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Biomedical subjects

F X Castellanos

Publications and source records attributed to F X Castellanos.

At least 19 recordsLinked to original sources
PubMed2002

Attention-deficit/hyperactivity disorder (ADHD): feasibility of linkage analysis in a genetic isolate using extended and multigenerational pedigrees.

Segregation analyses converge in explaining the predisposition to attention-deficit/hyperactivity disorder (ADHD) as the consequence of a major gene and exclude purely environmental or cultural transmission. As a result of the ADHD phenotype restrictions, collection of extended families or design of linkage studies using families has been extremely difficult and thus currently linkage studies have been performed using only concordant or discordant sib-pairs rather than large families. On the other hand, intergenerational studies are represented by the transmission disequilibrium test (TDT) using trios. We collected pedigree data on ADHD from the Paisa community from Antioquia, Colombia, a genetic isolate. The goal of this study was to genetically map a putative gene predisposing to ADHD in a set of 27 multigenerational Paisa families. Here we present the results of a power simulation using SIMLINK to detect linkage of ADHD. ADHD was assumed to be a dichotomous trait with incomplete penetrance and a phenocopy rate of 3% in males and 0.2% in females. We simulated cosegregation of the trait and a marker locus in our pedigrees. We assumed Hardy-Weinberg and linkage equilibrium, equally frequent marker alleles and evaluated power at several recombination fractions between the trait and marker loci. Also, the ADHD trait was assumed to be genetically heterogeneous and different functions of age-dependent penetrance were simulated. We found exceptionally good power to detect linkage (expected LOD > 14 if theta is 0.1 or less), and that the presence of heterogeneity up to 50% does not affect substantially the projected LOD scores even for a theta recombination value of 0.05 (eLOD > 5.87). Having now obtained blood samples and confirmatory interviews in five families (representing 20% of the projected number of families), we performed a new analysis. The expected mean LOD in these five families reached values close to 10 and remained invariant when heterogeneity and different penetrance models were considered. We discuss the relative benefits of using extended and multigenerational families for genetic mapping studies as opposed to using nuclear families, affected sib pairs or sporadic cases which require the collection of over 1000 analytical units to get the same power exhibited by the small number of pedigrees described here.

Adult↗
PubMed2001

Altered performance on an ocular fixation task in attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder without validated objective markers. Eye movement studies may be useful in providing objective criteria for characterizing the disorder. METHODS: We compared 53 children (29 girls) with ADHD to 44 healthy control children (18 girls) on a 21-sec fixation task. Large saccades (> 4 degrees ) away from the fixation point were analyzed. RESULTS: Children with ADHD made more large saccades that interrupted fixation than did control children (p =.001). Mean scores of the ADHD group did not change significantly with subsequent retesting on placebo (p =.11); however, there was poor intrasubject correlation (r =.16). CONCLUSIONS: Both boys and girls with ADHD made significantly more intrusive saccades during fixation than did control subjects, possibly reflecting intrinsic neurologic dysfunction; however, a probable "floor effect" obviates conclusions about the reliability of this measure.

Attention Deficit Disorder with Hyperactivity↗
PubMed2001

Quantitative brain magnetic resonance imaging in girls with attention-deficit/hyperactivity disorder.

BACKGROUND: Anatomic studies of boys with attention-deficit/hyperactivity disorder (ADHD) have detected decreased volumes in total and frontal brain, basal ganglia, and cerebellar vermis. We tested these findings in a sample of girls with ADHD. METHODS: Anatomic brain magnetic resonance images from 50 girls with ADHD, of severity comparable with that in previously studied boys, and 50 healthy female control subjects, aged 5 to 15 years, were obtained with a 1.5-T scanner with contiguous 2-mm coronal slices and 1.5-mm axial slices. We measured volumes of total cerebrum, frontal lobes, caudate nucleus, globus pallidus, cerebellum, and cerebellar vermis. Behavioral measures included structured psychiatric interviews, parent and teacher ratings, and the Wechsler vocabulary and block design subtests. RESULTS: Total brain volume was smaller in girls with ADHD than in control subjects (effect size, 0.40; P =.05). As in our previous study in boys with ADHD, girls with ADHD had significantly smaller volumes in the posterior-inferior cerebellar vermis (lobules VIII-X; effect size, 0.54; P =.04), even when adjusted for total cerebral volume and vocabulary score. Patients and controls did not differ in asymmetry in any region. Morphometric differences correlated significantly with several ratings of ADHD severity and were not predicted by past or present stimulant drug exposure. CONCLUSIONS: These results confirm previous findings for boys in the posterior-inferior lobules of the cerebellar vermis. The influence of the cerebellar vermis on prefrontal and striatal circuitry should be explored.

Adolescent↗
PubMed2001

Imaging normal and abnormal brain development: new perspectives for child psychiatry.

OBJECTIVE: The availability of non-invasive brain imaging permits the study of normal and abnormal brain development in childhood and adolescence. This paper summarizes current knowledge of brain abnormalities of two conditions, attention deficit hyperactivity disorder (ADHD) and childhood onset schizophrenia (COS), and illustrates how such findings are bringing clinical and preclinical perspectives closer together. METHOD: A selected review is presented of the pattern and temporal characteristics of anatomic brain magnetic resonance imaging (MRI) studies in ADHD and COS. These results are discussed in terms of candidate mechanisms suggested by studies in developmental neuroscience. RESULTS: There are consistent, diagnostically specific patterns of brain abnormality for ADHD and COS. Attention deficit hyperactivity disorder is characterized by a slightly smaller (4%) total brain volume (both white and grey matter), less-consistent abnormalities of the basal ganglia and a striking (15%) decrease in posterior inferior cerebellar vermal volume. These changes do not progress with age. In contrast, patients with COS have smaller brain volume due to a 10% decrease in cortical grey volume. Moreover, in COS there is a progressive loss of regional grey volume particularly in frontal and temporal regions during adolescence. CONCLUSIONS: In ADHD, the developmental pattern suggests an early non-progressive 'lesion' involving neurotrophic factors controlling overall brain growth and selected dopamine circuits. In contrast, in COS, which shows progressive grey matter loss, various candidate processes influencing later synaptic and dendritic pruning are suggested by human post-mortem and developmental animal studies.

Adolescent↗
PubMed2001

Double-blind, placebo-controlled study of single-dose amphetamine formulations in ADHD.

OBJECTIVE: To compare the efficacy and time course of single morning doses of Adderall, extended-release, and immediate-release dextroamphetamine sulfate. METHOD: Thirty-five children with attention-deficit/hyperactivity disorder, combined type, were given Adderall, immediate-release dextroamphetamine, dextroamphetamine Spansules, and placebo in a randomized, double-blind, crossover study. Behavior ratings, locomotor activity measurements, and academic measures were obtained over a period of 8 weeks. RESULTS: All three drugs exhibited robust efficacy versus placebo on nearly all measures. The effects of dextroamphetamine Spansules were less robust in the morning, particularly compared with Adderall, but they lasted 3 to 6 hours longer, depending on the measure. Although parent behavior ratings and locomotor activity showed improvements up to 12 hours after single doses of all three drugs, the number of math problems attempted and completed correctly 4 hours after dosing were only robustly increased by Spansules. CONCLUSIONS: Both immediate-release amphetamines demonstrated earlier onset of effects, but dextroamphetamine Spansules showed more sustained effects that were present on a wider range of measures.

Amphetamines↗
PubMed2001

Brain imaging of attention deficit/hyperactivity disorder.

Advances in imaging technology allow unprecedented access to the anatomy and physiology of the living, growing human brain. Anatomical imaging studies of individuals with attention deficit/hyperactivity disorder (ADHD) consistently point to involvement of the frontal lobes, basal ganglia, corpus callosum, and cerebellum. Imaging studies of brain physiology also support involvement of right frontal-basal ganglia circuitry with a powerful modulatory influence from the cerebellum. Although not currently of diagnostic utility, further extension and refinement of these findings may offer hope for greater understanding of the core nature of ADHD and possible subtyping to inform treatment interventions.

Adolescent↗
PubMed2000

Executive function oculomotor tasks in girls with ADHD.

OBJECTIVE: To assess executive function in girls with attention-deficit/hyperactivity disorder (ADHD) using oculomotor tasks as possible trait markers for neurobiological studies. METHOD: Thirty-two girls aged 6 to 13 years with DSM-IV ADHD and 20 age-matched, normal control girls were tested on a variety of oculomotor tasks requiring attention, working memory, and response inhibition, which included smooth pursuit, delayed response, and go-no go tasks. RESULTS: Girls with ADHD performed the delayed response task correctly on 32% of trials as measured by number of memory-guided saccades, in contrast to 62% of trials for control subjects (p = .0009). Patients made twice as many commission errors to no go stimuli (p = .0001) and 3 times as many intrusion errors (saccades in the absence of go or no go stimuli; p = .004) during the go-no go task compared with controls. Smooth pursuit performance was statistically equivalent across subject groups. Repeated testing in a subgroup of 15 patients revealed substantial practice effects on go-no go performance. CONCLUSIONS: The data confirm that girls with ADHD exhibit impairments in executive function, as has been reported in boys, implying a similar pathophysiology of ADHD in both sexes. However, practice effects may limit the utility of the oculomotor go-no go task for some neurobiological studies.

Adolescent↗
PubMed1999

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.

Adolescent↗
PubMed1999

Development of the human corpus callosum during childhood and adolescence: a longitudinal MRI study.

1. Interest in the morphologic development of the corpus callosum (CC) during childhood and adolescence stems from adolescent changes in cognitive functions subserved by the CC, reports of CC anomalies for a wide variety of childhood neuropsychiatric illnesses, and controversy regarding sexual dimorphism. 2. Characterization of the normal developmental pattern of the CC is hindered by enormous variability of its size. This is especially problematic for cross-sectional studies seeking to assess possible non-linear developmental curves. 3. To more accurately characterize developmental changes, a longitudinal brain magnetic resonance imaging study with subjects rescanned at approximately 2 year intervals was conducted resulting in 251 scans from 139 healthy children and adolescents. 4. Midsagittal area of the CC, especially the posterior regions, increased robustly from ages 5 to 18 years. 5. Although the genu of the CC was significantly larger in males there were no sex differences in mean area after adjustment for total cerebral volume and the growth patterns did not differ between sexes. 6. Analysis revealed a non-linear increase in the splenium, the most posterior region, with increases greatest in the younger years. 7. The results of this longitudinal study, in addition to confirming and extending previous cross-sectional reports, provide an increasingly accurate yardstick from which to assess pathological development.

Adolescent↗
PubMed1999

ADHD in girls: clinical comparability of a research sample.

OBJECTIVE: The investigation of attention-deficit/hyperactivity disorder (ADHD) in girls raises complex questions of referral bias and selection criteria. The authors sought to determine whether they could recruit a research sample of comparably affected girls using a combination of sex-independent diagnostic criteria and sex-normed cutoffs on teacher ratings. They also report on the largest placebo-controlled crossover comparison of methylphenidate and dextroamphetamine in girls with ADHD. METHOD: Subjects were 42 girls with DSM-III-R/DSM-IV ADHD (combined type) contrasted to 56 previously studied boys with ADHD on comorbid diagnoses, behavioral ratings, psychological measures, psychiatric family history, and stimulant drug response. RESULTS: Girls with ADHD were statistically indistinguishable from comparison boys on nearly all measures. Girls exhibited robust beneficial effects on both stimulants, with nearly all (95%) responding favorably to one or both drugs in this short-term trial. Dextroamphetamine produced significantly greater weight loss than methylphenidate. CONCLUSIONS: This highly selected group of ADHD girls was strikingly comparable with comparison boys on a wide range of measures. The results confirm that girls with ADHD do not differ from boys in response to methylphenidate and dextroamphetamine and that both stimulants should be tried when response to the first is not optimal.

Analysis of Variance↗
PubMed1998

Cognitive neuroscience of attention deficit hyperactivity disorder and hyperkinetic disorder.

Currently, diagnoses of attention deficit hyperactivity disorder (ADHD) and hyperkinetic disorder (HKD) are made on the basis of phenomenology, but information is accumulating from the neurosciences about the biological bases of these disorders. Recent studies addressing the neuropsychology, neuroanatomy, neurochemistry, and molecular biology of ADHD/HKD document abnormalities in well-defined neuroanatomical networks and neurochemical pathways. Magnetic resonance imaging (MRI) studies have shown that some regions of the frontal lobes (anterior superior and inferior) and basal ganglia (caudate nucleus and globus pallidus) are about 10% smaller in ADHD groups than in control groups of children, and molecular genetic studies have shown that diagnosis of ADHD is associated with polymorphisms in some dopamine genes (the dopamine D4 receptor gene and the dopamine transporter gene).

Animals↗
PubMed1998

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, adoption, and twin studies suggest that genetic factors contribute significantly. Polymorphisms of the dopamine 4 receptor (DRD4) affect receptor binding, and one allele with seven tandem repeats in exon 3 (DRD4*7R) has been associated with ADHD. 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, 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.

Alleles↗
PubMed1998

"Multidimensionally impaired disorder": is it a variant of very early-onset schizophrenia?

OBJECTIVE: To examine the validity of diagnostic criteria for a subgroup of children with atypical psychosis (n = 19), designated here as "multidimensionally impaired." These children are characterized by poor attention and impulse control, psychotic symptoms, and poor affective control. METHOD: Children and adolescents (n = 19) meeting our criteria for multidimensionally impaired syndrome with onset of psychotic symptoms at or before age 12 years were identified from a total of 150 in-person screenings for very early-onset schizophrenia between 1990 and 1996. We compared the premorbid adjustment, family history, follow-up status, and laboratory measures for a subgroup of these children with those of (1) a rigorously defined group of 29 children with DSM-III-R schizophrenia and (2) 19 children with attention-deficit hyperactivity disorder. RESULTS: Patients with multidimensionally impaired syndrome and patients with very early-onset schizophrenia shared a similar pattern of early transient autistic features, postpsychotic cognitive decline, and an elevated risk of schizophrenic-spectrum disorders among their first-degree relatives. This pattern was not seen in the attention-deficit hyperactivity disorder group. In contrast to very early-onset schizophrenia, the multidimensionally impaired group had significantly poorer scores on the Freedom From Distractibility factor on the WISC-R, a less deviant pattern of autonomic reactivity, and no progression to schizophrenia. CONCLUSIONS: The findings support the distinction of the multidimensionally impaired cases as separate from those with other psychiatric disorders, and there is somewhat greater evidence to suggest that this disorder belongs in the schizophrenia spectrum.

Adolescent↗
PubMed1998

Progressive reduction of temporal lobe structures in childhood-onset schizophrenia.

OBJECTIVE: A previous cross-sectional study of brain morphology in childhood-onset schizophrenia indicated sparing of the temporal lobes from processes reducing total cerebral volume in this population. In the present study, subjects with childhood-onset schizophrenia and healthy subjects were rescanned at 2-year follow-up to determine whether this pattern of temporal lobe sparing persists with ongoing illness. METHOD: Anatomic brain magnetic resonance imaging scans were acquired for 10 adolescent patients with average onset of schizophrenia at 10.4 years (SD = 1.7) and 17 healthy adolescents. Scans were obtained on initial admission and at 2-year follow-up by using identical equipment and measurement methodology. RESULTS: Schizophrenic subjects showed significantly greater decreases than healthy subjects in right temporal lobe, bilateral superior temporal gyrus and posterior superior temporal gyrus, right anterior superior temporal gyrus, and left hippocampal volumes during the follow-up interval. Decline in right posterior superior temporal gyrus was associated with high total scores on the Scale for the Assessment of Positive Symptoms at baseline and at follow-up. CONCLUSIONS: Progressive reduction of temporal lobe structures occurs with ongoing illness in childhood-onset schizophrenia.

Adolescent↗