Adult ADHD: association with the dopamine D4 receptor gene.
ADHD gene may have benefitted eary humans(1/902)
immune systime protein linked to ADHD(1/802)
Brain Image Scanning & Mapping with AD/HD: An Overview
Brain Image Scanning & Mapping with AD/HD: An Overview
154th Annual Meeting of the American Psychiatric Association,May 8, 2001
Perspectives on ADHD,
ADHD and Comorbidit
New CDC Report Looks at Attention-Deficit/Hyperactivity Disorder 5/21/02
Are Sleep Problems Linked to Inattention and Hyperactivity?
Sleep Apnea Steals More Than Sound Slumber From Kids
A quantitative trait locus analysis of the dopamine transporter gene in adults
Serotonin platelet-transporter measures in childhood attention-deficit/hyperactivity disorder     
controlled trial of transdermal nicotine in the treatment of ADHD        
How are the neurotransmitters dopamine and norepinephrine related to the pathophysiology of attention-deficit hyperactivity disorder (ADHD)?
Effects of Methylphenidate Discontinuation on Cerebral Blood Flow in Prepubescent Boys with Attention Deficit Hyperactivity Disorder.
Efficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder.
Neuropsychological profiles of adolescents with ADHD: effects of reading difficulties and gender.
Phonological processing in children with attention deficit hyperactivity disorder: Is methylphenidate effective?
Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.
CDC Study Confirms ADHD/Learning Disability Link
Smoking During Pregnancy Linked with ADHD

 Smoking During Pregnancy Linked with ADHD
Thu Nov 20, 3:17 PM ET  
NEW YORK (Reuters Health) - Women who smoke during pregnancy appear to have a greater risk of having a child with symptoms of attention deficit hyperactivity disorder (ADHD), according to UK researchers.

Dr. Anita Thapar, of the University of Wales College of Medicine, and colleagues used questionnaires to assess children's ADHD symptoms, maternal smoking during pregnancy, conduct disorder symptoms, and family adversity, in a sample population of 1452 pairs of twins.

Genetic factors accounted for most of the cases of ADHD, the investigators report in the November issue of the American Journal of Psychiatry. However, they also noted a significant association between smoking during pregnancy and the development of ADHD symptoms in the children.

When the team re-evaluated the data, after taking into consideration the effects of social adversity, birth weight, and antisocial symptom scores, maternal smoking had a significant influence on the development of ADHD symptoms.

"Our findings extend previous work by being the first to demonstrate that the association of prenatal smoking with ADHD remains even when the...genetic contribution to ADHD symptoms is included, " Thapar and colleagues conclude.

SOURCE: American Journal of Psychiatry, November 2003.

 CDC Study Confirms ADHD/Learning Disability Link
Mental Health Weekly 12(21):6-7, 2002. © 2002 Manisses Communications Group, Inc
About one-half of the 1.6 million elementary school-aged children diagnosed with attention-deficit/hyperactivity disorder (ADHD), a condition also known as attention-deficit disorder (ADD), have also been identified as having a learning disability (LD), according to a new study by the Centers for Disease Control and Prevention (CDC).
The report, Prevalence of Attention-Deficit Disorder and Learning Disability: United States, 1997-1998, is based on data from the CDC's National Health Interview Survey (NHIS), which focused on children ages 6 to 11. The NHIS was a national household survey that collected health status and sociodemographic information on the civilian noninstitutionalized population of the United States.
According to the report, from 1997-1998, more than 2.6 million children ages 6-11 were reported to have ever had a diagnosis of either ADD or LD. Three percent of the children had been diagnosed with only ADD, 4 percent with only LD, and 4 percent with both conditions, according to the NHIS.
The NHIS is the first national survey to include questions on the prevalence of both diagnosed ADD and LD in school-aged children. According to the study, the differences in the way in which ADD and LD were measured in other national and community-based studies makes it difficult to compare these estimates with the NHIS results.
"This report serves as a snapshot of a condition that has important consequences for the development of school-age children," said David Fleming, M.D., acting CDC director. "However, much more needs to be learned about ADHD and about the spectrum of impairments associated with ADHD."
The advocacy organization CHADD (Children and Adults with Attention-Deficit/Hyperactivity Disorder) applauded the CDC for highlighting the significance of ADHD and learning disabilities.
"This report reinforces what the leading scientific institutions have been telling us all along," said Clarke Ross, chief executive of CHADD. "Individuals affected by ADHD rarely have ADHD alone. Nearly 70 percent of those with ADHD simultaneously cope with other conditions such as learning disabilities, mood disorders, anxiety and more."
Ross said the complexity of the disorders combined with the challenge of appropriate treatment for individuals with ADHD points to the need for additional research, early intervention and appropriate assessment.
The report found that among children with the LD diagnosis, 54 percent were in special education. This was nearly five times greater than the percent observed for children with ADD and no LD and over 23 times the percent reported for children with neither ADD nor LD.
Among children with LD and no ADD, 46 percent attended special education, and among those with both ADD and LD, 65 percent were in special education. Among children with LD, the percent of boys and girls in special education was similar.
According to the report, the percent of boys with only ADD was almost three times greater than the percent of girls with ADD, and the percent of boys with both diagnoses was over two times greater than the percent of girls with both diagnoses. The percent of boys and girls with only LD was similar.
The findings also indicated that white non-Hispanic children were more often diagnosed with only ADD than black non-Hispanic or Hispanic children. However, the percent of children with only LD did not vary significantly by race or ethnicity.
The report found that in the last 30 years, behavioral and learning disorders in school-aged children have become major health concerns in the U.S. The study authors noted, however, that lack of health care insurance and limited access to mental health services have left some children undiagnosed and untreated.
"There has been concern in some circles that ADHD has been overdiagnosed among those with regular access to health care," said Fleming. "And there is equal concern that the problem may be underdiagnosed among those who have limited or no access to care. It's clearly important to accurately identify children with ADHD and ensure that they have appropriate health care."
Many adults have identified underachievement and failure in school as serious problems facing youth. At the same time, said the report, educators have reported a rise in the number of school-aged children with disabling behavioral and learning disorders.
Health Impact
The report found that health problems, including impaired vision and hearing, allergies, and chronic health conditions other than asthma, were reported more frequently for children with LD than for children with neither ADD nor LD.
The percent of children with four or more health care visits during the past 12 months was 34 percent for children with only LD, 45 percent for children with only ADD, and 51 percent for children with both diagnoses. Among children with neither ADD nor LD, 23 percent had four or more health care visits during the past 12 months.
Children with ADD more often had contact with a mental health professional, used prescription medication regularly, and had frequent health care visits, said the report.
The study noted that the regular use of prescription medication was highest among children with ADD: 54 percent for children with only ADD and 61 percent for children with both ADD and LD. Prescription medication use for children without ADD was lower: 14 percent for children with only LD and 6 percent for children with neither ADD nor LD.
The full report is available at

 How are the neurotransmitters dopamine and norepinephrine related to the pathophysiology of attention-deficit hyperactivity disorder (ADHD)?
The neurotransmitters dopamine (DA) and norepinephrine (NE) are implicated in the pathophysiology of ADHD. Dopamine is involved in reward, risk taking, impulsivity, and mood. Norepinephrine modulates attention, arousal, and mood. Brain studies on individuals with ADHD suggest a defect in the dopamine receptor D4 (DRD4) receptor gene and overexpression of DAT1. The DRD4 receptor uses DA and NE to modulate attention to and responses to one's environment. The DAT1 or dopamine transporter protein takes DA/NE into the presynaptic nerve terminal so it may not have sufficient interaction with the postsynaptic receptor. The implications of these limited receptor findings require further study; however, it seems clear that dopamine and norepinephrine are involved in the pathophysiology of ADHD.
Source: Dopheide JA.: ADHD Part 1: Current Status, Diagnosis, Etiology/Pathophysiology. Medscape Conference Summaries from the American Pharmaceutical Association 148th Annual Meeting; March 16-20, 2001; San Francisco, California. Medscape Pharmacists. 2001.

 A quantitative trait locus analysis of the dopamine transporter gene in adults with ADHD [In Process Citation] Neuropsychopharmacology 2002 Oct;27(4):655 (ISSN: 0893-133X) Muglia P; Jain U; Inkster B; Kennedy J
Neurogenetics Section, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Canada. Numerous lines of evidence have shown that attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, whether it is considered as a category or a dimension. We tested for an association between the dopamine transporter gene (DAT1) and ADHD considering the disorder as categorical as well as a continuous trait. Genotypes for the DAT1 variable number of tandem repeat (VNTR) alleles, along with Brown Attention Deficit Disorder Scale (BADDS) and Wender Utah Rating Scale (WURS) scores were available for 152 adult ADHD patients. In 72 of these patients DNAs from at least one parent were accessible to perform a family-based analysis (FBAT). The mean quantitative trait values of the whole sample of singleton patients were compared among the specific genotype groups using ANOVA. The family-based analysis did not reveal any association between DAT1 alleles and ADHD either when it was considered as a dichotomous trait (Z = 0.16, p =.86) or as a continuous trait (Wender Scale Z = -1.67, p =.09; Brown ADD Scale Z = 0.28, p =.77). No significant differences were detected in the mean symptom scores among the specific genotype groups. The results from our study do not support a major role for the DAT1 VNTR alleles in our sample of adult ADHD. In view of several positive reports in child ADHD, more work is required to elucidate the potential role of the DAT1 VNTR as a risk factor in ADHD. Language: English MEDLINE Indexing Date: 200210 Publication Type: Status: In-Process Publication Type: Journal Article PreMedline Identifier: 0012377402 Unique NLM Identifier: 22265955 Journal Code: IM

 Sleep Apnea Steals More Than Sound Slumber From Kids
Sun Sep 1, 7:05 PM ET
By Amanda Gardner
HealthScoutNews Reporter
SUNDAY, Sept. 1 (HealthScoutNews) -- The troubles of children with sleep apnea may stretch far beyond not getting a good night's sleep.
Researchers at the Baylor College of Medicine in Houston have found the more severe the condition, the more impaired the child's performance on tests of intelligence, memory, academic performance, social skills and attention.
These findings and others raise the possibility that attention-deficit hyperactivity disorder, or ADHD, and other behavioral and learning problems may sometimes be a symptom of obstructive sleep apnea syndrome (OSAS).
"I think it's a possibility," says Dr. Daniel G. Glaze, lead author of the study and an associate professor in the departments of pediatrics and neurology at Baylor. "If they don't sleep well at night, they can't function in an appropriate way during the day. One hypothesis is that the hyperactivity is a mechanism of trying to keep yourself awake."
Fortunately, many of the kids in this study experienced dramatic improvements in quality of life when they had their tonsils and adenoids surgically removed.
"The data is incomplete because the study is still ongoing, but we have enough data at the six-month follow-up period to see dramatic improvements in several aspects of quality of life," says Dr. Michael Stewart, a co-author of the study, which was presented at the recent annual meeting of the American Society of Pediatric Otolaryngology in Boca Raton, Fla.
Children with OSAS experience an obstruction of their upper airway -- often but not always because of enlarged tonsils and/or adenoids -- that disrupts their breathing while they sleep.
One telltale symptom is snoring. Although the condition is well-recognized in adults, it is just beginning to gain attention in the pediatric world. At least 2 percent of children are estimated to suffer from the condition.
In children, the condition tends to peak in elementary school-age children, which is when tonsils and adenoids tend to be larger, says Dr. Michael Light, a professor of clinical pediatrics at the University of Miami School of Medicine and author of the Clinician's Guide to Pediatric Chronic Illness. This is also the time when children are making huge strides in their cognitive development.
"The main job of kids is to go to school. If they're not sleeping well at night, they'll have problems concentrating. That has become very clear," Glaze says. "Our preliminary findings indicate that breathing problems during sleep impact on a number of parameters including intelligence, memory, academic performance, behavior. And it impacts on families as well as on the child."
The researchers looked at 23 boys and girls between the ages of 5 and 13 who had difficulty breathing while they slept. Intelligence, memory, academic performance, attention and adaptive behavior were measured both before and after they had tonsillectomies and adenoidectomies.
Six months after surgery, the children exhibited dramatic improvements in their quality of life. One question that remains is whether these improvements will be sustained at a year or longer.
"It was our finding that, following [the surgeries] at six months, there were significant improvements on quality-of-life questionnaires," Glaze says. "As to improvements in behavior and cognition, we have not shown this. The subjects will be retested at one year to see if there is improvement and, if so, in what areas."
The quality-of-life improvements also extended to the families of children diagnosed with OSAS.
"Often when I see kids come in, the biggest problem is with their parents," Glaze says. "Several mothers had to quit their jobs because they were up and down with the kids at night, they were driving when they were drowsy, and they were falling asleep on the job."
Heartening as these results are, not all cases of OSAS can be explained by the presence of enlarged tonsils and adenoids.
Obesity, for instance, is another major risk factor for the condition, says Light, who is about to start studying the relationship between sleep and obesity.
"We haven't even scratched the surface of it," he says.
What To Do
For more information on OSAS, visit ~dement/apnea.html"Stanford University or

 World J Biol Psychiatry 2002 Apr;3(2):96-100 Books
Serotonin platelet-transporter measures in childhood attention-deficit/hyperactivity disorder (ADHD): clinical versus experimental measures of impulsivity.

Oades RD, Slusarek M, Velling S, Bondy B. University Clinic for Child and Adolescent Psychiatry, Essen, Germany.

Impulsivity in terms of aggression, suicide or poor cognitive control has been associated with low synaptic availability of serotonin (5-HT) in adults and children. However, characteristics of the 5-HT transporter have not been studied in children with attention-deficit/hyperactivity disorder (ADHD: combined type), where impulsivity is a core symptom. Here, we explored in 20 children with ADHD the relationship of the density (Bmax) and affinity (Kd) of the platelet 5-HT transporter measured with [3H]paroxetine to both clinical ratings of impulsivity (Conners' Parent Questionnaire), and an experimental measure of impulsivity (the ability to withhold a prepotent response in the "stop-signal" paradigm). Decreases of affinity (increased Kd) correlated with a low probability of response inhibition, but not with the clinical ratings of impulsivity. However, ratings of distractibility and impulsivity correlated with the experimental measure of response-inhibition. In contrast, increased transporter affinity (low Kd) correlated modestly with higher ratings of aggressive and externalising behaviour. Bmax was not associated with any behavioural score. We conclude that the synaptic availability of 5-HT is under the control of the 5-HT transporter binding site affinity and that low affinity may be related to cognitive impulsivity (distractibility). Increased affinity of the transporter may also be related to conduct disturbance.

PMID: 12479082 [PubMed - in process]


 A pilot controlled trial of transdermal nicotine in the treatment of attention deficit hyperactivity disorder.

Shytle RD, Silver AA, Wilkinson BJ, Sanberg PR .World J Biol Psychiatry 2002 Jul;3(3):150-5 Books

Center for Infant and Child Development, Center for Aging and Brain Repair, Departments of Psychiatry, Neurosurgery, Neuroscience Program, University of South Florida, Tampa, Florida, USA.

OBJECTIVE: To test the hypothesis that transdermal nicotine would be efficacious for the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). METHOD: This was a double-blind, placebo-controlled, randomized, pilot trial that compared the effects of daily transdermal nicotine (5 mg/16 hrs) to placebo in children and adolescents with ADHD. There was a three-day washout period of all psychotropic medication followed by a one-week treatment period. RESULTS: All 10 subjects enrolled (six males, four females; mean age = 10 years, SEM = 0.8) completed the study. As assessed by the 48-item Conners Parent Rating Scale at endpoint and during the trial, there was a significantly greater reduction in ADHD symptoms on "Learning Problems" and "Hyperactivity" subfactors. Nausea, stomach ache, itching under patch and dizziness were the most frequently reported adverse effects associated with transdermal nicotine. CONCLUSIONS: While the results of this study support previous research indicating that nicotinic receptor modulation may be a potentially useful strategy for the treatment of ADHD, therapeutic uses of nicotine are limited due to side effects. Thus, future research should investigate ways of improving the therapeutic index of nicotinic ligands in the treatment of ADHD, such as testing selective nicotinic antagonists alone or in combination with cholinergic agonists.

PMID: 12478880 [PubMed - in process]


 Effects of Methylphenidate Discontinuation on Cerebral Blood Flow in Prepubescent Boys with Attention Deficit Hyperactivity Disorder.
J Nucl Med 2002 Dec;43(12):1624-1629

Langleben DD, Acton PD, Austin G, Elman I, Krikorian G, Monterosso JR, Portnoy O, Ridlehuber HW, Strauss HW.

Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. The Community/Academia Coalition, Mountain View, California. Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts. Division of Nuclear Medicine, Stanford University School of Medicine, Palo Alto, California.

Methylphenidate (MPH) is an effective symptomatic treatment of attention deficit hyperactivity disorder (ADHD), but the mechanisms of its therapeutic action have not been fully elucidated. To address this issue, we assessed the effects of discontinuation of chronic MPH treatment on regional cerebral blood flow (rCBF) in ADHD patients. METHODS: Twenty-two prepubescent boys with ADHD (age range, 8.2-11.5 y) and 7 healthy volunteers were studied with SPECT on and off MPH. Their rCBF data were automatically normalized to whole-brain counts and coregistered with standard anatomic space. rCBF changes were evaluated with statistical parametric mapping based on voxel-by-voxel ANOVA. RESULTS: When the subjects were not taking MPH, rCBF was higher in the motor, premotor, and the anterior cingulate cortices (Brodmann's areas 4, 6, and 32). CONCLUSION: Brief discontinuation of MPH treatment is associated with increased motor and anterior cingulate cortical activity. Our findings suggest that MPH treatment modulates motor and anterior cingulate cortical activity directly or indirectly. Alternatively, our findings may be related to MPH withdrawal. These data provide novel information on the potential mechanisms of the therapeutic action of MPH. Furthermore, they are clinically relevant to the commonly occurring brief interruptions in MPH treatment.

PMID: 12468511 [PubMed - as supplied by publisher]


E ficacy of atomoxetine versus placebo in school-age girls with attention-deficit/hyperactivity disorder.

Biederman J, Heiligenstein JH, Faries DE, Galil N, Dittmann R, Emslie GJ, Kratochvil CJ, Laws HF, Schuh KJ; Atomoxetine ADHD Study Group.
Massachusetts General Hospital, Boston, Massachusetts, USA.

OBJECTIVE: The efficacy of atomoxetine was assessed in school-age girls with attention-deficit/hyperactivity disorder (ADHD). Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other noradrenergic receptors or for other neurotransmitter transporters or receptors. METHODS: A total of 291 children who were 7 to 13 years of age and met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for ADHD participated in 1 of 2 combined, double-blind, placebo-controlled, multisite, identical clinical trials. This intent-to-treat subset analysis examined the effects of atomoxetine versus placebo in 51 girls who were randomized to atomoxetine (n = 30) or placebo (n = 21) for 9 weeks. ADHD symptoms were assessed using parent- and investigator-rated scales. RESULTS: Atomoxetine was superior to placebo on the following measures: the Attention-Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored Total Score; the Inattentive and Hyperactive/Impulsive subscales of the Attention-Deficit Hyperactivity Disorder Rating Scale-IV-Parent Version: Investigator Administered and Scored Total Score; the ADHD Index subscale of the Conners' Parent Rating Scale-Revised: Short Form; and the Clinical Global Impressions of Severity of ADHD. Statistically significant efficacy was seen 1 week after randomization and remained so for the duration of the study. One patient from each of the atomoxetine and placebo groups discontinued the study as a result of an adverse event. CONCLUSION: Atomoxetine was found to be effective and well tolerated for the treatment of ADHD in school-age girls.

 Neuropsychological profiles of adolescents with ADHD: effects of reading difficulties and gender.
J Child Psychol Psychiatry 2002 Nov;43(8):988-1003 Related Articles, Books, LinkOut  

Rucklidge JJ, Tannock R.  
The Hospital for Sick Children, Toronto, Canada.

BACKGROUND: Executive function, particularly behavioral inhibition, has been implicated as a core deficit specific to Attention-Deficit/Hyperactivity Disorder (ADHD) whereas rapid naming has been implicated as a core deficit specific to reading disabilities (RD). Females may be less impaired in executive function although adolescent females with ADHD have yet to be studied. METHOD: Neuropsychological profiles of four adolescent groups aged 13-16 with equal female representation were investigated: 35 ADHD, 12 RD, 24 ADHD+RD, and 37 normal controls. A semi-structured interview (K-SADS-PL), the Conners Rating Scales and the Ontario Child Health Study Scales were used to diagnose ADHD. RD was defined as a standard score below 90 on at least one of the following: Reading or Spelling of the WRAT3 or Word Attack or Word Identification of the WRMT-R. The WISC-III, Rapid Automatized Naming, Stroop and Stop tasks were used as measures of cognitive and executive function. RESULTS: The two ADHD groups (ADHD, ADHD+RD) showed deficits in processing speed, naming of objects, poor behavioral inhibition and greater variability in reaction times whereas the two RD groups (RD, RD+ADHD) showed verbal working memory deficits and slower verbal retrieval speed. Only the comorbid group was slower with naming of numbers and colors and had slower reaction times. Regression analyses indicated that incongruent color naming (Stroop) and variability in go reaction time were the best predictors of hyperactive/impulsive ADHD symptoms whereas variability in go reaction time and processing speed were the best predictors of inattentive ADHD symptoms. Speed of letter naming and verbal working memory accounted for the most variability in composite achievement scores. No gender differences were found on any of the cognitive tests. CONCLUSIONS: This study challenges the importance of behavioral inhibition deficits in ADHD and that naming deficits are specific to RD. Further investigation into cognitive deficits in these groups is required.

PMID: 12455921 [PubMed - in process]


27: Rev Neurol 2002 Feb 28;34 Suppl 1:S115-21 Related Articles, Books, LinkOut  

 [Phonological processing in children with attention deficit hyperactivity disorder: Is methylphenidate effective?]

[Article in Spanish]

Miranda Casas A, Ygual Fernandez A, Mulas F, Rosello B, Bo RM.

Universidad de Valencia. Facultad de Psicologia, Burjassot, Espa a.

Summary. Introduction. Although attention deficit hyperactivity disorder (ADHD) is usually associated with language disorders, there are few studies of phonological processing and the efficacy of psychostimulants (methylphenidate) on this. Objective. 1. To find whether there are differences in the development of phonological processing, evaluated using linguistic segmentation tests and tests of lexical fluency with a phonetic mediator, between children with ADHD and normal children; and 2. To analyze the effects of methylphenidate on the phonological processing of children with ADHD. Patients and methods. For the first objective, 37 children with ADHD and 37 normal children aged between 5 and 12 years were studied. Twenty were boys and 16 girls of lower middle class. Of these children, 18 of the ADHD and 18 of the normal group were studied for the second objective, 15 boys and 3 girls. Three different tests were used to evaluate aspects of phonological processing: induced phonological register, linguistic follow up and lexical fluency with phonetic mediation. Results. Significant differences were found between the experimental and control groups when carrying out all types of phonological processing tasks. In the experimental group, with or without methylphenidate, improvement was seen in lexical fluency tasks whereas linguistic segmentation test improvement was limited. Conclusions. These results show the importance of evaluating phonological processing in children with ADHD since this affects learning to read and write.

PMID: 12447801 [PubMed - in process]


38: Neuropsychopharmacology 2002 Nov;27(5):699-711 Related Articles, Books, LinkOut    
 Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder.

Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, Morin SM, Gehlert DR, Perry KW.

Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.

The selective norepinephrine (NE) transporter inhibitor atomoxetine (formerly called tomoxetine or LY139603) has been shown to alleviate symptoms in Attention Deficit/Hyperactivity Disorder (ADHD). We investigated the mechanism of action of atomoxetine in ADHD by evaluating the interaction of atomoxetine with monoamine transporters, the effects on extracellular levels of monoamines, and the expression of the neuronal activity marker Fos in brain regions. Atomoxetine inhibited binding of radioligands to clonal cell lines transfected with human NE, serotonin (5-HT) and dopamine (DA) transporters with dissociation constants (K(i)) values of 5, 77 and 1451 nM, respectively, demonstrating selectivity for NE transporters. In microdialysis studies, atomoxetine increased extracellular (EX) levels of NE in prefrontal cortex (PFC) 3-fold, but did not alter 5-HT(EX) levels. Atomoxetine also increased DA(EX) concentrations in PFC 3-fold, but did not alter DA(EX) in striatum or nucleus accumbens. In contrast, the psychostimulant methylphenidate, which is used in ADHD therapy, increased NE(EX) and DA(EX) equally in PFC, but also increased DA(EX) in the striatum and nucleus accumbens to the same level. The expression of the neuronal activity marker Fos was increased 3.7-fold in PFC by atomoxetine administration, but was not increased in the striatum or nucleus accumbens, consistent with the regional distribution of increased DA(EX). We hypothesize that the atomoxetine-induced increase of catecholamines in PFC, a region involved in attention and memory, mediates the therapeutic effects of atomoxetine in ADHD. In contrast to methylphenidate, atomoxetine did not increase DA in striatum or nucleus accumbens, suggesting it would not have motoric or drug abuse liabilities.

PMID: 12431845 [PubMed - in process]


43: Neurotoxicology 2002 Oct;23(4-5):645-51 Related Articles, Books, LinkOut  

Effects of neonatal dietary manganese exposure on brain dopamine levels and neurocognitive functions.

Tran TT, Chowanadisai W, Lonnerdal B, Le L, Parker M, Chicz-Demet A, Crinella FM.

Department of Nutrition, University of California, Davis, USA.

Neonatal exposure to high levels of manganese (Mn) has been indirectly implicated as a causal agent in attention deficit hyperactivity disorder (ADHD), since Mn toxicity and ADHD both involve dysfunction in brain dopamine (DA) systems. This study was undertaken to examine this putative relationship in an animal model by determining if levels of neonatal dietary Mn exposure were related to brain DA levels and/or behavioral tests of executive function (EF) when the animals reached maturity. We used 32 newborn male Sprague-Dawley rats and randomly assigned them to one of the four dietary Mn supplementation conditions: 0, 50, 250 and 500 microg per day, administered daily in water from postnatal days 1-21. During days 50-64, the animals were given a burrowing detour test and a passive avoidance test. At day 65, the animals were killed and brains were assayed for DA. There was a statistically significant relationship (P = 0.003) between dietary Mn exposure and striatal DA. On the burrowing detour and passive avoidance, greater deficits were observed for animals subjected to higher Mn exposure, but these differences did not reach statistical significance. However, tests for heterogeneity of variance between groups were statistically significant for all measures, with positive relationship between Mn exposure and degree of within-group behavioral variability. Kendall's nonparametric test of the relationship between the three behavioral measures and striatal DA levels was also statistically significant (P = 0.02). These results lend support to the hypothesis that neonatal Mn exposure is related to brain DA levels and neurocognitive deficit in the rodent.

PMID: 12428736 [PubMed - in process]


44: Neurology 2002 Nov 12;59(9):1388-94 Related Articles, Books, LinkOut  

Megalencephaly in NF1: predominantly white matter contribution and mitigation by ADHD.

Cutting LE, Cooper KL, Koth CW, Mostofsky SH, Kates WR, Denckla MB, Kaufmann WE.

aMRI Analysis Laboratory, Kennedy Krieger Institute, Baltimore, MD 21205, USA.

BACKGROUND: Megalencephaly is a frequent CNS manifestation in neurofibromatosis type 1 (NF1); however, its tissue composition, modification by attention deficit hyperactivity disorder (ADHD), and relationship with unidentified bright objects (UBO) remain controversial. METHODS: Eighteen male patients with NF1, seven of whom had ADHD (NF1+ADHD), were compared with 18 age- and sex-matched controls in terms of MRI-, Talairach-based brain, cerebral, lobar, and sublobar gray and white matter volumes. Twelve subjects with NF1 had UBO in the centrencephalic region, whereas six had no UBO or exclusively infratentorial lesions. RESULTS: Patients with NF1 without ADHD (NF1-pure) had the largest total cerebral, gray, and white matter volumes with larger parietal/somatosensory white matter volumes than controls, particularly if UBO were present in the basal ganglia. All subjects with NF1 (including NF1+ADHD) had larger total and frontal white matter volumes than controls. Smaller frontal/right prefrontal gray matter volumes were found in NF1+ADHD when compared with NF1-pure patients. CONCLUSIONS: The increase in frontal and parietal white matter volumes in male patients with NF1, including the preferential centrencephalic distribution, supports the hypothesis that NF1's white matter pathology encompasses but is not limited to visible UBO. Male patients with NF1+ADHD, as compared with NF1-pure patients, showed frontal reductions that are largely consistent with those found in idiopathic ADHD.

MeSH Terms:
Attention Deficit Disorder with Hyperactivity/pathology*
Attention Deficit Disorder with Hyperactivity/complications
Frontal Lobe/pathology*
Magnetic Resonance Imaging
Nerve Fibers/pathology
Neurofibromatosis 1/pathology*
Neurofibromatosis 1/complications
Parietal Lobe/pathology
Somatosensory Cortex/pathology
Support, U.S. Gov't, Non-P.H.S.
Support, U.S. Gov't, P.H.S.

Grant support:
P30 HD 24061/HD/NICHD
P50 NS 35359/NS/NINDS

PMID: 12427889 [PubMed - indexed for MEDLINE]


45: Psychiatry Res 2002 Nov 30;116(1-2):63-81 Related Articles, Books, LinkOut  

MRI parcellation of the frontal lobe in boys with attention deficit hyperactivity disorder or Tourette syndrome.

Kates WR, Frederikse M, Mostofsky SH, Folley BS, Cooper K, Mazur-Hopkins P, Kofman O, Singer HS, Denckla MB, Pearlson GD, Kaufmann WE.

Division of Psychiatric Neuroimaging, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Dysfunction of frontal-striatal-thalamic-frontal circuitry has been hypothesized to underlie both attention deficit hyperactivity disorder (ADHD) and Tourette syndrome (TS). Several research groups have therefore used anatomic magnetic resonance imaging (aMRI) to obtain volumetric measurements of subregions of the frontal lobe in these disorders. Most previous studies have relied on subparcellation methods that utilize callosal landmarks to derive subregions of the frontal lobe. In contrast, we present here an investigation of frontal lobe morphometry in ADHD and TS based on a reliable frontal subparcellation protocol that combines contiguous sulcal/gyral boundaries to derive frontal lobe modules based on prior functional studies. This highly reliable procedure subdivides the frontal lobe into five major modules: prefrontal, premotor, motor (precentral gyrus), anterior cingulate, and deep white matter. The first four modules are also segmented into gray and gyral white matter compartments. The protocol was applied to T1-weighted, SPGR coronal MRI images of 13 school-aged boys with ADHD, 13 boys with TS, and 13 age- and gender-matched controls. In ADHD, we found volumetric reductions in both the gray and white matter of the prefrontal cortex. These findings, in conjunction with previous reports on basal ganglia abnormalities, suggest that prefrontal-striatal pathways may be anomalous in ADHD. In TS, we found volumetric decreases in the left deep frontal white matter. Decreases in deep white matter suggest the presence of abnormalities in long associational and projection fiber bundles in TS. The findings of this study both confirm and extend our knowledge of the neurobiology of ADHD and TS, indicating that the reliable parcellation method presented has the potential of increasing our understanding of the role of the frontal lobe in developmental and psychiatric disorders.

PMID: 12426035 [PubMed - in process]


46: J Clin Exp Neuropsychol 2002 Sep;24(6):781-91 Related Articles, Books, LinkOut  

Training of working memory in children with ADHD.

Klingberg T, Forssberg H, Westerberg H.

Department of Neuropediatrics, Karolinska Institute, Stockholm, Sweden.

Working memory (WM) capacity is the ability to retain and manipulate information during a short period of time. This ability underlies complex reasoning and has generally been regarded as a fixed trait of the individual. Children with attention deficit hyperactivity disorder (ADHD) represent one group of subjects with a WM deficit, attributed to an impairment of the frontal lobe. In the present study, we used a new training paradigm with intensive and adaptive training of WM tasks and evaluated the effect of training with a double blind, placebo controlled design. Training significantly enhanced performance on the trained WM tasks. More importantly, the training significantly improved performance on a nontrained visuo-spatial WM task and on Raven's Progressive Matrices, which is a nonverbal complex reasoning task. In addition, motor activity--as measured by the number of head movements during a computerized test--was significantly reduced in the treatment group. A second experiment showed that similar training-induced improvements on cognitive tasks are also possible in young adults without ADHD. These results demonstrate that performance on WM tasks can be significantly improved by training, and that the training effect also generalizes to nontrained tasks requiring WM. Training improved performance on tasks related to prefrontal functioning and had also a significant effect on motor activity in children with ADHD. The results thus suggest that WM training potentially could be of clinical use for ameliorating the symptoms in ADHD.

PMID: 12424652 [PubMed - in process]


47: Psychopharmacology (Berl) 2002 Nov;164(3):277-84 Related Articles, Books, LinkOut  

Effects of stimulant medications on the EEG of children with attention-deficit/hyperactivity disorder.

Clarke AR, Barry RJ, Bond D, McCarthy R, Selikowitz M.

Brain and Behaviour Research Institute, and Department of Psychology, University of Wollongong, Wollongong 2522, Australia,

RATIONALE. Stimulant medications are the most commonly used treatments for attention deficit/hyperactivity disorder (ADHD) in North America and Australia, although it is still not entirely known how these medications work. OBJECTIVES. This study aimed to investigate the effects of stimulant medications on the EEG of children with the Combined subtype of ADHD. METHOD. An initial EEG was recorded during an eyes-closed resting condition and Fourier transformed to provide absolute and relative power estimates for the delta, theta, alpha and beta bands. Theta/alpha and theta/beta ratios were also calculated. Subjects were placed on a 6-month trial of a stimulant and a second EEG was recorded at the end of the trial. RESULTS. The ADHD group had significantly greater absolute delta and theta, less posterior absolute beta, more relative theta, and less relative alpha than the control group, which is typical of EEG studies of children with ADHD. The use of stimulant medications resulted in normalisation of the EEG, primarily evident in changes in the theta and beta bands. CONCLUSIONS. These results suggest that stimulants act to increase cortical arousal in children with ADHD, normalising their brain activity.

PMID: 12424551 [PubMed - in process]