Jeffrey M. Halperin - US grants

Attention-deficit hyperactivity disorder (ADHD) is defined by symptoms of inattention, impulsivity and hyperactivity, but the existence of all three concurrently is not required for a diagnosis. ADHD children also differ in associated features, such as the presence of aggressive behavior or cognitive deficits, and have disparate long-term outcomes. Due in part to this heterogeneity, diagnostic validity for ADHD has not been established, and as a result, it has been impossible to isolate the etiologic and prognostic determinants of this extremely prevalent disorder. It is proposed that ADHD is not a unitary or a valid syndrome, but rather, that two distinct groups of ADHD children can be identified based upon the presence o absence of aggressive behavior. It is hypothesized that non- aggressive ADHD children will comprise an Inattentive/Cognitively Impaired group characterized by inattention, impulsivity, cognitive deficits, and evidence of increased noradrenergic metabolism; and aggressive ADHD children will comprise an Impulsive/Aggressive group characterized by impulsivity, in the absence of inattention and cognitive problems, and evidence of reduced central serotonergic function and noradrenergic metabolism. The goal is to establish the concurrent validity of the diagnostic distinctions between these two groups of ADHD children. Three groups of 30 boys will participate in this research: aggressive ADHD boys, non-aggressive ADHD, and normal controls. The three groups will be compared on neuropsychological measures of attention, impulse control, and learning. The two patient groups will be compared on neurobiological measures of noradrenergic and serotonergic functioning.

Attention-deficit hyperactivity disorder (ADHD) is defined by symptoms of inattention, impulsivity and hyperactivity, but the existence of all three concurrently is not required for a diagnosis. ADHD children also differ in associated features, such as the presence of aggressive behavior or cognitive deficits, and have disparate long-term outcomes. Due in part to this heterogeneity, diagnostic validity for ADHD has not been established, and as a result, it has been impossible to isolate the etiologic and prognostic determinants of this extremely prevalent disorder. It is proposed that ADHD is not a unitary or a valid syndrome, but rather, that two distinct groups of ADHD children can be identified based upon the presence o absence of aggressive behavior. It is hypothesized that non- aggressive ADHD children will comprise an Inattentive/Cognitively Impaired group characterized by inattention, impulsivity, cognitive deficits, and evidence of increased noradrenergic metabolism; and aggressive ADHD children will comprise an Impulsive/Aggressive group characterized by impulsivity, in the absence of inattention and cognitive problems, and evidence of reduced central serotonergic function and noradrenergic metabolism. The goal is to establish the concurrent validity of the diagnostic distinctions between these two groups of ADHD children. Three groups of 30 boys will participate in this research: aggressive ADHD boys, non-aggressive ADHD, and normal controls. The three groups will be compared on neuropsychological measures of attention, impulse control, and learning. The two patient groups will be compared on neurobiological measures of noradrenergic and serotonergic functioning.

Attention-deficit hyperactivity disorder (ADHD) is defined by symptoms of inattention, impulsivity and hyperactivity, but the existence of all three concurrently is not required for a diagnosis. ADHD children also differ in associated features, such as the presence of aggressive behavior or cognitive deficits, and have disparate long-term outcomes. Due in part to this heterogeneity, diagnostic validity for ADHD has not been established, and as a result, it has been impossible to isolate the etiologic and prognostic determinants of this extremely prevalent disorder. It is proposed that ADHD is not a unitary or a valid syndrome, but rather, that two distinct groups of ADHD children can be identified based upon the presence o absence of aggressive behavior. It is hypothesized that non- aggressive ADHD children will comprise an Inattentive/Cognitively Impaired group characterized by inattention, impulsivity, cognitive deficits, and evidence of increased noradrenergic metabolism; and aggressive ADHD children will comprise an Impulsive/Aggressive group characterized by impulsivity, in the absence of inattention and cognitive problems, and evidence of reduced central serotonergic function and noradrenergic metabolism. The goal is to establish the concurrent validity of the diagnostic distinctions between these two groups of ADHD children. Three groups of 30 boys will participate in this research: aggressive ADHD boys, non-aggressive ADHD, and normal controls. The three groups will be compared on neuropsychological measures of attention, impulse control, and learning. The two patient groups will be compared on neurobiological measures of noradrenergic and serotonergic functioning.

This continuation project is designed primarily to explore the relationship between central serotonergic (5-HT) function and aggressive behavior in children with and without attention-deficit hyperactivity disorder (ADHD). Central 5-HT will be assessed by measuring the prolactin response to a challenge dose of the 5-HT releaser/reuptake inhibitor fenfluramine, as compared to a placebo challenge. The primary goal is to extend the previous assessment of central 5-HT function to aggressive non- ADHD children and normal controls, in addition to new groups of aggressive and non-aggressive ADHD children. Secondarily, the symptom dimensions of impulsivity and hyperactivity will be assessed to determine their differential relationships with central 5-HT junction and aggression, and the relationship between academic achievement and the norepinephrine metabolite MHPG will be examined in ADHD and non-ADHD children. Children participating in this study will be divided into four groups of seven to eleven year-old boys: ADHD non-aggressive (N = 20), ADHD aggressive (N = 20), aggressive non-ADHD (N = 20) and normal controls (N= 20). The primary questions that will be addressed in this study are: 1. Is the difference in prolactin (PRL) response to fenfluramine (FEN) between aggressive and non-aggressive ADHD children due to an enhanced response relative to normals in aggressive ADHD children, a diminished response in non-aggressive ADHD children relative to normals, or is the PRL response to FEN in both aggressive and non-aggressive ADHD children different from that of normal children? 2. Is the enhanced PRL response to FEN challenge in aggressive, relative to non-aggressive, ADHD children related to an interaction between ADHD and aggression or is it characteristic of aggressive behavior in children irrespective of ADHD? Secondary aims of this project are a) to determine whether-the relationship between the PRL response to FEN and measures of impulsivity and activity level are similar or different in ADHD and non-ADHD patient groups; and b) to replicate the previous finding of an inverse relationship between plasma MHPG and measures of academic achievement in ADHD children, and to determine whether this relationship is limited to children with ADHD.

biomedical equipment purchase;

This continuation project is designed primarily to explore the relationship between central serotonergic (5-HT) function and aggressive behavior in children with and without attention-deficit hyperactivity disorder (ADHD). Central 5-HT will be assessed by measuring the prolactin response to a challenge dose of the 5-HT releaser/reuptake inhibitor fenfluramine, as compared to a placebo challenge. The primary goal is to extend the previous assessment of central 5-HT function to aggressive non- ADHD children and normal controls, in addition to new groups of aggressive and non-aggressive ADHD children. Secondarily, the symptom dimensions of impulsivity and hyperactivity will be assessed to determine their differential relationships with central 5-HT junction and aggression, and the relationship between academic achievement and the norepinephrine metabolite MHPG will be examined in ADHD and non-ADHD children. Children participating in this study will be divided into four groups of seven to eleven year-old boys: ADHD non-aggressive (N = 20), ADHD aggressive (N = 20), aggressive non-ADHD (N = 20) and normal controls (N= 20). The primary questions that will be addressed in this study are: 1. Is the difference in prolactin (PRL) response to fenfluramine (FEN) between aggressive and non-aggressive ADHD children due to an enhanced response relative to normals in aggressive ADHD children, a diminished response in non-aggressive ADHD children relative to normals, or is the PRL response to FEN in both aggressive and non-aggressive ADHD children different from that of normal children? 2. Is the enhanced PRL response to FEN challenge in aggressive, relative to non-aggressive, ADHD children related to an interaction between ADHD and aggression or is it characteristic of aggressive behavior in children irrespective of ADHD? Secondary aims of this project are a) to determine whether-the relationship between the PRL response to FEN and measures of impulsivity and activity level are similar or different in ADHD and non-ADHD patient groups; and b) to replicate the previous finding of an inverse relationship between plasma MHPG and measures of academic achievement in ADHD children, and to determine whether this relationship is limited to children with ADHD.

This continuation project is designed primarily to explore the relationship between central serotonergic (5-HT) function and aggressive behavior in children with and without attention-deficit hyperactivity disorder (ADHD). Central 5-HT will be assessed by measuring the prolactin response to a challenge dose of the 5-HT releaser/reuptake inhibitor fenfluramine, as compared to a placebo challenge. The primary goal is to extend the previous assessment of central 5-HT function to aggressive non- ADHD children and normal controls, in addition to new groups of aggressive and non-aggressive ADHD children. Secondarily, the symptom dimensions of impulsivity and hyperactivity will be assessed to determine their differential relationships with central 5-HT junction and aggression, and the relationship between academic achievement and the norepinephrine metabolite MHPG will be examined in ADHD and non-ADHD children. Children participating in this study will be divided into four groups of seven to eleven year-old boys: ADHD non-aggressive (N = 20), ADHD aggressive (N = 20), aggressive non-ADHD (N = 20) and normal controls (N= 20). The primary questions that will be addressed in this study are: 1. Is the difference in prolactin (PRL) response to fenfluramine (FEN) between aggressive and non-aggressive ADHD children due to an enhanced response relative to normals in aggressive ADHD children, a diminished response in non-aggressive ADHD children relative to normals, or is the PRL response to FEN in both aggressive and non-aggressive ADHD children different from that of normal children? 2. Is the enhanced PRL response to FEN challenge in aggressive, relative to non-aggressive, ADHD children related to an interaction between ADHD and aggression or is it characteristic of aggressive behavior in children irrespective of ADHD? Secondary aims of this project are a) to determine whether-the relationship between the PRL response to FEN and measures of impulsivity and activity level are similar or different in ADHD and non-ADHD patient groups; and b) to replicate the previous finding of an inverse relationship between plasma MHPG and measures of academic achievement in ADHD children, and to determine whether this relationship is limited to children with ADHD.

DESCRIPTION: Heterogeneity among children with ADTHD raises concerns about whether it is a unitary disorder that can be differentiated from other psychiatric/cognitive disorders or from behavioral difficulties that represent one end of a normal distribution, but are not a true categorical disorder. Furthermore, little is know regarding the long-term impact of stimulant treatment. To help establish the validity and boundaries of AD/HD, and to examine the impact of stimulant treatment on long-term outcome, this prospective follow-up study focuses on identifying more homogeneous subgroups of patients that might be associated with distinct outcomes. This study will re-evaluate a large sample of clinically-referred children who were diagnosed with AD/HID between 1990 to 1997 using structured diagnostic interviews. Psychiatric comorbidity as well as cognitive and academic functioning were assessed at baseline. The primary goals are a) to conduct a comprehensive clinical re-evaluation of these children to determine their psychiatric, behavioral, and neuropsychological status as adolescents between the ages of 16 to 19 years-old; b) to ascertain the duration and nature of the treatment interventions they received; and c) to identify subgroups of children that are associated with distinct outcomes. As compared to carefully matched community controls, three competing hypotheses will be tested: Clinical outcome in children with AD/HD is accounted for primarily by comorbidity, rather than by the presence and/or severity of AD/HD; 2) Adverse outcome is related to the severity of AD/HD) symptomatology that persists into adolescence; 3) AD/HD during childhood poses increased risk for poor outcome above and beyond that accounted for by comorbidity and/or the persistence of AD/HID symptoms into adolescence. In addition, the extent to which stimulant medication treatment is associated with adolescent substance use/abuse will be examined, and, as compared to controls, the neuropsychological status of subgroups of adolescents who were diagnosed as having AD/HD during childhood will be characterized.

[unreadable] DESCRIPTION (provided by applicant): This longitudinal study is based upon the hypothesis that children with AD/HD represent a neurologically vulnerable group, but that the quality of parenting characteristics affects the manifestation and severity of symptoms. As such, evidence of neurological vulnerability, as assessed by neuropsychological tests in preschool children may be particularly useful for distinguishing between those "at risk" children who do and do not go on to develop AD/HD. Further, by assessing the quality of parenting skills during the preschool age, we hypothesize that there will be an interaction such that the combination of neuropsychological deficits and negative parenting characteristics will portend adverse outcome during the school-age years for at risk preschool children. [unreadable] The primary aim is to determine whether neuropsychological and parenting factors, independently and in combination, distinguish between inattentive/hyperactive preschool children who do and do not develop AD/HD. The goal is to recruit and follow a large sample of 3 and 4 year-old "at risk" and control children for whom behavioral, neuropsychological and parenting data are collected at baseline. Subsequently, behavioral ratings will be gathered every six months, and more in-depth clinical, neuropsychological and parenting assessments will be conducted annually. The primary dependent measures for this study will be collected when the children are six years-old. In addition, a secondary aim is to examine the extent to which genetic status has predictive validity for the emergence of ADHD, and the degree to which genetic status relates to neuropsychological findings and interacts with parenting factors in the emergence of AD/HD. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This application is based on the hypothesis that at least partially distinct neural and cognitive mechanisms are involved in the etiology of and recovery from Attention-deficit/Hyperactivity Disorder - combined type (ADHD-C). We posit that ADHD-C is due to a primary deficit in a neural system emerging from the reticular formation within the hindbrain/midbrain region that is present early in ontogeny and remains relatively static throughout the lifetime. Further, we posit that the diminution of symptoms frequently seen throughout development is related to the degree to which frontostriatal systems are able to compensate for these early deficits through the use of effort or "top-down" executive control. To test this hypothesis, we propose to use functional magnetic resonance imaging (fMRI) along with neurocognitive measures in three groups of young adults. Two groups consist of patients from a longitudinal sample, all of whom met criteria for ADHD-C during childhood. Among these, many can be clearly identified either as ADHD persisters (ADHD-P) or ADHD remitters (ADHD-R). In addition, we have well-matched controls who never met criteria for any subtype of ADHD. Thus, we will evaluate the neural correlates of diverse developmental pathways in ADHD-C. If our hypotheses are correct, behavioral and fMRI indices of the system emerging the reticular formation should differ from controls in those who had childhood ADHD-C irrespective of adult clinical status. In contrast, measures of frontostriatal function should vary as a function of adult status such that more severe ADHD symptoms in adulthood are associated with poorer efficiency on these measures while those no longer having significant ADHD symptoms should perform more similarly to never-ADHD controls.

[unreadable] DESCRIPTION (provided by applicant): This longitudinal study is based upon the hypothesis that children with AD/HD represent a neurologically vulnerable group, but that the quality of parenting characteristics affects the manifestation and severity of symptoms. As such, evidence of neurological vulnerability, as assessed by neuropsychological tests in preschool children may be particularly useful for distinguishing between those "at risk" children who do and do not go on to develop AD/HD. Further, by assessing the quality of parenting skills during the preschool age, we hypothesize that there will be an interaction such that the combination of neuropsychological deficits and negative parenting characteristics will portend adverse outcome during the school-age years for at risk preschool children. [unreadable] The primary aim is to determine whether neuropsychological and parenting factors, independently and in combination, distinguish between inattentive/hyperactive preschool children who do and do not develop AD/HD. The goal is to recruit and follow a large sample of 3 and 4 year-old "at risk" and control children for whom behavioral, neuropsychological and parenting data are collected at baseline. Subsequently, behavioral ratings will be gathered every six months, and more in-depth clinical, neuropsychological and parenting assessments will be conducted annually. The primary dependent measures for this study will be collected when the children are six years-old. In addition, a secondary aim is to examine the extent to which genetic status has predictive validity for the emergence of ADHD, and the degree to which genetic status relates to neuropsychological findings and interacts with parenting factors in the emergence of AD/HD. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This competitive renewal application is based on a novel model which posits that partially distinct neural and cognitive mechanisms are involved in the etiology and developmental trajectory of attention-deficit/hyperactivity disorder (ADHD). We hypothesize that ADHD is due to a primary deficit in regulatory functions, most probably of subcortical origin, that is present early in ontogeny, remains relatively static throughout the lifetime, and is unrelated to the commonly-present, although highly variable, diminution of symptoms and impairment often seem over development. We hypothesize that the variation in diminution of symptoms and impairment frequently seen throughout development is in part related to the degree to which cortically-mediated neural systems can compensate for these early deficits through the use of top-down executive control. Using a large sample of hyperactive/inattentive and typically-developing control children who were recruited when they were 3-4 years-old and evaluated annually since then, this study will examine trajectories of ADHD symptoms over the school-age years to determine the relationship between changes in ADHD severity and the development of regulatory and executive functions over time. Children will be comprehensively reevaluated annually using clinical and neuropsychological measures between the ages of 8 and 12 years. In addition, these annual assessments will be supplemented by semi-annual parent and teacher ratings of ADHD symptom severity and impairment in the home and school settings, which will greatly facilitate our ability to conduct analyses of individualized trajectories for ADHD severity. The primary aim of the proposed project is to test the hypothesis that the diminution of ADHD symptoms typically seen over development is associated with the development of top-down executive processes, but that bottom-up regulatory functions will remain impaired irrespective of clinical improvement. If this hypothesis is confirmed, it could have a significant impact on the development of novel treatment interventions.

DESCRIPTION (provided by applicant): The proposed application is to conduct the ground work for the development of "Training Executive, Attention and Motor Skills (TEAMS)," a novel intervention for preschool children with Attention-deficit/Hyperactivity Disorder (ADHD). TEAMS is designed to result in enduring reductions of ADHD symptoms and associated impairments in children, and thus prevent the chronic and highly impairing course that ADHD oftentimes takes throughout the lifespan. TEAMS is based on the notions that: 1) the behavioral manifestations of ADHD are the result of deficient neural networks that affect a wide array of neurocognitive and behavioral processes which are not necessarily identical in all children with the disorder;2) neurodevelopment is sensitive to and can be positively affected by appropriate environmental influences;3) effective environmental stimulation will be best achieved within a dynamic social context;and 4) the engagement of the child in the core activities of the treatment must be intrinsically rewarding (i.e., fun) rather than extrinsically reinforced (e.g., praise or tokens) in order to facilitate self- imposed continuation of the intervention which will lead to generalization over time and across settings. We propose that these goals can be achieved through the use of game-like activities which place demands on an array of neurocognitive and motor skills, interspersed with periods of physical exercise. TEAMS will be administered within the context of a small group setting (Approximately 5 children). A concurrently-occurring parent group will focus on helping them to engage their children in these game-like and exercise activities at home. In addition, parents will be asked to encourage such play among their child and his/her peers so as to facilitate implementation outside of our clinical setting.