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1.  Catecholamine Influences on Prefrontal Cortical Function: Relevance to Treatment of Attention Deficit Hyperactivity Disorder and Related Disorders 
The primary symptoms of Attention Deficit Hyperactivity Disorder (ADHD) include poor impulse control and impaired regulation of attention. Research has shown that the prefrontal cortex (PFC) is essential for the “top down” regulation of attention, behavior, and emotion, and that this brain region is underactive in many patients with ADHD. The PFC is known to be especially sensitive to its neurochemical environment; relatively small changes in the levels of norepinephrine and dopamine can produce significant changes in its function. Therefore, alterations in the pathways mediating catecholamine transmission can impair PFC function, while medications that optimize catecholamine actions can improve PFC regulation of attention, behavior, and emotion. This article reviews studies in animals showing that norepinephrine and dopamine enhance PFC function through actions at postsynaptic α2A-adrenoceptors and dopamine D1-receptors, respectively. Stimulant medications and atomoxetine appear to enhance PFC function through increasing endogenous adrenergic and dopaminergic stimulation of α2A-receptors and D1-receptors. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α2A-receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD.
doi:10.1016/j.pbb.2011.01.020
PMCID: PMC3129015  PMID: 21295057
guanfacine; prefrontal cortex; attention-deficit/hyperactivity disorder; catecholamines; norepinephrine; alpha-2A adrenergic receptors
2.  Neuroanatomical and Neuropsychological Correlates of the Cerebellum in Children with Attention-Deficit/Hyperactivity Disorder – Combined Type 
Objective
Studies of healthy individuals and those with cerebellar damage have implicated the cerebellum in a variety of cognitive and behavioral processes. Reduced cerebellar volume has been found in children with ADHD and differentially related to behavioral outcomes. In the current study, we sought to determine if reduced cerebellar vermis volume was present in children with ADHD-Combined type (ADHD-C) compared to controls and whether volume related to parent and teacher reported levels of ADHD symptomatology.
Method
2T MRI images and parent and teacher reported ADHD symptoms were acquired for 32 children diagnosed with ADHD-C and 15 typically-developing controls. Participants were right-handed, had no comorbid diagnoses of learning disabilities, conduct disorder, or affective/mood disorder, and were between the ages of 9 and 15.
Results
Participants with ADHD-C showed significantly reduced volume in the posterior inferior vermis compared to controls. No statistically significant differences were observed for cerebral volume, anterior vermis volume, posterior superior volume, or total cerebellar volume. Regression analyses indicated that a significant amount of the variance in parent-reported BASC-II Hyperactivity and Attention and Conners’ Restless/Impulsive ratings was explained by volume of the posterior inferior vermis.
Conclusions
Consistent with previous studies, children with ADHD had reduced volume in the posterior inferior vermis. New findings emerged with reduced volume of the posterior inferior vermis predicting significant amount of the variance in parent-reported hyperactivity, attention, and restlessness/impulsivity. Thus, symptoms of hyperactivity and inattention in ADHD may be partially explained by reduced volume of the cerebellar vermis and its connections within the cerebrum.
doi:10.1016/j.jaac.2011.02.014
PMCID: PMC3104210  PMID: 21621143
ADHD; cerebellum; vermis; hyperactivity; attention
3.  Adjunctive Divalproex Versus Placebo for Children With ADHD and Aggression Refractory to Stimulant Monotherapy 
The American journal of psychiatry  2009;166(12):1392-1401.
Objective
The purpose of the present study was to evaluate the efficacy of divalproex for reducing aggressive behavior among children 6 to 13 years old with attention deficit hyperactivity disorder (ADHD) and a disruptive disorder whose chronic aggression was underresponsive to a prospective psychostimulant trial.
Method
Children received open stimulant treatment during a lead-in phase that averaged 5 weeks. Agent and dose were assessed weekly and modified to optimize response. Children whose aggressive behavior persisted at the conclusion of the lead-in phase were randomly assigned to receive double-blind, flexibly dosed divalproex or a placebo adjunctive to stimulant for 8 weeks. Families received weekly behavioral therapy throughout the trial. The primary outcome measure was the proportion of children whose aggressive behavior remitted, defined by post-trial ratings of negligible or absent aggression.
Result
A significantly higher proportion of children randomly assigned to divalproex met remission criteria (eight out of 14 [57%]) than those randomly assigned to placebo (two out of 13 [15%]). Divalproex was generally well tolerated.
Conclusions
Among children with ADHD whose chronic aggressive behavior is refractory to optimized stimulant treatment, the addition of divalproex increases the likelihood that aggression will remit. A larger trial is necessary to specify with greater precision the magnitude of benefit for adjuvant divalproex.
doi:10.1176/appi.ajp.2009.09020233
PMCID: PMC2940237  PMID: 19884222
4.  An MRI Study of the Cerebellar Vermis in Chronically-Treated and Treatment-Naïve Children with ADHD-Combined Type 
Biological psychiatry  2009;65(7):620-624.
Background
Because of its dense connections to the prefrontal cortex and basal ganglia, the cerebellum is thought to play an important role in cognition. Numerous MRI studies have found abnormalities in the cerebellum in children with ADHD. While some studies in animal and human models suggest that the certain brain structures are affected by chronic stimulant medication, it is unclear whether the cerebellum is also affected. The purpose of the current study was to determine if cerebellar morphology was different in treatment-naïve vs. chronically-treated children with ADHD.
Methods
There were 32 boys and 15 girls total (N = 47) that comprised three groups: ADHD-C children with no history of stimulant medication treatment (n = 14), ADHD-C children chronically treated with stimulant medication (n = 18), and typically developing control children (n = 15).
Results
Treatment-naïve children with ADHD had significantly smaller area in the posterior inferior vermis (lobules VIII-X) than both chronically-treated children with ADHD (p = .004) and typically developing controls (p = .001). No differences were observed between chronically-treated children with ADHD and controls.
Conclusions
The results from this study suggest that chronic stimulant treatment may normalize the development of important areas of the cerebellar vermis in children with ADHD.
doi:10.1016/j.biopsych.2008.11.030
PMCID: PMC2675536  PMID: 19150052
ADHD; cerebellum; MRI; medication treatment; vermis
5.  Assessment of Personality Dimensions in Children and Adolescents with Bipolar Disorder Using the Junior Temperament and Character Inventory 
Abstract
Objective
We compared temperament and character traits in children and adolescents with bipolar disorder (BP) and healthy control (HC) subjects.
Method
Sixty nine subjects (38 BP and 31 HC), 8–17 years old, were assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime. Temperament and character traits were measured with parent and child versions of the Junior Temperament and Character Inventory.
Results
BP subjects scored higher on novelty seeking, harm avoidance, and fantasy subscales, and lower on reward dependence, persistence, self-directedness, and cooperativeness compared to HC (all p < 0.007), by child and parent reports. These findings were consistent in both children and adolescents. Higher parent-rated novelty seeking, lower self-directedness, and lower cooperativeness were associated with co-morbid attention-deficit/hyperactivity disorder (ADHD). Lower parent-rated reward dependence was associated with co-morbid conduct disorder, and higher child-rated persistence was associated with co-morbid anxiety.
Conclusions
These findings support previous reports of differences in temperament in BP children and adolescents and may assist in a greater understating of BP children and adolescents beyond mood symptomatology.
doi:10.1089/cap.2008.029
PMCID: PMC2762645  PMID: 19232019
6.  Assessment of Personality Dimensions in Children and Adolescents with Bipolar Disorder Using the Junior Temperament and Character Inventory 
Objective
We compared temperament and character traits in children and adolescents with bipolar disorder (BP) and healthy control (HC) subjects.
Method
Sixty nine subjects (38 BP and 31 HC), 8–17 years old, were assessed with the Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime. Temperament and character traits were measured with parent and child versions of the Junior Temperament and Character Inventory.
Results
BP subjects scored higher on novelty seeking, harm avoidance, and fantasy subscales, and lower on reward dependence, persistence, self-directedness, and cooperativeness compared to HC (all p < 0.007), by child and parent reports. These findings were consistent in both children and adolescents. Higher parent-rated novelty seeking, lower self-directedness, and lower cooperativeness were associated with co-morbid attention-deficit/hyperactivity disorder (ADHD). Lower parent-rated reward dependence was associated with co-morbid conduct disorder, and higher child-rated persistence was associated with co-morbid anxiety.
Conclusions
These findings support previous reports of differences in temperament in BP children and adolescents and may assist in a greater understating of BP children and adolescents beyond mood symptomatology.
doi:10.1089/cap.2008.029
PMCID: PMC2762645  PMID: 19232019

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