teacher ratings of overactivity, CPT performance, or parent ratings of ADHD, which raises questions regarding the nature and severity of the pathology in this group.

Inattentive and noninattentive ADHD children: do they constitute a unitary group?

Teacher-rated ADHD and normal control children were administered a continuous performance test (CPT), and were then further subdivided based upon the presence or absence of objectively assessed attentional deficits. In addition, children were assessed using several measures of cognitive and behavioral functioning. Attentional deficits were significantly more prevalent among the ADHD group, but about half of the ADHD children showed no evidence of objectively assessed attentional dysfunction. Further group analyses indicated that ADHD children with objectively assessed attentional dysfunction appeared cognitively impaired, while ADHD children without objective evidence of attentional dysfunction had more conduct problems. CPT inattention was not related to the presence of cognitive impairments or conduct problems in the control group. These data must be considered preliminary because teacher ratings were the only source of diagnosis and a single measure of inattention was used. However, they suggest that two subtypes of ADHD children can be identified, one characterized by inattention and learning problems, and the other by conduct problems.

The factor structure of ADHD items in DSM-III-R: internal consistency and external validation.

Previous research employing factor-analytic procedures to study the underlying dimensions of DSM-III attention deficit disorder with hyperactivity (ADDH) symptoms have consistently supported a two-factor model. Revision of the structure of the ADHD diagnosis in DSM-III-R, as well as inclusion of new items, has raised the question of comparability of the two diagnoses. To explore the significance of these changes, teacher ratings of DSM-III ADDH items and DSM-III-R ADHD items of 85 nonreferred school children were factor-analyzed to determine their underlying factor structures. A similar two-factor solution was obtained for each diagnostic scale. The factors consisted of items believed to reflect inattention and hyperactivity-impulsivity constructs. These factors were further evaluated against results of a cognitive test battery to ascertain whether objective, external validation could be demonstrated. The hyperactivity-impulsivity factor scores were related to continuous performance test measures of response inhibition, while inattention-disorganization factor scores were related to measures of attention and visual search. Implications for assessment and diagnosis of ADHD are discussed.

Validation of hyperactive, aggressive, and mixed hyperactive/aggressive childhood disorders: a research note.

Eighty-five non-referred school children were divided into four groups based upon the IOWA Conners Teacher's Questionnaire: pure hyperactive (HYP), pure aggressive (AGG), mixed hyperactive/aggressive (HYP/AGG), and normal controls. The groups were compared on neurobehavioral tests believed to assess inattention and impulsivity. A continuous performance test indicated that the HYP group was more inattentive than the other groups and the HYP/AGG group was most impulsive. The AGG group did not differ from controls. The data support the distinction between HYP, AGG and HYP/AGG groups of children selected by the IOWA Conners.

Presynaptic dopaminergic deficits in Lesch-Nyhan disease.

BACKGROUND: Lesch-Nyhan disease is a rare, devastating, X-linked recessive disorder of purine synthesis. Patients present with hyperuricemia, choreoathetosis, dystonia, and aggressive and self-injurious behavior. Although the genetic and biochemical abnormalities have been identified, the causes of the neuropsychiatric syndrome remain unclear. METHODS: We used positron-emission tomography to measure presynaptic accumulation of fluorodopa F 18 tracer in the dopaminergic regions of the brains of 12 patients with Lesch-Nyhan disease (age, 10 to 20 years) and 15 healthy controls (age, 12 to 23). The results were expressed as ratios of specific to nonspecific radioactive counts. A low ratio indicates decreased dopa decarboxylase activity and dopamine storage. RESULTS: The fluorodopa F 18 ratio was significantly lower in the putamen (31 percent of control values), caudate nucleus (39 percent), frontal cortex (44 percent), and ventral tegmental complex (substantia nigra and ventral tegmentum; 57 percent) in the patients with Lesch-Nyhan disease than in the controls. Uptake of the tracer was abnormally low even in the youngest patients tested, and there was no overlap in the values between patients and controls. CONCLUSIONS: Patients with Lesch-Nyhan disease have abnormally few dopaminergic nerve terminals and cell bodies. The abnormality involves all dopaminergic pathways and is not restricted to the basal ganglia. These dopaminergic deficits are pervasive and appear to be developmental in origin, which suggests that they contribute to the characteristic neuropsychiatric manifestations of the disease.