Biomedical subjects

J T McCracken

Publications and source records attributed to J T McCracken.

At least 19 recordsLinked to original sources

PubMed2006

Genomewide linkage scan for obsessive-compulsive disorder: evidence for susceptibility loci on chromosomes 3q, 7p, 1q, 15q, and 6q.

Obsessive-compulsive disorder (OCD) is the tenth most disabling medical condition worldwide. Twin and family studies implicate a genetic etiology for this disorder, although specific genes have yet to be identified. Here, we present the first large-scale model-free linkage analysis of both extended and nuclear families using both 'broad' (definite and probable diagnoses) and 'narrow' (definite only) definitions of OCD. We conducted a genome-scan analysis of 219 families collected as part of the OCD Collaborative Genetics Study. Suggestive linkage signals were revealed by multipoint analysis on chromosomes 3q27-28 (P=0.0003), 6q (P=0.003), 7p (P=0.001), 1q (P=0.003), and 15q (P=0.006). Using the 'broad' OCD definition, we observed the strongest evidence for linkage on chromosome 3q27-28. The maximum overall Kong and Cox LODall score (2.67) occurred at D3S1262 and D3S2398, and simulation based P-values for these two signals were 0.0003 and 0.0004, respectively, although for both signals, the simulation-based genome-wide significance levels were 0.055. Covariate-linkage analyses implicated a possible role of gene(s) on chromosome 1 in increasing the risk for an earlier onset form of OCD. We are currently pursuing fine mapping in the five regions giving suggestive signals, with a particular focus on 3q27-28. Given probable etiologic heterogeneity in OCD, mapping gene(s) involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods.

Chromosomes, Human↗

PubMed2004

Genome-wide scan of reading ability in affected sibling pairs with attention-deficit/hyperactivity disorder: unique and shared genetic effects.

Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are common highly heritable disorders of childhood, which frequently co-occur. Data from twin and family studies suggest that this overlap is, in part, due to shared genetic underpinnings. Here, we report the first genome-wide linkage analysis of measures of reading ability in children with ADHD, using a sample of 233 affected sibling pairs who previously participated in a genome-wide scan for susceptibility loci in ADHD. Quantitative trait locus (QTL) analysis of a composite reading factor defined from three highly correlated reading measures identified suggestive linkage (multipoint maximum lod score, MLS>2.2) in four chromosomal regions. Two regions (16p, 17q) overlap those implicated by our previous genome-wide scan for ADHD in the same sample: one region (2p) provides replication for an RD susceptibility locus, and one region (10q) falls approximately 35 cM from a modestly highlighted region in an independent genome-wide scan of siblings with ADHD. Investigation of an individual reading measure of Reading Recognition supported linkage to putative RD susceptibility regions on chromosome 8p (MLS=2.4) and 15q (MLS=1.38). Thus, the data support the existence of genetic factors that have pleiotropic effects on ADHD and reading ability--as suggested by shared linkages on 16p, 17q and possibly 10q--but also those that appear to be unique to reading--as indicated by linkages on 2p, 8p and 15q that coincide with those previously found in studies of RD. Our study also suggests that reading measures may represent useful phenotypes in ADHD research. The eventual identification of genes underlying these unique and shared linkages may increase our understanding of ADHD, RD and the relationship between the two.

Adolescent↗

PubMed2004

Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5.

Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop ADHD. Reports implicate variants of genes important for the synthesis, uptake, transport and receptor binding of dopamine in the etiology of ADHD, including DRD4, DAT1, DRD2, and DRD5. In the present study, we genotyped a large multiplex sample of ADHD affected children and their parents for polymorphisms in genes previously reported to be associated with ADHD. Associations were tested by the transmission disequilibrium test (TDT). The sample is sufficient to detect genotype relative risks (GRRs) for putative risk alleles. The DRD4 gene 120-bp insertion/deletion promoter polymorphism displayed a significant bias in transmission of the insertion (chi(2)=7.58, P=0.006) as suggested by an analysis of a subset of these families. The seven repeat allele of the DRD4 48-bp repeat polymorphism (DRD4.7) was not significantly associated with ADHD in the large sample in contrast to our earlier findings in a smaller subset. We replicate an association of a dinucleotide repeat polymorphism near the DRD5 gene with ADHD by showing biased nontransmission of the 146-bp allele (P=0.02) and a trend toward excess transmission of the 148-bp allele (P=0.053). No evidence for an association was found for polymorphisms in DRD2 or DAT1 in this sample. The DRD5 146-bp (DRD5.146) allele and the DRD4 240-bp (DRD4.240) allele of the promoter polymorphism emerge as the two DNA variants showing a significant association in this large sample of predominantly multiplex families with ADHD, with estimated GRRs of 1.7 and 1.37, respectively.

Adolescent↗

PubMed2003

Biased paternal transmission of SNAP-25 risk alleles in attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder, affecting 5-10% of school-age children. Although the biological basis of this disorder is unknown, twin and family studies provide strong evidence that ADHD has a genetic basis involving multiple genes. A previous study found an association between ADHD and two polymorphisms in the 3' untranslated region (UTR) of SNAP-25, a gene encoding a synaptic vesicle docking protein known to play a role in the hyperactivity observed in the Coloboma mouse strain. In this paper, we test biased transmission of the 3' UTR SNAP-25 haplotype using a larger ADHD sample of 113 families with 207 affected children. Using the transmission disequilibrium test (TDT), we found a trend consistent with biased transmission of the TC haplotype of SNAP-25 in all transmissions and detected a significant distortion (P=0.027) when paternal transmissions were evaluated.

Adolescent↗

PubMed2001

Medial temporal lobe in childhood-onset schizophrenia.

The majority of anatomic and neuroimaging studies in adult-onset schizophrenia demonstrate decreased volumes of the medial temporal lobe when compared with findings in normal individuals. The goal of this study was to investigate the hypothesis that subjects with childhood-onset schizophrenia would show decreased volumes of the medial temporal lobe when compared to normal children. Thirteen children meeting DSM-III-R criteria for schizophrenia (mean age 14.2+/-3.8 years) and 20 normal children (mean age 12.0+/-2.8 years) were investigated. MRI scans were performed on a 1.5-T GE Signa MR scanner using a coronal plane SPGR at 1.4-mm slice thickness. Volumes were assessed by manually tracing bilateral hippocampus, amygdala and temporal lobes. After adjustment for age and total brain volume, the amygdala was significantly larger in the schizophrenics than in the control subjects, and this volume increase was more pronounced on the left side. Hippocampus volumes did not differ significantly across groups. There was a nearly significant left-greater-than-right asymmetry of the amygdala in the schizophrenic group but not in the normal group. A nearly significant right-greater-than-left asymmetry was found in the anterior hippocampus for both schizophrenic and control groups. These findings are consistent with previous reports of at least initial sparing of temporal lobe regions in childhood-onset schizophrenia.

Adolescent↗

PubMed2001

Mapping cortical asymmetry and complexity patterns in normal children.

This study reports the first comprehensive three-dimensional (3D) maps of cortical patterns in children. Using a novel parametric mesh-based analytic technique applied to high-resolution T1-weighted MRI scans, we examined age (6-16 years) and gender differences in cortical complexity (the fractal dimension or complexity of sulcal/gyral convolutions) and asymmetry of 24 primary cortical sulci in normally developing children (N=24). Three-dimensional models of the cerebral cortex were extracted and major sulci mapped in stereotaxic space. Given the documented age-related changes in frontal lobe functions and several neuroimaging studies that have reported accompanying volumetric changes in these regions, we hypothesized that, with age, we would find continued modifications of the cerebrum in frontal cortex. We also predicted that phylogenetically older regions of the cerebrum, such as olfactory cortex, would be less variable in anatomic location across subjects and with age. Age-related increases in cortical complexity were found in both left and right inferior frontal and left superior frontal regions, possibly indicating an increase in secondary branching with age in these regions. Moreover, a significant increase in the length of the left inferior frontal sulcus and a posterior shifting of the left pre-central sulcus was associated with age. Three-dimensional asymmetry and anatomic variability maps revealed a significant left-greater-than-right asymmetry of the Sylvian fissures and superior temporal sulci, and increased variance in dorsolateral frontal and perisylvian areas relative to ventral regions of the cortex. These results suggest increases in cortical complexity and subtle modifications of sulcal topography of frontal lobe regions, likely reflecting ongoing processes such as myelination and synaptic remodeling that continue into the second decade of life. More studies in a larger sample set and/or longitudinal design are needed to address the issues of normal individual variation and sulcal development.

Adolescent↗

PubMed2001

Mental health problems and service use among female juvenile offenders: their relationship to criminal history.

OBJECTIVE: To describe (1) the level of mental health problems and lifetime use of specialty mental health services and special education programs among incarcerated female juvenile offenders and (2) how these indices relate to their criminal history. METHOD: Between 1997 and 1998, fifty-four female youths incarcerated in California were interviewed on-site using standardized self-report measures of depression and anxiety symptoms and substance use problems. RESULTS: Eighty percent of the youths had symptoms of an emotional disorder or substance use problem, and almost two thirds (63%) had a history of recidivism. Of those with emotional symptoms or a substance use problem, 51% had used specialty mental health services and 58% had been in a special education program during their lifetime. In addition, among recidivistic youths, 82% had a history of a substance use problem and 47% had used specialty mental health services during their lifetime. CONCLUSIONS: A substantial proportion of female juvenile offenders merit a mental health evaluation. Interventions for these high-risk youths should include an assessment for substance use disorders because of the association of recidivism and substance use problems in this population.

Adolescent↗

PubMed2000

Attention-deficit/hyperactivity disorder: perspectives from neuroimaging.

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood behavioral disorder most often characterized by inattentiveness, impulsivity, and hyperactivity. Current etiologic theories suggest that ADHD stems from abnormalities in dopaminergic and possibly noradrenergic brainstem nuclei that act to regulate a cortico-striato-thalamo-cortical network, believed to be critical for executive functions and the regulation of behavioral responses such as arousal, attention, and inhibition. Noninvasive structural and functional neuroimaging techniques provide a new avenue for exploring the validity of these theories. Despite their limitations, neuroimaging studies have provided a unique and otherwise inaccessible, biological perspective of ADHD. Collectively, the studies reviewed here reveal that dysfunction in arousal, behavioral inhibition, and attention associated with ADHD may result from structural abnormalities in frontostriatal regions that in turn result in diminished activity essential for normal function.

Attention Deficit Disorder with Hyperactivity↗

PubMed2000

Assessment in multisite randomized clinical trials of patients with autistic disorder: the Autism RUPP Network. Research Units on Pediatric Psychopharmacology.

Assessment of autistic disorder (autism) symptoms, primary and secondary, poses more challenging problems than ordinarily found in multisite randomized clinical trial (RCT) assessments. For example, subjects may be uncommunicative and extremely heterogeneous in problem presentation, and current pharmacological treatments are not likely to alter most core features of autism. The Autism Research Units on Pediatric Psychopharmacology (RUPP Autism Network) resolved some of these problems during the design of a risperidone RCT in children/adolescents. The inappropriateness of the usual anchors for a Clinical Global Impression of Severity (CGI-S) was resolved by defining uncomplicated autism without secondary symptoms as a CGI-S of 3, mildly ill. The communication problems, compromising use of the patient as an informant, were addressed by several strategies, including careful questioning of care providers, rating scales, laboratory tests, and physical exams. The broad subject heterogeneity requires outcome measures sensitive to individual change over a wide spectrum of treatment response and side effects. The problems of neuropsychologically testing nonverbal, lower functioning, sometimes noncompliant subjects requires careful instrument selection/adaptation and flexible administration techniques. The problems of assessing low-end IQs, neglected by most standardized test developers, was resolved by an algorithm of test hierarchy. Scarcity of other autism-adapted cognitive and neuropsychological tests and lack of standardization required development of a new, specially adapted battery. Reliability on the Autism Diagnostic Interview (currently the most valid diagnostic instrument) and other clinician instruments required extensive cross-site training (in-person, videotape, and teleconference sessions). Definition of a treatment responder required focus on individually relevant target symptoms, synthesis of possible modest improvements in many domains, and acceptance of attainable though imperfect goals. The assessment strategy developed is implemented in a RCT of risperidone (McDougle et al., 2000) for which the design and other methodological challenges are described elsewhere (Scahill et al., 2000). Some of these problems and solutions are partially shared with RCTs of other treatments and other disorders.

Antipsychotic Agents↗

PubMed2000

Evidence for linkage of a tandem duplication polymorphism upstream of the dopamine D4 receptor gene (DRD4) with attention deficit hyperactivity disorder (ADHD).

Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder. Evidence from twin, adoption, and family studies provide support for a genetic contribution to the etiology of ADHD. Several candidate gene studies have identified an association between a 7-repeat variant in exon 3 of the dopamine 4 receptor gene (DRD4) and ADHD. However, in spite of the positive reports finding association of the exon 3 VNTR with ADHD, several other polymorphisms within DRD4 have been identified that conceivably could contribute to risk for ADHD. Recently, another common polymorphism of the DRD4 gene has been described involving a 120-bp repeat element upstream of the 5' transcription initiation site. In this report, we describe results of analysis of the DRD4 120-bp repeat promoter polymorphism in a sample of 371 children with ADHD and their parents, using the transmission disequilibrium test (TDT). Results showed a significant preferential transmission of the 240-bp (long) allele with ADHD. Exploratory analyses of the Inattentive phenotypic subtype of ADHD strengthened the evidence for linkage. These data add further support for the role of DRD4 variants conferring increased risk for ADHD, and imply that additional studies of DRD4 and other related genes are needed.

Adolescent↗

PubMed2000

The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I. Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: Expert consensus methodology was used to develop evidence-based, consensually agreed-upon medication treatment algorithms for attention-deficit/hyperactivity disorder (ADHD) in the public mental health sector. Although treatment algorithms for adult mental disorders have been developed, this represents one of the first attempts to develop similar algorithms for childhood mental disorders. Although these algorithms were developed initially for the public sector, the goals of this approach are to increase the uniformity of treatment and improve the clinical outcomes of children and adolescents with ADHD in a variety of treatment settings. METHOD: A consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families was convened to develop evidence-based consensus algorithms for the pharmacotherapy of childhood ADHD. After a series of presentations of current research evidence and panel discussion, the consensus panel met and drafted the algorithms along with guidelines for implementation. RESULTS: The panel developed consensually agreed-upon algorithms for ADHD with and without specific comorbid disorders. The algorithms consist of systematic strategies for psychopharmacological interventions and tactics to ensure successful implementation of the strategies. While the algorithms focused on the medication management of ADHD, the conference emphasized that psychosocial treatments are often a critical component of the overall management of ADHD. CONCLUSIONS: Medication algorithms for ADHD can be developed with consensus. A companion article will discuss the implementation of these algorithms.

Adrenergic alpha-Agonists↗

PubMed2000

The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part II: Tactics. Attention-Deficit/Hyperactivity Disorder.

OBJECTIVES: Expert consensus methodology was used to develop a medication treatment algorithm for attention-deficit/hyperactivity disorder (ADHD). The algorithm broadly outlined the choice of medication for ADHD and some of its most common comorbid conditions. Specific tactical recommendations were developed with regard to medication dosage, assessment of drug response, management of side effects, and long-term medication management. METHOD: The consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, and families developed evidence-based tactics for the pharmacotherapy of childhood ADHD and its common comorbid disorders. The panel discussed specifics of treatment of ADHD and its comorbid conditions with stimulants, antidepressants, mood stabilizers, alpha-agonists, and (when appropriate) antipsychotics. RESULTS: Specific tactics for the use of each of the above agents are outlined. The tactics are designed to be practical for implementation in the public mental health sector, but they may have utility in many practice settings, including the private practice environment. CONCLUSIONS: Tactics for psychopharmacological management of ADHD can be developed with consensus.

Adrenergic alpha-Agonists↗

PubMed2000

Familial clustering of symptoms and disruptive behaviors in multiplex families with attention-deficit/hyperactivity disorder.

OBJECTIVE: To examine familial clustering of attention-deficit/hyperactivity disorder (ADHD), ADHD subtypes, symptoms, and oppositional behaviors in affected sibling pairs (ASPs) and their parents. METHOD: One hundred thirty-two ASPs, ranging in age from 5 to 25 years and ascertained through clinic and volunteer referrals, were examined for DSM-IV ADHD subtypes, oppositional defiant disorder (ODD), and conduct disorder (CD) with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL). Two hundred fifty-six parents in these families were assessed by means of the SADS-Lifetime version, Modified for the Study of Anxiety Disorders, Updated for DSM-IV (SADS-LA-IV), and the Behavioral Disorders supplement of the K-SADS-PL to determine ADHD, ODD, and CD. RESULTS: Fifty-five percent of families ascertained through an ASP have at least one parent with a lifetime diagnosis of ADHD. The frequency of ADHD in at least one parent was higher in families with at least one affected girl (63%) than in families with only affected boys (45%) (p = .02). There was no evidence that affected siblings or parents within ASP families showed similar patterns of ADHD symptoms, such as ADHD subtype classification. In contrast, CD significantly clustered in ASP families. CONCLUSIONS: The sex difference in prevalence of ADHD among ASPs is consistent with a model of inheritance in which girls require a greater loading of familial influences to develop ADHD. The lack of familial clustering of ADHD symptoms within ASP families suggests that hyperactive and inattentive symptoms reflect common familial underpinnings and not unique familial effects. In contrast, CD seems to reflect unique familial underpinnings distinct from those underlying ADHD.

Adolescent↗

PubMed2000

Assessment of attention deficit hyperactivity disorder: a review of recent literature.

Attention deficit hyperactivity disorder is one of the most common behavioral disorders of childhood and is frequently assessed and treated by pediatricians and other primary care physicians. The diagnosis of attention deficit hyperactivity disorder is based on the careful synthesis of clinical data derived from multiple sources, notably, the patient, parents, and teachers. Standard behavioral rating scales simplify and standardize collection of clinical data but by themselves are not sufficient for a diagnosis. Recognition and treatment of disorders comorbid with attention deficit hyperactivity disorder are necessary for optimal outcomes. Psychoeducational testing is useful in the assessment of suspected associated learning disabilities, but there is no evidence at present to support use of psychologic testing, laboratory measures of attention, electroencephalography, or neuroimaging studies in the clinical assessment of attention deficit hyperactivity disorder.

Adolescent↗

PubMed2000

Mood stabilizers in the treatment of juvenile bipolar disorder. Advances and controversies.

Controlled studies of mood stabilizer (mono and combination) therapy are needed in children and adolescents to develop safe and effective treatment strategies for a disorder that now has a cohort and that carries a high human and economic cost. Through the use of a variety of diagnostic instruments and novel outcome measures, we may continue to refine DSM categories into more sensitive and specific diagnostic constructs. In addition, identification of neurobiologic and genetic markers for early-onset BPD, ADHD, CD, and IED could provide powerful tools in the process of breaking down phenotypes and establishing biologic predictors of targeted pharmacologic interventions in the face of new drug developments.

Adolescent↗

PubMed2000

Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. Background and rationale for an initial controlled study of risperidone.

This article has reviewed the background and rationale for the choice of risperidone as the first drug to be studied by the RUPP Autism Network. Risperidone has potent effects on 5-HT and DA neuronal systems, both of which have been implicated in the pathophysiology of autism. Unlike the typical antipsychotics, haloperidol and pimozide, which have been shown to be effective for reducing many of the maladaptive behaviors associated with autism, risperidone's 5-HT2A/DA D2 ratio of receptor blockade appears to produce a lower risk of acute and chronic extrapyramidal side effects, as well as enhanced efficacy for the "negative" symptoms of autism. Indirect clinical and preclinical evidence supports the use of risperidone to treat impaired social behavior, interfering repetitive phenomena, and aggression, targets of pharmacotherapy for many patients with autism. Numerous published open-label trials in children and adolescents with autism and related PDDs and one double-blind, placebo-controlled study in adults suggest that risperidone has promise for the treatment of children and adolescents with autism. Because most of these studies have been short-term, open-label trials in small samples, however, a large-scale controlled study of risperidone in children and adolescents with autism is needed to confirm these results. Finally, because it is likely that children who demonstrate short-term benefit from risperidone will remain on the medication indefinitely, the longer-term effectiveness and safety of risperidone in this population also needs to be determined. The design of this study and the assessments used are described separately.

Adolescent↗

PubMed1999

REM sleep in depression is influenced by ethnicity.

The influence of ethnicity on the manifestation of EEG sleep changes in depression was studied in 95 patients (21 African-Americans [AA], 17 Asians [AS], 37 Caucasians [C] and 20 Hispanics [H]) with unipolar major depression. Subjects were studied twice for 2 consecutive nights. On the second night of each 2-night session, placebo or scopolamine (1.5 microg/kg, IM, at 23.00 h) was administered. On the baseline (placebo) night, sleep architecture, sleep continuity and rapid eye movement (REM) sleep variables were generally comparable among the groups. However, REM sleep was less in AA and AS subjects than in C and H subjects. Furthermore, the distribution of REM sleep over the course of the night in AA and AS subjects differed significantly from that in the C and H groups. Although scopolamine significantly affected sleep continuity and REM sleep measures, no significant differential effects of scopolamine were observed. Because many antidepressants suppress REM sleep, the differences in baseline REM sleep observed might be related to the greater sensitivity of some ethnic-minority depressed patients to pharmacotherapy.

Adult↗

PubMed1999

Cerebellar vermis lobules VIII-X in autism.

1. The aim was to investigate cerebellar vermis cross-sectional area in a group of high-functioning autistic children and normal control children. 2. Cerebellar vermis area measurements were completed on MRI scans from 8 autistic children (mean age 12.5 +/- 2.2, mean IQ 83.3 +/- 11.9) and 21 normal children (mean age 12.0 +/- 2.8, mean IQ 115 +/- 11). 3. The area of cerebellar vermis lobules VIII-X was significantly smaller in the autistic children than in the normal control subjects. ANCOVA demonstrated a confounding effect of IQ on these results. 4. Larger studies of autistic and normal subjects will be needed to assess the relationship between cerebellar abnormalities, autistic symptoms and IQ.

Adolescent↗