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NAME OF APPLICANT (Last, first, middle initial)
Bidwell, L. Cinnamon
Item 28b. Doctoral Dissertation
Not Applicable.
Item 28c. Publications.
Publications
Bidwell LC, Willcutt EG, Pennington BF. Executive functions in twins discordant for ADHD. Manuscript in
preparation.
Willcutt, EG, Bidwell LC, Hitt-Laustsen S, & Banich MT. Internal and external validity of DSM-IV
ADHD in young adults. Manuscript submitted for publication.
Chen Y, Bidwell LC, Norton D. (2005) Trait vs. state markers for schizophrenia: identification and
characterization through visual processes. Manuscript submitted for publication.
Chen Y, Grossman E, Bidwell LC, Yurgelun-Todd, D, Gruber S, Levy DL, Nakayama K, Holzman PS (2005).
Cortical activations during motion processing are reorganized in schizophrenia. Manuscript submitted for
publication.
Bidwell LC, Chen Y, Holzman PS. (2005). Aging and motion discrimination in normal adults and
schizophrenia patients. Psychiatry Research, in press.
Chen Y, Bidwell LC, Holzman PS (2005). Visual motion integration in schizophrenia patients, their first
degree relatives, and patients with bipolar disorder. Schizophr Res. 74(2-3):271-81.
Presentations
Bidwell LC, Holzman PS, Levy DL, Chen Y (October, 2005). Characterization of a co-familial trait of
schizophrenia: The role of contrast in velocity discrimination deficits in relatives of schizophrenia
patients. Poster presented at the World Congress on Psychiatric Genetics, Boston, MA.
Chen Y, Bidwell LC, Holzman PS (October, 2005). Trait vs. state markers in schizophrenia: The case of
visual motion processing. Poster presented at the World Congress on Psychiatric Genetics,
Boston, MA.
Bidwell LC, Willcutt, EG, Pennington BF (2005, June). Executive functions in dizygotic twins discordant for
ADHD. Poster presented at the International Society for Research in Child and Adolescent
Psychopathology, New York, NY.
Chen Y, Grossman E, Bidwell LC, Yurgelun-Todd, D, Gruber S, Levy DL, Nakayama K, Holzman PS (2004).
Cortical activations during motion processing are reorganized in schizophrenia. Neuropsychopharm. 29
(Supplement 1):s42.
Bidwell LC, Chen Y, Holzman PS (2004, April). Visual motion integration compared with motion
discrimination in schizophrenia patients and their biological relatives. Poster presented at the Society of
Biological Psychiatry, New York, NY.
Bidwell LC, Chen Y, Holzman PS (2004, April). Aging and visual motion discrimination in schizophrenia
patients and normal adults. Poster presented at the Society of Biological Psychiatry, New York, NY.
Bidwell LC, Chen Y (2003, March). Short-term learning for motion processing in schizophrenia. Poster
presented at Psychiatry Research Day, Harvard Medical School. Sponsored by the Mysell Committee,
Department of Psychiatry, Boston, MA.
Item 29. Revised Applications.
Not applicable.
Item 30. Research Training Plan
The overall objective of the proposed training is to prepare the applicant for an academic research
career concentrating on examining genetic contributions and pathophysiological processes in psychological
disorders. It is increasingly clear that interdisciplinary approaches will be essential to develop a better
understanding of the etiology of psychopathology. Bearing in mind the importance of interdisciplinary
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NAME OF APPLICANT (Last, first, middle initial)
Bidwell, L. Cinnamon
approaches, the applicant has developed a comprehensive training plan that will develop her abilities in three
areas of psychological research: behavioral genetics, neurocognition, and clinical psychology. Knowledge in
these three areas will allow the applicant to probe the course of psychopathology starting from genes to their
expression in the brain to the ultimate behavioral outcome. The facilities, faculty, and training program
available to the applicant at the University of Colorado provide a unique opportunity to receive extensive
training in each of the three subfields (behavioral genetics, neurocognition, and clinical psychology) and
work with experts to apply this training to innovative research. The interdisciplinary training plan will develop
a committed scientist who can integrate knowledge across disciplines to bear new understanding on
pathophysiological processes in psychological disorders.
Coursework necessary to fulfill requirements of an APA-approved doctoral program in Clinical
Psychology will be completed. In addition, the applicant has been accepted as a trainee at the Institute for
Behavioral Genetics (IBG) and will complete the requirements to obtain IBG’s Graduate Training and
Interdisciplinary Certificate. The certificate is designed to train the applicant in the study of genetic
contributions to individual differences in behavior. Elective courses are carefully selected to enrich the
applicant’s faculties in neurocognition, behavioral genetics, statistical analysis, and research methodology.
In addition to the proposed research, the applicant plans active collaborations on several ongoing projects
within her advisor’s (sponsor Erik Willcutt, Ph.D.) laboratory. These projects include examination of genetic
contributions and neuropsychological dysfunction in developmental disorders and an analysis of structural
magnetic resonance imaging data from a twin study of ADHD in collaboration with Dr. Bruce F. Pennington
at the University of Denver. Dr. Marie Banich will serve as a co-sponsor for this proposal. This mentoring
relationship will aid in training the applicant in neurocognitive and neuroscience methodology.
The immediate goal of this training plan is to prepare the applicant for a research-oriented predoctoral
internship. Subsequently, the applicant will seek two years of post-doctoral research experience. The
ultimate goal of the applicant’s training proposal is to forge an independent line of research integrating her
training in clinical psychology, neurocognition, and behavioral genetics.
Relevant training that will be completed before the proposed fellowship funding commences includes the
following:
 Foundation in etiology, epidemiology, and assessment of clinical disorders;
 Foundation in research methodology and scientific ethics;
 Foundation in cognitive and intellectual assessment;
 Foundation in psychometric principles and theory;
 Foundation in principles of genetic transmission and behavioral genetic methodology;
 Advanced coursework in molecular genetics;
 Data Analysis course with Dr. Gary McClelland;
 Genetics of Psychopathology seminar with Dr. Soo Rhee;
 Ethics and Professional Issues in Clinical Psychology course with Dr. Ed Craighead;
 Professional Issues and Prevention in Clinical Psychology course with Dr. Linda Craighead;
 Scientific Ethics & Integrity with Dr. Toni Smollen;
 Two year-long Research Practicum in Dr. Erik Willcutt’s laboratory;
 Year-long Clinical Practicum in Interpersonal Psychotherapy with Dr. Linda Craighead;
 Semester-long Child Clinical Practicum in Assessment with Dr. Erik Willcutt;
Item 30a. Activities Under Award
“Brief explanation of activities other than research”
Coursework
The applicant has already completed required coursework in both the clinical psychology and the
behavioral genetics programs that will aid her work on the proposed research project. These include
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NAME OF APPLICANT (Last, first, middle initial)
Bidwell, L. Cinnamon
required courses on basic research design, psychopathology, and statistics, as well as ethics seminars
related to both clinical practice and basic research. In addition to continuing to complete all course
requirements for the APA accredited clinical psychology training program and the Behavior Genetics
certificate program administered through IBG, the applicant will complete several additional courses in the
Cognitive and Behavioral Neuroscience areas and an advanced course in Statistics. A one-semester
teaching assistantship in Developmental Psychopathology is also proposed to prepare the applicant for
teaching responsibilities commonly expected of Assistant Professors of Psychology. This course was
selected because it will provide an excellent opportunity for the applicant to consolidate her knowledge in an
area relevant to her research project, and because it offers the opportunity to obtain direct teaching
experience as part of weekly lab sections. Please see Sponsor’s section 34A.1 for more details on the
chosen coursework.
Table 1
Coursework to be completed under award.
Course Title
Behavioral Genetics
Bioinformatics
Biometrical Methods
Quantitative Trait Loci
Classical Papers in Genetics
Neurocognition/Neuroscience
Introduction to Neuroscience
Cognitive Neuroscience
Magnetic Resonance Imaging Seminar
Psychopharmacology
Statistics
Structural Equation Modeling
Clinical Psychology
Genetics of Developmental Psychopathology
Seminar in Family Psychotherapy
Seminar in Developmental Psychopathology
Clinical Practicum
Child Assessment Practicum
Teaching Assistantship
Developmental Psychopathology
Professor
Date
Dr. Marissa Ehringer
Dr. John Hewitt
Dr. Mike Stallings
Dr. John Hewitt
Fall ‘06
Spring ‘07
Fall ‘07
Spring ‘08
Dr. Steven F. Maier
Dr. Tim Curran
Dr. Marie Banich (co-sponsor)
Dr. Linda R. Watkins
Fall ‘06
Fall ‘06
Spring ‘07
Spring ‘08
Dr. Chick Judd
Fall ‘07
Dr. Soo Rhee
Dr. David Miklowitz
Dr. Erik Willcutt (sponsor)
Drs. Linda Craighead, Ed Craighead,
& David Miklowitz
Drs. Nomita Chhabildas & Erik Willcutt
(sponsor)
Spring ‘07
Fall ‘08
Spring ‘09
Entire Award Period
Dr. Erik Willcutt (sponsor)
Spring ‘07
Entire Award Period
Specialized Training in Research Skills
In addition to coursework, the applicant will participate in a number of specialized training
opportunities that will bear directly on the proposed research. First, at the start of award period (Summer
2006) the applicant will be trained in DNA extraction and genotyping in collaboration with Dr. Andrew
Smolen’s laboratory at IBG. Second, during the following semester (Fall 2006) the applicant will gain
experience in structural magnetic resonance imaging data analysis within Dr. Banich’s (co-sponsor)
laboratory. Third, the applicant will attend both the beginning (Spring ’07) and advanced (Spring ’08) Twin
Workshops, offered annually by IBG to train graduate students and faculty in behavioral genetic analysis and
methodology. Please see Sponsor’s section 34A.2 for a description of the IBG Twin Workshops.
Career Development
Weekly meetings with the sponsor and co-sponsor will serve as a forum to discuss training, research,
and career development issues. A major focus of these meetings will be on manuscript and poster
preparation for presentation of the proposed research and corollary projects to the scientific community. The
meetings will initially focus on data collection and research training. After the first year, the focus will shift to
data analysis and interpretation of preliminary results. At this stage, these meetings will also address issues
related to professional networking and post-doctoral and internship applications.
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NAME OF APPLICANT (Last, first, middle initial)
Bidwell, L. Cinnamon
The applicant will attend regular scientific colloquia and meetings to augment her research training
and provide opportunities to interact with other investigators in her field. The applicant will attend weekly
IBG journal clubs, weekly colloquia at the Institute of Cognitive Science (ICS), the Department of Clinical
Psychology’s monthly Clinical Genetics Brown Bag, the Department of Cognitive Psychology’s weekly
Cognitive brown-bag, and laboratory meetings of the Developmental Neuropsychology Lab at the University
of Denver led by Bruce F. Pennington. Regular attendance at each of the above meetings will inform the
proposed research, extend the applicant’s knowledge in each of her sub-fields of interest, and create
opportunities for collaboration with other scientists in her field. Please see Sponsor’s sections 34A.2 and
34A.5 for a description of each of the above collaborative meetings.
Each year the applicant will attend at least one professional meeting at which innovative
neuroscience and/or behavioral and molecular genetic techniques are presented and their application to
complex behavioral phenotypes is discussed (e.g., American Society for Human Genetics, Behavior
Genetics Association, Cognitive Neuroscience Society, International Neuropsychological Society, World
Congress on Psychiatric Genetics). In addition, the applicant will attend at least one conference with a
stronger clinical emphasis. Attendance at these meetings will develop the applicant’s ability to speak in
public and share her findings with a broad audience. They will also provide another opportunity for her to
interact with senior and junior investigators in her field. These interactions are likely to facilitate the
development of collaborative projects and future job opportunities.
Item 30b. Research Training Proposal
1.Specific Aims
Despite strong evidence that attention deficit-hyperactivity disorder (ADHD) is heritable (Faraone &
Doyle, 2001), the complexity of the ADHD phenotype has complicated the identification of susceptibility
genes. Given the heterogeneity of the ADHD phenotype, intermediate cognitive phenotypes may provide a
closer link to the genetic pathway of the disorder than the clinical symptoms alone. ADHD is associated with
established weaknesses in executive control (King et al., 2003). Often broadly defined, executive functions
are processes mediated by prefrontal brain structures that maintain an appropriate problem solving set to
attain a later goal (e.g., Pennington, 2002). Within the scope of executive deficits in ADHD, weaknesses in
response inhibition (RI) and working memory (WM) are arguably the most robust (Willcutt et al., 2005). RI
and WM deficits have also been shown to be moderately heritable and due to a subset of the same genes
that influence ADHD (e.g., Ando et al., 2001; Chhabildas et al., submitted), and accumulating evidence
suggests that both RI and WM are largely mediated by the prefrontal cortex (PFC). In contrast, the specific
region of PFC that is most important may differ (Aron & Poldrack, 2005; Braver et al., 1997). Aron and
Poldrack (2005) suggest that the right inferior frontal cortex (rIFC) and striatum may be especially important
for RI (Aron & Poldrack, 2005), whereas the locus of control for WM is thought to be in the dorsolateral
prefrontal cortex (DLPFC) (e.g. Braver et al., 1997). Based on these results, the proposed project will
examine the utility of RI and WM as intermediate phenotypes that may mediate the relation between specific
candidate genes and neuroanatomical differences and the behavioral symptoms of ADHD.
The long-term objective of the proposed project is to characterize neurocognitive and neuroanatomic
phenotypes that may enhance the power to detect susceptibility genes for ADHD. More specifically, this
proposal tests the hypothesis that deficits in executive processing (in the domains of RI and WM) may be a
more penetrant indicator of candidate genes than the ADHD phenotype alone. Further, by taking
advantage of an ongoing neuroimaging study in Dr. Banich’s laboratory (co-sponsor), this proposal will test
the hypothesis that these deficits and specific candidate genes for ADHD may be associated with
structural abnormalities in PFC and striatum.
The specific objectives of this proposal are three-fold. The first objective is to quantify executive RI
and WM deficits in ADHD and control participants using neuropsychological tasks. The second objective is
to examine the associations between RI and WM task performance and prefrontal and striatal volume in
ADHD and control participants. The third objective is to examine genetic contributions to RI and WM,
prefrontal and striatal brain volumes, and ADHD symptoms. Specific aims are as follows:
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Bidwell, L. Cinnamon
Aim 1. The first aim is to replicate and extend previous research by comparing the performance of adults
with and without ADHD on measures of RI and WM. Two non-executive cognitive measures (processing
speed and simple vigilance) will be used to assess the discriminant validity of RI and WM deficits.
Hypothesis 1a. ADHD will perform significantly more poorly than controls on tasks of RI and WM.
This difference between the groups will be independent of IQ and reading ability.
Hypothesis 1b. This group effect will be stronger for RI and WM tasks than for tasks of processing
speed and simple vigilance.
Hypothesis 1c. Replicating previous research in children (e.g., Chhabildas et al., 2001), the group
difference in RI and WM will be mediated by inattention rather than hyperactive symptoms.
Aim 2. The second aim is to use whole brain optimized voxel-based morphometry to quantify volume in
apriori regions of interest in the PFC (5 sub-regions), striatum (3 sub-regions), and cerebellum, a control
region that is implicated in ADHD but not in executive control, and to examine relations between volume of
each of these brain regions, RI and WM performance, and ADHD symptomatology.
Hypothesis 2a. Replicating previous research, regional brain volume will be significantly smaller in
ADHD than in control participants in the PFC, striatum, and cerebellum. The significance of these
group differences will be maintained while controlling for whole brain volume.
Hypothesis 2b. PFC volume will be inversely correlated with performance on tasks of RI and WM.
Hypothesis 2b1. rIFC volume will correlate most strongly with RI performance.
Hypothesis 2b2. DLPFC volume will correlate most strongly with WM performance.
Hypothesis 2c. Striatal volume will be correlated with RI performance, but not WM performance.
Hypothesis 2d. Cerebellum volume will not be correlated with RI or WM performance in either group.
Aim 3. The third aim is to examine genetic influences on RI and WM, regional brain volumes, and ADHD
The relative influence of six candidate genes thought to contribute to ADHD (i.e. DAT1, DRD4, SNAP-25,
DRD5, 5HT1B, and COMT), on task performance, volume of the PFC, striatum, and cerebellum, and the
ADHD phenotype will be explored.
Hypothesis 3a. Risk alleles for all candidate genes except COMT will be associated with ADHD.
Hypothesis 3b. Risk alleles for DAT1 and DRD4 will be associated with RI deficits.
Hypothesis 3c. The COMT risk allele will be associated with WM deficits.
Exploratory Hypothesis 3d. DAT1 and DRD4 risk alleles will be associated with smaller PFC and
striatal volume.
Exploratory Hypothesis 3e. The COMT risk allele will be associated with smaller prefrontal volume.
2. Background and Significance
Diagnostic Validity of ADHD
Continuing controversy surrounds the nature and validity of ADHD as a diagnostic syndrome (e.g.,
Barkley, 1998; Lahey et al., 1998). Although substantial evidence supports the diagnostic validity of ADHD
(e.g., Barkley, 1998; Lahey et al., 1998), some authors argue that ADHD symptoms describe the exuberant
behavior of normal children and adults rather than indicate a clinical disorder (Safer, 1992). At least two
considerations contribute to this controversy. First, ADHD has undergone many changes in name and
diagnostic criteria. Most recently, based on factor analytic studies and results of the DSM-IV clinical field
trials for the disruptive behavior disorders (Lahey et al., 1994), the diagnostic criteria for ADHD in DSM-IV
ADHD include separate lists for symptoms of inattention and hyperactivity-impulsivity. Although the DSM-IV
definition of ADHD distinguishes among groups with maladaptive levels of both inattention and hyperactivityimpulsivity (combined type), maladaptive levels of inattention only (predominantly inattentive type), and
maladaptive levels of hyperactivity-impulsivity alone (predominantly hyperactive-impulsive type), the validity
of the inattentive and hyperactive-impulsive types remains uncertain (e.g., Barkley, 1998; Lahey & Willcutt,
2002). Second, and perhaps more importantly, the symptoms of ADHD are not distinctly different from
typical behavior, but rather are defined in terms of degree of severity and associated impairment.
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The potential utility of intermediate cognitive phenotypes in genetic studies of ADHD
The identification of an underlying neurocognitive deficit or deficits would provide strong support for
the validity of ADHD as a clinically significant disorder distinct from normal behavior (Nigg et al., 2005).
Various authors have proposed possible core deficits in ADHD, such as general executive dyscontrol, more
specific executive processes such as RI, arousal dysregulation, and delay aversion (e.g., Barkley, 1997;
Sergeant, 2000; Sonuga-Barke, 2002; Nigg, 2001). Such theories have spurred research and advanced
understanding of ADHD, but have led to little consensus regarding its pathophysiology. Similarly, the
identification of replicable susceptibility genes has been difficult, due at least in part to the phenotypic and
neurocognitive complexity of ADHD.
It has been suggested that a novel way to pursue genotypic vulnerabilities for a complex trait such as
ADHD is to quantify cognitive indices of genetic liability that predict susceptibility to ADHD in the same way
that serum cholesterol predicts the risk of cardiovascular disease (Castellanos & Tannock, 2002). Although
the ideal characteristics of an optimal intermediate phenotype has been a subject of ongoing discussion,
there is general agreement that an intermediate phenotype should meet at least the following four criteria
(e.g., Aron & Poldrack, 2005; Castellanos & Tannock, 2002; Doyle et al., 2005):
1) The intermediate phenotype should distinguish patients with ADHD from healthy controls.
2) The phenotype should be anchored in a strong neuroscience model based on known properties of
neural systems.
3) Individual differences in the intermediate phenotype should be familial and heritable.
4) The relation between ADHD and the phenotype should be due at least in part to common
genetic influences.
Response Inhibition and Working Memory as Intermediate Cognitive Phenotypes of ADHD
Multiple studies suggest that deficits in executive functions distinguish between ADHD and control
subjects (Willcutt et al., 2005). Executive processes are defined broadly as functions that maintain an
appropriate problem solving set to attain a later goal (e.g., Pennington, 2002). In addition to RI and WM,
definitions of executive functions often include neurocognitive processes such as vigilance, planning, setshifting, and interference control (Barkley, 1997; Pennington & Ozonoff, 1996; Nigg, 1999; Willcutt et al.,
2005). Although the broad concept of executive processing encompasses a number of cognitive functions,
tasks within the domains of RI and WM have consistently shown the most robust group differences between
ADHD and control groups (Willcutt et al., 2005). In addition, RI and WM have been posited as highly
promising candidate intermediate phenotypes for ADHD based on the above criteria (Slaats-Willemse et al.,
2003; Castellanos & Tannock, 2002; Aron & Poldrack, 2005). Therefore, the proposed study will focus RI
and WM deficits as candidate intermediate phenotypes for ADHD. The following sections review evidence
for the 4 criteria in RI and WM.
Behavioral Studies of RI and WM in ADHD
Response inhibition (RI), defined as behavioral inhibition of a prepotent response. RI has been
operationalized using measures such as the Stop Task and the Continuous Performance Task, which
require subjects to suddenly cease an ongoing action or suppress information from an interfering or
conflicting stimulus. Robust weaknesses on these and analogous tasks have been demonstrated
consistently in both children and adults with ADHD (see Willcutt et al., 2005 for a meta-analysis of child
studies and Boonstra, et al., 2005 for a review of adults studies). Similarly, weaknesses in both verbal and
spatial WM have been demonstrated using a variety of tasks in groups with ADHD (Martinussen, et al.,
2005). Therefore, while it is clear that RI and WM are not the only cognitive tasks that distinguish between
ADHD and control groups (Sergeant, 2000; Sonuga-Barke, 2002), there is strong evidence that they play an
important role in the neuropsychology of ADHD. In the proposed study we will administer a range of tasks
that putatively tap RI and WM, and two non-executive cognitive domains (i.e. processing speed and simple
vigilance), facilitating a direct assessment of the association between each individual measure and ADHD,
as well as any additive or interactive effects between measures.
Neural Correlates of Response Inhibition and WM
If a cognitive process can be traced to specific neural substrates, this facilitates its ability to serve as
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an intermediate phenotype between susceptibility genes for the disorder and clinical symptoms. In this
regard, RI has been extensively studied in healthy subjects and is well-anchored in neural systems. RI is
thought to be mediated by frontalstriatal regions, with a possible more specific locus of control within the
right inferior frontal cortex (rIFC) (Aron & Poldrack, 2005). WM has also been linked to frontalstriatal neural
correlates, with a more specific locus in the bilateral dorsolateral prefrontal cortex (DLPFC) (Braver et al.,
1997). In the proposed study we have selected RI and WM tasks that have established neural correlates in
order to facilitate the assessment of the association between these cognitive constructs and ADHD.
Neuroimaging of ADHD
The combination of dysfunctions in inhibitory control in ADHD and the involvement of the PFC in
response inhibition implicates prefrontal regions in the symptomatology of ADHD (e.g. Barkley, 1997;
Pennington & Ozonoff, 1996; Swanson, et al., 1998a). Consistent evidence from structural imaging studies
in ADHD demonstrates smaller total cerebral volume and smaller volumes in many regions of the prefrontal
cortex (PFC), with these effects greater in the right hemisphere (Castellanos, et al., 2002; Castellanos, et al.,
1996; Filipek, et al., 1997). A recent report, using automated cortical analysis techniques, found that
greatest morphological reducations in right IFC for child and adolescent patients compared with matched
control subjects (Sowell et al., 2003). Additional converging evidence is provided by psychopharmacological
investigations. Prefrontal regions receive substantial dopaminergic innervation via the mesocortical system
(e.g. Volkow et al., 1997), and much evidence suggests that dopamine plays a causal role in ADHD (see
Swanson, et al., 1998a, for a discussion). For example, presynaptic dopaminergic function is abnormal in
medial and left prefrontal regions in treatment-naïve adults with ADHD (Ernst et al., 1998). Treatment with
methylphenidate, which increases the availability of dopamine (e.g., Pliszka, McCracken & Maas, 1996),
normalizes activation of prefrontal regions in both adults (Matochik et al., 1993) and children (Kim, Lee, Cho
& Lee, 2001) with ADHD. The proposed study will take advantage of an ongoing functional magnetic
resonance imaging investigation (R01 MH 70037) to collect structural brain images. Whole brain optimized
voxel-based morphometry will be used to parcel the brain into grey matter, white matter, and cerebral spinal
fluid volume (Milham et al., submitted). To control for type 1 error common to whole brain analysis, apriori
hypotheses in specific regions of interest are listed in Aim 2. Specifically, the relations between the volumes
of five frontal regions (inferior, dorsolateral, middle, ventrolateral, and superior prefrontal cortices), RI, WM,
and ADHD will be examined. Because particular regions of the prefrontal cortex, (i.e. rIFC and DLPFC)
have shown more consistent involvement in RI and WM (Aron & Poldrack, 2005), we hypothesize that
volume in these subregions will correlate most strongly with task performance and ADHD symptomatology.
In addition to the PFC, the striatum (the caudate, putatmen, and basal ganglia) has also been
implicated in ADHD, and structural findings of lower striatal volumes in groups ADHD are fairly consistent
(Castellanos, et al., 1996, Aylward, et al.,1996; Mataro, et al., 1997). Some of proposed that circuits
involving the striatum mediate RI in healthy subjects (Alexander, DeLong, & Strick, 1986), but evidence is
still mixed on the striatum’s role in inhibitory processes (Aron & Poldrack, 2005). Given strong evidence for
involvement of a frontalstriatal pathway in ADHD, the proposed study will also examine striatal structures in
relation to RI, WM, and ADHD. Finally, associations between RI and WM, ADHD and the cerebellum,
another region of interest consistently shown to be structurally abnormal in ADHD (see Giedd et al., 2001 for
a review), but not thought to directly mediate executive processes, will be examined in the same way.
Genetics of Response Inhibition and Working Memory Deficits in ADHD
Family and twin studies. In order for RI and WM to serve as valuable intermediate phenotypes for
ADHD, measures of these cognitive constructs should be heritable and co-familial and co-heritable with
ADHD. In a study of ADHD probands with a family history of ADHD, their clinically unaffected siblings, and
normal control subjects, Slaats-Willemse et al. (2003) demonstrated that the unaffected siblings had RI
deficits that fell between the scores of control subjects and ADHD probands. Similarly, Crosbie and
Schachar (2001) found that RI deficits were associated with increased familial prevalence of ADHD. While
these studies are consistent with the possibility of genetic influence on RI, family studies cannot rule out
shared environment as a factor in RI deficits. Recent evidence from twin studies suggests that RI and WM
deficits are moderately heritable and influenced by a subset of the same genes as ADHD (Ando et al., 2001;
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Chhabildas et al., submitted).
Candidate gene studies. Candidate genes for the proposed study have been identified based on
previous studies showing a replicable association with ADHD or a significant association with RI or WM.
Molecular genetic studies of ADHD have largely focused on candidate genes linked to the dopaminergic
(Swanson et al., 2000) or noradrenergic pathways (Faraone at al., 2005 for a review), brain systems
implicated in hyperactivity, executive control, and reward circuitry. The majority of association studies of
ADHD have examined polymorphisms at two loci: the dopamine transporter (DAT1) (e.g. Cook et al., 1995,
Gill et al., 1997; Daly et al., 1999 Waldman et al., 1998) and the dopamine D4 receptor (DRD4) (Comings et
al., 1999, Faraone et al., 1999; LaHoste et al., 1996; Rowe et al., 1998; Smalley et al., 1998; Swanson, et
al., 1998b). Significant associations between ADHD and DAT1 and DRD4 have been consistently
replicated. Moreover, a few studies have examined the relevance of these two genes in cognition. In a
candidate gene association study, ADHD children with a 7-repeat allele for the DRD4 gene had significantly
faster reaction times on Go trials compared with ADHD children without the 7-repeat allele (Langley et al.,
2004). Another study examined dopamine transporter (DAT1) 10-repeat versus 9-repeat allele status in
ADHD children using EEG and a version of the CPT (Loo et al., 2003). Children in the 10-repeat group made
significantly more commission errors and responded differently to methylphenidate as measured by EEG,
showing a reduction of theta activity (increased arousal) specific to the right frontal cortex. Moreover, in a
Dutch sample, Durston et al. (2005) showed that the 10-repeat allele for DAT1 is associated with smaller
caudate volume in the striatum and allele variants in DRD4 preferentially influence prefrontal grey matter
volume. The proposed study will explore these associations and probe them further by examining whether
genetic influences on RI deficits are at least partially mediated though volume in putative prefrontal or striatal
structures.
In addition to DAT1 and DRD4, associations with the dopamine d5 receptor (DRD5), synaptosomalassociated protein 25 (SNAP-25) and the serotonin transporter (5-HTT) have been frequently found in
ADHD (see Faraone at al., 2005 for a review). Despite a strong association with ADHD, the role of each of
these genes in cognitive deficits has not been explored. Another gene, catechol-o-methyltransferase
(COMT) has been implicated in executive processing, working memory, activation in prefrontal systems,
and, more recently, ADHD (Castellanos & Tannock, 2002; Goldberg & Weinberger, 2004). Although only two
of seven studies have found an association with ADHD (Faraone, et al., 2005), numerous studies support a
role for COMT genotype in prefrontal cognitive tasks (Mattay et al., 2003; see Goldberg & Weinberger, 2004
for a review), making it a strong choice for a candidate gene in the proposed study. The impact of risk
alleles for the above candidate genes (DRD4, DAT1, DRD5, SNAP-25, 5HTT, and COMT) on ADHD, task
performance, and regional brain volume will be examined in the proposed study. Table 2. contains the
candidate genes, their putative risk alleles, estimated frequencies of the allele in the U.S. population, and the
pooled odds ratio for finding an association with ADHD.
Table 2
Pooled Odds Ratios in Studies of ADHD and Allelic Frequencies for Gene Variants to be Examined in the
Proposed Study.
Gene
Risk Allele
Frequency of Risk Allele
Dopamine D4 Receptor (DRD4)
Dopamine D5 Receptor (DRD5)
Dopamine Transporter (DAT1)
Serotonin Transporter (5HTT)
Synaptosomal-associated Protein 25 (SNAP-25)
Catechol O-methyltransferase (COMT)
exon III VNTR, 7-repeat
CA repeat, 148 bp
VNTR, 10-repeat
5-HTTLPR long
T1065G
Val
.48
.36
.70
.61
.34
.61
1
(Chang et al., 1996)
(Vanyukov et al., 1998)
(Vandenbergh et al., 1992)
(Steffens et al., 2002)
(Barr et al., 2000)
(Malhotra et al., 2002)
2
Pooled Odds Ratio
1.16
1.24
1.13
1.31
1.19
1.0
1. Allele frequencies from representative studies using North American population samples.
2. Odds Ratio (OR) as calculated for a meta-analysis by Faraone et al., 2005. An OR represents the magnitude of the association between ADHD and the putative risk
alleles. An OR of 1.0 indicates no association, those greater than 1.0 indicate that the allele increased risk for ADHD, and those less than 1.0 indicate that allele
decreases risk for ADHD.
In summary, the proposed study aims to further specify the etiology of RI and WM deficits in ADHD.
RI and WM, both heritable, executive processes that have solid grounding in the neurosciences, will be
explored relative to neural and genetic mediators of ADHD symptoms. Associations between task
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performance and volume in prefrontal and striatal structures. In addition, to test the discriminant validity of
these associations, we will examine RI and WM in relation to cerebellum volume, a brain region implicated in
ADHD by not executive processing. Assocations between risk alleles in candidate genes, RI and WM,
putative regional volumes, and ADHD will be delineated.
3. Research Design and Methods
Overview
The objectives of the proposed investigation are to delineate associations between executive task
performance, brain structure, genetic variation, and ADHD. Structural MRI, DNA and performance on
neuropsychological measures in the domains of RI, WM, processing speed, and vigilance will be collected
from 84 undergraduates who met DSM-IV criteria in childhood and continue to experience significant
impairment and 84 control undergraduates matched for age, sex, and ethnicity who do not meet criteria for
ADHD. Expected completion time for the proposed investigation is 36 months.
Study Participants
All subjects will be recruited as part of an ongoing NIMH-funded study (R01 MH 70037) of the neural
correlates of adult ADHD that is being conducted in the laboratories of Dr. Banich and Dr. Willcutt, the cosponsor and sponsor of this application. 168 undergraduate students age 18-24 will be systematically
ascertained through the recruitment methods described below. As described in detail in the data analysis
section, this sample size will yield adequate power for our primary analyses.
Recruitment and Evaluation. Ongoing screening and recruitment procedures from a general sample of
undergraduates will be used to obtain a sample of 84 participants who meet lifetime criteria for the DSM-IV
combined subtype of ADHD and a matched comparison sample of 84 individuals without ADHD. As part of
an on-going study taking place within the sponsor’s (Willcutt) laboratory a sample of undergraduates is being
recruited from the Psychology 1001 subject pool without regard to ADHD status. Psychology 1001 is
completed by more students at the University of Colorado than any other course, and includes students
from virtually all majors on campus. As part of the course, students participate in a small number of
research projects. Therefore, this screening procedure will facilitate recruitment of a sample that is likely to be
more representative of the student population at large than a sample referred to an assessment clinic. In
addition, non-referred samples tend to include a higher proportion of females and ethnic minorities, two
populations that have historically received less research attention (e.g., Reid, 1995). We have screened over
3,500 students over the past three years and continue to screen between 600 and 700 new participants each
semester. Projections based on this rate of recruitment indicate that this pool of potential participants will be
sufficient to recruit the proposed sample. Selection procedures are described below.
Procedures
1. Selection Procedures
Measures used to assess ADHD and related symptomatology. Consistent with the method utilized in
other studies of ADHD in adults (e.g., O’Donnell et al., 2001), each participant in this on-going project is
asked to complete self-report rating scales assessing current and childhood symptoms of DSM-IV ADHD.
In addition, because a valid diagnosis requires a demonstration that ADHD symptoms lead to dysfunction,
several measures are administered to assess the impact of symptoms on a range of domains of functioning.
After informed consent is obtained from the student, the parents of each participant are also contacted by mail
and asked to complete similar ratings of current and lifetime ADHD symptoms and associated impairment.
Approximately 75% of the students provide consent for their parent to be contacted. By obtaining both selfreport ratings and parent ratings in the proposed study, we are able to test directly the validity of each
measure and their combination by assessing the degree to which they predict functional impairment.
The Current Symptoms Scale (Barkley & Murphy, 1998) is used to assess the extent to which each DSMIV ADHD symptom is currently true for the participant on a 4-point Likert scale with the anchors “Not at All”,
“Once in a While”, “Often” and “Very Often”. The Childhood Symptoms Scale (Barkley & Murphy, 1998) is
similar in format, but asks the individual to rate the extent to which each symptom was true when she or he
was a child 5-12 years of age. These scales also provide a brief assessment of the impact of these
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symptoms on the individual’s functioning as a child in areas such as social interactions, occupational
functioning, educational activities, and management of daily responsibilities.
In addition to these functional impairment screening items, two additional questionnaires are administered
to allow documentation of whether or not a participant’s reported symptoms of ADHD lead to significant
dysfunction. The Life Skills Impairment and Functioning Evaluation (LIFE) is a more detailed questionnaire
that includes 10-15 items assessing functioning in each of the following domains:1. Past academic
performance (e.g., high school GPA, repeated grades, special education assistance) and current academic
functioning (college GPA, academic probation, completion of assignments) 2. Interpersonal relationships with
friends, partners, and employers; 3. Management of money (e.g., bounced checks, debt, failure to pay rent,
ability to save); 4. Driving performance (e.g., tickets, accidents, self-reported frequency of traffic violations); 5.
Occupational functioning (e.g., ability to retain jobs and obtain promotions, completion of assigned tasks).
Finally, an estimate of overall adaptive functioning is obtained by asking the participant and parent to rate
the individual’s current functioning and lowest functioning during the past year on a Global Assessment of
Functioning Scale that corresponds directly to Axis V in DSM-IV-TR (American Psychiatric Association, 2000).
Identification of individuals with and without ADHD. To be invited to participate as part of the group with
ADHD, participants must meet operational criteria for a lifetime diagnosis of DSM-IV ADHD - Combined Type.
The identification of the Combined Type in adulthood is complicated by the systematic developmental shift in
symptoms of hyperactivity exhibited by individuals who meet criteria for the combined type in childhood.
Specifically, symptoms of inattention remain relatively stable with increasing age but symptoms of
hyperactivity-impulsivity decline with age (e.g., DuPaul et al., 1998; Nolan et al., 2001), suggesting that
many children who meet criteria for the Combined Type in childhood may meet criteria for the Inattentive
Type later once their symptoms of hyperactivity-impulsivity fall below the diagnostic threshold. Hence, the
following criteria are being used to select individuals with ADHD for the neurocognitive assessment: (1)
retrospective ratings by the participant or the parent indicating that he or she met criteria for the combined
type in childhood; (2) evidence that the participant currently meets criteria for any subtype of DSM-IV ADHD;
(3) agreement between reporters on lifetime ADHD status (although not necessarily subtype); (4) evidence
that symptoms of ADHD have caused significant impairment in functioning. A comparison sample matched to
the ADHD sample on age, gender, ethnicity, and parental socioeconomic status is being recruited from the
overall sample of participants who do not meet current or lifetime criteria for any ADHD subtype.
Those that meet the above criteria are invited to participate in the neuropsychological assessment. 84
ADHD and 84 control participants will participate in a 90 minute testing session administered by the applicant.
A subset of the subjects will also participate in structural neuroimaging data collection (36 in the ADHD group
and 18 controls) as part of an ongoing functional neuroimaging study. Subjects with a prescription for stimulant
medication will be asked to refrain from taking their medication for 12 hours prior to testing.
2. Neurocognitive Battery
The battery of cognitive measures was selected carefully to include multiple measures of response
inhibition, and verbal and spatial working memory. Measures of simple vigilance and processing speed are
included to facilitate the assessment of the discriminant validity of RI and WM deficits. In addition, measures
of general cognitive ability and academic achievement will be administered to facilitate the assessment of
the impact of these factors on the relation between ADHD and RI and WM performance.
a. Overall cognitive ability. Each participant’s general cognitive ability will be estimated using the Matrix
Reasoning and Vocabulary subtests from the widely-used Wechsler Adult Intelligence Scale, Third Edition
(WAIS-III; Wechsler, 1997). Matrix Reasoning and Vocabulary are commonly utilized to estimate Full Scale
IQ because they correlate more highly than any other subtest with the overall Performance IQ and Verbal IQ
scores, respectively.
b. Reading achievement. Previous research suggests that overall reading ability and specific learning
disabilities may moderate the relation between disruptive disorders and performance on neurocognitive
tasks (e.g., Seidman et al., 2001; Willcutt et al., 2001). Therefore, two brief screening instruments will be
used to estimate the reading ability of each participant. 1) The Letter-Word Identification subtest from the
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Woodcock-Johnson Tests of Achievement, Third Edition (WJ-III); Woodcock et al., 2001) is a reliable,
widely-used test of single-word reading that can be administered in 3 - 5 minutes. 2) The parent of each
participant will complete a brief questionnaire designed to screen for reading disability and other academic
difficulties (Willcutt, Boada, Pennington, et al., submitted). Factor analysis of this measure has yielded a
reliable seven-item reading factor in four independent samples and a composite based on this factor
correlates highly with scores on several standardized measures of reading achievement (r = .60 - .70).
c. Response inhibition. The Stop-Signal Task (e.g., Logan et al., 1997) is a computerized measure of
inhibitory control that was developed based on the dual-process “race model” of inhibition proposed by
Logan and colleagues (e.g., Logan, 1994). Stop-signal reaction time (SSRT) provides an index of the
duration of the inhibitory process in response to an auditory stop signal, independent of the participant’s
mean response time. In addition, variability in response time is also assessed by the standard deviation of
the response times on “go trials” without a stop signal, providing an index of arousal regulation. Both SSRT
and go-signal response time variability have consistently discriminated groups with and without ADHD in
previous studies (e.g., Nigg, 1999; Oosterlaan & Sergeant, 1998; Swanson et al., 2000; Willcutt et al.,
2001) and are sensitive to the effects of psychostimulant medication (e.g., Tannock et al., 1989). A
Continuous Performance Test (CPT) developed by Conners (1995) will be administered to assess
response inhibition (errors of omission) and vigilance (errors of commission) during a lengthy visual task.
During the first segment of the task letters are presented one at a time in the center of the computer
monitor, and the participant is instructed to press the space bar in response to every letter with the
exception of “X”. Because the X appears on only ten percent of the trials, these trials assess the ability of
the participant to inhibit a strong prepotent response. The second half of the task is a traditional A-X CPT,
which requires the participant to respond only if the letter X appears immediately after the letter A in a
sequence of letters presented one at a time. Although important concerns have been raised regarding the
ecological validity of the CPT as a measure of ADHD (Barkley, 1991), children and adults with ADHD
consistently exhibit more errors of omission and commission on a variety of different tasks based on the
CPT paradigm (e.g., Barkley, DuPaul, & McMurray, 1990; Epstein et al., 1998; Willcutt et al., 2001), and a
review by Corkum and Siegel (1993) concludes that CPT performance discriminates children with and
without ADHD more reliably than any other cognitive measure.
d. Verbal working memory. We will use the Digit Span Forward test from the Wechsler Adult Intelligence
Scale, Third Edition (WAIS-III; Wechsler, 1997) as a measure of the maintenance aspects of working
memory. The Digit Span Backwards test will be used as a measure of the manipulation aspects of
working memory. In this task individuals hear a series of digits and must repeat them either in the same
order or backwards order. The Sentence Span task is a working memory measure adapted by Siegel &
Ryan (1989) from the procedure developed by Daneman and Carpenter (1980). This task requires the
participant to continually process new verbal information while storing the results of this process for later
recall. As such it involves not only maintenance but also selection processes of working memory. The
participant is instructed to provide the last word for a set of simple sentences read by the examiner (e.g., “I
throw the ball up and then it comes...”), and is told that they will be asked to reproduce the words that they
provided after all sentences in that set have been completed. The task begins with a block of three twosentence sets, and increases in difficulty by adding one additional sentence per block up to a total of six
sentences. The dependent measure is the number of sets completed correctly.
e. Spatial working memory. The Spatial Span task is a spatial WM analogue to WISC-IV Digit Span that is
similar to the Corsi blocks test. Outlines of nine boxes are presented on a white screen. Boxes are filled one
per second in a pseudo-random order. During the first half of the task the participant must touch the boxes in
the same order in which they appeared during the trial, whereas in the second half the boxes must be
touched in the reverse of the order that they appeared. The Spatial Span forward and backwards tests will
be used as measures of the maintenance and manipulation aspects of spatial working memory, respectively.
The Spatial 2-back task uses the same stimulus as the Spatial Span task. Subjects are asked to press a
key to indicate whether or not the box that lights up is the same as the box that lit up two boxes previously.
f. Other measures. Additional measures of reaction time, processing speed, and simple vigilance will be
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collected as non-executive cognitive measures to assess the discriminant validity of RI or WM deficits.
3. Genetic Data Acquisition. At the end of the testing session, a DNA sample will be obtained. Genomic DNA
will be isolated from buccal cells using a procedure modified from published procedures (Freeman et al., 1997;
Lench et al., 1988). Participants will be given 10 ml of sucrose solution (4% tap water) in a 2 oz Dixie cup. Three
sterile corron-tipped wooden swaps will be dipped in the sucrose solution and used to rub the cheeks and gums
of 20-30 sec. The swabs will be placed in a sterile 50 ml polypropylene centrifuge tube containing 500 μl of 1M
Tris-EDTA buffer (1M Tris-HCL, 200 mM disodium EDTA, pH 8.0), 500 μl of 5% sodium docecyl sulfate (SDS),
and 100 μl of 5M sodium chloride (final concentrations are approximately 50 mM Tris-HCL, 10 mM EDTA, o.5%
SDS and 50 mM NaCl). Immediately following, the participants will be instructed to rinse out the mouth forcibly
with the sucrose solution. After approximately 30 sec, the contents of the mouth will be returned to the Dixie
cup, the tester will pour the entire contents into the tube containing the lysis buffer and swabs, and the tubes will
be capped. Samples are stable for at least one week at room temperature under these conditions. Immediately
following the testing session the tubes will be refrigerated until the DNA is extracted, usually within 48 hours.
DNA will be extracted using an in-house procedure that is essentially identical to the Puregene method. The
yield of DNA will be quantified by Picogreen (Molecular Probes, Eugene OR) fluorescence in duplicate.
Each sample will be run on an agarose gel to assess the quality of the DNA, and samples with low yield or
low quality DNA will be recollected. We have used this method to extract DNA from several thousand
samples to date with an average yield of 40 +/- 2 μg and 99% success as judged by DNA of sufficient
quantity and quality to perform 1000 or more routine PCR amplifications. We expect to obtain similar results
in this project, which will easily be sufficient to genotype all of the candidate genes.
Data Analysis
1. Genotyping will take place in the core genotyping facility in Dr. Andrew Smolen’s laboratory at IBG using
OPRM1 and CNR1 Assays. This method relies on allele-specific hybridization of oligonucleotide probes.
They have performed numerous assays (~ 1000 samples) in duplicate and triplicate. The error rate for
these assays is less than .5% (i.e., less than 1 out of 200 calls are not consistent across duplicates). For the
present study, polymorphisms for each of the primary risk alleles will be analyzed. All assays will be run in
duplicate and any inconsistencies will be resolved with a third run.
2. Structural Imaging Data Analysis. Structural magnetic resonance imaging (MRI) data acquisition and
analysis will take place in collaboration with the co-sponsor’s (Dr. Banich’s) laboratory as part of the ongoing
project funded by NIMH (R01 MH 70037). The applicant will work with a postdoctoral member of the Banich
laboratory to gain experience in this type of analysis, but we recognize that it will not be possible within the
scope of the proposed fellowship to gain sufficient expertise to be able to acquire and analyze MRI data
independently. Instead, the goal of the fellowship is to understand these methods sufficiently to enable the
applicant to use them in the future as an independent researcher in collaborative studies with MRI experts.
Whole brain optimized voxel-based morphometry will be used to parcel the brain into white matter, grey
matter, and cerebral spinal fluid according to the methods outlined in Milham, et al. (submitted). This study
was successful in finding significant group differences between 14 adolescences with substance abuse and
14 controls in regional grey matter and white matter volume. Whole brain analysis will be implemented to
ensure that the analysis is comprehensive. However, to control for type 1 error common to whole brain
analysis specific hypotheses regarding apriori regions of interest will be tested. Significance thresholds will
be more stringent to detect associations in regions where there was no apriori hypothesis.
3. Data Adjustments. The distribution of each age-adjusted variable will be assessed for outliers prior to any
additional analyses. Outliers will be defined as scores that fall more than three standard deviations (SD) from
the mean of the overall sample and more than 0.5 SD beyond the next most extreme score. After confirming
that the task was run correctly and that these outlying scores were entered correctly in the datafile, each outlier
will be adjusted to a score 0.5 SD units beyond the next highest score, with multiple outliers rescored to 0.1 SD
apart. After these adjustments, the distribution of each variable will be assessed for significant deviation from
normality, and appropriate transformations will be implemented to approximate a normal distribution for
variables with skewness or kurtosis greater than one.
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4. Defining ADHD. Groups with and without ADHD will be defined for categorical analyses based on the
criteria described previously. In addition, because a growing body of research suggests that categorical
diagnostic cutoffs for ADHD dichotomize what may be a continuous dimension of liability (e.g., Barkley,
1998; Willcutt et al., 2000), we will also examine the relation between dimensional measures of DSM-IV
inattention and hyperactivity-impulsivity and the neuropsychological and neuroanatomical variables.
Although the regression procedures that we will use for most analyses are fairly robust to normality
violations, statistical power is weakened if the phenotypic measure is highly skewed. Therefore, to select
optimal phenotypes for the primary dimensional analyses we evaluated the psychometric characteristics of
each potential measure (Willcutt, Bidwell, Litt-Hautsen, & Banich, submitted). These analyses revealed that
the optimal measures of inattention and hyperactivity-impulsivity were derived from an algorithm similar to
the ‘or rule’ used to combine parent and teacher ratings in the DSM-IV field trials (Lahey et al., 1994).
Specifically, parent and self-report ratings were combined by using the higher of the two ratings for each
symptom on the 0-3 ADHD rating scale, then summing across all inattention or hyperactivity-impulsivity
symptoms to create an overall “symptom severity” composite score for each dimension of interest. We will
also conduct exploratory analyses to test if results differ for parent versus self-report ratings.
5. Hypothesis Testing.
Aims 1 &2. Compare the performance of adults with and without ADHD on measures of RI and WM.
Examine relations between prefrontal (5-subregions), striatal (3-subregions), and cerebellar volume, RI and
WM performance, and ADHD. The same sequence of analyses will be conducted to test for differences
between groups with and without ADHD and differences between the ADHD symptom dimensions on the
neurocognitive and neuroanatomical measures. Logistic regression models will be fitted to test for differences
between groups with and without ADHD on each measure, and parallel linear regression models will be used to
test if these results are stronger for inattention or hyperactivity-impulsivity. Secondary models will test if
performance on RI and WM predict ADHD and neuroanatomical measures more strongly than performance
on processing speed and simple vigilance tasks. For example, we will test whether RI performance predicts
prefrontal volume while controlling for whole brain volume and processing speed. Additional models will test
if this relationship differs between ADHD and control groups. Age, ethnicity, and sex will be considered as
potential covariates in the initial model for each dependent variable, and covariates that are significantly
associated with the dependent variable will be retained in the final model. Some authors (e.g. Werry, Elkind,
& Reeves, 1987) have argued that IQ should be included as a covariate in all analyses in order to ensure
that deficits associated with ADHD cannot be explained more parsimoniously by group differences in
intelligence. In contrast, others (e.g. Barkley, 1997) suggest that ADHD may directly cause mild IQ deficits
relative to individuals without ADHD, and that controlling for IQ therefore removes a portion of the variance
that is associated specifically with ADHD. Because this issue has not been resolved conclusively, we will
examine all findings with and without IQ covaried.
Aim 3. Examine the effects of candidate genes (i.e. DAT1, DRD4, SNAP-25, DRD5, 5HT1B, and COMT),
on RI and WM task performance, volume of the PFC, striatum, and cerebellum, and the ADHD. Association
analysis will be conducted to test directly whether risk alleles for the candidate genes are associated with
ADHD symptoms, performance on each task, and volume in each brain region. Univariate analyses will be
conducted individually for each candidate gene to test 1) whether the risk allele is associated with ADHD
symptom status, 2) for differences in task performance in risk allele vs. non risk allele groups, and 3) for
structural differences in each putative brain region in risk allele vs. non-risk allele groups. Additional models
will then be used to test whether the relationships between 1) allele status and task performance, and 2)
allele status and regional volume differs between ADHD and control groups. Multivariate analysis will be
used to test for more complex associations. For example, based on previous research supporting a role for
DAT1 allele status in RI tasks (Loo et al., 2003) and, in a separate study, striatal volume in the caudate
(Durston et al., 2005), a multivariate regression model will test whether DAT1 allele status explains RI and
lower caudate volume, and whether this relationship differs between ADHD and control group,.
Power Analysis. A sample size of 84 ADHD and 84 control participants was selected to examine the
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hypothesized relationships between ADHD symptoms, neuropsychological task performance, and candidate
gene allele status at an alpha level of .05. Structural imaging data will be collected in a subset of this sample
(36 ADHD and 18 control participants). This sample size has been selected to examine hypothesized
associations between volume in putative brain regions and ADHD, task performance, and allele status.
Table 3 summarizes the statistical power for key comparisons based on these projected sample sizes
(Cohen, 1988). Estimates of effect size for most comparisons were obtained from previous published
studies. If few studies were available (i.e., candidate genes and neuropsychological tasks), a medium effect
size (Cohen, 1988) was used to estimate power. The proposed sample size will provide high power to detect
differences on neuropsychological measures between the ADHD and control groups and along inattentive
and hyperactive symptom dimensions. Power will also be high to detect even relatively small effects of the
candidate genes on ADHD symptoms and task performance. Although there is little consensus regarding the
estimation of power for neuroimaging studies, based on previous studies using similar methods (Milham et
al., submitted; Durston et al., 2005) the proposed sample size will provide adequate power to detect 1)
differences in regional volume between the ADHD and control groups and 2) the hypothesized relationships
between regional volume and task performance. There will be lower power to detect hypothesized
associations between regional volume and allele status; these analyses are considered exploratory.
Table 3.
Summary of statistical power for key comparisons
Analysis
Estimated effect size
d = 0.6
Correlational analyses of ADHD symptom dimensions
Candidate genes and neuropsychological tasks
r = .3
.97
c
P1 - P2 = .15
.76 - .93
d = 0.5
.84 - .94
Structural MRI analyses
b
.89
a
b
Candidate genes and risk for ADHD
a
Estimated power
a
ADHD vs. control on neuropsychological tasks
c
see text
c
Willcutt, in press, e.g., Faraone et al., 2005; Waldman et al., 1998;
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5. Human Subjects Research
Protection of Human Subjects
Risks to the subjects
Human Subjects Involvement and Characteristics
The characteristics of the proposed sample are explained above in the Study Participants section. 168
undergraduates will be recruited through ongoing recruitment procedures.
Sources of Materials
The source of all research data will be the participants’ responses to questions asked during the
screening selection and neurocognitive battery. In addition, genomic DNA will be isolated from buccal cells
on the inside of participants’ cheeks, using a noninvasive procedure (cotton swab) modified from published
procedures (Freeman et al., 1997). Structural brain imaging data will be collected using noninvasive MRI
procedures. All data will be used exclusively for research purposes.
Potential Risks
There is negligible risk to subjects from participating in psychological testing. Minimal physical
discomfort may result from being in a supine position for a prolonged period while structural imaging data is
collected. Participants are informed of all procedures beforehand, and must read, agree to, and sign
informed consent forms and each has the option to withdraw consent at any time. Every attempt will be
made to ensure the comfort, safety, and confidentiality of all participants.
Adequacy of Protection Against Risks
Recruitment and Informed Consent
Recruitment procedures are described in the Study Participants section. Participants will provide
written consent for their participation which will inform them of possible risks to participation. Participants will
be given a copy of the consent form to take with them and any questions asked by the participant will be
answered prior to testing. Each participant can withdraw consent at any time for any reason.
Protection Against Risk
Data collected in this research will be held strictly confidentially. No information will be released.
Participant data will be identifiable only by numerical identification code (ID code). The list linking ID code to
the participant’s identifying information will be maintained separate and secure from the data, under the
supervision of Drs. Willcutt and Banich. This list and all personal information will be destroyed at the
conclusion of data collection. The data (test results, DNA, and brain images) will be securely maintained at
the University of Colorado, and will be identified by ID code only. All data will be destroyed no longer than
five years after completion of the project.
Potential Benefits of the Proposed Research to Subjects and Others
There are unlikely to be any direct benefits to individual participants in this study. Indirect benefits to
participants include increased knowledge about the etiology of ADHD. In addition, participants will be
compensated $50 for their participation.
Importance of the Knowledge to be Gained
The proposed research represents an important step in understanding genetic and neurocognitive
pathways for ADHD. The research will increase the understanding of the links between genetic variations,
brain development, cognitive processing, and psychopathology. Eventually, this research can be used to
inform treatment and prevention efforts for ADHD and other attentional disorders. Minimal participant risk
balances the potential for significant findings that inform the fields of clinical psychology, neuroscience, and
behavioral genetics.
Inclusion of Women and Minority Subjects
Ongoing recruitment procedures have obtained a sample consisting of approximately 40-50% female
and 15% minority participants. We expect that recruitment efforts will continue to provide similar proportions
of female and minority participants.
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Inclusion of Children
As noted previously, the participants include adolescents between ages 18-21. Each participant is of
legal age to give his/her own informed consent before participation commences.
Item 30d. Selections of Sponsor and Institution
The Clinical Psychology program at the University of Colorado at Boulder is widely recognized as
one of the top research training programs in the country. Futhermore, the program’s active collaborations
with the Institute for Behavioral Genetics (IBG) and the Institute of Cognitive Science (ICS) provide an
exceptional environment for interdisciplinary training in genetics, brain functioning, and human behavior.
Sponsors. Dr. Erik G. Willcutt was chosen as the applicant’s sponsor for this proposal. Dr. Willcutt
specializes in the genetics and neuropsychology of development disorders, including ADHD. His impressive
track record of research in this area and first-rate laboratory facilities makes him an ideal advisor for the
applicant’s proposed research. Dr. WIllcutt is an Assistant Professor in the Department of Clinical
Psychology and Faculty Fellow at IBG. As such, Dr. Willcutt has extensive clinical experience in recruitment
and assessment of the proposed population as well as an expertise in behavioral genetics methodology.
Dr. Willcutt has served as academic advisor and research mentor for the applicant throughout her graduate
career. The relationship has been both productive and supportive, resulting in a number of collaborative
projects.
Dr. Marie Banich was enlisted as a co-sponsor to facilitate the applicant’s overall training in cognitive
neuroscience. Dr. Banich has worked as a professor and cognitive scientist for over two decades. She
currently serves as Professor of Psychology and Director of ICS at the University of Colorado at Boulder and
Professor of Psychiatry at the University of Colorado Health Sciences Center. She has successfully
mentored many graduate students and postdoctoral fellows in cognitive psychology and neuroscience. Her
published work reflects a special interest in neuroimaging of cognitive control and human neuropsychology.
Her specialization in cognitive neuroscience, coupled with her access to state-of-the-art magnetic resonance
imaging technology and analysis tools, make her a clear choice to co-sponsor this proposal. In addition,
prior to the inception of this proposal, the applicant and Dr. Banich have established a mentoring relationship
through the applicant’s work as graduate research assistant in Dr. Banich’s laboratory.
Additional support. Dr. Andrew Smolen, Senior Research Associate at IBG, will train the applicant
in genotyping techniques and provide the applicant the facilities she needs to complete the genotypic
analysis for the proposed research. Dr. Kent Hutchinson, Professor of Psychology at the University of
Colorado, will collaborate on issues related to candidate gene analysis. Dr. Hutchinson is an expert in the
genetics of addiction and his experience in conducting numerous candidate gene association studies will be
vital to the project. Dr. Gary H. McClelland, Professor of Psychology at the University of Colorado, will assist
in statistical modeling and analysis for the proposed research. Dr. McClelland is regarded nationally as a
statistical expert and has co-authored a widely used textbook on statistical analysis using the general linear
model approach. Dr. Bruce F. Pennington, Professor, Department of Psychology, and Director of the
Developmental Cognitive Neuroscience Program, University of Denver, will collaborate on data analysis,
data interpretation, and manuscript preparation. Dr. Pennington’s is a renowned neuropsychologist whose
research focuses on disorders of cognitive development. Dr. Pennington’s expertise in developmental
neuropsychology will be invaluable to the proposed research and corollary projects.
Institution. The Department of Psychology at the University of Colorado, at Boulder is in a unique
position to train students in clinical psychology, behavioral genetics, and neuroscience. The Department of
Clinical Psychology offers comprehensive advanced training in research methods, statistics, and ethics as
well as a solid foundation in clinical practice. In addition to pursuing her doctorate through the Department
of Clinical Psychology, the applicant is also working towards the completion of IBG’s Graduate Training and
Interdisciplinary Certificate. The University of Colorado is one of the few institutions to offer a formal
mechanism for dual graduate training in clinical psychology and behavioral genetics. Under the auspices of
IBG, the applicant will be mentored in the study of the genetics of simple and complex behavioral traits.
Moreover, this exceptional training opportunity is augmented further by the state-of-the-art resources
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available through Dr. Banich and ICS. The proposed training in cognitive neuroscience, through coursework
and collaborative research projects, will develop the applicant’s understanding of human brain function and
anatomy. This knowledge base will provide a crucial link in the applicant’s study of the impact of genes on
behavior and is invaluable to the applicant’s ability to research pathophysiological mechanisms in clinical
disorders.
Item 30e. Responsible Conduct of Research
The applicant has already successfully completed two of the three required courses addressing
ethical concerns in clinical research. The first course, Introduction to the History and Ethics of Clinical
Psychology focused on the APA Ethical Code. Class discussions addressed myriad ethical dilemmas facing
clinical researchers. The second course, Professional Issues and Ethics focused on ethics of clinical
treatment and practice. The third course in the required triad of ethics training is Scientific Ethics and
Integrity. This course, a requirement for the IBG certificate, will be offered in the Spring of 2006. The
foundation of this course will be ethical considerations surrounding genetic research.
Other past coursework has incorporated ethical discussion into class discourse. For example, both
personality (Spring 2004) and intellectual assessment (Fall 2004) courses extensively address issues of
client privacy and responsible conduct for providing client feedback. In addition, instructors (Drs. Whisman
and Richardson, respectively) in both courses encouraged discussion about ethical issues for specific
populations (women, ethnic minorities, children, etc.). In another course, Research Problems in Clinical
Psychology (Spring, 2005), the professor (Dr. Hutchinson) facilitated discussion of issues surrounding the
inclusion of human subjects in research protocols. Discussion topics also included the ethics of authorship
on collaborative research projects.
The applicant has successfully completed the University of Colorado’s Human Research
Committee’s required tutorial on ethical issues in human subject research. The tutorial outlines the
University’s policies as well as facilitates general understanding of relevant issues.
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