Susan D. Hamburger

Quantitative MRI of the temporal lobe, amygdala, and hippocampus in normal human development: Ages 4–18 years

The volume of the temporal lobe, superior temporal gyrus, amygdala, and hippocampus was quantified from magnetic images of the brains of 99 healthy children and adolescents aged 4–18 years. Variability in volume was high for all structures examined. When adjusted for a 9% larger total cerebral volume in males, there were no significant volume differences between sexes. However, sex‐specific maturational changes were noted in the volumes of medial temporal structures, with the left amygdala increasing significantly only in males and with the right hippocampus increasing significantly only in females. Right‐greater‐than‐left laterality effects were found for temporal lobe, superior temporal gyrus, amygdala, and hippocampal volumes. These results are consistent with previous preclinical and human studies that have indicated hormonal responsivity of these structures and extend quantitative morphologic findings from the adult literature. In addition to highlighting the need for large samples and sex‐matched controls in pediatric neuroimaging studies, the information from this understudied age group may be of use in evaluating developmental hypotheses of neuropsychiatric disorders.

Cerebellum in attention-deficit hyperactivity disorder A morphometric MRI study

Clinical, neuroanatomic, neurobehavioral, and functional brain-imaging studies suggest a role for the cerebellum in cognitive functions, including attention. However, the cerebellum has not been systematically studied in attention-deficit hyperactivity disorder (ADHD). We quantified the cerebellar and vermal volumes, and the midsagittal areas of three vermal regions, from MRIs of 46 right-handed boys with ADHD and 47 matched healthy controls. Vermal volume was significantly less in the boys with ADHD. This reduction involved mainly the posterior inferior lobe (lobules VIII to X) but not the posterior superior lobe (lobules VI to VII). These results remained significant even after adjustment for brain volume and IQ. A cerebello-thalamo-prefrontal circuit dysfunction may subserve the motor control, inhibition, and executive function deficits encountered in ADHD.

Neuropsychological findings in high-functioning men with infantile autism, residual state.

Ten men (ages 18-39) with clear histories of Infantile autism and approximately average verbal and nonverbal intelligence were studied with a comprehensive battery of neuropsychological tests. Comparisons with 10 matched normal controls showed no significant differences in many visuoperceptual or memory skills or in sensory-perceptual or motor skills or their lateralization. Differences seen on language measures were small, but statistically significant. In contrast to this, the autistic group demonstrated dramatic deficits on simple and complex, verbal and nonverbal problem-solving tasks, such as the Wisconsin Card Sorting Test, selected tasks from the Stanford-Binet, and the Trail Making Test. A left-hemisphere hypothesis of autism was not supported, nor was there compelling evidence of any posterior cortical deficit. Results are compatible with frontal-system dysfunction or with more widespread pathology.

A QUANTITATIVE MRI STUDY OF THE CORPUS CALLOSUM IN CHILDREN AND ADOLESCENTS

Total midsagittal area and seven subdivisions of the corpus callosum were measured on magnetic resonance images of 114 healthy boys and girls, aged 4 to 18. Striking variability of size was noted for all measures. Total midsagittal corpus callosum area increased in a robust and linear fashion from ages 4 to 18 (slope = 13.1 mm2/year, P = 0.0001 and slope = 11.1 mm2/year, P = 0.0001 for females and males, respectively). Posterior and mid regions demonstrated greater age-related changes than anterior regions with the rostrum and genu (anterior regions) having reached adult sizes in the youngest of our subjects. There were no significant effects of sex for any measures. These findings support anatomical studies indicating ongoing myelination of higher association areas throughout adolescence, but raise intriguing questions about anterior-posterior gradients of interhemispheric myelination.

THE ROLE OF THE ANTERIOR CINGULATE IN AUTOMATIC AND CONTROLLED PROCESSES :A DEVELOPMENTAL NEUROANATOMICAL STUDY

This study examines the role of the anterior cingulate in the development of attention. Task performance relying predominantly on either automatic or controlled processes was correlated with magnetic resonance imaging based measures of the anterior cingulate in 26 normal children ages 5 to 16 years. Attentional measures were assessed with a visual discrimination paradigm. Parasagittal slices from a 3-D, T1-weighted volume data set were used to obtain area measurements of the anterior cingulate. Response latencies decreased with age for both tasks. There were significant correlations between attentional performance and right, but not left, anterior cingulate measures. Performance was faster and more accurate during trials requiring predominantly controlled processes for those children with larger right anterior cingulate measures. The results are consistent with adult neuroimaging findings of activation in the right anterior cingulate during attention tasks and with lesion studies implicating greater right hemisphere involvement in attentional processes.

A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections

BACKGROUND Some children with obsessive-compulsive disorder (OCD) and tic disorders appear to have symptom exacerbations triggered by group A beta-hemolytic streptococcal infections in a manner that is similar to rheumatic fever and its neurologic variant, Sydenhams chorea. Because penicillin prophylaxis has proven to be effective in preventing recurrences of rheumatic fever, it was postulated that it might also prevent streptococcal-triggered neuropsychiatric symptom exacerbations in children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS). These children are identified by five clinical characteristics: presence of OCD or tic disorder, prepubertal onset, episodic symptom course, neurologic abnormalities (i.e., choreiform movements) and streptococcal-triggered symptom exacerbations. METHODS Thirty-seven children with PANDAS were enrolled in an 8 month, double-blind, balanced cross-over study. Patients were randomized to receive either 4 months of the active compound (twice daily oral 250 mg penicillin V) followed by 4 months of placebo, or placebo followed by penicillin V. Tic, OCD, and other psychiatric symptoms were monitored monthly. Throat cultures and streptococcal antibody titers were also obtained. RESULTS There were an equal number of infections in both the active and placebo phases of the study. There was no significant change seen in either the obsessive-compulsive or tic symptom severity between the two phases. CONCLUSIONS Because of the failure to achieve an acceptable level of streptococcal prophylaxis, no conclusions can be drawn from this study regarding the efficacy of penicillin prophylaxis in preventing tic or OCD symptom exacerbations. Future studies should employ a more effective prophylactic agent, and include a larger sample size.

Childhood-onset schizophrenia: progressive brain changes during adolescence

BACKGROUND Previous NIMH childhood onset schizophrenia (COS) anatomic brain MRI studies found progression of ventricular volume and other structural brain anomalies at 2-year follow up across mean ages 14 to 16 years. However, studies in adult patients generally do not show progression of ventricular volume or correlation of ventricular volume with duration of illness. To address issues of progression of brain anomalies in schizophrenia, this report extends previous studies to include a third longitudinal scan, uses a larger sample size, and includes measures of the amygdala and hippocampus. METHODS Volumes of the total cerebrum, lateral ventricles, hippocampus, and amygdala were quantified on 208 brain magnetic resonance imaging scans from 42 adolescents with COS (23 with one or more repeat scan) and 74 age- and gender-matched controls (36 with one or more repeat scan). A statistical technique permitting combined use of cross-sectional and longitudinal data was used to assess age-related changes, linearity, and diagnostic group differences. RESULTS Differential nonlinear progression of brain anomalies was seen during adolescence with the total cerebrum and hippocampus decreasing and lateral ventricles increasing in the COS group. The developmental curves for these structures reached an asymptote by early adulthood for the COS group and did not significantly change with age in the control group. CONCLUSIONS These findings reconcile less striking progression of anatomic brain images usually seen for adult schizophrenia and complement other data consistent with time-limited, diagnostic-specific decreases in brain tissue. Adolescence appears to be a unique period of differential brain development in schizophrenia.

Controlled Stimulant Treatment of ADHD and Comorbid Tourette's Syndrome: Effects of Stimulant and Dose

OBJECTIVE To determine the effects of methylphenidate (MPH) and dextroamphetamine (DEX) on tic severity in boys with attention-deficit/hyperactivity disorder (ADHD) comorbid with Tourettes syndrome. METHOD A 9-week, placebo-controlled, double-blind crossover using a wide range of doses was completed by 20 subjects in three cohorts. RESULTS Relatively high doses of MPH and DEX in the first cohort produced significant increases in tic severity which were sustained on higher doses of DEX but which attenuated on MPH. Overall, 14 of 20 subjects continued stimulant treatment for 1 to 3 years, generally in combination with other psychotropics. Stimulant-associated adverse effects, including tic exacerbations, were reversible in all cases. CONCLUSION A substantial minority of comorbid subjects had consistent worsening of tics on stimulants, although the majority experienced improvement in ADHD symptoms with acceptable effects on tics. MPH was better tolerated than DEX.

Sydenham's chorea Magnetic resonance imaging of the basal ganglia

Analysis of cerebral magnetic resonance images of 24 subjects with Sydenhams chorea and 48 age-, height-, weight-, gender-, and handedness-matched controls demonstrated increased sizes of the caudate, putamen, and globus pallidus in the Sydenhams chorea group. In contrast, neither total cerebral, prefrontal, or midfrontal volumes or thalamic area were increased. These results indicate the selective involvement of the basal ganglia in Sydenhams chorea. NEUROLOGY 1995;45: 2199-2203

Lack of an association between a dopamine-4 receptor polymorphism and attention-deficit/hyperactivity disorder: genetic and brain morphometric analyses

Although the etiology of attention-deficit/hyperactivity disorder (ADHD) is likely multifactorial, family,1 adoption,2 and twin studies3 suggest that genetic factors contribute significantly. Polymorphisms of the dopamine 4 receptor (DRD4) affect receptor binding,4 and one allele with seven tandem repeats in exon 3 (DRD4*7R) has been associated with ADHD.5,6 We examined this putative association in 41 children with severe ADHD and 56 healthy controls who were group matched for ethnicity and sex. The frequency of the DRD4*7R allele did not vary by diagnosis (0.220 vs 0.205 in patients and controls, respectively). Behavioral and brain anatomic MRI measures, previously found to discriminate patients from controls,7 did not differ significantly between subjects having and those lacking a DRD4*7R allele. These data do not support the reported association between DRD4*7R and the behavioral or brain morphometric phenotype associated with ADHD.