Motor cortex inhibition: a marker of ADHD behavior and motor development in children.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset behavioral diagnosis in which children often fail to meet age norms in development of motor control, particularly timed repetitive and sequential movements, motor overflow, and balance. The neural substrate of this motor delay may include mechanisms of synaptic inhibition in or adjacent to the motor cortex. The primary objective of this study was to determine whether transcranial magnetic stimulation (TMS)-evoked measures, particularly short interval cortical inhibition (SICI), in motor cortex correlate with the presence and severity of ADHD in childhood as well as with commonly observed delays in motor control. METHODS: In this case-control study, behavioral ratings, motor skills, and motor cortex physiology were evaluated in 49 children with ADHD (mean age 10.6 years, 30 boys) and 49 typically developing children (mean age 10.5 years, 30 boys), all right-handed, aged 8-12 years. Motor skills were evaluated with the Physical and Neurological Examination for Subtle Signs (PANESS) and the Motor Assessment Battery for Children version 2. SICI and other physiologic measures were obtained using TMS in the left motor cortex. RESULTS: In children with ADHD, mean SICI was reduced by 40% (p < 0.0001) and less SICI correlated with higher ADHD severity (r = -0.52; p = 0.002). Mean PANESS motor development scores were 59% worse in children with ADHD (p < 0.0001). Worse PANESS scores correlated modestly with less SICI (r = -.30; p = 0.01). CONCLUSION: Reduced TMS-evoked SICI correlates with ADHD diagnosis and symptom severity and also reflects motor skill development in children.

Quantifying excessive mirror overflow in children with attention-deficit/hyperactivity disorder.

OBJECTIVES: Qualitative observations have revealed that children with attention-deficit/hyperactivity disorder (ADHD) show increased overflow movements, a motor sign thought to reflect impaired inhibitory control. The goal of this study was to develop and implement methods for quantifying excessive mirror overflow movements in children with ADHD. METHODS: Fifty right-handed children aged 8.2-13.3 years, 25 with ADHD (12 girls) and 25 typically developing (TD) control children (10 girls), performed a sequential finger-tapping task, completing both left-handed (LHFS) and right-handed finger sequencing (RHFS). Phasic overflow of the index and ring fingers was assessed in 34 children with video recording, and total overflow in 48 children was measured by calculating the total angular displacement of the index and ring fingers with electrogoniometer recordings. RESULTS: Phasic overflow and total overflow across both hands were greater in children with ADHD than in TD children, particularly during LHFS. Separate gender analyses revealed that boys, but not girls, with ADHD showed significantly more total phasic overflow and total overflow than did their gender-matched control children. CONCLUSIONS: The quantitative overflow measures used in this study support past qualitative findings that motor overflow persists to a greater degree in children with ADHD than in age-matched TD peers. The quantitative findings further suggest that persistence of mirror overflow is more prominent during task execution of the nondominant hand and reveal gender-based differences in developmental neural systems critical to motor control. These quantitative measures will assist future physiologic investigation of the brain basis of motor control in ADHD.

Assessing quality and normalization of microarrays: case studies using neurological genomic data.

BACKGROUND: Genomic analysis using microarray tools has the potential benefit of enhancing our understanding of neurological diseases. The analysis of these data is complex due to the large amount of data generated. Many tools have been developed to assist with this, but standard methods of analysis of these tools have not been established. OBJECTIVE: This study analyzed the sensitivity and specificity of different analytical methods for gene identification and presents a standardized approach. METHODS: Affymetrix HG-U133 plus 2.0 microarray datasets from two neurological diseases - chronic migraine and new-onset epilepsy - were used as source data and methods of analysis for normalization of data and identification of gene changes were compared. Housekeeping genes were used to identify non-specific changes and gender related genes were used to identify specific changes. RESULTS: Initial normalization of data revealed that 5-10% of the microarray were potential outliers due to technical errors. Two separate methods of analysis (dChip and Bioconductor) identified the same microarray chips as outliers. For specificity and sensitivity testing, performing a per-gene normalization was found to be inferior to standard preprocessing procedures using robust multichip average analysis. CONCLUSIONS: Technical variation in microarray preprocessing may account for chip-to-chip and batch-to-batch variations and outliers need to be removed prior to analysis. Specificity and sensitivity of the final results are best achieved following this identification and removal with standard genomic analysis techniques. Future tools may benefit from the use of standard tools of measurement.

Altered mesolimbocortical and thalamic dopamine in Tourette syndrome.

We used [F-18]fallypride PET in six adults with Tourette syndrome and age-matched controls to assess extrastriatal dopamine 2 (D2) receptors. D2 receptor availability was significantly lower in the orbitofrontal cortex, primary motor cortex, anterior cingulate gyrus, mediodorsal nucleus of thalamus, and hippocampus, areas important for motivation and reward, sensory gating, movement, and attention. Altered dopaminergic function in mesolimbocortical systems and thalamus may contribute to increased motivational salience of tics.

Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders.

OBJECTIVE: To test the hypothesis that atomoxetine does not significantly worsen tic severity relative to placebo in children and adolescents with attention deficit/hyperactivity disorder (ADHD) and comorbid tic disorders. METHODS: Study subjects were 7 to 17 years old, met Diagnostic and Statistical Manual of Mental Disorders-IV criteria for ADHD, and had concurrent Tourette syndrome or chronic motor tic disorder. Patients were randomly assigned to double-blind treatment with placebo (n = 72) or atomoxetine (0.5 to 1.5 mg/kg/day, n = 76) for up to 18 weeks. RESULTS: Atomoxetine treatment was associated with greater reduction of tic severity at endpoint relative to placebo, approaching significance on the Yale Global Tic Severity Scale total score (-5.5 +/- 6.9 vs -3.0 +/- 8.7, p = 0.063) and Tic Symptom Self-Report total score (-4.7 +/- 6.5 vs -2.9 +/- 5.2, p = 0.095) and achieving significance on the Clinical Global Impressions (CGI) tic/neurologic severity scale score (-0.7 +/- 1.2 vs -0.1 +/- 1.0, p = 0.002). Atomoxetine patients also showed greater improvement on the ADHD Rating Scale total score (-10.9 +/- 10.9 vs -4.9 +/- 10.3, p < 0.001) and CGI severity of ADHD/psychiatric symptoms scale score (-0.8 +/- 1.1 vs -0.3 +/- 1.0, p = 0.015). Discontinuation rates were not significantly different between treatment groups. Atomoxetine patients had greater increases in heart rate and decreases of body weight, and rates of treatment-emergent decreased appetite and nausea were higher. No other clinically relevant treatment differences were seen in any other vital sign, adverse event, or electrocardiographic or laboratory measures. CONCLUSIONS: Atomoxetine did not exacerbate tic symptoms. Rather, there was some evidence of reduction in tic severity with a significant reduction of attention deficit/hyperactivity disorder symptoms. Atomoxetine treatment appeared safe and well tolerated.

Glycine decarboxylase mutations: a distinctive phenotype of nonketotic hyperglycinemia in adults.

Three unrelated adult patients with mild hyperglycinemia, infantile hypotonia, mental retardation, behavioral hyperirritability, and aggressive outbursts were screened for glycine decarboxylase (GLDC) mutations; two novel missense mutations (A389V and R739H) were found. Both mutations had a 6 to 8% of normal GLDC activities when expressed in COS7 cells.

Valproic acid blood genomic expression patterns in children with epilepsy - a pilot study.

OBJECTIVE: Valproic acid (VPA) is a commonly used anticonvulsant with multiple systemic effects. The purpose of this pilot study is to examine the blood genomic expression pattern associated with VPA therapy in general and secondly VPA efficacy in children with epilepsy. MATERIALS AND METHODS: Using oligonucleotide microarrays, gene expression in whole blood was assessed in pediatric epilepsy patients following treatment with VPA compared with children with epilepsy prior to initiation of anticonvulsant therapy (drug free patients). RESULTS: The expression of 461 genes was altered in VPA patients (n = 11) compared with drug free patients (n = 7), among which a significant number of serine threonine kinases were down-regulated. Expression patterns in children seizure free on VPA therapy (n = 8) demonstrated 434 up-regulated genes, many in mitochondria, compared with VPA children with continuing seizures (n = 3) and drug free seizure patients (n = 7). CONCLUSION: VPA therapy is associated with two significant and unique blood gene expression patterns: chronic VPA monotherapy in general and a separate blood genomic profile correlated with seizure freedom. These expression patterns provide new insight into previously undetected mechanisms of VPA anticonvulsant activity.

Tic reduction with pergolide in a randomized controlled trial in children.

OBJECTIVE: To determine whether pergolide, a mixed D1/D2/D3 dopamine agonist, is efficacious and safe in the treatment of children with chronic tic disorders and Tourette syndrome. BACKGROUND: Neuroleptics, which block dopamine transmission, are currently used to treat children with severe tics, but major side effects and limited efficacy reduce clinical utility. Prior open-label and crossover studies of pergolide suggest potential benefit. METHODS: The authors enrolled 57 children and adolescents, ages 7 to 17 years, randomizing them in a 2:1 ratio to either pergolide (0.15 to 0.45 mg per day) or placebo. Tic symptoms had to be >30 on the Yale Global Tic Severity Scale (YGTSS). The primary outcome measure was change in tic severity assessed by YGTSS. RESULTS: Compared to placebo treatment, pergolide treatment was associated with lower tic severity scores (treatment effect 8.8, pergolide vs placebo; 95% CI 0.1 to 17.6; p = 0.05) and attention-deficit hyperactivity disorder symptoms scores (treatment effect 3.8; 95% CI 0.7 to 6.8; p = 0.02). No patient had a serious adverse event and pergolide was well tolerated. CONCLUSIONS: In this randomized, placebo-controlled trial, pergolide appeared to be an efficacious and safe medication for tic reduction in children, and may also improve attention-deficit hyperactivity disorder symptoms.

Adequacy of a new chlorhexidine-bearing polyurethane central venous catheter for administration of 82 selected parenteral drugs.

OBJECTIVE: To screen 82 commonly used parenteral medications for compatibility with a new chlorhexidine-bearing central venous catheter, the ARROWg+ard Blue Plus. Evaluations were performed for completeness of drug delivery and impact, if any, of the drugs on the amount of chlorhexidine removed from the internal lumens. DESIGN: Drug solutions were prepared in dextrose 5% injection or NaCl 0.9% at common concentrations. Three 10-mL aliquots of each drug solution were delivered over 10 minutes, one aliquot through each lumen of the triple-lumen catheter. The initial drug concentrations of the admixtures and the effluent samples were analyzed by HPLC for chlorhexidine content and for the amount of drug delivered relative to its initial concentration. RESULTS: The delivery of the infusion solutions alone through sample catheters resulted in no more than trace amounts of chlorhexidine in the solution. Background amounts ranged from < 2.5 to 6.1 micrograms/mL in the first 10 mL of solution. Administration of none of the drugs tested resulted in a substantial increase in chlorhexidine delivery. Furthermore, delivery of most of the drugs was at least 95% and usually was in excess of 97% of the initial concentration. Concentrations of five drugs, amikacin sulfate, cefoperazone sodium, cefotaxime sodium, cefepime HCl, and netilmicin sulfate were somewhat lower than the initial concentration (range 91-95%), but were still considered acceptable. CONCLUSIONS: The ARROWg+ard Blue Plus central venous catheter can be recommended for use with all of the 82 parenteral drugs tested.

Compatibility screening of linezolid injection during simulated Y-site administration with other drugs and infusion solutions.

OBJECTIVE: To evaluate the physical compatibility of linezolid injection (Zyvox-Pharmacia) during simulated Y-site administration with 8 infusion solutions and 110 selected other drugs. DESIGN: Controlled experimental trial. SETTING: Laboratory. INTERVENTIONS: Five-milliliter samples of linezolid injection 2 mg/mL were mixed with 5 mL samples of the selected infusion solutions and the selected other drugs diluted in 5% dextrose injection, or, if necessary to avoid incompatibility with the diluent, 0.9% sodium chloride injection. MAIN OUTCOME MEASURES: Visual examinations of the samples were performed in normal fluorescent light with the unaided eye and using a Tyndall beam (high-intensity monodirectional light source) to enhance visualization of small particles and low-level haze. The turbidity of each sample was measured, and for samples that did not exhibit visible precipitation, the particle content was measured, as well. All of the samples were assessed initially and at 1 and 4 hours. RESULTS: All of the infusion solutions and most of the test drugs were physically compatible with linezolid injection during the 4-hour observation period. Physical incompatibilities resulted when linezolid injection was combined with five of the drugs: amphotericin B, chlorpromazine hydrochloride, diazepam, pentamidine isethionate, and phenytoin sodium. Precipitation, turbidity formation, and/or unacceptable changes in measured haze levels were observed. CONCLUSION: Linezolid 2 mg/mL was physically compatible for 4 hours at room temperature with all 8 infusion solutions tested and 105 of the drugs tested. Simultaneous Y-site administration of linezolid injection with the five drugs resulting in physical incompatibilities should be avoided.

Cardiac complications in pediatric patients on the ketogenic diet.

Cardiac complications of the ketogenic diet, in the absence of selenium deficiency, have not been reported. Twenty patients on the ketogenic diet at one institution were investigated. Prolonged QT interval (QTc) was found in 3 patients (15%). There was a significant correlation between prolonged QTc and both low serum bicarbonate and high beta-hydroxybutyrate. In addition, three patients had evidence of cardiac chamber enlargement. One patient with severe dilated cardiomyopathy and prolonged QTc normalized when the diet was discontinued.

Fifty years of radical ideas.

My role in the free radical theory of oxygen toxicity is discussed. Rebeca Gerschman and I published several papers on this subject. This sparked my interest in geochemistry and I developed the idea that oxygen was the best qualified biological potential energy source for the following reasons: great abundance, easily accessible, possession of a high thermodynamic potential, and its slow reaction rate. Ionization radiation can be viewed as a catalyst for reactive oxygen species since a killing dose imparts an infinitesimal small amount of energy. Next, Carol A. Colton and I showed that in the mammalian brain that stimulated microglia produce the superoxide radical anion and its implications in Alzheimer's disease is discussed. More recently, I have become interested in the role of sulfhydryl groups in transcription factors.

Microglial contribution to oxidative stress in Alzheimer's disease.

Microglia are the CNS macrophage and are a primary cellular component of plaques in Alzheimer's disease (AD) that may contribute to the oxidative stress associated with chronic neurodegeneration. We now report that superoxide anion production in microglia or macrophages from 3 different species is increased by long term exposure (24 hours) to A beta peptides. Since A beta competes for the uptake of opsonized latex beads and for the production of superoxide anion by opsonized zymosan, a likely site of action are membrane receptors associated with the uptake of opsonized particles or fibers. The neurotoxic fibrillar peptides A beta (1-42) and human amylin increase radical production whereas a non-toxic, non-fibrillar peptide, rat amylin, does not. We also report that the effect of A beta peptides on superoxide anion production is not associated with a concomitant increase in nitric oxide (NO) production in either human monocyte derived macrophages (MDM) or hamster microglia from primary cultures. Since NO is known to protect membrane lipids and scavenge superoxide anion, the lack of A beta-mediated induction of NO production in human microglia and macrophages may be as deleterious as the over-production of superoxide anion induced by chronic exposure to A beta peptides.

Tourette's syndrome improvement with pergolide in a randomized, double-blind, crossover trial.

OBJECTIVE: To determine whether pergolide, a mixed D1-D2-D3 dopamine agonist, is efficacious and safe in the treatment of children with Tourette's syndrome. BACKGROUND: Neuroleptics, which block dopamine transmission, are currently used for treatment of children with severe tics, but major side effects and limited efficacy reduce clinical utility. Prior open-label reports of pergolide suggest potential benefit. METHODS: The authors enrolled 24 children age 7 to 17 years with Tourette's disorder, chronic motor tic disorder, or chronic vocal tic disorder by Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria, plus severity criteria on the Yale Global Tic Severity Scale (YGTSS) of > or =20, in a double-blind, placebo-controlled, crossover study. Children were randomized to receive either placebo or up to 300 microg/day pergolide for the first 6-week treatment period, with a 2-week placebo washout, followed by crossover to the alternate treatment. The primary outcome measure was tic severity assessed by YGTSS. RESULTS: Compared with placebo treatment, pergolide treatment was associated with significantly lower YGTSS scores (42.0 +/- 20.4 versus 23.5 +/- 18.7; F = 12.0, df = 1, 17, p = 0.0011). No patient had a serious adverse event and pergolide was well tolerated. CONCLUSIONS: In this randomized, placebo-controlled, crossover trial, pergolide appeared to be a safe and efficacious treatment for Tourette's syndrome in children.

Effect of process parameters on compressibility of granulation manufactured in a high-shear mixer.

Various processing variables that can influence granulation characteristics of a lactose-based formulation were evaluated using a Plackett-Burman experimental design. These parameters were impeller speed, granulating solution addition rate, total amount of water added in the granulation step, wet massing time, moisture content of the granulation after drying, and screen size used for the dry milling. Results showed that granulation growth was enhanced by the increase in the amount of added water, high impeller speed, and short wet massing time. On the other hand, moisture content had the largest impact on granulation compressibility, followed by the wet massing time and impeller speed. Increasing moisture content of the granulation and decreasing wet massing time or impeller speed increased granulation compressibility. Increasing impeller speed and/or wet massing time decreased granule porosity and fragmentation propensity, which led to decreased granulation compressibility. Granulation compressibility was extremely sensitive to processing conditions. Tablets from all runs showed acceptable weight variation and friability, suggesting that the parameters evaluated had little effect on these responses in the ranges tested.

An EEG should not be obtained routinely after first unprovoked seizure in childhood.

OBJECTIVE: To quantify and analyze the value of expected information from an EEG after first unprovoked seizure in childhood. BACKGROUND: An EEG is often recommended as part of the standard diagnostic evaluation after first seizure. METHODS: A MEDLINE search from 1980 to 1998 was performed. From eligible studies, data on EEG results and seizure recurrence risk in children were abstracted, and sensitivity, specificity, and positive and negative predictive values of EEG in predicting recurrence were calculated. Linear information theory was used to quantify and compare the expected information from the EEG in all studies. Standard test-treat decision analysis with a treatment threshold at 80% recurrence risk was used to determine the range of pretest recurrence probabilities over which testing affects treatment decisions. RESULTS: Four studies involving 831 children were eligible for analysis. At best, the EEG had a sensitivity of 61%, a specificity of 71%, and an expected information of 0.16 out of a possible 0.50. The pretest probability of recurrence was less than the lower limit of the range for rational testing in all studies. CONCLUSIONS: In this analysis, the quantity of expected information from the EEG was too low to affect treatment recommendations in most patients. EEG should be ordered selectively, not routinely, after first unprovoked seizure in childhood.

The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones.

The objective of this study was to determine the relationship between beta-hydroxybutyrate levels and seizure control in children on the ketogenic diet. Seventy-four children on the ketogenic diet presenting for routine follow-up visits had blood levels of beta-hydroxybutyrate correlated with their seizure control. Forty-two children admitted for initiation of the ketogenic diet had urine ketones measured by dipstick and correlated with simultaneous blood levels of beta-hydroxybutyrate. Blood beta-hydroxybutyrate levels statistically correlated with seizure control (P = .003). Children with blood beta-hydroxybutyrate levels greater than 4 mmol/L were significantly more likely to have a decrease in seizure frequency than those with levels less than 4 mmol/L. Urine ketones of 4+ (160 mmol/L) were found on dipstick when blood beta-hydroxybutyrate levels exceeded 2 mmol/L. Seizure control correlates with blood beta-hydroxybutyrate levels and is more likely when blood beta-hydroxybutyrate levels are greater than 4 mmo/L. The traditional measurement of urine ketones by dipsticks in children on the ketogenic diet provides a less than optimal assessment of the degree of blood ketosis. Three to four plus (80-160 mmol/L) urine ketones are necessary, but not necessarily sufficient, to achieve optimal seizure control in children on the ketogenic diet. At present, however, urine ketones are the only readily available inexpensive approach to ketone assessment.