Clinical trial NCT02630017
Conditions: ADHD
Sponsor: University of Arkansas
Start date: 2016-03-07; Completion date: 2018-09-21
Enrollment: 51 participants; Allocation: NON_RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To investigate the effects of methylphenidate on motivated behavior in adults with and without ADHD

Detailed description:
This study has a mixed between- and within-subject design. Participants are young adults (aged 18-45) with ADHD and non-ADHD matched controls. They will be recruited from locations around the community, consented, screened for eligibility, then scheduled for 2 study days. Study days will be at least 48 hours apart. Thus, there will be a total of 3 lab visits across a 3 week period. Participants will be administered study drug on one study day and placebo on the other study day. They will complete a battery of cognitive/behavioral tasks and answer questionnaires on both study days.

Arms: arm 1: Adults with ADHD arm 2: Adults without ADHD
Interventions: intervention 1: ADHD methylphenidate first, placebo second intervention 2: ADHD placebo first, methylphenidate second intervention 3: Non-ADHD methylphenidate first, placebo second intervention 4: Non-ADHD placebo first, methylphenidate second
Intervention descriptions: intervention 1: double-blind, counter-balanced administration intervention 2: double-blind, counter-balanced administration intervention 3: double-blind, counter-balanced administration intervention 4: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
Motivated behavior in adults with and without ADHD 
 
 
 
NCT 02630017 
 
 
 
9/6/2018 
 
 


 
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Study Title: 
Motivated behavior in adults with and without ADHD (MOBE) 
 
Principal Investigator: 
Merideth Addicott PhD 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 843 
Little Rock, AR 72205 
Telephone: 501-526-2436 
Email: maddicott@uams.edu 
 
Study Physician: 
Margaret Weiss, MD PhD FRCP© 
University of Arkansas for Medical Sciences 
Child Study Center 
1210 Wolfe St. 
Little Rock, AR 72202 
Telephone: 
 
Email: 
 
 
 
Study Coordinator: 
Deborah Hodges 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 843 
Little Rock, AR 72205 
Telephone: 
 
Email: 
 
 
 
Study location: 
Psychiatry Research Institute, 4th floor 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 843 
Little Rock, AR 72205 
 


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Background and Rationale 
The number of attention-deficit hyperactivity disorder (ADHD) diagnoses has increased 
dramatically in the last decade, and methylphenidate (MPH) – a common medication for ADHD 
– is at risk of being over-prescribed. While some patients experience significant symptom 
improvement from MPH, as many as 90% of adults discontinue use within one year [1]. The 
clinical presentation of ADHD is heterogeneous, and this heterogeneity may arise from 
differences in the underlying neurobiology of ADHD symptoms. These symptoms are believed 
to arise from either hypo- or hyperactive dopamine (DA) and/or norepinephrine systems. This 
etiological complexity presents a challenge in prescribing appropriate medication to ADHD 
patients, but patients whose behavioral problems stem from DA-ergic deficits may gain the most 
benefit from MPH, which indirectly increases extracellular DA in the brain. However, there are 
no noninvasive tools currently available that can identify DA dysfunction, despite an urgent need 
for improved classification of ADHD subtypes in order to maximize treatment efficacy. This 
proposal seeks to refine the clinical heterogeneity of ADHD symptoms based on a 
neurobiological mechanism. 
ADHD has been proposed to consist of 2 subtypes, one subtype consists of disordered 
thought and action typified by poor inhibitory control, and the other subtype consists of 
decreased motivation typified by delay aversion [2]. There is direct evidence that decreased 
motivation in ADHD is specifically related to hypoactive DA function. In particular, trait 
motivation scores among ADHD participants positively correlated with biological markers of DA 
function [3]. However, obtaining biological markers of DA function is expensive, invasive, and 
not a feasible diagnostic tool. There are also some well-established behavioral reinforcement 
deficits of the motivation subtype, including failure to delay gratification, impaired response to 
partial schedules of reinforcement, and preference for small immediate rewards over larger 
delayed rewards. However, delay discounting/aversion paradigms have not been directly linked 
to DA function in ADHD [4], nor do they offer predictions about the underlying neurobiological 
mechanisms of these behaviors. An excellent paradigm of behavioral reinforcement that 
provides a theoretically-driven model of DA function, and has been directly linked to DA 
function, is the explore/exploit trade-off. This paradigm could be used to characterize ADHD 
subtypes based on DA function; however, behavior on this paradigm has not yet been 
investigated in the context of ADHD. 
The explore/exploit trade-off is a decision between exploiting a known source of reward 
versus exploring the environment for a new source of reward with potentially greater value, in 
order to maximize long-term reward. This trade-off plays a fundamental role in survival and 
many species have been shown to follow predictable rules of reward maximization [5]. DA 
regulates the explore/exploit trade-off by modulating the extent that reward information biases 
behavioral activity: Diminished DA biases behavior towards exploitation of known rewards, 
whereas enhanced DA favors exploration [6]. Furthermore, diminished DA increases the 
sensitivity to costs and/or delays associated with obtaining rewards, which is consistent with the 
reward delay aversion typical of the decreased motivation ADHD subtype. Importantly, trait- and 
state-based enhancement of DA function has been shown to increase exploratory behavior [6-
8], suggesting that this behavior could be modulated by both ADHD (i.e., trait-based hypoactive 
DA function) and MPH (i.e., state-based enhanced DA function). 
The explore/exploit trade-off could have vital importance to psychiatry as a behavioral 
measure of DA function and predictor of MPH efficacy; however, more research is needed to 
establish the distribution of explore/exploit behavior among ADHD patients and healthy controls, 
and to demonstrate that explore/exploit behavior is sensitive to changes in brain DA function. 
This proposal seeks to address these points by administering a paradigm of explore/exploit 


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behavior known as the 6-armed bandit task (6ABT) [9] to individuals with and without ADHD. 
Inattention deficits, in particular, have been related to trait motivation [3] and will be the primary 
ADHD symptom of interest. The 6ABT will be administered at baseline and during 2 testing 
sessions in which participants will receive MPH or placebo in a counter-balanced, double-blind 
design. During the testing sessions, participants will be administered a battery of neurocognitive 
tests in addition to the 6ABT. 
The primary goal of this preliminary study is to collect data to perform power analyses for a 
larger project. 
Specific Aims 
Aim 1: Relate explore/exploit behavior to ADHD symptomatology. 
Hypothesis 1a: At screening, nonmedicated ADHD participants will make fewer exploratory 
choices than controls. 
Hypothesis 1b: At screening, the number of exploratory choices among nonmedicated ADHD 
participants will negatively correlate with inattention symptom severity and positively correlate 
with trait motivation. 
Aim 2: Relate explore/exploit behavior to dopamine function and medication efficacy 
Hypothesis 2a: At testing, ADHD and control participants will make more exploratory choices 
after MPH compared to placebo. 
Hypothesis 2b: At testing, neurocognitive improvements from placebo to MPH among ADHD 
participants will negatively correlate with the number of exploratory choices made at screening. 
Study Design and Procedures 
Overview: This study has a mixed between- and within-subject design. Participants are 
young adults (aged 18-45) with ADHD and non-ADHD matched controls. They will be recruited 
from locations around the community, consented, screened for eligibility, then scheduled for 2 
study days. Study days will be at least 48 hours apart. Thus, there will be a total of 3 lab visits 
across a 3 week period. Participants will be administered 40 mg methylphenidate (MPH) on one 
study day and placebo on the other study day. They will complete a battery of 
cognitive/behavioral tasks and answer questionnaires on both study days. 
Recruitment/Screening: We will advertise on internet, flyers, and in the newspapers for 
volunteers for the study. Participants who qualify over the phone and are interested in 
participating will be scheduled for further screening at the study site. We are submitting a HIPAA 
Waiver for the purposes of conducting this phone screen. The informed consent and screening 
session will last approximately 3 hr. All aspects of the study will be described and informed 
consent will be obtained by the PI or study coordinator. Breath and urine samples will be 
collected in order to screen for drug use and recent alcohol use. Women of child-bearing 
potential will undergo urine pregnancy testing. Detailed inclusion/exclusion criteria are described 
below in the Study Population section. ADHD participants will meet DSM-IV criteria for a primary 
diagnosis of ADHD. The non-ADHD group will be age, education level, and sex matched to the 
ADHD group by targeted recruitment or selective enrollment. 
During the informed consent process and prior to participation, participants will be 
informed that they will receive drugs that are commonly used to treat ADHD (i.e MPH) and/or 
placebo. Participants will be told that the purpose of the study is to measure the effects of 
stimulants used to treat ADHD and to see how these drugs affect mood and behavior. Other 
than receiving this general information about MPH versus placebo, participants will be unaware 


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of the type of drug administered. Participants will be given no instructions regarding what they 
are “supposed” to do or what outcomes might be expected. 
As part of the screening, all participants will undergo standardized diagnostic procedures 
for ADHD, including the Conners Adult ADHD Rating Scales to assess ADHD status (all 
participants) and the Conners Adult ADHD Diagnostic Interview for DSM (prospective ADHD 
participants only). Participants will be administered the MINI International Neuropsychiatric 
Interview to assess the presence of other Axis I disorders. The ADHD diagnostic interview will 
be administered by the Principal Investigator or the study coordinator, under the supervision of 
the study physician. The MINI will be administered by the Principal Investigator or study 
coordinator. Any answers given by the participant that may indicate the presence of an Axis I 
disorder will be further reviewed by the study physician. 
Participants will also complete a physical examination of their vital signs (height, weight, 
pulse, blood pressure) and complete a medical history to screen for contraindications for MPH 
administration. The participants will also complete a drug use history interview. This exam, 
medical, and drug use history will be overseen by the study physician. The study physician will 
follow-up with questions about family history of heart disease or other illnesses as necessary. 
Study days: Participants who meet all eligibility criteria will complete baseline behavioral 
tasks (see below) and some questionnaires, and will then be scheduled for their 2 study days. 
Each study day will be scheduled at the same time of day (either morning or afternoon). 
Participants scheduled for the morning session will be asked to skip breakfast, participants 
scheduled for the afternoon session will be asked to skip lunch. A small meal will be provided 
(e.g., 2 granola bars and a fruit cup) for all participants after capsule administration. On each 
study day, participants’ blood pressure and pulse will be measured and they will fill out a mood 
questionnaire (Positive and Negative Affect Schedule: PANAS). Women will provide a urine 
sample for a urine pregnancy test due to potential increased risks of stimulant drug 
administration. Women who return a positive pregnancy test will be excluded from further 
participation and will meet with the PI or study physician to provide appropriate follow up. 
Participants who continue to meet eligibility criteria will be administered 40 mg immediate-
release MPH (MPH IR, Ritalin, Novartis) or a matching placebo with 8oz of water using a 
double-blind, counterbalanced design. Participants will sit quietly in a private waiting room while 
the drug is absorbed and eat the provided meal. After 60 min, participants will be administered a 
battery of behavioral tasks. Then, participants will complete questionnaires regarding mood, 
side-effects, and drug effects. Additional measurements of blood pressure and pulse will be 
taken approximately every 60 min after capsule administration and before participants are 
dismissed (4x per study day). Each study day will last approximately 3 hours. 
Behavioral Tasks: 
Bandit Task. Participants are shown a computer screen with 6 slot machines depicted. 
Each machine, when selected, will pay off points around a mean probability that changes 
randomly and independently from trial to trial. Participants must actively sample from a machine 
to discover its pay-out. As the average pay-out changes across trials, participants must decide 
whether to continue to exploit the current machine, or explore other machines. This task takes 
approximately 15 minutes to complete. 
Patchy Foraging Task. Subjects choose between 2 targets on each trial. Choosing to 
stay in the current patch yields a short delay (0.5 s) and reward whose value diminishes on 
each trial. Choosing to leave the patch yields no reward and a long delay (travel time) whose 
duration is indicated on screen while participants make their selection. Choosing this option 
resets the value of the current patch. This task takes 8 min to complete. 


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Effort Expenditure for Reward Task (EffRT). This task measures effort-based decision 
making. On each trial, participants choose between two different task difficulty levels to obtain 
monetary rewards. For all trials, participants make repeated manual button presses within a 
short amount of time. Each button press raises the level of a “bar” viewed onscreen. If the bar is 
raised to the top within the allotted time period, the participants wins the points for that trial. 
Each trial offers a choice between two levels of difficulty: a “hard” task and an “easy” task. Hard 
task trials required the subject to make 100 button presses using the non-dominant little finger 
within 21 seconds, while easy task trials require the subject to make 30 button presses using 
the dominant index finger within 7 seconds. Completion of easy task trials will earn 1 point. Hard 
task trials could earn between 1.24 and 4.30 points. However, the probability of earning the 
points for successful task completion is 88%, 50%, or 12%. The probability of earning points is 
indicated onscreen at the start of each trial. At the end of each trial, participants are shown 
whether they completed the task on time or not, and earned the points or not. Participants have 
20 min to play as many trials as they can. 
Motivated Memory Task (MMT): This task measures the effects of reward motivation on 
expectancy violation processing. The design of this task is based on the monetary incentive 
delay task and is described in detail in Murty & Adcock, Enriched encoding: Reward motivation 
organizes cortical networks for hippocampal detection of unexpected events (Cerebral Cortex 
2013). Each trial consists of 3 phases: 1) a cue indicating whether the participant could earn a 
high ($2) or low ($0) reward, 2) a variable delay during which color images are flashed on the 
screen 10 or 11 times, and 3) the formerly color image is presented in grayscale (the target 
image), which signals to the participant to make a speeded button press to earn a reward. 
During phase 2: the color images are either control (all images are identical) or expectancy 
violation trials, in which a novel distractor image is presented among the serial presentation of a 
color image. During phase 3: participants will perform a 2-alternative forced-choice recognition 
computerized memory task for images that constituted expectancy violations for both the high-
reward and low-reward trials. This task takes 20 min. 
Conner’s Continuous Performance Task (CPT). This task measures sustained attention 
and inhibitory control. Subjects are asked to press a space bar on a computer as letters are 
sequentially displayed on the computer screen (unless an “x” appears). Subjects are asked to 
inhibit their response whenever an “x” appears. This task lasts approximately 15 minutes. 
The Spatial Span consists of two parts: Spatial Span Forward and Spatial Span 
Backward. For each part, the examiner taps a series of cubes at the rate of about one cube per 
second. Following presentation, the examinee either taps the cubes in the same order as the 
examiner (Spatial Span Forward) or in reverse order (Spatial Span Backward). For both Spatial 
Span Forward and Spatial Span Backward, the test begins with series of two cubes and 
continues to a maximum of eight cubes. Examinees are given two trials at each series length, 
and the test continues until both trials of a series length are failed. One point is awarded for 
each trial the examinee answers correctly. The maximum possible score for the Spatial Span 
subtest is 32 (16 points each for Spatial Span Forward and Backward). This task takes up to 10 
min. 
Attention Network Test (ANT). This test measures different types of attention. At the start 
of each trial, a cue is displayed onscreen followed by flanker displays (i.e., horizontal arrows). 
There are four cue conditions and three flanker conditions. The task on each trial is to classify 
the central arrow as either pointing left or right. Participants respond using the computer 
keyboard. This task lasts 30 min. 
Effort Discounting Task. Effort discounting is a computerized choice task designed to 
measure of the willingness to accept a smaller reward that requires less effort to obtain. During 


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this task, participants will be presented with a series of choices between a small, easy to obtain 
reward (between $0 and $20, available for no effort), and a larger reward requiring effort to 
obtain ($20, available after typing a number of words backward). The monetary value of the 
smaller reward and the effort (i.e., number of words) required to obtain the larger reward will be 
systematically varied across the series of choices in order to determine the participant’s 
indifference point (i.e., the point at which the larger reward is no longer “worth it” to work for, and 
the preference switches to the smaller amount. Participants will be presented with each pair of 
options on a computer screen and will make their selections with a button press. Before 
beginning the task, participants will first type 5 words backward in order to gain experience with 
the effort. They will then complete the choice portion of the task. Participants will be instructed 
that one of their choices will be selected at random at the end of the task, and they will receive 
whichever that option. If the participant chooses the larger, effortful option, they will be required 
to type the specified number of words backward at the conclusion of the session before earning 
the reward. The task takes about 15 minutes to complete and will only be administered during 
the Screening/Baseline Day. 
Table 1. Outline of planned study activities 
Screen/Baseline 
Study Day 1 & 2 
20 min Consent & HIPPA brochure 
5 min Measure BP & pulse. Urine pregnancy 
test (women only) 
10 min Urine Drug Screen & pregnancy 
screen  
2 min Mood questionnaire (PANAS) 
10 min Drug Use History 
5 min Administer capsule (placebo or MPH) 
15 min Medical History & Physical Exam 
Wait 60 min – eat meal while waiting 
2 hours Conners Adult ADHD Diagnostic 
Interview and Rating Scales & MINI 
Psychiatric Interview 
2 hours Tasks (Bandit Task, Patchy 
Foraging, EffRT, CPT, MMT, Spatial Span, 
ANT) 
BP/pulse/side effects taken every 60 min. 
 
5 min PANAS, side-effects, and drug effects 
questionnaires 
1 hour Baseline Tasks (Bandit Task, Effort 
Discounting Task) & questionnaires 
5 min Measure BP & pulse before dismissal 
Study Interventions 
Drug administration: Ritalin will be used to provide methylphenidate (MPH) in the 
methylphenidate condition. MPH is a mild central nervous system stimulant that blocks 
dopamine and norepinephrine reuptake. Ritalin was approved by the FDA to treat ADHD. In the 
central nervous system, 40 mg IR MPH results in a peak dopamine transporter receptor 
occupancy (at approximately 70%) between 1-3 hours after ingestion. This 40mg IR dose of 
methylphenidate has been administered to healthy adults previously by our research team and 
was well tolerated [10-13]. 
The UAMS pharmacy facility will prepare the MPH and placebo capsules for the study. The 
matching placebos will contain lactose. The drug and placebo capsules will look identical, 
except the base of the bottles will be marked with two different letters, one denoting the MPH 
capsules and the other the placebo capsules. The PI will be unblinded during the study to both 
the MPH and the placebos, and will therefore be able to identify which capsule was used if there 


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are any significant adverse effects felt by the participant after administration. The PI will not 
have direct contact with the participants during the experimental visits. The MPH and placebo 
capsules will not be given to participants to take home. These two products will be obtained by 
the study team and used only in the research setting. 
Questionnaires evaluating both participant and experimenter judgments about the capsule 
condition will be acquired. Should a participant report severe side effects associated with a high 
dose of MPH (e.g., nausea, headache) they will be reminded of their right to withdraw from the 
study. Any reports of unexpected or severe side-effects will be logged and reported to the IRB 
as adverse effects. Heart rate, blood pressure, and side-effects will be measured approximately 
every 60 min after drug administration and prior to dismissal. 
Compensation: No compensation is provided for the phone screen or the screening session 
(including consenting, drug screening, medical exam, drug use history, CAARS questionnaire, 
and MINI). Prospective participants who undergo the CAADID interview will be compensated 
$10/hour. Participants who are eligible for the study will receive $45 for the baseline visit and 
$100 for completing each study day. In addition, participants can earn up to $15 on the baseline 
day and up to $20 on each study day based on behavioral task performance. Thus, the total 
compensation for completing all parts of the study will be $245-300. Participants that decide to 
withdraw from the study before completion will be compensated $20/hour of participation on a 
pro-rated basis for the part(s) of the study that they have completed. 
Study Population 
We propose to obtain consent from 150 individuals in order to find 80 eligible 
participants and obtain useable data from 60 participants (30 per group). Prospective 
participants, ages 18-45, will be recruited from the surrounding area. During an initial phone 
screen, they will be given a brief description of our studies and will be asked questions to 
determine interest and eligibility. 
Inclusion criteria for all subjects: 
1) Capable of informed consent and able to complete all aspects of the study. 
2) between the ages of 18-45 
negative urine drug screen for drugs (other than those allowed for depression or anxiety) 
and negative breath alcohol concentration 
Inclusion criteria for non-ADHD subjects: 
1) do not meet criteria for ADHD diagnosis or any subtype as determined by the Conners Adult 
ADHD Rating Scale (CAARS) T-Score < 55 on Inattentive Symptoms, Hyperactive-
Impulsive Symptoms, Total Symptoms or ADHD Index subscales of the CAARS. 
Inclusion criteria for ADHD subjects 
1) meet criteria for a primary diagnosis of ADHD, any subtype, based on the Conners Adult 
ADHD Diagnostic Interview for DSM-IV and the CAARS. 
Exclusion criteria for all subjects: 
1) inability to attend all required experimental sessions 
2) significant health problems (e.g., current and uncontrolled liver, lung, or heart problems, 
current or past seizure disorder, serious head trauma) 
3) primary diagnosis of Axis I psychiatric disorders other than ADHD with the exception of 
depression or anxiety 
4) meet DSM-5 criteria for substance use disorder other than nicotine in the past 12 months 


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5) use of psychoactive medications in the past 6 months as indicated by self-report with the 
exception of first-line medications for depression or anxiety (e.g., selective serotonin 
reuptake inhibitors or benzodiazepines) 
6) contraindications for MPH (including use of monoamine oxidase inhibitors, have motor tics, 
Tourette syndrome, severe anxiety, or glaucoma – based on self-report) 
7) among women, nursing or a positive pregnancy test 
8) ≤ 8th grade education 
9) allergy to lactose 
10) hypertension (If subject has blood pressure over 140/90) 
Risks and Benefits 
Women of childbearing potential: Due to unknown risks and potential harm to the unborn fetus, 
women of child-bearing potential will be screened with a urine pregnancy test at the beginning 
of the study. Positive pregnancy tests are exclusionary. At each study day visit, urine pregnancy 
tests will be administered. 
Undiagnosed ADHD: We will provide comprehensive feedback to subjects who have 
undiagnosed ADHD. Appropriate referrals will be provided when necessary. 
Methylphenidate Administration: The most salient risk to participants will be the possibility of 
side effects of the MPH. The most commonly reported side effects of MPH have been 
headache, decreased appetite, stomach ache, nervousness, trouble sleeping, and nausea. 
MPH is not recommended for people with certain conditions or taking some medications. 
MPH should not be taken if the person is very anxious, tense, or agitated; has glaucoma; has 
tics or Tourette’s syndrome, or a family history of Tourette’s syndrome; is taking or have taken 
within the past 14 days an anti-depression medicine called a monoamine oxidase inhibitor or 
MAOI; or is allergic to any of the inactive ingredients found in Ritalin (D&C Yellow No.10, 
lactose, magnesium stearate, polyethylene glycol, sucrose, talc, and tragacanth). 
MPH use should be supervised by a doctor if the patient is taking any of these 
medications: anti-depression medicines including MAOIs; seizure medicines; blood thinner 
medicines; blood pressure medicines; and cold or allergy medicines that contain decongestants 
(information from http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089090.pdf). 
It is important to note that we will collect subjective effects data and vital signs 
throughout all experimental sessions and subjects will be discontinued from the protocol if 
significant adverse events occur. Moreover, the study physician will carefully screen participants 
for eligibility, including health and medication history, and will be on site or on call during all 
visits and can be consulted regarding AE’s if they arise. Based on experience among our 
research team, we do not anticipate significant side events. 
During the study, the study physician (Dr. Weiss) will be notified if there is an increase in 
pulse by more than 20 beats per minute from that day’s baseline (i.e., vitals taken upon arrival), 
or if the pulse is greater than 120 beats per minute and the blood pressure is greater than 
140/90, or if the participant complains of palpitations. If these symptoms occur or persist at the 
end of the study visit, the participant may be asked to remain in the lab for monitoring. The 
participant will be released or referred for treatment per Dr. Weiss’ decision. 
Placebo Administration: Placebo capsules will contain powdered lactose to match the color and 
consistency of the methylphenidate capsules. Lactose is a sugar found in milk and dairy 
products. People who are lactose intolerant may experience gas, abdominal pain, diarrhea, and 
bloating after ingesting lactose. People who are allergic to lactose may experience these 


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symptoms as well as swelling of the lips or throat and trouble breathing. For these reasons, 
people who self-report having lactose allergies will not be eligible for participation. 
Costs to subjects: Subjects will not incur any costs associated with participating in the study. All 
the study costs, including any procedures related directly to the study, will be paid for by the 
study. 
Confidentiality: There is a potential risk of loss of confidentiality. Measures to protect the 
confidentiality of study participants will be implemented as described in the Data Handling and 
Recordkeeping section below. 
Benefits: There will be no direct benefits to the study participants; however, knowledge gained 
from the study could potentially benefit patients in the future. 
Data Handling and Recordkeeping 
The Principal Investigator will carefully monitor study procedures to protect the safety of 
research subjects, the quality of the data and the integrity of the study. All study subject material 
will be assigned a unique identifying code or number. The key to the code will be kept in a 
locked file in the principal investigator’s office. Only the study coordinator will have access to the 
code and information that identifies the subject in this study. At the conclusion of the study, the 
data will be permanently de-identified and retained for seven years after final reporting or 
publication of the project. 
Data Analysis 
We base our sample sizes on previous studies that have found within- and between-group 
differences with sample sizes ranging from 20 to 30 subjects. Based on a previous study [9], we 
will be adequately powered to detect at significant effects with this sample size. The goal of this 
preliminary study is to collect data to perform power analyses for a larger project. The primary 
variable of interest is exploratory performance on the Bandit task. Behavior and self-report data 
will be analyzed using SPSS (Chicago, Ill), with significance set to alpha = .05. We plan to 
compare ADHD symptomatology and behavioral performance across all subjects using Pearson 
correlations, and to compare performance between groups using independent-samples t-tests. 
The interaction between within-subject differences in performance between MPH and placebo 
and between-subject differences in ADHD status will be investigated using a mixed-design 2x2 
ANOVA. 
Ethical Considerations 
This study will be conducted in accordance with all applicable government regulations and 
University of Arkansas for Medical Sciences research policies and procedures. This protocol 
and any amendments will be submitted and approved by the UAMS Institutional Review Board 
(IRB) to conduct the study. 
The formal consent of each subject, using the IRB-approved consent form, will be obtained 
before that subject is submitted to any study procedure. All subjects for this study will be 
provided a consent form describing this study and providing sufficient information in language 
suitable for subjects to make an informed decision about their participation in this study. The 
person obtaining consent will thoroughly explain each element of the document and outline the 
risks and benefits, alternate treatment(s), and requirements of the study. The consent process 
will take place in a quiet and private room, and subjects may take as much time as needed to 
make a decision about their participation. Participation privacy will be maintained and questions 
regarding participation will be answered. No coercion or undue influence will be used in the 
consent process. This consent form must be signed by the subject, and the individual obtaining 
the consent. A copy of the signed consent will be given to the participant, and the informed 


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consent process will be documented in each subject’s research record. 
Dissemination of Data 
Results of this study may be used for presentations, posters, or publications. The publications 
will not contain any identifiable information that could be linked to a participant. 
References 
1. Olfson, M., et al., Continuity in methylphenidate treatment of adults with attention-
deficit/hyperactivity disorder. J Manag Care Pharm, 2007. 13(7): p. 570-577. 
2. Sonuga-Barke, E.J.S., Psychological heterogeneity in AD/HD - a dual pathway model of 
behaviour and cognition. Behavioural Brain Research, 2002. 130(1-2): p. 29-36. 
3. Volkow, N.D., et al., Motivation deficit in ADHD is associated with dysfunction of the 
dopamine reward pathway. Mol Psychiatr, 2011. 16(11): p. 1147-1154. 
4. Kollins, S.H. and R.A. Adcock, ADHD, altered dopamine neurotransmission, and disrupted 
reinforcement processes: Implications for smoking and nicotine dependence. Prog Neuro-
Psychoph, 2014. 52: p. 70-78. 
5. Cohen, J.D., S.M. McClure, and A.J. Yu, Should I stay or should I go? How the human brain 
manages the trade-off between exploitation and exploration. Philosophical Transactions of 
the Royal Society B, 2007. 362(1481): p. 933-42. 
6. Beeler, J.A., C.R. Frazier, and X. Zhuang, Putting desire on a budget: dopamine and energy 
expenditure, reconciling reward and resources. Front Integr Neurosci, 2012. 6: p. 1-22. 
7. Rutledge, R.B., et al., Dopaminergic drugs modulate learning rates and perseveration in 
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immediate-release methylphenidate. Experimental and Clinical Psychopharmacology, 1998. 
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without attention deficit hyperactivity disorder (ADHD). Psychopharmacology (Berl), 2009. 
204(1): p. 73-83. 
12. Kollins, S.H., et al., Methylphenidate does not influence smoking-reinforced responding or 
attentional performance in adult smokers with and without attention deficit hyperactivity 
disorder (ADHD). Exp Clin Psychopharmacol, 2013. 21(5): p. 375-84. 
13. Kollins, S.H., et al., An exploratory study of the combined effects of orally administered 
methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, 
subjective effects, and performance in healthy adults. Journal of Substance Abuse 
Treatment, 2015. 48(1): p. 96-103. 
 
Appendices 
None 

SAP_001.pdf: 
 
 
 
 
 
Motivated behavior in adults with and without ADHD 
 
 
 
NCT 02630017 
 
 
 
08/13/2019 


 
 
2.0 Methods 
2.1 Participants. Participants were recruited from the Durham, North Carolina (n = 14 ADHD, 9 
non-ADHD) and Little Rock, Arkansas (n = 14 ADHD, 9 non-ADHD) communities via social 
media, flyers, and word-of-mouth. Participants completed a phone interview and in-person 
screening session to determine eligibility. Eligible participants were between the ages of 18-45 
years. To be eligible, ADHD participants had to have T-scores ≥ 65 for inattentive and/or 
hyperactive-impulsive symptoms on the Conners’ Adult ADHD Rating Scale (CAARS) (Conners 
et al., 1998), and were evaluated to meet criteria for a primary diagnosis of ADHD based on the 
Conners’ Adult ADHD Diagnostic Interview for DSM-IV (CAADID) (Epstein et al., 2001). Non-
ADHD participants had to have T-scores < 55 for inattentive, hyperactive-impulsive, and total 
symptoms. 
Participants were excluded if they reported serious health problems (e.g., uncontrolled 
cardiovascular disease) or neurological problems (e.g., seizure disorder or traumatic brain 
injury), met criteria for a psychiatric disorder other than ADHD (except for symptoms of 
depression or anxiety co-morbid with ADHD) based on the MINI International Neuropsychiatric 
Interview (Sheehan et al., 2009), reported drug or alcohol dependence in the past 12 months 
(other than tobacco), reported daily use of medication for ADHD in the past 6 months, had 
hypertension (i.e., blood pressure > 140/90 mmHg), or had contraindications for MPH (e.g., 
motor tics). Participants were also excluded if they tested positive for drugs (iCup, Alere 
Toxicology Services Portsmouth, VA), alcohol (Alco-Sensor III, Intoximeters Inc St. Louis, MO), 
or pregnancy (QuickVue+, Quidel Corporation San Diego, CA). 
Seventy-nine individuals were consented and screened to participate in the study, and 28 
participants were ineligible because they did not meet ADHD/non-ADHD criteria (n = 11), had 
hypertension (n = 6), had a positive drug screen (n = 4) had another Axis I diagnosis (n = 3), 
withdrew before the study day (n = 4). Of the 51 participants that met eligibility criteria and 
began the study, 46 participants completed all aspects of the study and were included in the 


 
 
data analysis. Participants provided written informed consent and this protocol was approved by 
Duke University’s and University of Arkansas for Medical Sciences’ Institutional Review Boards. 
2.2 Effort Expenditure for Rewards Task (EEfRT) (Treadway et al., 2009): In each trial of the 
EEfRT, participants choose between two task options to earn money. Both task options consist 
of repeated manual button presses within a short amount of time, and completed button presses 
are represented onscreen by the height of a vertical bar. The low effort option requires 30 button 
presses with the dominant index finger within 7 sec. The high effort option requires 100 button 
presses with the nondominant little finger within 21 sec. Participants were monitored during the 
task to ensure they used the correct finger. 
In low-effort trials, participants could receive $1.00 if they completed the task on time. In high-
effort trials, participants could receive a variable amount between $1.24 and $4.30 (i.e., reward 
magnitude). Across trials, the likelihood of receiving money upon successful completion of the 
task was either 12%, 50%, or 88% (i.e., reward probability). The probability level applied to both 
the low and high effort tasks. At the start of each trial, participants were shown the reward 
magnitude for both task options and the probability level. They had 5 sec to make a choice or 
else they would be randomly assigned to a task. Then, they completed the button press task 
and received feedback informing them if the task was completed successfully or not, and 
whether they received money for that trial. Participants were told a single trial that resulted in 
money reward would be selected at random at the end of the EEfRT, and the participant would 
be given this amount as bonus pay. See Figure 1. 
Low-effort trials lasted approximately 15 sec, and high-effort trials lasted approximately 30 sec. 
Participants were told they had 20 min to play as many trials as possible. They were informed of 
the trade-off between choosing too many high-effort tasks and missing out on playing large-
magnitude, large-probability trials later in the game to discourage the exclusive selection of 
either the low-effort or high-effort task. This also helped ensure that decisions were based on 
the expected value of the reward, and not based on a strategy to always select high-effort or 


 
 
low-effort trials. Trials were presented in the same randomized order to all participants. The 
primary dependent variable was the percent high-effort selections by reward probability and 
magnitude (divided into 4 bins with an equal number of trials for analysis). Other performance 
metrics consisted of total number of trials completed and the ratio of high-effort trials 
completed/selected. 
2.3 Attention Network Test (ANT) (Fan et al., 2002). The ANT combines a cued reaction-time 
test and flanker test to measure the efficiency and accuracy of three cognitive networks: 
alerting, orienting, and conflict (Posner and Petersen, 1990). On each trial, a row of five 
horizontal black lines, with arrowheads pointing left or right, is shown onscreen above or below 
a center fixation cross. The target is the center arrow. The target is flanked by arrows pointing in 
the same direction (congruent condition), or in the opposite direction (incongruent condition) or 
by lines (neutral condition). Participants indicate the direction of the target arrow using the arrow 
keys. The arrows are preceded by four types of cues (no cue, center cue, double, spatial cue), 
which either indicate the arrows will appear soon and/or predict the location of the arrows above 
or below the fixation cross. The primary dependent variables were the alerting, orienting, and 
executive function scores. The alerting score is the difference in reaction time between the 
temporally informative cue condition and the temporally uninformative cue condition. The 
orienting score is the difference in reaction time between the spatially informative cue condition 
and the spatially uninformative cue condition. The conflict score is the difference in reaction time 
between the congruent flanker condition and the incongruent flanker condition. Other 
performance metrics consisted of overall percent accuracy and average reaction time. 
2.4 Procedure. After consenting and eligibility evaluation, the participants were scheduled for 
two study visits. These study visits were scheduled within two weeks of each other, but were at 
least 48 hours apart. For each participant, both study visits occurred either in the afternoon or 
the morning. Participants were instructed to skip the meal prior to the study visit (i.e., either 
breakfast or lunch). Participants were administered either immediate-release methylphenidate 


 
 
(MPH: 40 mg) or a matching placebo (PLA) under double-blind conditions. Drugs were ordered 
and compounded through a pharmacy, and the placebo consisted of lactose. The prescription 
and medical oversight was provided by a study physician. After administration, participants were 
given two cereal bars, a fruit cup, and 8 oz of water and rested for 1 hour to allow for drug 
absorption. The study visit lasted for a total of 3 hours, and the EEfRT and ANT were completed 
approximately 2.5 hours after drug administration. The Positive and Negative Affect Scale 
(PANAS) (Watson et al., 1988) was administered prior to drug administration and at the end of 
the study visit. At the end of the visit, participants also rated to what extent they felt a drug effect 
on a scale from 1 (not at all) to 10 (extremely). Compensation for participation was provided at 
the end of the study and participants were told they could earn up to $5 in bonus pay for each 
task, depending on their task performance. 
2.5 Data Analysis. Participant demographics were analyzed using independent-samples t-tests 
and Chi-Square tests. Age was included as a covariate in subsequent analyses due to 
differences between groups. The drug effects questionnaire, PANAS positive and negative 
scales, performance metrics in the EEfRT and ANT, and ANT dependent variables were 
analyzed using separate 2 (Group) x 2 (Drug) repeated-measures ANCOVAs. Percent high-
effort selections in the EEfRT were analyzed using a 2 (Group) x 2 (Drug) x 4 (Reward 
Magnitude) x 3 (Reward Probability) repeated-measures ANCOVA. Follow-up comparisons 
were univariate ANCOVAs. Since participants could complete a variable number of trials during 
the 20 min of the EEfRT, only data from the first 50 trials were used for consistency (Treadway 
et al., 2012a). Associations between CAARS scores and the EEfRT and ANT dependent 
variables were performed using partial correlations (controlling for age). Data were analyzed 
using SPSS v24 (Chicago: SPSS Inc). 
An initial exploration of the EEfRT and ANT performance metrics revealed no differences by site 
(UAMS vs Duke); thus, site was not included as a covariate in the analyses.