Clinical trial NCT02225106
Conditions: Cognition Disorder Attention Deficit Disorder Traumatic Brain Injury
Keywords: Dopamine Receptors Methylphenidate Traumatic Brain Injury C-11 Raclopride Dopamine Release
Sponsor: University of Pennsylvania
Start date: 2014-08-06; Completion date: 2017-06-21
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Deficits in memory, attention, cognitive, and executive functions are the most common disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is implicated in these neural functions and dopaminergic pathways are recognized to be frequently disrupted after TBI. Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine transporters (DAT) and blocking re-uptake.

The objectives of this study are to use PET imaging with \[11C\]-raclopride, a D2/D3 receptor ligand, before and after administering methylphenidate, to measure endogenous DA release in patients who are experiencing problems with cognition, attention and executive function in the chronic stage after TBI. In addition, we will use TMS to test short intracortical inhibition, a gamma-aminobutyric acid receptor A (GABAA) - mediated phenomenon, which is under partial DA control, as a measure of dopaminergic activity on and off

Detailed description:
Deficits in memory, attention, cognitive, and executive functions are the most common disabilities after traumatic brain injury (TBI). Dopamine (DA) neurotransmission is implicated in these neural functions and dopaminergic pathways are recognized to be frequently disrupted after TBI. One of the most widely used DAergic drugs is methylphenidate (Ritalin ). Methylphenidate increases synaptic DA levels by binding to presynaptic dopamine transporters (DAT) and blocking re-uptake. PET with methylphenidate challenge to measure tonic DA release provides valuable insight into the molecular basis of attention-deficit hyperactivity disorder (ADHD) and addiction, as well as practical information regarding likely effectiveness of therapy (1). The objectives of this study are to use PET imaging with \[11C\]-raclopride, a D2/D3 receptor ligand, before and after administering methylphenidate, to measure endogenous DA release in patients who are experiencing problems with cognition, attention and executive function in the chronic stage after TBI. In addition, we will use TMS to test short intracortical inhibition, a gamma-aminobutyric acid receptor A (GABAA) - mediated phenomenon, which is under partial DA control, as a measure of dopaminergic activity on and off

methylphenidate.

STUDY POPULATION:

Males and females (n=30), between the ages of 18 and 55 years in the chronic stage after TBI who experience deficits in neuropsychological function from TBIs incurred 6 months after the injury, will be recruited from military treatment facilities or civilian clinics when presenting for clinical management of TBI or postconcussive symptoms.

DESIGN:

1. Study participants will be evaluated using brain MRI, psychometric measures adapted from the TBI Common Data Elements, attention tests and information about details of the injury and experience of post-concussive symptoms will be recorded. Transcranial magnetic stimulation (TMS) with placebo and with methylphenidate (60 mg by mouth) challenge will be performed to predict a stimulant response.
2. Subjects will be studied with \[11C\]-raclopride PET in two imaging sessions. One session will be after administration of placebo and the other after methylphenidate, 60 mg by mouth. Both placebo and methylphenidate will be given 60 minutes prior to injection of \[11C\]-raclopride to allow for peak uptake of methylphenidate in the brain. The binding potential of \[11C\]-raclopride relative to a non-displaceable reference region (cerebellum), BPND, will be used as a measure of D2/D3 receptor availability. The difference in BPND between methylphenidate and placebo ( BPND) is used to measure of tonic DA release.
3. Subjects will then be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated.

OUTCOME MEASURES:

The primary outcome is change in information processing speed

during neuropsychologic testing

Arms: arm 1: Forced titration with methylphenidate up to a dose of 30 mg administered orally twice daily.
Interventions: intervention 1: Methylphenidate
Intervention descriptions: intervention 1: Subjects will be treated with oral methylphenidate, using a forced titration up to a dose of 30 mg given twice daily for 4 weeks. At that point, the neuropsychologic tests are repeated.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
PI name: Wassermann E.  
Date 2/19/16 
Protocol number: 14-N-0169 
Version 3.1 
CNS IRB Protocol Template (rev 9.21.11) 
Protocol Title: Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in 
Chronic TBI  
Abbreviated Title: Dopamine Receptor Imaging in TBI  
Protocol Number: 14-N-0169  
Date of This Submission: 2/20/16 
Principal Investigator 
Name, Degree Branch/Institute Bldg/Rm 
Phone 
E-mail
Eric 
Wassermann, 
MD 
BNU/NINDS 
Building 
10, 
7D41 
301-496-0151
eric.wassermann@nih.gov 
Adjunct Principal Investigator  
Name, Degree Branch/Institute 
Bldg/Rm 
Phone 
E-mail
Diaz-Arrastia, 
Ramon 
MD, PhD 
USUHS/ 
CNRM/ NINDS 
4301 Jones 
Bridge Road,  
Bethesda, 20811 
301-295-5537 Ramon.Diaz-arrastia@usuhs.edu 
Ramon. Diaz-Arrastia@nih.gov 
Lead associate Investigator 
Name, Degree Branch/Institute 
Bldg/Rm 
Phone 
E-mail
Tanya 
Bogoslovsky 
MD, PhD  
USUHS/ 
CNRM, 
NINDS 
12725 
Twinbrook 
Pkwy, Rockville, 
20852 
301-319-
0612
Tanya.Bogoslovsky. 
CTR@usuhs.edu 
Associate Investigators 
Name, Degree Branch/Institute 
Bldg/Rm 
Phone 
E-mail
Volkow, 
Nora, MD 
NIDA 
Bldg/Rm NSC 
BG RM 5274, 
ROCKVILLE 
MD 20892 
301-443-
6480
 NVolkow@nida.nih.gov 
Herscovitch, 
Peter BEng,  
MD, CM  
NIH CC 
BG 10 RM 
1C495 
10 CENTER DR 
301-451-
4248
herscovitch@nih.gov E-mail 
Dzung Pham, 
PhD 
CNRM/ 
NIHCC 
Building 10, 
Room B1N264B 
301-435-
1673
dzung.pham@nih.gov 
John Butman, 
MD 
NIH CC 
Building 10, 
Room 1C373X 
301-402-
5827
john.butman@nih.gov 
John Dsurney, 
PhD 
NIH CC 
BG 10-CRC  
Room 1-1469 
301-496-
4733
dsurneyj@mail.nih.gov 
Kimbra 
Kenney, MD 
USUHS/ 
CNRM 
Twinbrook 
301-295
6420 
KKenney@usuhs.edu 
Carol Moore, 
MA, CCRC 
USUHS/ 
CNRM 
Twinbrook 
301-295-
6439
Carol.Moore.CTR@usuhs.edu 
Bao-Xi Qu, 
MD 
USUHS/ 
CNRM 
Twinbrook 
301-319-
0608
Bao-Xi.Qu.CTR@usuhs.edu 


 
 
2 
 
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T otal re q ueste d accr ual    
 
   ( 3 0) Patie nts       
   ( 0) Healt h y V ol u nteers   
  
  
 
Pr oject Uses I o nizi n g Ra diati o n:    N o  
X Yes ( att ac h R S C/ R D R C d oc u me nt ati o n)  
    
 

M e dicall y-i n dicate d o nl y 
    
  
XR esear c h -r elate d o nl y 
    
 
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 N o    
X Yes ( att ac h F D A d o c u me nt ati o n) 
    
Dr u g/ De vice/ # _ _ _ [ 1 1 C]-racl o pri d e N 5 4, 1 3 5. 
    
S p o ns or: Hersc o vitc h, Peter,  M D  
 
D ura ble P o wer of Att or n e y     
X N o    
 Y es 
 


 
 
3 
 
M ulti -i nstit uti o nal Pr oject  
 
X N o    
 Y es    
  
  
 
  
  
I nstit uti o n # 1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    F W A # _ _ _ _ _ _ _ _ _  
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I nstit uti o n # 2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    F W A # _ _ _ _ _ _ _ _ _  
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Data a n d Saf et y M o nit ori n g B oar d  
X N o    
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 N o    
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A gree me nt t y pe a n d n u m ber _I n pr o gress _ _ E x pirati o n Date _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Sa m ples are bei n g st or e d   
  
 
 N o     
X Yes  
 
Flesc h - Ki ncai d r ea di n g l e vel of c o ns e nt f or m: _ _ _ _ 9 _ _ _ _ _ _  
 
 


 
 
4 
 
 
Précis 
 
Objectives: Deficits in memory, attention, cognitive, and executive functions are the most 
common 
disabilities 
after 
traumatic 
brain 
injury 
(TBI). 
Dopamine 
(DA) 
neurotransmission is implicated in these neural functions and dopaminergic pathways are 
recognized to be frequently disrupted after TBI. One of the most widely used DAergic 
drugs is methylphenidate (Ritalin®).  Methylphenidate increases synaptic DA levels by 
binding to presynaptic dopamine transporters (DAT) and blocking re-uptake. PET with 
methylphenidate challenge to measure tonic DA release provides valuable insight into the 
molecular basis of attention-deficit hyperactivity disorder (ADHD) and addiction, as well 
as practical information regarding likely effectiveness of therapy 1. The objectives of this 
study are to use PET imaging with [11C]-raclopride, a D2/D3 receptor ligand, before and 
after administering methylphenidate, to measure endogenous DA release in patients who 
are experiencing problems with cognition, attention and executive function in the chronic 
stage after TBI.  In addition, we will use TMS to test short intracortical inhibition, a 
gamma-aminobutyric acid receptor A (GABAA) - mediated phenomenon, which is under 
partial DA control, as a measure of dopaminergic activity on and off methylphenidate.   
 
Study population: Males and females (n=30), between the ages of 18 and 55 years in the 
chronic stage after TBI who experience deficits in neuropsychological function from 
TBIs incurred 6 months after the injury, will be recruited from military treatment 
facilities or civilian clinics when presenting for clinical management of TBI or post-
concussive symptoms. 
 
Design:  
1. Study participants will be evaluated using brain MRI, psychometric measures adapted 
from the TBI Common Data Elements, attention tests and information about details of the 
injury and experience of post-concussive symptoms will be recorded. Transcranial 
magnetic stimulation (TMS) with placebo and with methylphenidate (60 mg by mouth) 
challenge will be performed to predict a stimulant response.  
2. Subjects will be studied with [11C]-raclopride PET in two imaging sessions.  One 
session will be after administration of placebo and the other after methylphenidate, 60 mg 
by mouth.  Both placebo and methylphenidate will be given 60 minutes prior to injection 
of [11C]-raclopride to allow for peak uptake of methylphenidate in the brain.  The binding 
potential of [11C]-raclopride relative to a non-displaceable reference region (cerebellum), 
BPND, will be used as a measure of D2/D3 receptor availability.  The difference in BPND 
between methylphenidate and placebo (ΔBPND) is used to measure of tonic DA release. 
3. Subjects will then be treated with oral methylphenidate, using a forced titration up to a 
dose of 30 mg given twice daily for 4 weeks.  At that point, the neuropsychologic tests 
are repeated. 
 
Outcome measures:  The primary outcome is change in information processing speed 
during neuropsychologic testing. 


 
 
5 
 
Contents 
 
 
 
1. Introduction .............................................................................................................. 8 
2. Study objectives ..................................................................................................... 12 
3. Subjects .................................................................................................................. 13 
4. Study Design and Methods .................................................................................... 15 
4.1   Study overview ................................................................................................. 15 
4.2   Recruitment ....................................................................................................... 16 
4.3   Screening........................................................................................................... 17 
4.4   Study Procedures .............................................................................................. 19 
4.5.  End of Participation .......................................................................................... 32 
5.  Storage of Data and Samples ................................................................................... 32 
6.  Additional Considerations ....................................................................................... 36 
7.  Risks/Discomforts .................................................................................................... 36 
8.  Subject Safety Monitoring ....................................................................................... 42 
9. Outcome measures ................................................................................................. 45 
10.  Statistical Analysis ................................................................................................. 45 
11.  Human Subjects Protection .................................................................................... 48 
12.  Anticipated Benefits ............................................................................................... 53 
13.  Classification of Risk ............................................................................................. 53 
14.  Consent Documents and Process ........................................................................... 53 
15.  Data and Safety Monitoring ................................................................................... 54 
16.  Quality Assurance .................................................................................................. 55 
17. Reporting of Unanticipated Problems, Adverse Events and Protocol Deviaions ... 55 
18. Alternatives to Participation or Alternative Therapies ........................................... 56 
19.  Confidentiality ....................................................................................................... 56 
20.  Conflict of Interest ................................................................................................. 57 
21.  Technology Transfer .............................................................................................. 57 
22. Research and Travel Compensation........................................................................ 58 
23. References ............................................................................................................... 58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
6 
 
 
List of Abbreviations  
 
 
ADC  
Apparent Diffusion Coefficient 
BBB 
Blood Brain Barrier 
BSI  
Brief Symptom Inventory 
BMI 
Body Mass Index 
CBF 
Cerebral Blood Flow 
CDE 
Common Data Elements 
CLIA 
Clinical Laboratory Improvement Amendments 
CNRM 
Center for Neuroscience and Regenerative Medicine 
CNS 
Central Nervous System 
CTE 
Chronic Traumatic Encephalopathy 
CVLT  
California Verbal Learning Test 
CVLT-II 
California Verbal Learning Test – 2nd Edition 
D2R   
Dopamine 2 receptor 
DA 
Dopamine 
DAT 
Dopamine transporter 
DMN 
Default mode network 
DOD 
Department of Defense 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders 
DTI 
Diffusion Tensor Imaging 
DWI  
Diffusion Weighted Imaging 
EMG 
Electromyogram 
FA   
Fractional Anisotropy 
FDA 
Food and Drug Administration 
FLAIR 
Fluid Attenuated Inversion Recovery  
fMRI 
Functional Magnetic Resonance Imaging 
FWA 
Federal Wide Assurance 
GCS  
Glasgow Coma Score 
GABAA 
Gamma-aminobutyric acid 
GOS-E  
Glasgow Outcome Score – Extended 
GUID   
Global Unique Identifier 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MEP 
Motor evoked potential 
MPRAGE 
Magnetization Prepared Rapid Gradient Echo 
MRI 
Magnetic Resonance Imaging 
mTBI 
Mild Traumatic Brain Injury 
MTT   
Mean Transit Time 
NiCOE 
National Intrepid Center of Excellence  
NIH CC 
National Institutes of Health Clinical Center 
NINDS 
National Institutes of Neurological Disorders and Stroke 


 
 
7 
 
NSI 
Neurobehavioral Symptom Inventory 
PET 
Positron Emission Tomography 
PFC 
Prefrontal cortex 
PWI 
Perfusion Weighted Imaging 
rfcMRI 
Resting state functional connectivity MRI 
SICI 
Short interval intracortical inhibition 
SPECT 
Single photon emission computerized tomography 
SWI 
Susceptibility Weighted Imaging 
SWLS 
Satisfaction with Life Scale 
TBI 
Traumatic Brain Injury 
TMS 
Transcranial magnetic stimulation 
TTP   
Time to Peak 
USUHS 
Uniformed Services University of the Health Sciences 
VA 
Veterans Affairs 
VS 
Ventricular striatum  
WRAT  
Wide Range Achievement Test 
WRNMMC 
Walter Reed National Military Medical Center 
 
 


 
 
8 
 
1. Introduction  
 
Background/Preliminary Data: Dopaminergic pathways are recognized to be 
frequently disrupted after TBI.  In humans, there are three major dopaminergic fiber 
systems, all of which share the basic organization of cell bodies located in midline 
structures and long projection neurons innervating widespread cortical and subcortical 
regions (Fig 1).  Because of the organization of DA pathways, they are susceptible to 
shearing and rotational forces common in TBI.   
 
 
 
 
 
 
1. Evidence that DA pathways are damaged after TBI.   
 
There is evidence to suggest that DA pathways are often disrupted as a result of trauma 2.  
First, patients with TBI frequently have problems with attention, concentration, 
processing speed, executive function, fatigue, and memory, functions that are recognized 
to involve DA pathways.  Second, brain regions such as the prefrontal cortex, limbic 
structures and striatum, which are known to be rich in DA innervation, are frequently 
injured after TBI 3, 4.  Finally, a series of reports and small studies dating back 25 years 
indicate that neurostimulants working on the DA system are beneficial in improving 
cognitive and attentional deficits after TBI.  This evidence is reviewed below (Table 1) in 
more detail regarding methylphenidate, but similar data exist for amphetamine, 
amantadine, and bromocriptine (reviewed in detail by Bales et al.) 2.  
     Direct (but limited) evidence of dopaminergic dysfunction after TBI comes from 
SPECT studies using radioligands that bind the presynaptic DA transporter (DAT) and 
the DA D2 receptor (D2R).  Donnemiller et al. 5 used 123I-β-CIT to label DAT and 123I-
IBZM to image DR2 in 10 patients with primarily severe TBI 4-5 months after injury.  
Compared with age-matched controls, patients with TBI had significantly lower 123I-β-
Fig 1.  Dopaminergic Pathway in human brain.  The 
nigrostriatal DA system has cell bodies in the substantia 
nigra pars compacta in the ventral midbrain, and project 
to the caudate and putamen, referred collectively as the 
neostriatum. The nigrostriatal pathway is important for 
regulating motor control and learning motor programs 
and habits. The mesolimbocortical DA system has cell 
bodies in the ventral tegmental area, just medial and 
posterior to the substantia nigra, and projects to limbic 
and cortical structures, such as the nucleus accumbens, 
prefrontal 
cortex, 
and 
cingulate 
cortex. 
 
The 
mesolimbocortical pathway regulates both cognitive and 
emotive functions, and plays a major role in the reward 
pathway.  Finally, the tuberoinfundibular DA system has 
cell bodies in the arcuate nucleus of the ventral 
hypothalamus and projects to the median eminence, 
where it plays an important role in regulating hormone 
release from the anterior pituitary.   
 


 
 
9 
 
CIT and 123I-IBZM binding in the striatum.  This was found even in cases with no 
anatomical evidence of direct striatal injury.  Despite the increased availability of PET 
and SPECT ligands for both the pre- and postsynaptic DA system, this study, published 
over 10 years ago, remains the only one to directly image the DA system after TBI. 
 
2.  Evidence that drugs working on the DAergic system are useful after TBI.  
 
There have been multiple attempts over the last two decades pharmacologically 
manipulate the DA systems to improve functional outcome. Neuropharmacologic 
therapies are commonly used off label to enhance arousal and behavioral responsiveness, 
on the premise that injury‐induced derangements in dopaminergic and noradrenergic 
neurotransmitter systems can be improved through supplementation. Amantadine 
hydrochloride is one of the most commonly prescribed medications for patients with 
disorders of consciousness who are undergoing inpatient neurorehabilitation 6. Recently, 
Giacino et al. 7 conducted a multicenter trial of 184 patients who were in a vegetative or 
minimally conscious state 4 to 16 weeks after TBI and who were receiving inpatient 
rehabilitation.  During the 4-week treatment period, recovery was significantly faster in 
the amantadine group than in the placebo group, indicating a benefit with respect to the 
primary outcome measure. This study was the first ever Class I randomized controlled 
trial which shows the benefit of a pharmacologic agent after TBI.   
     Methylphenidate is another drug acting on DA neurotransmission commonly used off 
label by physiatrists attempting to improve recovery after TBI. It acts by blocking 
catecholamine reuptake DA and norepinephrine (NE) levels in the synapse. Table 1 
summarizes the published data on cognitive outcomes using methylphenidate in TBI 
(adapted from Bales 2).  Most studies focused on the chronic stage after TBI. 
 
 
Table 1.  Cognitive outcomes with the use of methylphenidate in TBI 
Citation 
n 
Phase treatment 
administered 
Cognitive Outcomes 
Measured 
Conclusion 
Gualtieri (1988) 
15 
Chronic 
Memory, attention 
Benefit in memory 
Mooney 
and 
Haas 
(1993) 
38 
Chronic 
Memory, 
attention, 
anger 
Benefit in memory 
Speech et al (1993) 
12 
Chronic 
Attention, 
learning, 
cognitive processing 
No significant effects 
Kaelin et al (1996) 
10 
Subacute 
Attention, 
Disability 
Rating Scale (DRS) 
Improvement in recovery 
of attention 
Plenger et al (1996) 
23 
Recovery 
Attention, 
memory, 
diligence, DRS 
Enhanced rate of recovery 
Whyte et al (1997) 
19 
Chronic 
Attention 
Improvement in speed of 
mental processing 
Whyte et al (1997) 
10 
Recovery-
Chronic 
Attention, 
memory, 
behavior, 
processing 
speed 
No significant effects 
Whyte et al (1997) 
14 
Recovery-
Chronic 
Attention 
Improvement in attention 
and concentration 
Whyte et al (2004) 
34 
Chronic 
Attention 
Improvements in speed of 
processing, caregiver 
ratings of attention 
Kim et al (2006) 
18 
Chronic 
Working memory, 
Improvement in cognitive 


 
 
10 
 
visuospatial attention 
function, e.g., working 
memory reaction time 
Lee et al (2005) 
10 
Subacute 
Memory, attention 
Improvement in cognitive 
function and maintaining 
daytime alertness 
Pavslovskaya et al 
(2007) 
6 
Chronic 
Visuospatial attention 
Improvement in attentional 
shifts 
 
Despite this body of largely consistent studies, methylphenidate is not considered 
standard of care in the treatment of disorders of cognition, attention, or behavior after 
TBI.  Frenette et al. 8 published a systematic review of randomized controlled trials on 
the efficacy and safety of DA agonists in TBI.  They concluded that significant clinical 
heterogeneity was observed between and within studies, which precluded any pooling of 
data. They stated that: “Considering the absence of consensus regarding clinical outcome, 
the lack of safety assessment, and the high risk of bias in the included trials, more 
research is warranted before DA can be recommended in TBI patients.”  
 
3. Imaging of pre- and post-synaptic DA markers is useful for assessing DAergic function 
in neuropsychiatric disease, and for predicting response to therapy.   
 
Several radiotracers for positron emission tomography (PET) and SPECT were recently 
developed and successfully applied to assess the integrity of presynaptic DA neurons and 
postsynaptic DA receptors in humans. Of these, [11C]-raclopride, a D2/D3 receptor ligand 
whose specific binding is sensitive to competition by endogenous DA, has been 
extensively 
 
 
used to indirectly assess DA release (Fig. 2) 1, 9-11.  This technique was used to identify 
deficits in DA circuitry in ADHD and addiction disorders, but was never used to assess 
cognitive and behavioral deficits after TBI. Dr. Volkow has pioneered these studies over 
the past 15 years 9, 11, 12, and Dr. Herscovitch has adapted them at the NIH PET Center in 
studies of alcohol dependence 10.  These methods are well established and their 
application to patients with neuropsychiatric disorders after TBI is a promising and 
timely application of this technique. 
 
4.  Functional connectivity of prefrontal cortex and DA receptor availability.  Large-scale 
brain networks underlie many of the complex behaviors influenced by DA pathways, 
Fig 2. Impact of dopamine release 
subsequent 
to 
methylphenidate 
administration on outcome in adult 
patients with ADHD. Voxel-wise 
correlation 
between 
intravenous 
MP-induced changes in DA D2/D3 
receptor 
availability 
in 
ventral 
striatum (measures taken after 
long-term MP treatment) and the 
improved scores of symptoms of 
inattention (CAARS A).  (From 
Volkow et al 2012) 1 


 
 
11 
 
including reward, executive function and addiction 13, 14.  Functional MRI (fMRI) in the 
resting state can identify functional brain networks such as the default mode network 
(DMN) which underlie complex behaviors such as cognitive control, salience processing, 
and reward-related brain activity. Recently, the functional connectivity of the 
orbitofrontal cortex in the DMN was associated with D3 receptor availability in the 
midbrain 15.  This observation provides the rationale for our proposal to investigate 
resting state functional networks, and to explore any changes in functional connectivity 
of the PFC as a result of methylphenidate therapy.  The ability to assess the integrity of 
DAergic circuits with fMRI would have major clinical implications, since fMRI is a 
much more widely available technology compared to [11C]-raclopride PET.     
 
5.  Transcranial magnetic stimulation (TMS) of motor cortex as a biomarker of integrity 
of DA circuits.    
The motor cortex (M1) receives direct dopaminergic input 16 which inhibits corticospinal 
output neurons 17. The response of the motor cortex to transcranial magnetic stimulation 
(TMS) is affected by DA agonists and antagonists 18 and amphetamine 19 in healthy 
subjects.  Dr. Wassermann and colleagues measured the effect of methylphenidate and 
the specific NE reuptake inhibitor, atomoxetine, on the same measures in ADHD, where 
decreased M1 inhibition correlates with symptom severity 20, 21, suggesting deficient DA 
input.  These medications both produced an increase in inhibition similar to that seen 
with DA agonists. We propose using the same TMS paradigm to measure M1 inhibition 
before and after administration of methylphenidate.  Our expectation is that patients who 
respond to treatment behaviorally and with greater [11C]-raclopride displacement on PET 
will show a greater increase in M1 inhibition on methylphenidate than those who do not.  
Ideally, TMS might be used to predict stimulant response. 
 
5.  Behavioral effect of methylphenidate on motivation and rewardability in TBI. 
 
Fatigue and loss of motivation are frequently observed after TBI 22, 23, but are difficult to 
quantitate. This problem has been attributed to dysfunction in the dopaminergic reward 
system and there is a presumption that dopaminergic treatment can restore this function.  
We have designed and tested a quantitative way to measure the willingness of individuals 
to perform muscular contractions for different reward values and propose to use it here, 
on and off methylphenidate, as an exploratory measure of motivation and rewardability.  
 
This study is sponsored by the Center for Neuroscience and Regenerative Medicine 
(CNRM). To address the profound issues related to the diagnosis and treatment of TBI, 
the United States Congress, through Public Law 110-252, established the Center for 
Neuroscience and Regenerative Medicine (CNRM) as a collaborative intramural program 
in May 2008.  The Congressional Record of May 15, 2008, expressed Congressional 
intent that the CNRM study actual combat casualties cared for at Walter Reed Army 
Medical Center (WRAMC) and the National Naval Medical Center (NNMC) using 
advanced neuroimaging technology in collaboration with the National Institutes of Health 
(NIH).    
 
 


 
 
12 
 
 
2. Study objectives  
 
Primary Objective:   
 
To assess the relationship between tonic DA release (assessed by displacement of [11C] 
raclopride by oral methylphenidate) and improvement in processing speed after 4 weeks 
of treatment with oral methylphenidate.  
  
Secondary Objectives: 
 
(1). Assess the relationship between D2/D3 receptor availability in the VS and PFC with 
neuropsychological deficits in the chronic stage after TBI. 
(2). Assess the relationship between tonic DA release in the VS and PFC with 
neuropsychological deficits after TBI. 
(3). Determine the relationship between D2/D3 receptor availability and functional 
connectivity of the PFC with nodes of the default mode network.   
(4). Assess the relationship between TMS-induced short-interval cortical inhibition 
(SICI) of M1 and tonic DA release, as well as response to methylphenidate therapy. 
(5).   To test motivation and reward on and off methylphenidate in TBI patients. 
 
Exploratory Objectives: 
(6).  Use diffusion tensor imaging (DTI) to explore the relationship between structural 
connectivity between the VS, PFC, and ventral tegmental area (VTA), and tonic DA 
release in patients in the chronic stage after TBI.    
 
 


 
 
13 
 
3. Subjects   
 
a. Description of study populations  
 
The study population includes male and female volunteers with TBI between the ages of 
18 and 55 years. The accrual ceiling will be 30.  Dropouts and loss to follow-up will be 
considered under intention-to-treat principles.   
 
 
b. Inclusion criteria 
To be included in the protocol, study participants must meet the following criteria: 
 
1. Age 18 – 55 years, inclusive 
2. A history of having sustained a moderate or severe TBI > 6 months prior to 
enrollment. Evidence will be any one of the following 3 criteria: 
a) GCS 3 – 12 (GCS obtained in Emergency Room and noted in medical record) 
b) Post-traumatic amnesia > 24 hours 
c) TBI-related abnormality on neuroimaging (either CT or MRI).  
(Some missing information about the initial injury [i.e., documentation of initial 
GCS] is not necessarily exclusionary if the bulk of the available history indicates that 
the patient suffered a TBI and meets the inclusion criteria) 
3. Persistent post-concussive symptoms, according to the DSM-IV Research Criteria for 
Post-Concussional Disorder, including: 
a) Difficulty in attention or memory.  
b) One or more  of the following symptoms, which started shortly after the trauma 
and persist for at least three months: 
i) Fatigability 
ii) Disordered sleep 
iii) Changes in personality  
iv) Apathy or lack of spontaneity 
c) Symptoms in criteria (a) and (b) must have their onset after trauma, or there was a 
significant worsening of pre-existing symptoms after trauma. 
d) Disturbance from these symptoms causes significant impairment of social or 
occupational functioning and represents a significant decline from previous level 
of functioning. 
4. Ability to read, write and speak English 
5. Ability to give informed consent.  
 
 
 
 
 
 
 
 
 


 
 
14 
 
c. 
Exclusion criteria 
 
1.  Evidence of penetrating brain injury. 
2.  Contraindication to methylphenidate therapy: 
1. Known glaucoma (consistently raised intraocular pressure with or without associated 
optic nerve damage)  
2. Motor tics or a family history of Tourette’s syndrome (diagnosed by presence of both 
multiple motor and one or more vocal tics over the period of a year, with no more than 
three consecutive tic-free months) 
3. Known hypersensitivity to methylphenidate (hives, difficulty breathing, and swelling 
of face, lips, tongue, or throat) 
4. Known severe anxiety or restlessness which prevents from doing day to day activities. 
5. Known preexisting hypertension, heart failure, myocardial infarction, or ventricular 
arrhythmia 
6. Known preexisting psychosis, bipolar illness 
7. History of seizures, or interictal epileptiform discharges (IEDs) on EEG in absence of 
seizures 
8. Known peripheral vasculopathy, including Raynaud’s phenomenon 
9. History of drug dependence or alcoholism 
10. Concomitant treatment with coumadin anticoagulants, anticonvulsants (e.g., 
phenobarbital, phenytoin, primidone), and tricyclic drugs (e.g., imipramine, 
clomipramine, desipramine)  
11. Concomitant therapy with monoamine oxidase inhibitors (such as Marplan 
(isocarboxazid), Nardil (phenelzine), Emsam (selegiline), and Parnate 
(tranylcypromine))  
12. Concomitant treatment with blood pressure medication (both for high and low blood 
pressure)  
13. Pregnancy  
14. Breastfeeding. 
3. History or evidence of disabling pre-existing or co-existing disabling neurologic  or 
psychiatric disorders not related to TBI, such as: 
1. Multiple sclerosis, pre- or co-existing 
2. Stroke (other than stroke at the time of TBI) 
3. Pre-existing disabling developmental disorder 
4. Pre-existing epilepsy  
5. Pre-existing major depressive disorder, aggressive behavior, hostility 
6. Pre-existing schizophrenia. 
 
4. Contraindication to MRI scanning: 
1. Ferromagnetic metal in the cranial cavity or eye, e.g., aneurysm clip, implanted neural 
stimulator, cochlear implant, or ocular foreign body 
2. Implanted cardiac pacemaker or auto-defibrillator or pump 
3. Non-removable body piercing 
4. Claustrophobia 
5. Inability to lie supine for two hours. 
5. Contraindication to TMS, such as metal in the cranial cavity or implanted electronic 
hardware. 


 
 
15 
 
6. Current participation in other interventional clinical trial. 
7. Non-adherence to use of effective method of contraception for females of able to become 
pregnant for time from enrollment to the study until 2 weeks after completion of the study 
drug. 
8.   Present history of alcohol and substance abuse disorder determined by DSM-IV.   
9.    Body mass index (BMI) > 40.  
10. NIH employees 
4. 
Study Design and Methods 
  
4.1   Study overview  
 
Summary of study design: This is an open-labeled 4 week methylphenidate 
administration, 30 mg twice daily by mouth.  Placebo and methylphenidate will also be 
administered as a single dose before one of the two PET and TMS sessions, in a single 
blinded manner (the participant will not know whether active drug or placebo was 
administered). PET imaging with [11C]-raclopride, a D2/D3 receptor ligand will be 
performed after administration of placebo or oral methylphenidate to measure 
endogenous DA release in TBI patients. Structural MRI will be performed before 
methylphenidate administration. TMS after placebo or methylphenidate will be 
performed 
to 
measure 
intracortical 
inhibition 
and 
dopaminergic 
activity. 
Neuropsychological tests will be performed before and after methylphenidate 
administration for 4 weeks.  The participants will be individuals, who are experiencing 
chronic problems with fatigue, cognition, attention, and executive function after TBI. 
 
 
Site location: NIH Clinical Center. 
 
Length of participation in the study:  Participants enrolled in the study will have four 
outpatient study visits during an approximate 2 - month timeframe. Visits last from three 
to five hours. The study includes a diagnostic phase and an interventional phase and 
consists of   three diagnostic visits and one follow up visit.  


 
 
16 
 
 4.2 Recruitment 
 
Source of subjects and recruitment venues:  Study participants will be recruited from 
Walter Reed National Military Medical Center, National Intrepid Center of Excellence, 
Ft. Belvoir Community Hospital , McGuire Veterans Administration Medical Center in 
Richmond, Virginia, other area Veterans Administration clinics, the NIH, and CNRM’s 
Facebook website (Appendix C)  and Twitter page  (Appendix A).  
They also may be recruited from among volunteers who participated in other CNRM 
studies who signed consent and indicated that they would like to be contacted by 
investigators of other CNRM studies. 
 
How potential subjects will be approached: Recruitment materials may be distributed 
at educational presentations. The IRB-approved brochure (Appendix C) will be 
distributed with the permission of the clinics’ administration or IRB where applicable. 
Same recruitment brochure will be used as Facebook advertisement (Appendix C).  
One of the investigators or study coordinator named in the protocol may contact 
participants from other CNRM studies who consented to be contacted for other studies.  
Investigators from other CNRM studies in which volunteers consent to be contacted for 
other studies may also be given the telephone number or email address of the study 
contact. The study telephone number is on the front of the brochure and will be 
advertised on the CNRM website and twitter page.  We will also employ the NIH Clinical 
Center and the CNRM Recruitment Core resources.  They may refer patients who call the 
centers inquiring about TBI studies to our central study number. Otherwise it will be up 
to the participant to call the study number. Self-referral is also permitted.   
  
Accrual Rate:  We plan to enroll 30 participants over a 2-year period.   
Pre-screening questions for recruiters: Pre-screening will be performed by the study 
coordinator, investigators, and research assistants over the telephone or in-person. If the 
potential subject is unfamiliar with the details of the study and time requirements, the 
prescreener will use the pre-screening Script (Appendix D) along with the Eligibility 
Checklist to determine preliminary eligibility." 
The members of the research team who will be qualified to administer the Eligibility 
Checklist will have to complete a Good Clinical Practice course and the class, “Elements 
of a Successful Consent” offered by HSPU.  
 
If the potential participant  expresses interest in the study, the person doing the pre- 
screening will ask if they have time to answer a short questionnaire that would allow 
him/her to evaluate their eligibility and safety for inclusion into the study (Eligibility 
checklist, Appendix F). 
 
If based on this interaction, it appears that the subject might meet the inclusion criteria for 
the study, an appointment will be scheduled for the patient to come to NIH.  To prepare 
for this visit, the potential participant will be asked for his/her full name (first and last), 
address, telephone number, and date of birth to be entered into the Admissions and Travel 
and Vouchers program.   


 
 
17 
 
 
Research staff may ask for medical records (recent history, medication list, recent 
imaging and pertinent records related to the subject’s recent injury) to further evaluate 
their eligibility for the study. The subjects may bring their own medical records when 
they come to NIH for testing. The data may be reviewed by the investigator before the 
initial clinic visit, and if it is clear that the patient does not meet the inclusion criteria, we 
will contact them and cancel their appointment.  Data obtained in this manner may be 
used to refine our inclusion and exclusion criteria; however, it will not be used for any 
research purposes. We will send their medical records back to them if they do not meet 
criteria.   
 
Identifying information will be destroyed within one week of learning about a potential 
participant’s pre-screening failure. 
 
 
4.3 Screening 
   
Informed consent will be obtained before any study procedures 
 
Study Eligibility Evaluation 
  
Potential study participants will come to the NIH Clinical Center and will be greeted by a 
research staff member. Participants will be checked in to the Clinical Center at the 
Outpatient Neurology Center, 5th floor by a clinic nurse.   
 
The subject will undergo the following procedures: 
 
1) Informed Consent:  One of the physician investigators will obtain consent before any 
research and screening procedures are conducted. The consent is written in language 
appropriate for the subject to comprehend. The study physician will discuss the study 
with the potential participant, review all parts of the consent form, answer questions 
about the study, give a copy of the consent form to the participant and ask them to review 
it, consider it, ask questions, and discuss it with friends or family.  If the participant 
decides to sign the form, a copy will be given to them to take home.  The study 
coordinator or research assistant may assist the physician in reviewing the consent form 
in detail and in collecting information from the patient in order to complete the case 
report forms. 
 
2)  Screening by physician and study coordinator or research assistant  
 
As a Clinical Center requirement, an NIH staff nurse will take vital signs including pulse, 
temperature, blood pressure, and respiration rate. The nurse may record a list of the 
participant’s current medications and a brief medical history. One of the study physicians 
will do a history and physical exam, including a neurological exam which will be entered 
into CRIS.   


 
 
18 
 
 
 
Screening includes:  
 
a.  Medical history including information about the traumatic brain injury  
b.    Interview with the study physician  
        c.    Urine pregnancy test if applicable. 
        d.    Physician’s determination of participant eligibility for the study 
 
Determination of Subject Eligibility:  Subject’s eligibility for the study will be 
documented using the Eligibility Checklist, which is based on the Inclusion/Exclusion 
criteria.  The checklist should be reviewed with each potential participant prior to the 
subject’s initial visit. Final determination of eligibility will be determined by the 
physician investigator, using the patient’s medical records, medical history, and in-
person interview. Medical history including history of TBI will be collected from all 
subjects to assist the physician in eligibility determination. If medical records are 
unavailable, data such as time of injury, loss of consciousness, and post traumatic 
amnesia, are to be summarized from interviews with the subject. 
  
Urine Pregnancy Test:  If applicable, the study participant will provide a urine 
pregnancy test required for screening women able to become pregnant, unless they have 
had a surgical procedure permanently preventing pregnancy.  This is part of the 
eligibility requirement. 
 
Enrolled or screen failed:  If the patient is deemed eligible by the investigator, then 
she/he will begin the study procedures. If the patient is not eligible, she/he will be 
considered a screen failure and will not go through study procedures.  Signed consent 
forms for screen failures will be maintained with study records in Dr. Wassermann’s 
research office. The research records will be kept in locked cabinets and the office will 
be locked when not in use. Their contact information will not be kept.  
 
Volunteers who fail the enrollment criteria for this study will be considered screening 
failures.  Screening failures will be counted separately than those that drop out for other 
reasons.  Subjects who come into the Clinical Center will sign a consent form before 
engaging in any study procedures. If they do not meet eligibility for the study, even 
though they have signed a consent form, they will be considered screening failures. 
Once a participant has met eligibility criteria and engaged in a study procedure and 
chooses not to participate in the protocol, are lost to follow-up, or voluntarily withdraw 
or are involuntarily withdrawn from the study by the investigator, they will be counted 
as drop-outs for statistical purposes.  
 
Contraception:  Sexually active women who are able to become pregnant must agree to 
use an effective method of contraception (birth control) from the time they enroll in the 
study until 2 weeks after they have completed taking the study drug, methylphenidate. 
 


 
 
19 
 
4.4 Study Procedures  
Informed consent will be obtained before any study procedures. All evaluations and 
procedures are done only for research purposes.  Table 2 is a schedule of procedures for 
each study visit.  While the stated target time points and assessment batteries will be 
attempted for subjects in this study, it is anticipated that some subjects will not be able to 
undergo all tests at all times and may refuse assessments. Procedures may be done in a 
different order after consent and determination of eligibility depending on Imaging 
Center, Phlebotomy Center, and neuropsychometrician’s schedules and availability. 
 
  
 
 
Table 2 :  Study Schematic 
 
Study Procedure 
Visit 1, 
Diagno 
stic 
 
Visit 2, 
Diagno
stic 
Visit 
3, 
Diagn
ostic 
Visit 4, 
Follow-
up 
Time for 
the 
procedu
res 
1. Informed Consent 
X 
 
 
 
30 min 
2. Inclusion/Exclusion Criteria 
X 
 
 
 
15 min 
3. Pregnancy test 
X 
X 
X 
X 
5 min 
4. Examination and medical 
history by 
physician/Investigator 
X 
 
 
 
30 min 
5. Blood draw for research 
biomarkers and DNA 
X 
 
 
X 
15 min 
6. Structural MRI; T1 
MPRAGE, FLAIR, DTI,  
3DTI-SPGR, rfcMRI, GRE, 
SWI,  
X 
 
 
 
45 min 
7. fMRI and Resting Functional 
Connectivity 
X  
 
 
X  
15 min 
8. Neuropsychometric Common 
Data Elements 
 
X 
 
X 
60 min  
9. Attention tests 
 
X 
 
X 
60 min 
10. TMS and motivation tests 
before and after 
methylphenidate* 
 
X 
 
 
2 X 80 
min  
11. PET scans (x 2) after 
administration placebo and 
then after  methylphenidate** 
 
 
X 
 
2 X 2 h    
12. Dispensing study drug 
(methylphenidate)  
 
 
X 
 
5 min  
13. Examination by physician and 
pill counting for compliance 
 
 
 
X 
20 min 
14. Monitoring for adverse effects X 
X 
X 
X 
15 min  
Time   
2 h 50  
min 
 5 h   
4 h 25 
min  
3 h 10 
min 
 
 


 
 
20 
 
* TMS and motivation tests with placebo or methylphenidate can be administered 
separately on visits #1 or #3  
** PET with placebo or methylphenidate can be done on visits #1 or #2   
 
4.4.1 History and Physical examination 
 
Subjects who are eligible for the study will have a physical examination which includes a 
neurological examination and medical history review by a study physician.  All TBI 
subjects evaluated by the study investigators will be asked for written permission if they 
require medical records data, including imaging, collected as part of their regular medical 
care for research purposes.   
 
This physical examination is for research purposes only and does not replace any 
examination they may receive from their own physicians. The study physician will write 
orders for imaging procedures, biospecimen collection, and methylphenidate dispensing. 
 
Incidental findings on brain imaging, laboratory evaluation or physical examination: 
The physician will inform the patient about any finding that may require further 
evaluation or care. Evaluation or treatments of these conditions are not provided at NIH. 
If needed, the study physician will refer the patient to a health care provider. The study 
team may not inform the patient about minor abnormalities that do not have importance 
for their health or well-being.  
 
 
 
4.4.2 Biospecimen Sample Collection 
 
  a. Urine sample:  Prior to MRI or PET scanning or TMS, urine specimens will be 
collected from women able to become pregnant for pregnancy tests. A urine pregnancy 
test must be done within 24 hours prior to MRI or PET or TMS. Subjects who have a 
positive pregnancy test will not undergo MRI, PET or TMS and will be excluded from 
the study.  Urine will not be stored. 
 
   b. Blood sample: Venous blood samples will be collected from study participants by a 
trained phlebotomist or nurse at the Clinical Center during Visits #1 and #4.  Blood 
samples will be drawn for research purposes.  
 
For research purposes during this study, approximately 25 ml (approximately 5 
teaspoons) of blood will be collected from participants at Visits #1 and #4. A total of 50 
ml (approximately 11 teaspoons) will be collected over the 4 weeks of the study. 
No specific genetic tests will be performed under this protocol because the sample size of 
this study is not sufficient to perform these studies. Since the sample size of this study is 
relatively small, it is not possible to determine the type of genetic polymorphism which 
will be analyzed in the future. The specimens will be transferred to the CNRM 
Biorepository and will be combined with similar types of samples for future studies.  
 


 
 
21 
 
Results of genetic testing obtained at NIH are often preliminary and difficult to interpret 
because the testing is being done for research purposes only and the laboratories are not 
CLIA-certified.  Results will not be shared with participants, their families, or insurance 
companies. 
 
4.4.3 Magnetic Resonance Imaging (MRI) 
  
1.  All women able to become pregnant will provide a urine sample for a pregnancy test 
performed no more than 24 hours before MRI. Women who are discovered to be 
pregnant on their follow-up visit #4 will not participate in the imaging portion of this 
study.  
2.  The research coordinator or assistant will escort the participant to the Tesla MR 
System in the CNRM Neuroimaging Core, housed at the NIH Clinical Center and will 
monitor the participant throughout the procedure.   
3.  Subjects will be screened for MRI safety using the Screening Questionnaire used by 
the Radiology and Imaging Sciences Program of the Clinical Center (Appendix F). Final 
approval to continue with study MRI procedures will be the responsibility of study 
investigators.  
4. Subjects may be asked to lie still for up to 7 minutes at a time. They will be fitted with 
earplugs or earmuffs to lessen the loud knocking noise before being placed in the 
scanner. They can communicate with the MRI staff at all times during their scan, and 
they may ask to be moved out of the machine at any time.  
5. Participants will have a structural MRI scan that does not require contrast.  They are 
not required to do any tasks during the structural MRI.  Sequences used for the structural 
MRI include T1 Magnetization Prepared Rapid Gradient Echo (MPRAGE),  Fluid 
Attenuated Inversion Recovery (FLAIR), Diffusion Tensor Imaging (DTI), resting state 
functional connectivity (rfMRI), diffusion weighted imaging (DWI), Arterial Spin 
Labeling (ASL) to assess resting CBF, gradient echo (GRE) and/or T2* susceptibility 
weighted imaging (SWI).  If the image quality of a given sequence is inadequate due to 
patient motion for example, these may be repeated at the discretion of the MRI 
technologist or radiologist. The structural scan takes approximately 45 minutes. 
6. Subjects will also have a scan to measure resting functional connectivity at diagnostic 
visit and at follow up visit after 1 month of treatment with methylphenidate.  Recent 
studies conducted by Dr. Volkow in cocaine addiction participants showed that short-
term methylphenidate administration within 2 hours reduced an abnormally strong 
connectivity of the ventral striatum with the dorsal striatum (putamen/ globus pallidus), 
suggesting that methylphenidate can remodel abnormal circuitry 24. Therefore, one month 
will be a sufficient interval between two fMRI scans to study functional connectivity 
after methylphenidate administration.  
For this purpose an fMRI scan is obtained while subjects rest with their eyes open in the 
scanner without any stimulation. An echo-planar imaging (EPI) time series (TE/TR: 
20/1600 ms, 200 kHz bandwidth, 64 × 64 matrix size, 20 × 20-cm2 field-of-view, 35 
coronal slices, 4-mm thickness, 1-mm gap, 187 time points, scan time) will be acquired. 
RFC will take approximately 15 minutes to obtain.  
 
 


 
 
22 
 
4.4.4   Neuropsychological Assessments 
 
Clinical phenotyping is critical for studying the effect of TBI on memory, behavior and 
functioning, because clinical representation of consequences after TBI can vary 
significantly 25. All testing will be performed by Clinical Center NIH staff.  Testing will 
be administered by a neuropsychologist or psychometrist.  We anticipate that the core 
phenotyping assessments will require approximately 1 hour to complete.  These 
assessments will be done on diagnostic visit #2 and follow up visit # 4.  Baseline 
assessment can be done on visit #1. 
 
Subjects will be given frequent rest breaks.  The subject may refuse to answer any 
question or to stop a test at any time and for any reason. 
 
TBI phenotyping instruments recommended for evaluation in all TBI cohort or natural 
history studies have been labeled the TBI Common Data Elements (CDEs).  The subject 
will be interviewed, complete questionnaires, take pen-and-paper tests, and perform 
simple actions. 
 
  
In this study, we will include the following selected subset of assessments taken from the 
CDE’s: 
1. Glasgow Outcome Scale-Extended (GOS-E): is an assessment of the 
general functioning.  This scale evaluates 8 categories: Dead, Vegetative 
State, Lower Severe Disability, Upper Severe Disability, Lower Moderate 
Disability, Upper Moderate Disability, Lower Good Recovery, and Upper 
Good Recovery (10 min).   
2. Learning trials portion of the California Verbal Learning Test (CVLT-II): 
measures long and short delay free and cued recall, the effects of 
interference, recognition, and efficiency of learning (5 min). 
3. The Trail Making Tests A and B (TMT):  visual conceptual and visual 
motor tracking motor speed and attention The test requires visual 
scanning, numeric sequencing and visual motor speed  (5 min). 
4. Subsets of the Wechsler Adult Intelligence Scale (WAIS-IV) (Digit 
Symbol and Symbol Search): perceptual organization and processing 
speed (10 min). 
5. Brief Symptom Inventory 18 (BSI-18) is used to identify self-reported 
clinically relevant psychological symptoms in adolescents and adults.  The 
shortened form of the BSI instrument provides a highly sensitive 
assessment of psychological factors (10 min). 
6. Satisfaction with Life Scale (SWLS): is a short 5-item instrument designed 
to measure global cognitive judgments of satisfaction with one's life (1 
min).  
7. Word Reading subtest of Wide Range Achievement Test (WRAT)-4: 
measures the basic academic skills of reading, spelling, and math 
computation (15 min). 


 
 
23 
 
8. Rivermead Post-Concussion Symptom Questionnaire: rate the severity of 
16 different symptoms commonly found after a TBI (5 min). 
 
The attention tasks chosen according to Whyte (6) will be administered twice 
(approximately 60 min).  
A neuropsychometrist or neuropsychologist will administer these tests to participants in a 
private room. Some of the tests are pencil/paper tests; others are computer tests; and 
some will be verbal question and answer tests. The participant may take breaks. These 
assessments will be performed twice. 
 
The tests used for measurement of various aspects of attention are shown below:  
 
1. 
Continuous Performance Test 
The Conners Continuous Performance Test 3rd Edition™ (Conners CPT 3™) is a task-
oriented computerized assessment of attention-related problems in individuals aged 8 
years and older. By indexing the respondent’s performance in areas of inattentiveness, 
impulsivity, sustained attention, and vigilance, the Conners CPT 3 can be useful to the 
process of diagnosing Attention-Deficit/Hyperactive Disorder (ADHD) and other 
neurological conditions related to attention. 
Administration time: 14 minutes.  
2. 
Auditory Attention 
SeaShore Rhythm Test (HRNB). This is a test which requires the subject to attend to two 
rhythms which are played one after the other and determine if they are the same or 
different.  This test assesses auditory attention.   
Administration time: 10 minutes. 
3. 
NIH Tool Box test descriptions from manual Attention 
Flanker Inhibitory Control and Attention Test 
The Flanker task measures both a participant’s attention and inhibitory control. The test 
requires the participant to focus on a given stimulus while inhibiting attention to stimuli 
(fish for ages 3-7 or arrows for ages 8-85) flanking it. Sometimes the middle stimulus is 
pointing in the same direction as the “flankers” (congruent) and sometimes in the 
opposite direction (incongruent). Scoring is based on a combination of accuracy and 
reaction time, and the test takes approximately 3 minutes to administer. This test is 
recommended for ages 3-85. 
Administration time: 4 minutes.  
 
The NIH Toolbox is a multidimensional set of brief measures assessing cognitive, 
emotional, motor and sensory functions, meeting the need for a standard set of measures 
that can be used as a common currency across diverse study designs and settings.  In a 
short period of time the NIH Toolbox has become the standard psychometric tool in the 
TBI field, and is being used in two large recently launched multicenter studies 
(Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) and Chronic 
Effects of Neurotrauma Consortium (CENC)).  It has been adapted in academic medical 
centers, VA, and Military Treatment Facilities.    
The NIH Toolbox was developed by NINDS in cooperation with Northwestern 
University Research Data Center and is administered through the Assessment Center web 


 
 
24 
 
site (http://assessmentcenter.net).  Investigators set up a password-protected account with 
the Assessment Center, which is specific for each study.  Access to the study-specific 
website is only available to study personnel who are provided with a username and 
password by the Principal Investigator (PI). Testing is carried out through the website. 
Participant files can include only a study number, age, and gender.  We will upload no 
protected health information to the Assessment Center website.  The software program 
administers the test and provides the scores, which are further normalized for age and 
gender.   
The assessment instruments reside on Northwestern University’s server and are only 
accessible through the secure Assessment Center website.  Assessments which have been 
administered remain on the Northwestern server and are available for use by study 
personnel who are given access by the PI.  The Assessment Center staff does not look at 
the data for quality control purposes or any other purposes.   
For this study, we will use the NIH Toolbox tests (Flanker Inhibitory Control and 
Attention Test and the Pattern Comparison Processing Speed Test)  as it has become the 
standard in the field, and particularly appropriate for measuring Processing Speed, using 
computerized assessment tools.  No PHI will be entered into the Assessment Center 
website.   
 
4. 
Processing speed 
 
Pattern Comparison Processing Speed Test 
This test measures speed of processing by asking participants to discern whether two 
side-by-side pictures are the same or not. Participants’ raw score is the number of items 
correct in a 90-second period. The items are designed to be simple to most purely 
measure processing speed. The test overall takes approximately 3 minutes to administer. 
This test is recommended for ages 7-85.  
Administration time: 4 minutes.  
 
Total Administration time for the attention battery is 32 minutes. 
 
The tests to be used to identify processing speed are the WAIS-IV Processing Speed 
Index (PSI) and the NIH Tool Box, Processing Speed (Pattern Comparison Processing 
Speed Test).  The PSI is a TBI CDE and Pattern comparison is an NIH Tool Box 
component.   Both of these tests yield demographically adjusted standard scores with a 
mean of 100 and standard deviation of 15.   
 
A unified score can be the average of the two scores either as an average standard score 
or after conversion to a deficit score.  The retention of the standard score allows for a 
maintenance of a wider score range and likely easier statistical analysis.    
 
The tests used to identify attention will be the Conners Continuous Performance Test 3rd 
Ed.(CPT 3), the SeaShore Rhythm Test (SSRT) from the HRNB and the Flanker 
Inhibitory Control and Attention Test from the NIH tool box.  The results from the CPT 3 


 
 
25 
 
and the SSRT are reported as demographically adjusted T-scores (mean of 50 and SD or 
10).  While the NIH tool box reports scores in standard score format (mean of 100 and 
SD of 15).  In addition the CPT 3 provides measures of multiple aspects of attention.  
Attention being more complex a construct than processing speed it is recommended that 
the various scores are all used independently to examine if the treatment differentially 
affects various aspects of attention.  Thus a unified score is not recommended for this 
cognitive domain.  
 
 
4.4.5. TMS (measurement of intracortical inhibition) 
 
The TMS procedure will be performed before and 60 minutes after methylphenidate (60 
mg by mouth) administration.  EMG electrodes will be applied to the optimum position 
for recording the MEP response from the abductor pollicis brevis or first dorsal 
interosseous muscle. TMS will be delivered through a round coil at the optimal position 
for producing an MEP in the target muscle. Resting and active motor threshold (RMT 
and AMT) will be measured after oral methylphenidate.  Then, short-interval cortical 
inhibition (SICI) will be measured with a conditioning pulse just before the test pulse.  
Twenty trials at each interval and 20 unconditioned test pulses will be delivered in 
random order.   
 
TMS without and with oral methylphenidate will be performed on Visit #2. Tests with 
placebo or methylphenidate can be also administered separately  at visits #1 #2 or #3.  
TMS with placebo and with methylphenidate requires 2 hours 40 min in total.  
 
4.4.6. Effort and reward task (motivation test) 
 
This experimental task measures the subject’s preference for making hard and easy 
efforts (muscle contractions) under differentially rewarded conditions.  We consider the 
willingness to perform a given effort for a given reward values a measure of motivation 
and rewardability.   
 
In this task, visual feedback showing the degree of muscle activation is given to subjects 
as they make a contraction with the left hand; the EMG is recorded continuously with 
surface electrodes.  During each trial, two targets appear on a feedback display, 
corresponding to 20% and 60% of the individual’s maximum voluntary contraction.  
Each target is randomly assigned a monetary reward value: One target is labeled ‘$0.75’ 
and the other is labeled with a value ranging from $0.75 to $1.25, chosen from a random 
distribution of $0.75 – x with mean of x = 0 (i.e., the mean difference between the target 
values is $0 across trials).  Subjects are asked to choose which monetary value they 
would like to earn by making a contraction to bring the feedback bar to the corresponding 
target.  Rewards are given intermittently, such that in half the trials (randomly assigned), 
the subject receives the chosen value and for the other half, they receive no money.  
  
For each trial, the stimulus screen and the subject has up to 10 s to make one of the two 
muscle contractions.  The contraction must be held for 1.5s for the response to be 


 
 
26 
 
registered.  As soon as a response is entered, the stimulus disappears.  The next screen 
either reads, “You won $X.xx [the chosen value]” or “Sorry, no prize”.  Finally, after 2s, 
a fixation cross appears for 6s.   
 
In previous experiments in healthy subjects, we found a consistent preference for the 
lower effort and that the effort intensity choice is a function of the difference in reward 
values associated with the 20% and 60% contractions.  The probability of choosing the 
high effort at a given difference in reward values approximates a logistic function, which 
we would expect to shift to the left (higher likelihood of choosing high effort for a given 
difference in reward) when motivation and rewardability are higher. This study will be 
performed on Visit #2. Experiments can be performed on separate days. Part of the test 
can be also administered on visits #1 or #3 and requires 40 min. 
 
4.4.7 Study Medication  
 
Participants will take methylphenidate (Ritalin), which is FDA-approved and used most 
often in children to treat attention deficit hyperactivity disorder (ADHD).  
Methylphenidate is a drug acting on DA neurotransmission commonly used off label by 
physiatrists attempting to improve recovery after TBI. It acts by directly stimulating 
release of DA and NE, as well as blocking catecholamine reuptake. In this study, the drug 
will be taken in a therapeutic dose which significantly increased extracellular DA in the 
brain 11.  Duration of treatment is chosen based  on a prior randomized controlled trial of 
oral methylphenidate in patients with chronic deficits after TBI,  which demonstrated 
increased processing speed after 3 weeks of oral administration of methylphenidate 6. The 
dosage of methylphenidate 60 mg/day was given to moderate to severe TBI patients in 
this study. In this study the participants received methylphenidate in double blind, 
placebo-controlled study in dosage 0.3 mg/kg twice a day, with a range 15-40 mg twice a 
day (30 mg twice a day mg per day per 100 kg body weight) for 6 weeks. From total 39 
participants consented for the study, only one subject receiving methylphenidate 
withdrew (due to possible exacerbation of baseline hypertension). This study provides 
evidence that dosage of 60 mg/ day is safe in TBI participants.   
 
The participants will receive oral methylphenidate 60 mg before the second TMS study 
during Visit #2. The participants will receive oral methylphenidate 60 mg before the 
second PET scan during Visit #3. This single dose is chosen based on evidence of 
increased intracellular DA after oral dose of methylphenidate 11. Single dose of 60 mg 
methylphenidate will be used for PET and TMS studies to block dopamine transporters.  
Justification of use of single dose 60 mg for PET comes from two studies of Dr. Volkow.  
In the first study the researchers used PET with [ 11C]raclopride (D2 receptor ligand that 
competes with endogenous DA for binding to the receptor) to evaluate if oral  60 mg 
methylphenidate changes extracellular DA in 11 healthy controls. The study showed that 
oral  60 mg methylphenidate significantly increased extracellular DA in brain, as 
evidenced by a significant reduction in Bmax/Kd (measure of D2 receptor availability) in 
striatum (20 ±12%; p <0.0005). These results provide evidence that oral methylphenidate 
at dose 60 mg significantly increases extracellular DA in human brain. No adverse events 
were reported (The Journal of Neuroscience, 2001, Vol. 21 RC121).  Another study by 


 
 
27 
 
Dr. Volkow group showed that oral methylphenidate produced dose dependent blockage 
of dopamine transporter (measured by PET with 11 cocaine) and the dose 60 mg per os 
produced the highest, up to 74 % blockage of dopamine transporters. No adverse events 
after 60 mg administration of methylphenidate were reported on healthy volunteers (Am J 
Psychiatry 1998; 155:1325–1331). The purpose of this part the study is to measure tonic 
DA release, which will be evaluated by measuring of binding potential of raclopride 
(relative to non-displaceable reference region after placebo and methylphenidate 
administration). In order to be able to show the difference with placebo administration, 
the highest dosage which shown to be safe and effective (60 mg) in the cited studies will 
be used in our study. 
 
The participants will receive the study medication during Visit #3.   
The maximal dose of methylphenidate in this study will be 30 mg orally twice daily, the 
dosage was chosen according to Whyte et al. 6. “Dose titration will be incremental within 
6 days (dose-escalation phase), starting at 5 mg orally twice daily for 2 days, and 10 mg 
twice daily for the next 2 days and then 20 mg twice daily for next 2 days”. Then the dose 
will be increased to 30 mg twice daily starting from day 7 (Table 3).  
 
 
Table 3. Dose escalation and time on methylphenidate 
 
Phases of 
methylphenidate 
administration  
Days of methylphenidate 
administration  
Dosage 
Dose-escalation phase 
1-2 
5 mg twice a day 
3-4 
10 mg twice a day 
5-6 
20 mg twice a day  
Stable phase  
7- 28  
30 mg twice a day 
 
 
During dose-escalation phase the participants will have a telephone follow-up to evaluate 
adverse events (Table 4). Adverse events of methylphenidate which lead to 
discontinuation are presented on Table 4A.  Adverse events of methylphenidate which 
lead to dose pausing and restarting of the drug are presented (but not limited to) on Table 
4B. 
 
 
 
 


 
 
28 
 
Table 4. Adverse events and action plan for dose-escalation phase of methylphenidate 
administration. 
A 
1. Hypersensitivity (skin rash, 
urticaria, fever, arthralgia, 
exfoliative dermatitis, 
erythema multiforme, and 
thrombocytopenic purpura)  
2. Angina; cardiac arrhythmia; 
abdominal pain  
3. Dyskinesia, Tourette’s 
syndrome 
4. Toxic psychosis  
5. Abnormal liver function 
(transaminase elevation)  
6. Cerebral arteritis and/or 
occlusion 
7. Leukopenia and/or anemia  
8. Transient depressed mood,  
aggressive behavior  
9. Scalp hair loss 
Discontinue the drug 
B 
1. Nervousness and insomnia  
2. Anorexia; nausea 
3. Dizziness; palpitations 
4. Headache, drowsiness  
5. Blood pressure and pulse 
changes, both up and down 
6. Tachycardia 
Reduce dosage by half.  Omit the 
drug in the afternoon or evening. 
Follow up for 3 days. 
1. If symptoms disappear, 
return to the previous dosage.  
Continue on this dosage 
through the study.  
2. If symptoms persist, decrease 
the dosage by half 
• Follow up for 3 days. 
Continue on the 
reduced dosage, if 
symptoms resolve.   
• Discontinue the drug, 
if symptoms persist at 
the minimal dose 5 
mg/day.   
 
 
If participants do not experience adverse events, they will continue with this dose for the 
remaining 3 weeks of the study (stable phase). The participants will have two telephone 
follow ups during stable dosing.  
 
The target duration of intake of the medication in the stable phase is 3 weeks.  In this 
study all visits can be scheduled within 2 weeks from the target date.  In order to provide 
sufficient medication for 3 weeks’ treatment and 2 additional weeks for scheduling, the 


 
 
29 
 
patients will receive study medication for 5 weeks. The remaining pills will be returned 
and will be counted on Visit #4 to evaluate compliance. The leftover drug will be 
destroyed through NIH CC pharmacy once a research participant completed all 
procedures, returned unused drugs, and all the data is recorded.   
 
 
4.4.8 PET Scanning and processing 
 
Scans will be performed with the High Resolution Research Tomograph (HRRT) which 
has a transverse resolution of about 2.5 mm. An intravenous line will be inserted for 
administration of the ligand. A swimming cap with small light reflectors will be put on 
the subject’s head. It is used to monitor head position and movement during the scan; the 
information is used in the PET image reconstruction process to reduce any blurring of the 
PET images. Subjects will be positioned in the scanner with the brain in the field of view. 
Prior to the [11C]raclopride administration, a transmission scan will be obtained with a 
rotating 137Cs source for attenuation correction. Subsequently, approximately 20 mCi of 
the [11C]raclopride will be injected through an intravenous catheter in an arm vein over 
about 1 min using a Harvard ® pump and a 90-min dynamic scan will be obtained.  
 
The PET imaging data from the placebo day will be used as a measure of baseline 
raclopride binding potential, calculated using the Simplified Reference Tissue Model. 
PET measurements taken following methylphenidate administration will be compared to 
those derived after placebo administration. This will permit measurement of the reduction 
in specific binding of raclopride due to competition with DA endogenously released by 
the methylphenidate challenge (10). The percent change from baseline was proportional 
to the magnitude of DA release.  
 
Oral methylphenidate in a 60-mg dose or a placebo will be administered and the scan will 
be done 60 min later, according to the schedule used by Volkow et al. (11). The oral 
placebo will be administered before the first PET scan and the methylphenidate will be 
administered before the second one. The subjects will be blind as to whether placebo or 
oral methylphenidate is administered. They will have about a 2-hr break between the PET 
scans, or PET scans can be performed on separate days. The participants will have two 
90-min PET scans with [11C]-raclopride, a D2/D3 receptor ligand 11.  
 
Total PET scan time will be 4 hrs, and break time will be at least 2 hrs. PET will be done 
on visit #3. PET with placebo and with methylphenidate can be done on separate days, on 
visit #1 or visit #2.    The radionuclide (C11) half-life is 20 min, and it is rapidly cleared 
from plasma and whole blood with biliary elimination   The first scan lasts for 90 
minutes, then the second scan will be done 60 min after administration of dose of 
methylphenidate, which makes time from the first injection of raclopride to second 
injection 150 min, which time less than 0.75% of the 1st raclopride dose will be left.  
 
Regions of interest (ROIs) are obtained directly from coregistered [11C]-raclopride scans 
and structural MRIs as described previously.(1)  ROIs are identified for the caudate, 
putamen, ventral striatum (VS), and prefrontal cortex (PFC) using multiple planes.  


 
 
30 
 
D2/D3 receptor availability was measured as the binding potential relative to a 
nondisplaceable reference (BPND), the ratio of the distribution volume in each ROI to that 
in cerebellum minus 1.  The difference in BPND (∆BPND) between MP and placebo was 
used as the measure of DA release.    
 
Findings from the ROI analysis will be confirmed and extended using Voxel-Based 
Analysis and Statistical Parametric Mapping (SPM).(1)  SPM will also be used in 
exploratory analysis to assess the effect of MP on DA release in extrastriatal brain 
regions.  SPM analysis will be performed on BPND images (obtained by computing the 
BPND for each pixel).  A spatial normalization template matching the average BPND 
image contrast in the brain was developed using the BPND images from 20 healthy age-
matched controls who participated in prior [11C]-raclopride studies done by Drs. Volkow 
and Herscovitch using the same instrument and scanning sequence.  A 12-parameter 
affine transformation with 16 nonlinear iterations will be used to register the images to 
the MNI template provided with the SPM package.   
 
 
4.4.9 Summary of the study procedures  
 
Missed visits will be rescheduled within 2 weeks of the target date whenever possible.  
Study physicians may ask the patient to come in for an examination between visits if the 
patient has persistent side effects.  Investigators may refer the patients to their personal 
physicians to treat adverse side effects or for negative symptoms relating to the TBI. 
 
4.4.9.1 Diagnostic Visit #1:  
 
During Visit #1, participants will see a study physician for examination and medical 
history. (30 min), will have blood collected (15 min), and urine samples will be taken 
from women able to become pregnant. Participants will have structural MRI (45 min), 
and Resting Functional Connectivity (15 min). Visit #1 requires approximately 2 hr 50 
min in total. 
 
4.4.9.2 Diagnostic Visit #2: 
 
During Visit #2, urine pregnancy test will be repeated on the same day for women able to 
become pregnant. Participants have neuropsychological tests (60 min), attention tests (60 
min) and TMS with motivation tasks without and with methylphenidate challenge (2 hr 
40 min), adverse events will be monitored (15 min).  
 
Visit # 2 can be performed within two weeks of Visit #1.    Neuropsychological tests (60 
min) and attention tests (60 min) can be performed during Visit #1.Visit #2 requires 
approximately 5 hours in total. 
 
 
 
 


 
 
31 
 
 
4.4.9.3Diagnostic Visit # 3: 
 
At Visit #3, women able to become pregnant will have urine pregnancy test, [11C]-
raclopride PET scans after placebo and after oral methylphenidate will be performed (4 
hr). The study drug will be dispensed to participants (5 min) and adverse events will be 
monitored (15 min). Visit #3 requires approximately 4 hr 25 min of research time in total. 
 
4.4.9.4 Telephone follow-ups: 
 
All participants will be contacted by a research assistant or study coordinator by 
telephone to inquire about possible adverse symptoms after methylphenidate 
administration.   
 
1. The participants will have a telephone follow-up to evaluate adverse events 
during dose-escalation part of interventional phase of the study (1-6 days 
after initiation of methylphenidate administration).  
2. The first telephone follow up at the stable part of interventional phase of 
the study will be done 7-14 days after initiation of the drug administration. 
3. The second follow-up at stable part will be done 15-28 days after initiation 
of the drug administration.   
 
The research staff member will review a checklist of the most common side effects.  If 
the participant reports any bothersome side effects, the research assistant or coordinator 
will inform one of the physician investigators who will follow-up by telephone or in-
person with the participant.  Instructions for following medication intake will be given, as 
described in 4.4.7.  
 
 
4.4.9.5 Follow-up visit # 4:   
 
At Visit #4, participants will see a study physician (15 min), have about 5 teaspoons of 
blood collected (15 min), have neuropsychological testing (2 hr). Women able to become 
pregnant will have urine pregnancy test. Participants will have an MRI scan for resting 
functional connectivity (15 min) and will be monitored for adverse effects (15 min).  The 
MRI and neuropsychological testing tests will be done while patients are under the 
effects of their medication (methylphenidate taken 1-3 hr before).  Patients will return 
unused study medication (20 min). 
 
Total time for research procedures during Visit #4 is approximately 3 hr 10 min.  The 
time will vary depending on how long it takes the patient to complete the neurocognitive 
testing if schedules are not running on time. 
 
 
 


 
 
32 
 
4.5. End of Participation   
 
Participation will end upon completion of Visit #4, unless there is an adverse event that 
needs to be resolved. Participants remain under the care of their own health care 
providers during study participation and after the end of participation.   
 
 
 4.5.1 Communication of Incidental Findings 
 
MRI:  A radiologist will officially read all MRI exams. Professional fees associated with 
research MRIs will be paid for by the CNRM project and will not be billed to subjects or 
the subjects’ insurance. All imaging data that are germane to clinical interpretation will 
be interpreted by a credentialed neuroradiologist. Clinically relevant findings will be 
reviewed by the medically responsible investigators and, in the context of the entire 
medical assessment, appropriate treatment and or follow-up will be recommended to the 
participant as indicated.  Unexpected findings on brain imaging that require clinical 
intervention may occur.  Therefore, any research findings on brain images, laboratory or 
other evaluation that may require further evaluation or impact the subject’s medical care 
will be shared with subjects and their health care providers by a physician investigator.  
However, this study does not provide treatment and does not replace any therapy that a 
subject may be receiving as part of standard medical care for TBI. 
 
The study physician/investigator may share some of the results from the MRI and general 
feedback from the neuropsychological testing on the patient’s strengths and areas of 
difficulty.  There are no psychiatric tests in this battery.  There is one checklist for 
depression.  If any question about suicidal ideation is answered in the affirmative, the 
study physician will talk with the patient and call in the CNRM psychiatrist, Dr. Dsurney 
or an NIH staff psychiatrist if there is a concern about the patient’s stability and safety. 
NIH policy will be followed concerning a patient who may be a danger to himself.  
 
Blood:  Blood samples are used for research purposes only.    
5.  Storage of Data and Samples 
 
5.1   Disposition of Samples at the end of the study 
 
Some of the blood sample from each subject will be analyzed in Dr. Diaz-Arrastia’s, 
(Adjunct PI) laboratory at CNRM.  Any samples not immediately analyzed by the co-
investigator, Dr. Diaz-Arrastia, will be stored in the CNRM Biorepository. Biospecimens 
and data provided to the CNRM Repository, which is operated under USUHS Protocol 
No. CNRM-004 “Biorepository and Informatics Warehousing”, with Dr. Brian M. Cox as 
PI, will be coded using a Global Unique Identifier (GUID).  Access to specimens 
maintained by CNRM at the Biorepository is under the supervision of Dr. Cox.  An MTA 
is under negotiation between NINDS and DOD regarding the blood samples and data 
collected at NIH and stored at the CNRM Biorepository. Biorepository protocol (see 
Appendix H).   


 
 
33 
 
 
Blood samples will be stored in secured freezers at the CNRM Biorepository.  The 
subject’s name and identifying information will not be on the samples; we will assign 
them a code. The samples will be stored for up to 20 years. The purpose of the repository 
is to store a large number of samples and related data so that we can learn more about 
TBI and how to rehabilitate people who may have it. The CNRM is a Federal medical 
research program of the U.S. Department of Defense (DOD), and DOD is the custodian 
of the samples. The Uniformed Services University operates the CNRM and the USU 
IRB reviews the repository for patient protection and receives reports from a 
Biorepository Steering Committee on the operations of the repository. 
  
Dr. Eric Wassermann is responsible for samples at the NIH and until they are received at 
the CNRM Biorepository. Before sending blood samples, we will remove the subject’s 
name and identifying information; we will assign them a code. The key to the code will 
be kept in a separate, secure area. Once the coded samples arrive at the CNRM 
Biorepository, a repository manager will be responsible for maintaining the samples and 
sending them to others who may use the samples for research. Subject’s blood samples 
will only be accessible by current and future CNRM investigators after approval by all 
relevant IRBs.  
  
The investigators may share data including imaging data, with outside investigators or 
collaborators but only after all identifying information is removed.  The subject’s data, 
including imaging data, will be stored t the CNRM Image Processing Core database at 
NIH. These data may be used for a variety of research purposes including future genetic 
research that we may not be able to specify at this time.  
  
If a subject wishes to remove his samples, they may contact the principle investigator, Dr. 
Wassermann, in writing or verbally. If the samples are in the CNRM Biorepository, this 
person will notify the CNRM of the subject’s code and his samples and all associated 
data, including processed images, will be removed from the repository and related 
databases and destroyed.  
 
5.1.1 Data identifiers – GUID 
 
The CNRM Informatics Core is ultimately responsible for storing all de-identified data 
collected under this protocol on behalf of the DoD. Prior to the transfer of the de-
identified data from the PI to the CNRM data repository, the PI is responsible for the 
data.  The PI remains responsible for the identified data. The CNRM Informatics Core 
does not have access to identified data. 
 
The Informatics Core is led by a Principal Investigator, Yang Fann, PhD, who reports 
directly to the Informatics Core Steering Committee.  Data entry into the CNRM 
Informatics Core database will be limited to the PI of the Informatics Core, Dr. Yang 
Fann and database administrative staff.  The PI of the Informatics Core or a designated 
database administrator will be responsible for uploading data to the CNRM database. 
 


 
 
34 
 
All data will be coded (de-identified) by removing the 18 specific elements of protected 
health information (PHI) as defined within the HIPAA Privacy Rule including: 
 
1. Names. 
2. All geographic subdivisions smaller than a state, including street address, city, county, 
precinct, ZIP Code, and their equivalent geographical codes, except for the initial three 
digits of a ZIP Code if, according to the current publicly available data from the Bureau 
of the Census: 
a. The geographic unit formed by combining all ZIP Codes with the same three initial 
digits contains more than 20,000 people. 
b. The initial three digits of a ZIP Code for all such geographic units containing 20,000 or 
fewer people are changed to 000. 
3. All elements of dates (except year) for dates directly related to an individual, including 
birth date, admission date, discharge date, date of death; and all ages over 89 and all 
elements of dates (including year) indicative of such age, except that such ages and 
elements may be aggregated into a single category of age 90 or older. 
4. Telephone numbers. 
5. Facsimile numbers. 
6. Electronic mail addresses. 
7. Social security numbers. 
8. Medical record numbers. 
9. Health plan beneficiary numbers. 
10. Account numbers. 
11. Certificate/license numbers. 
12. Vehicle identifiers and serial numbers, including license plate numbers. 
13. Device identifiers and serial numbers. 
14. Web universal resource locators (URLs). 
15. Internet protocol (IP) address numbers. 
16. Biometric identifiers, including fingerprints and voiceprints. 
17. Full-face photographic images and any comparable images. 
18. Any other unique identifying number, characteristic, or code, unless otherwise 
permitted by the Privacy Rule for re-identification. 
 
Of these 18 elements, the only one that represents a key clinical/scientific value is the 
date-related fields.  In the coded (de-identified) data submissions, age will be reflected as 
years, as permitted.   
 
In order to de-identify the specimens, the CNRM Informatics Core will establish an 
encrypted system to generate a globally unique identifier (GUID) from PHI data.  The 
GUIDs approach was originally created for the National Database for Autism Research 
(NDAR) and the Simons Foundation Autism Research Initiative.  The GUID system of 
the CNRM was established in collaboration with the NDAR staff at the NIH Center for 
Information Technology, but operates independently of the existing NDAR GUID 
system, under the support of the CNRM Informatics Core.  The GUID is a computer-
generated alphanumeric code that is unique to each research participant and, through the 
use of a one-way hash algorithm, does not allow mapping back to an individual.  The 


 
 
35 
 
process of assigning a GUID keeps any personally identifying information from ever 
being transmitted or stored in the CNRM database and prevents such identifying 
information from appearing with the clinical data. 
   
5.2 Repository for Data  
 
The PI of this protocol will maintain master keys matching GUIDs to samples and data.  
Electronic master keys will be kept on password protected terminal(s) in locked rooms 
with limited access.  Electronic master key records will be backed up electronically at 
least weekly.  Physical printouts/copies of master keys will be kept in a locked cabinet in 
fire- and water-proof enclosures with controlled access and will be updated monthly or at 
more frequent intervals.  The mapping from PHI to GUID will not be stored by or known 
to the CNRM Informatics Core or NIH CIT personnel, but by the central registration of 
issued GUIDs and the protocol PI with the master keys.  
  
All specimens and data will be stored linked to this GUID.  CNRM master keys will 
contain the following information: GUID, last name, last 4 digits SSN, date of birth, 
and/or medical record number.  
 
The CNRM Biorepository will maintain a web-based Biorepository Information 
Management System. The system includes the following types of information: specimens 
received, specimens processed, method of specimen storage, method of specimen 
transport, contacts for specimen transport to specific studies, specimens distributed to 
other CNRM studies, as well as quality control information (acquisition of correct 
specimen, rapid specimen preservation, timely transportation to the Biorepository, routine 
and continuous monitoring). 
   
Access to data will only be available to the CNRM Biorepository Manager, PI on this 
protocol, or designated staff on this protocol. All data and samples under this protocol 
will be obtained in an identifying manner.  Once the specimens and pertinent clinical 
records or accompanying data are confirmed for quality care purposes, all specimens and 
data will be de-identified (coded)  (maintained/stored remotely) without protected health 
identifiers.  The PI of this protocol will maintain master keys, matching de-identified 
(coded) samples and data. We will act consistently with the HIPAA regulations. The 
CNRM Bioinformatics Repository will provide for the imaging and CTDB data to be 
periodically transferred to NIH CIT, where the data repository is to be housed.  All paper 
records regarding subjects will be kept in folders in locked, secure areas.  
 
5.3 Withdrawal and destruction of data and samples: Participants will be allowed to 
withdraw from the study at any point. The study investigators may also withdraw 
participants for medical, administrative or issues of noncompliance. If a participant 
withdraws voluntarily or is withdrawn from the study, any remaining unused samples 
and/or data identified as theirs will be destroyed at their request. If they do not request 
that their samples and data be withdrawn/destroyed, they will continue to be used in the 
analysis as applicable. 
 


 
 
36 
 
5.4 Repository for Samples   
 
The draft of MTA is in the process of being finalized. The samples belong to CNRM 
(collaboration between NIH and DOD) and will be stored at the CNRM Biorepository at 
12725 Twinbrook Parkway, Rockville, MD, 20852.   The draft is attached as Appendix 
E. 
 
6.  Additional Considerations 
 
 6.1 Research with Methylphenidate:  Investigational New Drug Exemption from FDA.  
FDA has granted an exemption from IND regulations for this study (see attached letter).  
The number is (TBD) (Appendix I) 
         
6.1.1 Source of methylphenidate and placebo storage and handling: 
The research pharmacists at the NIH research pharmacy will manufacture the 
methylphenidate (30 mg) so that they are without markings. The storage bottles will have 
child-proof caps. The NIH research pharmacists will be in charge of storing, 
randomizing, dispensing to study personnel, and destroying the study medication.  The 
study coordinator, research assistant, or investigator may retrieve the medication from the 
NIH pharmacy and deliver it to the physician investigator.  A licensed physician 
investigator listed in this protocol as having this privilege will dispense the study 
medication to subjects.  
 
6.1.2 Package Insert (Appendix B) 
 
6.2 Gene Therapy:  There is no gene therapy in this study.   
 
1. Risks/Discomforts  
 
7.1 The known risks and discomforts associated with the study procedures include the 
following: 
 
7.1.1 Blood Collection 
 
Subjects may experience minor discomfort associated with blood sampling. Minor 
bruising or infection may occur at the site of needle entry.  There is a very small risk of 
fainting during the procedure.  Standard phlebotomy procedures will be used, including 
seating the patient during the procedure and a short period of observation afterwards. 
 
7.1.2   MRI 
Subjects are at risk for injury from the MRI magnet if they have pacemakers or other 
implanted electrical devices, brain stimulators, some types of dental implants, aneurysm 
clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins 
and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery 


 
 
37 
 
pump, or shrapnel fragments. Welders and metal workers are also at risk for injury 
because of possible small metal fragments in the eye of which they may be unaware. 
Volunteers will be screened for these conditions before having an MRI, and if any are 
present, the MRI scan will not be performed.  Volunteers will be asked specifically about 
metal objects being present in their body. If it is unknown whether metal is present and or 
if there is any question, MRI will not be performed.  
 
Subjects with fear of confined spaces may become anxious during an MRI. Those with 
back problems may have back pain or discomfort from lying in the scanner.  The noise 
from the scanner is loud enough to damage hearing, especially in people who already 
have hearing loss.  
 
It is not known if MRI is completely safe for a developing fetus. Therefore, all women 
able to become pregnant will have a pregnancy test performed no more than 24 hours 
before each MRI scan. The scan will not be done if the pregnancy test is positive.  
 
Steps taken to minimize risks associated with MRI:   
Potential participants will be screened for safety by the Imaging Center tech using the 
NIH screening checklist prior to each MRI.   
 
During the MRI and PET scans, monitoring equipment (blood pressure, oxygen 
saturation and/or heart monitoring) will be utilized as medically indicated, and the subject 
can be observed directly through a window between two rooms or via closed circuit 
television.  In addition, audible communication between the patient and the scanning 
personnel is possible via intercom.  Subjects can be removed from the scanner 
immediately upon request or in case of medical necessity.  
All subjects having a research MRI will be fitted with hearing protection.  
Pregnant women are excluded from this study. 
 
7.1.3 Neuropsychological Testing 
 
There are no known risks to participants answering questions about distress, pain, fatigue, 
depression or anxiety.  Possible adverse experiences include mild psychological distress 
or discomfort by rating one’s distress or boredom from answering questions.   
 
Steps taken to minimize risk:  Prior to testing, the investigator administering the tests will 
encourage subjects to try their best, remind them that no one performs perfectly on these 
tests, and that the tests may be stopped at any time and for any reason.  If a participant 
becomes emotionally distressed while completing any of the instruments, they will be 
informed that they may postpone or stop the procedure and decline participation 
altogether.  
 
The psychological measures will be monitored by the investigator after administration for 
clinically significant symptoms.  If a participant discloses information during completion 
of the assessment form that suggests a danger to themselves or others, or suggests a need 
for psychiatric intervention, the PI will be notified and will offer referral as appropriate 


 
 
38 
 
for psychiatric or other evaluation with a clinician and/or for psychiatric assistance with a 
provider in their home community together with follow-up by telephone to assure that 
psychiatric intervention was obtained.  Moreover, should the questionnaires in this study 
raise issues a participant would like to discuss further, the PI will be available to him or 
her.   
 
7.2 Risks associated with methylphenidate 
 
Nervousness and insomnia are the most common adverse reactions but are usually 
controlled by reducing dosage and omitting the drug in the afternoon or evening.  
Other reactions include: hypersensitivity (including skin rash, urticaria, fever, arthralgia, 
exfoliative dermatitis, erythema multiforme with histopathological findings of 
necrotizing vasculitis, and thrombocytopenic purpura); anorexia; nausea; dizziness; 
palpitations; headache; dyskinesia; drowsiness; blood pressure and pulse changes, both 
up and down; tachycardia; angina; cardiac arrhythmia; abdominal pain; weight loss 
during prolonged therapy.  
 
There have been rare reports of Tourette’s syndrome. Toxic psychosis has been reported. 
Although a definite causal relationship has not been established, the following have been 
reported in patients taking this drug: instances of abnormal liver function, ranging from 
transaminase elevation to hepatic coma; isolated cases of cerebral arteritis and/or 
occlusion; leukopenia and/or anemia; transient depressed mood; aggressive behavior; a 
few instances of scalp hair loss. There are very rare reports of neuroleptic malignant 
syndrome (NMS), and, in most of these, patients were concurrently receiving therapies 
associated with NMS. 
 
Table 5 lists adverse effects reported in a temporal relationship using methylphenidate 
during the post-marketing experience. Frenette 8 evaluated the safety of methylphenidate 
used for severe TBI in 14 randomized controlled trials and the following side effects were 
reported:  
 
Table 5. Evaluation of Safety and Side Effects of MPH in patients with severe 
TBI (adapted from 8): 
  
Side effects 
Number 
of events 
Studies 
Comments 
Rash/itching 
 
 
5 
 
Alban et al., 
200426. 
 
Seizures 
2 
 
Moein et al., 
2006 27. 
 
Delirium/ confusion/ 
hallucinations 
4 
 
Alban et al., 2004 26, 
27 
 
Hemodynamic 
changes 
? 
 
 
Lee et al., 200528, 
Alban et al.,2004 26,  
Moein et al., 
200627. 
Statistically more prevalent 
than with placebo (p < 0.05) 
(Moein et al., 200627, Alban 
et al., 200426). 
Dizziness/ 
lightheadedness 
2 
1 patient withdrawn 
because of 
lightheadedness 
 


 
 
39 
 
and 1 patient 
withdrawn because 
of dizziness (Whyte 
et al., 2008). 
Diarrhea/ 
constipation 
2 
 
  
 
Alban et al., 
200426. 
 
 
Nausea/vomiting 
2? 
 
 
Alban et al., 
2004;26  
Lee 
et al 200528. 
 
Headache 
? 
Plenger et al., 
199629. 
 
Anxiety 
7 
 
 
 
Plenger et al.,1996 29 
Alban et al., 200426. 
 
Tremors 
4 
 
 
 
Alban et al.,200426. 
 
Sleep disorder/ 
drowsiness 
12 
 
 
 
Alban et al.,200426. 
Statistically more prevalent 
than with placebo 
(p < 0.05) (Alban et al., 
2004)26. 
Others 
4 Irritability;  
11 reduction in appetite; 
2 difficulty in urinating; 
2 blurred vision; 
6 dry mouth; 
2 weakness; 
1 sexual disability 
Alban et al., 
200426, 
Willmott 
et al., 200930. 
Irritability and 
reduction in appetite 
statistically more 
prevalent than with 
placebo. 
 
 
 
Steps taken to minimize risks of methylphenidate:   
 
There will be a telephone follow-up 2 weeks after Visit #2 with all participants. 
Instructions with methylphenidate dosage will be given, as described in 4.4.7, to 
participants experiencing adverse events. Telephone follow-up and clinic visits will give 
physician investigators an opportunity to interface with participants.  Participants will be 
instructed to call 911 or go to the nearest emergency room in the event of a serious 
symptom that requires immediate medical attention.   Investigators will carry a pager and 
will be available to the study participants for questions or concerns about side effects that 
are not judged to be emergencies. 
 
Study participants will be cautioned against taking medications that may have possible 
adverse interactions with methylphenidate. Licensed physician/investigators may 
prescribe medication for headache or other minor side effects.  Otherwise, patients will 
be instructed to seek medical attention from their personal physician. 
 
Emergency medical problems will be managed by the NIH Rapid Response Team or the 
Code Blue Team. Participants will be evaluated and can be admitted to 7SWN Neurology 
Unit, or 3SWS Intensive Care Unit, as needed, under circumstances including, but not 
limited to: 


 
 
40 
 
•Seizure 
•Severe psychiatric symptoms, such as anxiety, akathisia, psychosis 
•Any other unforeseen complication requiring acute medical stabilization 
 
Care will be provided until the subject is stable, can continue research participation or 
until care can be transferred to the subject’s own health care providers. For medical 
problems or conditions that occur outside the NIH Clinical Center, participants will need 
to seek care and treatment from their primary care physician or a local emergency room. 
 
To prevent risks of methylphenidate on the fetus, sexually active women who are able to 
become pregnant must agree to use an effective method of contraception as stated at 11.6 
of the protocol.  In addition, women able to become pregnant will have pregnancy tests 
done before PET, MRI and TMS.  
 
7.3 Risks of review of records  
 
Subjects may be at risk if medical record data are released or viewed by individuals not 
associated with this research study.  IRB-approved investigators will review all subject 
data only and information obtained for research purposes will be stored in locked offices 
as described in Section 19, “Confidentiality”.  
 
7.4 Risks of sharing research data  
 
Samples and data provided to the CNRM Repository, which is operated under USUHS 
Protocol No. CNRM-004 “Biorepository and Informatics Warehousing”, Dr. Brian M. 
Cox, PI will be coded using a Global Unique Identifier (GUID) derived from PII and 
generated locally.  Re-identification of data and samples collected at the NIH would be 
possible if repository data and samples are released with the GUID to other CNRM 
investigators who have access to the same subjects PII through participation in other IRB 
approved studies as they will generate the same GUID at their site.  Re-identification is 
unlikely, however, as the CNRM Repository intends in most cases to release data and 
samples without the GUID. 
 
Steps taken to minimize risks of breach of confidentiality of records or data: 
The following measures will be made to minimize foreseeable risks: 
• All research procedures will be conducted by staff qualified to perform the procedure 
and with monitoring as defined in sections 8 and 11. 
• Confidentiality will be protected as described in Section 19. 
• Use of subject data that is re-identified through PHI used to generate a GUID is 
permitted only under IRB approved protocols with pre-defined research questions.  
 
 
 
 
 
 


 
 
41 
 
7.5 Risk of TMS  
 
There is an extremely small but existent possibility of a seizure during TMS. The danger 
is even lower with non-repetitive single or paired pulse TMS (<1 Hz), as in this study. 
Extensive use in our laboratory has not resulted in any difficulties with the device that 
could pose a hazard to healthy volunteers or patients. TMS can lead to hearing loss in 
experimental animals by means of the click produced by the stimulating coil when the 
inducing current is passed through it. However, we found no evidence of chronic hearing 
loss in several of our normal subjects who were extensively studied with TMS, nor did 
we find transient changes in several subjects tested before, and immediately after, 
stimulation. TMS does not appear to pose any hazard to the brain beyond that of electric 
stimulation, which has been in clinical use for decades. The procedure appears to be safe 
and without any side effects. Some of the original subjects have been stimulated many 
thousands of times. The World Health Organization task group and the Food and Drug 
Administration concluded that brief exposure to static magnetic fields up to 2 Tesla 
would have no adverse effects on human health. Currently available single pulse or 
bistim module stimulators do not produce thermal damage to tissues. No significant 
changes could be documented in cortisol or prolactin levels after TMS. After studying 
thousands of patients world-wide, only 3 seizures were reported that were possibly 
related to single-pulse TMS. These occurred in patients with underlying epileptogenic 
brain lesions. The only known transient side effect is headache, which usually fades over 
a few hours and responds well to non-steroidal anti-inflammatory drugs. 
 
7.6 Risk of PET  
 
Radiation exposure during the PET scan: This research study involves exposure to 
radiation from 2 PET scans that use a total of 20 mCi X 2 (40 mCi). 
of the [11C]raclopride, plus a small amount of radiation from the transmission scan done 
to calibrate the scanner. The amount of radiation subjects will receive in this study is 1.0 
rem which is below the guideline of 5 rem per year allowed for research subjects by the 
NIH Radiation Safety Committee. The average person in the United States receives a 
radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, 
and the earth's air and soil. While there is no direct evidence that the amount of exposure 
received from participating in this study is harmful, there is indirect evidence it may not 
be completely safe. There may be a very slight increase in the risk of cancer.  
 
Risks of intravenous catheterization: Subjects may experience minor discomfort 
associated with intravenous catheterizations. Minor bruising or infection may occur at the 
site of needle entry.  There is a very small risk of fainting during the procedure.  Standard 
procedures will be used, including seating the patient during the procedure and a short 
period of observation afterwards. There is no known allergy to raclopride.  
 
 
 
 


 
 
42 
 
8.  Subject Safety Monitoring  
 
8.1 Monitor for individual subjects during participation in study procedures   
 
Physicians and study staff in this study will monitor subjects throughout the protocol 
procedures. Physicians and study coordinator or other research staff member will be with 
the participant and will monitor for any anxiety and will assess any issues that arise such 
as suicide ideation.  Procedures are done at the NIH Clinical Center and medical 
emergency services are available to participants in this study, if needed. 
 
The study coordinator or research assistant and MRI technician will be present during all 
MRI and PET procedures.  A study physician will be available by telephone and pager. 
The study coordinator or research assistant will monitor adverse effects from a single 
dose of 60 mg methylphenidate administered during either the PET or TMS session.  
 
Additionally, the coordinator or research assistant will contact all participants three times 
by telephone during four weeks of interventional phase of the study, to inquire about 
possible adverse effects and review the Symptoms Checklist.  Women able to become 
pregnant will have pregnancy tests at each clinic visit. 
Participants remain under the care of their own physicians during participation in this 
study. Any adverse events reported to their own physicians will be recorded.  
 
8.2 Parameters to be monitored   
 
Physiological side effects (adverse events) of study medication will be monitored in this 
study. Medication administration compliance will also be monitored.  
 
8.3 Toxicity 
 
Signs and symptoms of acute overdosage, resulting principally from overstimulation of 
the central nervous system and from excessive sympathomimetic effects, may include the 
following: vomiting, agitation, tremors, hyperreflexia, muscle twitching, convulsions 
(may be followed by coma), euphoria, confusion, hallucinations, delirium, sweating, 
flushing, headache, hyperpyrexia, tachycardia, palpitations, cardiac arrhythmias, 
hypertension, mydriasis, and dryness of mucous membranes. 
 
Treatment consists of appropriate supportive measures. The patient will be protected 
against self-injury and against external stimuli that would aggravate overstimulation 
already present. Gastric contents may be evacuated by gastric lavage. In the presence of 
severe intoxication, a carefully titrated dosage of a short-acting barbiturate will be used 
before performing gastric lavage. Other measures to detoxify the gut include 
administration of activated charcoal. Intensive care will be provided to maintain adequate 
circulation and respiratory exchange; external cooling procedures may be required for 
hyperpyrexia. 
 
 


 
 
43 
 
8.4 Criteria for Stopping Procedures in an Individual 
 
Participants will be instructed that if they develop adverse effects from the study drug 
(either methylphenidate or placebo) they are to call the study coordinator to report and 
document the adverse effects.  If the participants will have specific adverse events listed 
in Table 6, the actions will be taken according to the plan below. 
 
Table 6.  Adverse events and criteria for stopping methylphenidate and for reducing the 
dosage (stable phase)  
 
Adverse events 
Action plan 
 
Nervousness and insomnia  
Reduce dosage by half. If symptoms resolve, 
restart the drug in the minimal dose which did 
not result in adverse events during the 
escalation phase. If the symptom persists, 
discontinue the drug. 
Weight loss 
Reduce dosage by half If symptoms resolve, 
restart the drug in the minimal dose which did 
not result in adverse events during the 
escalation phase.  If the symptom persists, 
discontinue the drug. 
Anorexia; nausea; dizziness; palpitations; 
headache, drowsiness 
Reduce dosage by half. If the symptom persists, 
discontinue the drug 
Blood pressure and pulse changes, both up and 
down, defined as:  
1) Increase or decrease of systolic or diastolic 
blood pressure registered on 3 measurements 
on two separate days by 10 mm Hg  
2) or increase of BP over 140/90 mm Hg or 
decrease below 80/60 mm Hg on 3 
measurements on 2 separate days  
Tachycardia defined as increase of heart rate to 
100  or more beats per minute when a person is 
at rest  
Bradycardia defined as decrease of resting 
heart rate below 50 beats per minute 
  
Reduce dosage by half. If the symptom persists, 
discontinue the drug 
Hypersensitivity (skin rash, urticaria, fever, 
arthralgia, exfoliative dermatitis, erythema 
multiforme, and thrombocytopenic purpura) 
Discontinue the drug 
Angina; cardiac arrhythmia; abdominal pain 
Discontinue the drug 
Dyskinesia, Tourette’s syndrome, toxic 
psychosis  
Discontinue the drug 
Abnormal liver function (transaminase 
elevation) defined as increase of ALT > 3 X 
Discontinue the drug 


 
 
44 
 
upper limit of normal ( > 123 U/L for  NIH 
CC) 
Cerebral arteritis and/or occlusion 
Discontinue the drug 
Leukopenia and/or anemia 
Discontinue the drug 
Transient depressed mood,  aggressive 
behavior  
Discontinue the drug 
Scalp hair loss 
Discontinue the drug 
 
If study participants will have other adverse effects, which in the opinion of the 
participant, the investigator, or the participant’s physician are sufficiently bothersome to 
lead to discontinuation, the participant will be asked to discontinue the study drug for 3 
days. If the adverse event resolves within three days and there is ambiguity about the 
causal relationship and the adverse event and the study drug and the adverse event is 
minor in the judgment of study physician then we may attempt to restart therapy.  If the 
adverse effect disappears with discontinuation of the drug and reappears upon its 
reintroduction, it will be determined that it is definitely related to the study medication.  
Participants will then be asked to discontinue the medication, but to remain in the study 
and return for all scheduled study visits. Data analysis will be carried out under intention-
to-treat principles. If it is discovered that a woman is pregnant who has been taking study 
medication, we will stop medication.  She will be followed for the remainder of the study 
and will be referred to her physician for further follow-up.  This will be reported to the 
IRBs of record. 
 
 
8.5 Subject Withdrawal  
 
Participants may withdraw from this study for any reason and at any time without 
penalty. Participants who elect to withdraw from all study procedures will be asked to 
return the unused medications and will be terminated from the study.   
 
Subjects will be allowed to withdraw from participation in the study at any point without 
adversely affecting their medical management.  Subjects may decline some of the 
procedures and tests and still participate in this research study.  The investigators may 
also withdraw subjects from the study for medical, administrative or issues of non-
compliance.  If subjects withdraw, any remaining unused samples that can be identified 
as theirs will be discarded.  Subjects will be offered the opportunity to withdraw their 
data from the study.   
  
 
 
 
 
 
 
 


 
 
45 
 
9. Outcome measures   
 
Outcome measures will be neuropsychological tests of CDE (1-8) and tests of various 
aspects of attention 6 (9-12). These tests will be administered twice, at the visit 2 initial 
and after 4 weeks of methylphenidate therapy.  
 
1. Glasgow Outcome Scale-Extended (GOS-E) 
2. Learning trials portion of the California Verbal Learning Test (CVLT-II):  
3. The Trail Making Tests A and B (TMT) 
4. Subsets of the Wechsler Adult Intelligence Scale (WAIS-IV) (Digit Symbol and 
Symbol Search) 
5. BSI-18 
6. Satisfaction with Life Scale (SWLS)  
7. Word Reading subtest of Wide Range Achievement Test (WRAT)-4  
8. Rivermead Post-Concussion Symptom Questionnaire 
9. The Conners Continuous Performance Test  
10. Sea Shore Rhythm Test (HRNB)  
11. Flanker Inhibitory Control and Attention Test 
12. Pattern Comparison Processing Speed Test 
 
 
10.  Statistical Analysis 
 
10.1 Analysis of Data for Primary Objective Primary Hypothesis: Tonic DA release 
(ΔBPND) will be associated with improvement over 4 weeks (i.e., patients with higher 
tonic DA release will demonstrate greater improvement in processing speed), 
independent of baseline DA D2/DR receptor binding.  Spearman correlation analysis will 
be used to evaluate relationship of ΔBPND in the striatum and the processing speed. 
Regression analysis will be used to analyze relationship of tonic DA release in in 
additional anatomical structures (caudate, putamen, and PFC ROIs) (left and right sides 
will be averaged) to the processing speed as a primary outcome measure.  
 
The primary objective is to assess the relationship between tonic DA release and change 
in processing speed after 4 weeks of treatment with oral methylphenidate. The primary 
endpoint of the study will be change of processing speed. Change of processing speed 
will be measured separately by WAIS-IV Processing Speed Index (PSI) and by the 
Processing Speed (Pattern Comparison Processing Speed Test) and will be used as a 
composite derived as an average of two scores.  NIH tool box tests have not been 
validated in TBI which justifies use of the composite and individual measures of 
processing speed.  We will use individual and composite scores for assessing processing 
speed.  
 
The primary outcome is change in information processing speed during neuropsychologic 
testing.   


 
 
46 
 
During data review, it was noted that the PSI was not administered to five subjects 
because of an error in the list of tests the neuropsychology technicians were using.  
The Toolbox PS was not administered to one subject.  The Conners CPT was not 
administered to one subject due to a technical problem with the computer used for 
the test.  Six subjects were affected. 
Due to this oversight, half of the primary neurocognitive outcomes were not 
collected on 6 out of the 11 subjects we tested.  
 
We propose to use a subset of the tests which have already been administered to 
most of the enrolled participants for our outcome analysis.  The Conners Continuous 
Performance (CPT) test and Toolbox Processing Speed were administered to 10 out 
of 11 currently enrolled subjects.  
 
Conners CPT was recently tested on military veterans with an average age of 35 
years and average education of 14 years, which corresponds to the population in 
our study31.  The military test results showed good sensitivity of Conners CPT for 
memory problems and good ability to discriminate individuals with decreased 
attention32.  
The Toolbox Pattern Comparison Processing Speed Test was successfully tested on 
4,859 participants33: the study found that it is appropriate for use in the age cohort 
of participants in our study and the test has good test-retest and discriminant 
validity.   
Therefore, we propose to use the Conners CPT and Toolbox Processing Speed Test 
as outcome measures for measurements of processing speed and attention in this 
study.   This will allow us to use the data already collected from our patients with 
confidence that these measures will allow us to reach our outcome goals. 
 
Analysis plan: 
1.  We plan to analyze outcomes of all (enrolled and planned) participants using 
Toolbox Pattern Comparison Processing Speed Processing Speed and the Conners 
CPT. 
2.  We will continue to collect all outcome measures of processing speed for all 
future participants when the study is once again open to recruitment.  
3. After we complete data collection, we plan to conduct data analysis including the 
4 outcome measures of processing speed on the subset of participants who have all 
data collected.  
 
 
 
10.2 Power Analysis for Primary Objective. 
The change in processing speed over 4 weeks of methylphenidate therapy will be 
correlated using Spearman’s non-parametric test to ∆BPND, a measure of tonic DA 
release.  We hypothesize that there will be a positive correlation between the change 
(improvement) in processing speed and both the level of baseline DA receptor binding as 
well as with tonic DA release, but that the correlation will be stronger with the latter. 


 
 
47 
 
With a sample size of 30, power = 0.80, alpha = 0.05, the study is powered to detect a 
correlation coefficient of 0.45.  This is considered a medium correlation, and is lower 
than the correlation of 0.55 found in the study on ADHD by Dr. Volkow et al 11. Power 
calculations 
done 
using 
web-based 
calculator 
found 
at: 
www.stattools.net/SSizcorr_Pgm.php. 
 
The third and fourth secondary hypotheses are purely exploratory and there are 
insufficient preliminary data to allow a power calculation.   
 
We initially excluded participants with BMI > 30 because of potential uncertainty about 
how obesity and overweight might affect dopamine receptor availability for binding 
raclopride. Then we increased the allowable maximum body mass index (BMI) from 30 
to 40 in the exclusion criteria. The study is unlikely to have the statistical power to use 
BMI as an independent variable.   
 
The initial sample size for the study was calculated based on a similar study 
conducted by Volkow (Volkow et al., 2001).  That study measured the correlation 
between dopamine release (as measured by 11C-raclopride PET) and improvement 
in attention tests after methylphenidate treatment and found a significant 
correlation with R = 0.55.  Initially, for the current study we calculated a sample size 
of 30 using a more conservative correlation of 0.45.  Based on this sample size 
calculation, we received funding from CNRM to enroll 30 patients.  
 
During implementation of the protocol it was noticed that the attention tests which 
represent the main outcome of the study were inadvertently not collected on 6 of 11 
patients, diminishing the number of subjects available for analysis of the main study 
outcome.   This was reported to the IRB as Problem Report III (submitted 
07/08/2015).   
 
Furthermore, after one year of the study the charges for PET studies which were 
significantly more than anticipated. The study is funded by CNRM, and funding was 
allocated for 30 scans ($4000 each) or $120,000 for the study. In August 2015 the 
project was billed for the first time at $164,877.07 for 46 PET studies.   Our study 
team was not aware that the PET Department only sends out a single annual bill and 
charges for all reserved PET time slots, even when a slot is canceled over 2 weeks in 
advance.  While we anticipate receiving additional funding to allow us to complete 
the study, we feel it is judicious to recalculate the sample size based on the results of 
the original 11 patients enrolled regarding the correlation between dopamine 
release and improvement in attention scores.   
 
We intentionally used conservative assumptions to initially calculate the sample 
size.  After consultation with the USUHS statistician, Dr. Cara Olsen, the sample size 
can be less conservative and if we assume the same correlation as found in the study 
by Volkow.  Using 0.55, 22 patients will be sufficient to test our hypothesis 
demonstrating a relationship between dopamine release and change in processing 
speed after methylphenidate treatment.   


 
 
48 
 
 
We additionally elected to do an interim analysis of the data collected to obtain 
further support use of the 0.55 correlation as a basis for the power calculation.   Of 
11 participants enrolled in the study, 2 did not complete methylphenidate treatment 
due to adverse events, and one subject was not administered one of the 
neurocognitive tests.  Data on 8 participants were available for analysis. We 
measured non-displaceable binding potential (BPND) before and after 
administration of 60 mg methylphenidate (MP) in the ventral striatum (VS) as the 
change in BPND after administration of MP (BPND) is used as a measure of 
dopamine (DA) release.   We selected 10 areas in the VS with maximal DA release and 
correlated DA release in each ROI with improvement of attention measured by the 
cognitive outcome measure, the Connors CPT. Per consultation with Dr. Dsurney, a 
CNRM Neuropsychology Director, a variable Detectability can be selected as the 
representative outcome.  We used Fisher's z Test for Pearson Correlation and SAS 
program for sample size calculation.  The Pearson correlation between DA release in 10 
ROIs and change in Detectability was determined as r=0.56036 (0.1039) (mean (SD)) and 
with range (0.8043-0.4646). This is very close to the value reported by Volkow et al. 
With r=0.56 and alfa=0.05 and power 0.8, 22 patients will be a sufficient sample size for 
our study.   
 
Therefore, our interim data analysis supports the use of correlation r=0.55 as 
originally used in the study by Dr. Volkow and that it can be applied to the sample 
size calculation for the current study.  
 
11. 
Human Subjects Protection 
 
11.1 Subject selection:  Selection equitability:  Subject selection will be equitable.  
Participants will be recruited from Walter Reed National Military Medical Center 
(WRNMMC), National Institutes of Health Clinical Center (NIH CC), CNRM 
Phenotyping Core, CNRM Recruitment Core, regional Veterans Affairs (VA) hospitals, 
and the National Intrepid Center of Excellence (NiCOE).  Subject selection will be 
equitable. This study allows adults up to age 55 because after that age the incidence of 
age-related cardiovascular disease significantly increases, potentially confounding 
results. The racial and ethnic distribution will reflect those of the clinical population 
affected by TBI in the military as well as in civilian populations.  No preference or 
exclusion will be granted according to gender or ethnic/racial background.  We anticipate 
that approximately 90% of the subjects will be male, because recruitment will include 
military individuals.  
 
11.2  Justification for exclusion of children: Participants younger than 18 are not included 
because some of the neuropsychometric measures included in the CDE battery used in 
this study are not normed for children under age 18. There is no sufficient information 
how methylphenidate may affect development and recovery of children’s brain after TBI.   
 


 
 
49 
 
11.3 Justification for the exclusion of vulnerable populations:  pregnant women, mentally 
ill, and cognitively impaired subjects. We are uncertain whether methylphenidate, PET, 
MRI or TMS  are  safe for a pregnant woman or a fetus; thus, pregnant women are 
excluded from this research study cognitively impaired subjects are excluded because 
they would not be able to consent for themselves, follow instructions, complete the 
neurocognitive measures, and be responsible for study medication. Potential participants 
with mental illness sufficiently severe to impair their ability to provide informed consent 
will be excluded. 
 
 
11.4   Justification for sensitive procedures: use of placebo 
This trial uses placebo crossover design, but only for PET imaging and for TMS. All 
participants will receive the active drug during the 4-week administration phase. 
 
11.5   Justification for exclusion of non-English speaking subject: Non-English speakers 
will be excluded because the neuropsychological assessment instruments we are using are 
not all validated or normed in other languages.  Furthermore, many of the tests we are 
performing would require a native-speaking psychometrist to administer; such an 
individual is not available.   
 
11.6 Safeguards for Vulnerable Subjects: Given the morbidity common in symptomatic 
chronic TBI, we anticipate that several medical or psychiatric complications might arise 
during the course of the study visits.  Participants who exhibit psychiatric complications 
will then undergo a structured interview by a qualified on-site professional and referred 
for appropriate medical care by their clinical care provider. Other emergent psychiatric 
evaluation and treatment will be performed under the guidance of the NIMH Psychiatry 
Consultation Service. 
11.7 Justification for exclusion of NIH Employees 
 
We do not anticipate that NIH employees would be eligible for this study because they 
would be unlikely to fulfill the inclusion criteria of having a TBI with persistent memory 
and attention problems and significant impairment of social and/or occupational 
functioning and be employed full time at NIH.  Further, the study procedures are time-
consuming and are carried out during office hours over a few days’ time.  This would 
require NIH employees to take 3 or 4 days of leave to participate and this would further 
decrease the likelihood of their participation. 
 
Prior to any PET or MRI scan, urine specimens will be collected and pregnancy tests will 
be performed on women of child bearing potential. Subjects with positive pregnancy tests 
will not undergo MRI. Contraception is required for women able to become pregnant as 
stated at 11.6 of the protocol.  
 
Emergency medical problems will be managed by the NIH Rapid Response Team or the 
Code Blue Team. Participants will be evaluated and can be admitted to 7SWN Neurology 
Unit, or 3SWS Intensive Care Unit, as needed, under circumstances including, but not 
limited to: 


 
 
50 
 
•Seizure 
•Severe psychiatric symptoms, such as anxiety, akathisia, psychosis 
•Any other unforeseen complication requiring acute medical stabilization. 
 
Care will be provided until the subject is stable, can continue research participation or 
until care can be transferred to the subject’s own health care providers. 
For medical problems or conditions that occur outside of the NIH Clinical Center, 
participants will need to seek care and treatment from their primary care physician or a 
local emergency room. 
 
Contraception requirement for females able to become pregnant 
   
Women able to become pregnant will be required to have a pregnancy test at each clinic 
visit.  Sexually active women who are able to become pregnant must agree to use an 
effective method of contraception (birth control) from the time they enroll in the study 
until 2 weeks after they have completed taking the study drug, methylphenidate or 
placebo. 
Effective methods of contraception for this study include: 
1. hormonal contraception (birth control pills, injected hormones or vaginal ring)  
2. intrauterine device 
3. barrier methods (condom or diaphragm) combined with spermicide.  
4. surgical sterilization (hysterectomy, tubal ligation, or vasectomy in a partner. 
 
It will be explained to them that it is important to know that no method of birth control is 
totally effective in preventing pregnancy except for surgical sterilization (hysterectomy or 
tubal ligation for women and vasectomy for men) and total abstinence from sexual 
relations. 
 
If it is discovered that a woman is pregnant who has been taking study medication, we 
will stop medication.  She will be followed for the remainder of the study and will be 
referred to her physician for further follow-up.  This will be reported to the IRBs of 
record. 
Rationale for BMI>40 exclusion 
In the study we initially excluded participants with BMI > 30 because of potential 
uncertainty about how obesity and overweight might affect dopamine receptor 
availability for binding raclopride.  Our concern came from a study of Volkow et al.341 in 
obese people with BMI 42-60 (mean 51), compared to subjects with BMI 21-28 (mean 
25).  They found that dopamine receptor availability was decreased in proportion to BMI 
in the obese participants.   
 
Now, however, we are finding that BMI in the 30-40 range is quite prevalent in the 
moderate TBI population we are targeting for recruitment.  Weight loss, while desirable, 
is not possible on the timescale required for participation and this criterion is proving a 
significant barrier to recruitment.  We note the complexity of the study and the fact that 
most of our subjects are employed and many have family responsibilities, in addition to 
the burdens imposed by their injuries.  While dopamine receptor availability at baseline 


 
 
51 
 
or the change with methylphenidate administration could still differ in our study group 
under a liberalized BMI exclusion threshold, there are no data to suggest this in the 
literature. 
 
11.7 Qualifications of Investigators 
 
The Principal Investigator (PI) and associate investigators (AIs) have extensive 
experience as investigators in acute brain injury including traumatic brain injury, stroke, 
epilepsy, and Alzheimer’s disease, including investigational drug trials.  Physicians and 
clinical investigators will obtain informed consent for this protocol.   Trained study 
investigators will perform medical records data collection and assessment scales. 
 
The specific qualifications of individual investigators are as follows: 
 
Principal Investigator:  Eric Wassermann, MD, is a neurologist experienced in 
traumatic brain injury and neuroimaging.  He is head of the NINDS Behavioral 
Neurology Unit.  He will manage and oversee the safety issues of the study, perform 
physical examinations, determine patient eligibility, obtain informed consent, and 
respond to patients who call with problems resulting from the study medication. Dr. 
Wassermann will implement TMS for study participants and may participate in all 
aspects of the study. 
 
Adjunct Principal Investigator:  Ramon Diaz-Arrastia, MD, PhD is a neurologist with 
more than 20 years of experience in clinical practice and research.  He has been a PI for 
several NIH- and industry-sponsored clinical trials. Dr. Diaz-Arrastia will assist Dr. 
Wassermann in study management, interview and examine patients, determine patient 
eligibility, collect blood samples, obtain informed consent, participate in all aspects of the 
study, and respond to patients who call with problems regarding the study medication. 
 
Associate Investigators: 
 
Nora Volkow, MD, is the director of NIDA. Dr. Volkow has extensive experience in 
using dopamine agonists in various clinical studies and in use of PET.  She will 
participate in designing and implementing PET imaging studies, methylphenidate 
administration schedule and dosage, and determining biomarker measurements.   
 
 
Peter Herscovitch, MD, is the director of the PET department. He will oversee all 
procedures related to PET imaging.  
 
Tanya Bogoslovsky, MD, is a senior staff scientist at CNRM. She will participate in 
study design, all aspects of protocol preparation and implementation.  
 
 
John Butman, MD, is the PI of the CNRM Human Image Analysis core, as well as Staff 
Neuroradiologist at the NIH Clinical Center.  He will assist with all aspects of the MRI 
and other data analysis. 
 


 
 
52 
 
Dzung Pham, PhD, is the director of the Image Processing Core for CNRM. Dr. Pham 
will assist with all aspects of the MRI and other data analysis. 
 
John Dsurney, PhD, clinical psychologist, is experienced in clinical trials and will 
oversee implementing the neuropsychological tests to the study participants and will 
review and comment on the findings.   
 
Yunhua Gong, MD, will process and assay plasma and serum biomarkers.  He will also 
be responsible for the functional and immunological and other laboratory work.  
 
Bao-Xi Qu, MD, will process the blood samples and assay the plasma and serum 
biomarkers. He will also be responsible for the functional and immunological assays and 
other laboratory work.  
  
Kimbra Kenney, MD, is a board-certified neurologist, and Assistant Professor of 
Neurology at USUHS.  Dr. Kenney’s role in this project will be to assist Dr. Diaz-
Arrastia with patient interviews, obtain consent, blood sample collection, and 
neurological and physical examinations. She will also respond to patients who call with 
questions or concerns about the study medication. 
 
Carol Moore, MA, CCRC, will screen, schedule, interview, and follow-up with patients.  
She will complete case report forms, manage the study, report all types of adverse events. 
Ms. Moore may also process blood samples in the laboratory. 
 
Christian Shenouda, MD, will interview and examine patients, determine patient 
eligibility, collect blood samples, obtain informed consent, participate in all aspects of the 
study, and respond to patients who call with problems regarding the study medication. 
 
Franck Amyot, PhD, is a Research Fellow with the CNRM under Dr. Diaz-Arrastia.  His 
responsibility will be to analyze MRI data and write papers. 
 
Michael Tierney, MA, NINDS (National Institute of Neurological Disorders and Stroke), 
will perform TMS studies and does not obtain informed consent. 
 
 
Philip Koshy, BA, NINDS (National Institute of Neurological Disorders and Stroke), will 
perform TMS, he does not obtain informed consent. 
 
Lisa Christine Turtzo, MD, PhD.  Dr. Turtzo is a board-certified neurologist, and Adjunct 
Assistant Professor of Neurology at USUHS.  Dr. Turtzo’s role in this project will be to 
assist Dr. Diaz-Arrastia with the patient interviews, obtain consent, blood sample 
collection, and neurological and physical examinations. She will also respond to patients 
who call with questions or concerns about the study medication. 
 
Kris M. Knutson, PhD, NINDS, will analyze MRI and PET data. She will not obtain 
informed consent. 


 
 
53 
 
  
Erica Silverman, BS, CNRM will screen, schedule, interview, and follow-up with 
patients.  She will complete case report forms, report AE’s and SAE’s. She will not 
obtain informed consent. 
 
 
 
 
Listed below are those individuals allowed to obtain consent: 
 
Eric Wassermann, MD 
 
Ramon Diaz-Arrastia, MD 
 
Kimbra Kenney, MD 
 
Christian Shenouda, MD   
 
Lisa Christine Turtzo, MD, PhD. 
 
 
 
 
12 Anticipated Benefits  
 
12.1 Direct Benefit 
This study does not offer direct benefit to participants.  
 
12.2 Indirect Benefit 
The information we gain from this study may help us more effectively diagnose and treat 
subjects with TBI in the future.  Participants may indirectly benefit from administration 
of methylphenidate, and that information may be of value in seeking medical care from 
their primary care physicians.   
13.  Classification of Risk 
 
This protocol is classified as a more than minimal risk study due to the use of 
methylphenidate and administration of [11C]-raclopride before PET.  Risk is reasonable 
in relation to anticipated benefit. 
14.  Consent Documents and Process 
14.1 Designation of those obtaining consent:  Study investigators designated as able to 
obtain consent in section 11.6 above, will obtain informed consent.  
14.2 Consent procedures:  Informed consent will be obtained directly from the participant 
(no surrogate).  At the diagnostic visit, the investigator able to obtain consent listed in 
section 11.6 above, will explain study procedures, respond to any questions, and obtain 
consent by obtaining the participants signature on the consent document.  A copy of the 
consent form will be given to the subject, and the consent process will be documented in 
the subject’s chart. All participants will receive a verbal explanation in terms suited to 
their comprehension of the purposes, procedures and potential risks of the study and of 


 
 
54 
 
their rights as research participants.  Participants will have the opportunity to carefully 
review the written consent form and ask questions regarding this study prior to signing. 
 
14.3 Consent documents:  The standard consent form contains all required elements. 
15. Data and Safety Monitoring 
 
15. 1   Data and Safety Monitor 
 
Data and safety will be monitored by the PI and an independent Medical Monitor.  
Dr. William Theodore, an NIH neurologist acting as the independent Medical Monitor, 
will supervise patient safety. 
 
15.2   Data and Safety Monitoring Plan 
 
The independent Medical Monitor will monitor data and safety in an ongoing manner.  
The Medical Monitor will be contacted immediately after every serious adverse event 
(SAE) that is related to the protocol and all deaths and at least quarterly for other SAEs in 
compliance with NIH and IRB requirements.  The study team will provide the Medical 
Monitor with a report every six months so that he can check for any safety issues and 
threatening trends.  He will provide yearly reports.  
 
As the principal investigator, Dr. Wassermann will be contacted after every SAE that is 
related to the protocol and notified of all deaths. The Medical Monitor, Dr. Theodore, 
will also be notified of SAEs by telephone and email.  He will provide yearly reports that 
will be submitted to the NIH and USUHS IRBs with the continuing review.  He will 
promptly report discrepancies or problems to the IRB and shall have the authority to stop 
the study, remove individual subjects from the study, and take whatever steps are 
necessary to protect the safety and well-being of research subjects until the IRB can 
assess the independent medical monitor's report. 
 
15.3 Criteria for stopping the study or suspending enrollment or procedures 
 
As Medical Monitor, Dr. Theodore will have the authority to halt the study, remove 
individual subjects from the study, and take whatever steps are necessary to protect the 
safety and well-being of research subjects.  
 
The Medical Monitor, PI, and IRBs will assess the measures taken by the study team in 
response to safety issues that caused the study to be stopped or suspended. Revised safety 
measures taken by the study team will be in a written report submitted to the Medical 
Monitor, and IRBs of record. Only when these entities agree in writing that the problems 
have been satisfactorily addressed can the protocol be re-activated.  
There will be an annual continuing review of this study at the NIH and USUHS IRBs. 


 
 
55 
 
16.  Quality Assurance 
This protocol will undergo periodic review by the NINDS Quality Assurance (QA) Audit 
Committee as outlined in the NINDS QA Standard Operating Procedure.  The purpose of 
the QA audit is to assess compliance with applicable regulatory requirements, good 
clinical practice guidelines, NINDS policy, as well as to provide recommendations for 
improving the management of clinical research data.  The protocol will be audited 
according to the decision algorithm as described in the NINDS SOP. 
 
In addition, the NINDS QA team will do extra QA monitoring of the protocol.  After the 
first 3-5 participants are enrolled and every 6 months afterwards, the team will monitor 
the protocol by reviewing the regulatory documents and to check that the data has been 
collected in compliance with the protocol and regulations. Any noted deviations and 
violations will be reported to the PI.  The team will issue complete reports of monitoring 
visits to the PI.   
17. Reporting of Unanticipated Problems, Adverse Events and 
Protocol Deviations 
 
The Principal Investigator is responsible for detecting, documenting, and reporting 
unanticipated problems, adverse events (AEs), including serious adverse events (SAEs), 
and deviations in accordance with NIH policy, IRB requirements, and federal regulations. 
Relatedness to the research of all serious adverse events will be determined by the PI in 
consultation with the CD. 
  
Serious unanticipated problems and serious protocol deviations will be reported to the 
IRB and CD as soon as possible and in writing on the Problem Report Form not more 
than 7 days after the PI first learns of the event.  Not serious unanticipated problems and 
not serious deviations will be reported to the IRB and CD as soon as possible and in 
writing on the Problem Report Form not more than 14 days after the PI first learns of the 
event.  
 
Deaths will be reported to the Clinical Director within 7 days after the PI first learns of 
the event.  
 
All adverse events, deviations, and unanticipated problems will be summarized and 
reported at the time of Continuing Review. 
 
The PI will immediately report SAEs to the Sponsor according to the requirements of 21 
CFR 312.64(b) and as agreed upon with the sponsor. The PI will record non serious AEs 
and report them to the Sponsor. There is no requirement from the sponsor to report non 
serious SAE's within specified time frame.  
 


 
 
56 
 
18. Alternatives to Participation or Alternative Therapies 
This study does not replace any therapy that subjects may receive as part of standard care 
for TBI from their own physician.  Subjects may choose not to participate in this study. 
An alternative may be for his or her own physician to prescribe methylphenidate off 
label. 
19. Confidentiality 
Confidentiality of patient files will be maintained at all times.  Paper records and case 
report forms will be maintained in locked rooms, or in computer files protected by 
computer passwords.  The collected data will be accessible only by research personnel.  
In the presentation of research results, no information will be given that may reveal the 
identity of the research subjects.  The consent form will discuss patient confidentiality 
protection. 
 
Confidentiality of the patient records will be protected to the extent possible under 
existing regulations and laws but cannot be guaranteed.  Complete confidentiality cannot 
be promised, especially to military personnel, because information bearing on their health 
may be required to be reported to appropriate medical or command authorities. 
Representatives of the study sponsor (CNRM), the Henry M Jackson Foundation, US 
Department of Defense (DoD), and NIH may have access to the study data for audit 
purposes. 
 
Since we are collecting sensitive information, including data on patient’s functional 
capacity, there is a risk of the release of sensitive information.  The risk of breaches of 
patient confidentiality will be minimized by quickly coding the blood samples and 
imaging data.  In addition, all identified clinical data will be stored in servers that are 
backed up and password protected, or in locked files in secure areas.  Only NIH study 
investigators will have access to the key to the codes and identifiable data.  
 
Each study participant will be assigned a study number that will be used on study data 
collection forms and samples. The link between the study number and participants’ 
identity will be kept on a password-protected computer.  Only study researchers and 
members of the IRB will have access to identified information.  Data transmitted to the 
Data Coordinating Center will be coded. Investigators at the clinical site where consent 
was obtained will have access to identifying information for the patients enrolled in the 
study at their site.  Only coded de-identified information will be shared with persons 
outside of the enrolling site, except for audits.  
 
NIH will assign a Global Unique Identifier (GUID) to all data submitted to the CNRM 
Repository. The purpose of the GUID is to allow data on the same subject, from multiple 
protocols and from different institutions, to be identified as coming from a single 
individual and to be combined in the repository.  PII will be entered on a local server and 
a one-way encryption using a keyed-hash algorithm will be used to assign the GUID.  
CNRM will not receive PII.  The one-way encryption assures that the GUID cannot be 
used to back-generate PII.  Data that were delinked may then be sent to other non-CNRM 
Biorepository. 


 
 
57 
 
 
Blood will be processed and frozen according to CNRM Biorepository guidelines for 
confidentiality. Samples will be assigned a unique identifier at time of blood draw. The 
key for the re-identification of samples will be maintained on a master list in the PI’s 
office and accessible only to his designees. Some information will be on a password-
secured server in one of the Investigator’s offices on the NIH campus.  
To help us protect the study participant’s privacy, we have obtained a Certificate of 
Confidentiality from the National Institutes of Health. With this Certificate, the 
researchers cannot be forced to disclose information that may identify the participant, 
even by a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. The researchers will use the Certificate to resist any 
demands for information that would identify the participant, except as explained below. 
 
The Certificate cannot be used to resist a demand for information from personnel of the 
United States Government that is used for auditing or evaluation of federally funded 
projects or for information that must be disclosed in order to meet the requirements of the 
federal Food and Drug Administration (FDA). 
We explained in the consent form that a Certificate of Confidentiality does not prevent 
the participant or a member of their family from voluntarily releasing information about 
themselves or their involvement in this research. If an insurer, employer, or other person 
obtains their written consent to receive research information, then the researchers may 
not use the Certificate to withhold that information. 
 
The Certificate of Confidentiality does not prevent the researchers from disclosing 
voluntarily, without  consent, information that would identify them as a participant in the 
research project if they discover child, spousal, or elder abuse or that the participant has 
an intent to hurt himself or others.  
 
Military: In addition to the voluntary disclosures listed above, participants who are active 
members of the military will not have guarantees that their information will be kept 
completely confidential from their Command and their military health care provider. This 
exception is stated in the Consent Form. 
20. Conflict of Interest 
NIH guidelines on conflict of interest have been distributed to all investigators. No NIH 
investigator involved in this study receives payments or other benefits from any company 
whose drug, product or device is being tested. 
There is no commercial company or sponsor involved in this study. 
21.  Technology Transfer 
A Materials Transfer Agreement (MTA) is being negotiated between NIH/NINDS and 
DOD.  A draft of MTA between DoD and NIH is being prepared and is attached as 
Appendix E.  
The NINDS tech transfer office will require specific information on planned transfer and 
use of materials or data and documentation of IRB approval for each request from other 
investigators. 


 
 
58 
 
22. Research and Travel Compensation 
Study participants will be compensated for their participation in the study. They will 
receive these amounts for attempting or completing the following procedures:  
Blood collection: $20.00, Neuropsychological testing including attention tests: $75.00, 
MRI: $50.00, each PET $50.00 ($100 for PET with placebo and with methylphenidate). 
TMS for both placebo and methylphenidate will be $75.  
Visit 1 will be compensated $70, Visit 2 $150, Visit 3 $100 and Visit 4 $145. Maximal 
possible compensation will be $465 for all completed 4 visits. Study participants may 
also be reimbursed for travel expenses. 
  
 
 
23. References  
 
1. 
Volkow ND, Wang GJ, Tomasi D, Kollins SH, Wigal TL, Newcorn JH, et al. 
Methylphenidate-elicited dopamine increases in ventral striatum are associated 
with long-term symptom improvement in adults with attention deficit 
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2. 
Bales JW, Wagner AK, Kline AE, Dixon CE. Persistent cognitive dysfunction 
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3. 
Mah L, Arnold MC, Grafman J. Impairment of social perception associated with 
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Mah LW, Arnold MC, Grafman J. Deficits in social knowledge following damage 
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Donnemiller E, Brenneis C, Wissel J, Scherfler C, Poewe W, Riccabona G, et al. 
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Whyte J, Hart T, Vaccaro M, Grieb-Neff P, Risser A, Polansky M, et al. Effects 
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Giacino JT, Whyte J, Bagiella E, Kalmar K, Childs N, Khademi A, et al. Placebo-
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Frenette AJ, Kanji S, Rees L, Williamson DR, Perreault MM, Turgeon AF, et al. 
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Volkow ND, Wang GJ, Newcorn J, Telang F, Solanto MV, Fowler JS, et al. 
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Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, et al. 
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13. 
Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology : 
official publication of the American College of Neuropsychopharmacology. 
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14. 
Zhou J, Gennatas ED, Kramer JH, Miller BL, Seeley WW. Predicting regional 
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Cole DM, Beckmann CF, Searle GE, Plisson C, Tziortzi AC, Nichols TE, et al. 
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dopamine d3 receptor availability. Cerebral cortex. 2012;22:2784-2793 
16. 
Berger B, Trottier S, Verney C, Gaspar P, Alvarez C. Regional and laminar 
distribution of the dopamine and serotonin innervation in the macaque cerebral 
cortex: A radioautographic study. The Journal of comparative neurology. 
1988;273:99-119 
17. 
Awenowicz PW, Porter LL. Local application of dopamine inhibits pyramidal 
tract neuron activity in the rodent motor cortex. Journal of neurophysiology. 
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Ziemann U, Tergau F, Bruns D, Baudewig J, Paulus W. Changes in human motor 
cortex excitability induced by dopaminergic and anti-dopaminergic drugs. 
Electroencephalography and clinical neurophysiology. 1997;105:430-437 
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Ziemann U, Tam A, Butefisch C, Cohen LG. Dual modulating effects of 
amphetamine on neuronal excitability and stimulation-induced plasticity in human 
motor cortex. Clinical neurophysiology : official journal of the International 
Federation of Clinical Neurophysiology. 2002;113:1308-1315 
20. 
Gilbert DL, Ridel KR, Sallee FR, Zhang J, Lipps TD, Wassermann EM. 
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methylphenidate and atomoxetine on motor cortex. Neuropsychopharmacology : 
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21. 
Gilbert DL, Wang Z, Sallee FR, Ridel KR, Merhar S, Zhang J, et al. Dopamine 
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physical medicine & rehabilitation / Association of Academic Physiatrists. 
2004;83:131-137; quiz 138-141, 167 
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Moein H, Khalili HA, Keramatian K. Effect of methylphenidate on icu and 
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Clinical neurology and neurosurgery. 2006;108:539-542 
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Lee H, Kim SW, Kim JM, Shin IS, Yang SJ, Yoon JS. Comparing effects of 
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CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Institute of Neurological Disorders and Stroke 
 
 
STUDY NUMBER: 
T-N-2856 
PRINCIPAL INVESTIGATOR:  Eric Wassermann, MD 
 
 
STUDY TITLE: Dopamine Receptor Imaging to Predict Response to Stimulant Therapy in Chronic TBI  
 
 
Initial Review Approved by the IRB on 
 
 
 
Date Posted to Web: 
 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (#) 
 
 
  
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional. 
 
 
Purpose  
 
You are participating in this protocol because you have suffered a traumatic brain injury (TBI). You may have memory 
and attention problems . We want to measure the effect of methylphenidate (Ritalin®)  on your brain using various brain 
scans and memory and thinking tests and questionnaires. This will help us to know if methylphenidate is affecting your 
brain.  
 
 
Background 
 
Problems in memory, attention, and decision-making are  very common after TBI. A brain chemical called dopamine helps 
with attention and memory. A traumatic brain injury can affect this chemical, dopamine.. Increasing dopamine has been 
shown to improve attention and memory in some people.  Drug called methylphenidate (Ritalin) can increase dopamine 
levels It is used in people who have problems with attention. We want to see if methylphenidate  increases dopamine in a 
person who had a TBI.   
We will use a type of brain scan called positron emission tomography (PET) and another procedure called transcranial 
magnetic stimulation (TMS).  These procedures will show us if methylphenidate is working on your dopamine levels.  
 We will use a brain scan called magnetic resonance imaging (MRI). It helps us see if you have any injury to your brain.   


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 2  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
.  
 
.. You will also have memory and thinking tests before and after methylphenidate to see if methylphenidate improves your 
memory and attention.  
 
 
 
 
 
Study Population.  
 
We will recruit 30 men and women who had a TBI 6 months ago who are still having problems after their injury.  
 
Inclusion Criteria  
 
You may be eligible for this research study if you: 
 
1. Are 18 – 55 old  
2. Had a TBI with any one of the following: 
A. You had a coma score between 3 and 12 
B. You did not remember anything for 24 hours after the accident   
C. You had a brain scan that showed a brain injury  
 
3. Had a TBI and still have problems with memory or attention and at least one or more of the following: 
a) 
unusual tiredness 
b) 
sleep problems 
c) 
irritability  
d) 
you or others notice changes in your personality   
e) 
you have a hard time getting going, making decisions, or starting activities  
 
These problems or behaviors started after your TBI.  Or the problems have gotten much worse if you had some before 
the accident. These symptoms cause significant problems in the way you now function in your social life or at 
work.  You are not functioning quite as well as you used to before your accident.  
4.  Can read, speak, and write in English. 
5.  Can give consent by yourself.  
 
Exclusion Criteria 
 
You may not be eligible for this research study, if you:  
 
1. have penetrating brain injury, like a gunshot 
2. cannot take methylphenidate because:  
a. have glaucoma (high eye pressure) 
b. have motor tics or a family history of Tourette’s syndrome  
c. have an allergy to methylphenidate (hives, difficulty breathing, swelling of face, lips, tongue, or throat) 
d. anxiety or restlessness which prevents you from doing day to day activities  


 
  
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   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 3  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
e. have high blood pressure, heart failure, heart attack, or ventricular arrhythmia (a specific kind of irregular 
heartbeat). 
f. 
have had psychosis or bipolar illness 
g. have had seizures, or known EEG abnormalities in absence of seizures 
h. have had spasms in arteries in your arms and legs (Raynaud’s phenomenon) 
i. 
have a history of drug dependence or alcoholism (use of drugs or alcohol again despite repeated bad 
consequences) 
j. 
take Coumadin, a blood thinner, anticonvulsants (such as phenobarbital, phenytoin, primidone) usually 
used to prevent seizures, and tricyclic drugs (such as imipramine, clomipramine, desipramine) often used 
for depression, obsessive compulsive disorder, and attention deficit disorder. 
k. take monoamine oxidase inhibitors (such as Marplan (isocarboxazid), Nardil (phenelzine), Emsam 
(selegiline), and Parnate (tranylcypromine)) usually taken for depression and anxiety  
l. 
take blood pressure medication (for high or low blood pressure)   
m. are pregnant   
n. are breastfeeding 
 
3.  Have a disabling neurological or psychiatric disorder not due to your brain injury.  Examples of these include 
multiple sclerosis, stroke (other than stroke at the time of TBI), disabling developmental disorder, epilepsy, major 
depressive disorder, aggressive behavior, hostility, schizophrenia. A “disabling” neurological or psychiatric disorder is 
one that prevents you from holding a job or completing your education. 
 
4. Cannot have an MRI, and TMS because you have: 
 
         1.  
metal in or around your eye, such as clip, implants, or other foreign bodies 
2. 
a cardiac pacemaker or auto-defibrillator or pump 
3. 
non-removable body piercing 
4. 
claustrophobia or fear of close spaces 
5. 
inability to lie flat for approximately two hours. 
 
5. You are not able to have TMS if you have a history of seizures. 
6. You are already in a drug study. 
7. You are able to get pregnant and do not want to use an effective method of contraception during this study. 
8.   You have a body mass index (BMI) of more than 30. (Waist size multiplied by height is BMI). 
 
 
Procedures  
 
You will come to the NIH Clinical Center (CC) for four visits during a 2-month period.   One of the research staff members 
will meet and take you to the Neurology Clinic. Visits will last from about 3 to 6 hours.  
 
Consent:  One of the study doctors will review the consent form and discuss details of the study with you.  You may ask 
questions and think about whether you want to be in the study.  You may also talk about it with your family or friends.  If 
you want to participate in the study, you and the study doctor will sign a consent form.  We will give you a copy to keep. 
 
Screening:  A nurse will check some of your vital signs such as blood pressure, pulse, and temperature. The study 
doctor and research assistant will ask you about your health and medical history. They will also ask what medications 
you take. 


 
  
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   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 4  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
We will ask you about your head injury. We may be able to get some of this information from your medical records. If 
you are a female who is able to become pregnant, we will ask you for a urine sample  for a pregnancy test. 
 
If you meet all of the requirements for the study, you will continue with the study procedures. 
 
Procedures after you qualify for the study:   
 
1) Physical and neurological exam:  The doctor will listen to your heart and look at your eyes and ears. The doctor 
will also check your reflexes watch you walk, and do a few other tests. This physical examination is for research purposes 
only and does not replace any exam your own doctor may do. 
 
2) Blood Drawing: Blood will be drawn through a needle in your arm.  We will draw no more than 5 teaspoons (25 
ml) of blood at any one time and no more than 11 teaspoons (50 ml) during the entire study.   
 
Study blood tests   
We will take blood for genetic studies to see how genes may affect recovery from TBI. No specific genetic tests will be 
done under this protocol. The blood samples will be stored in CNRM Biorepository and combined with samples from other 
studies.  We will take blood for study of other biomarkers that can tell us about your brain injury. . There will be no 
screening for illegal drug use. 
 
 
 Future use of samples 
testing is one part of the research which may be done on samples submitted to the  CNRM Biorepository.   
We will not be testing your blood for other clinical purposes. 
Please initial one of the following statements regarding your wishes for genetic testing.  
 
_______YES, I give permission for genetic testing on my blood samples.  
 
 ______ NO, I do NOT give permission for genetic testing on my blood samples. 
  
______  YES, I give permission for biological marker testing that relates to TBI 
 
______  NO, I do NOT give permission for biological marker testing that relates to TBI 
 
Urine sample:, Women who are able to become pregnant will have a urine pregnancy test before participating in this 
study, before each MRI, PET, and TMS.  You will not be able to participate in this study if the pregnancy test is positive.  
If you become pregnant during the study, you cannot take the drug any more.  You also cannot have any more MRIs or 
PET or TMS. If you become pregnant, you do not have to drop out of the study.  We will follow you until the end of the 
study but we will not give you any more drug or brain scans. 
 
3) Magnetic resonance imaging (MRI):  A research assistant will walk with you to the imaging center where you will 
have your MRI.  The MRI technician will ask questions to make sure you can safely have an MRI.    You will have an MRI 
two times during the study.  They will happen at Visits 1 and 4. There is no contrast, no shots, or pills to take for the 
MRI. 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 5  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
MRI uses a strong magnetic field and radio waves to take pictures of your brain. The MRI scanner is a metal cylinder 
surrounded by a strong magnetic field. During the MRI, you will lie on a table that can slide in and out of the cylinder. 
You will be in the scanner about 1 hour. We may ask you to lie still for up to 15 minutes at a time. While in the scanner 
you will hear loud knocking noises, and you will be fitted with earplugs to muffle the sound. You will be able to 
communicate with the MRI staff at all times during your scan. You may ask to come out of the scanner at any time. You 
do not do anything during the MRI. 
 
4) Neuropsychological Testing  
Neuropsychological testing may include tests of your memory, attention, concentration and thinking.  We may interview 
you and ask you to complete questionnaires. You may also take pen-and-paper or computerized tests and perform 
simple actions.  This will take about 2 hours. You will have these tests two times during the study, which may be at 
visits 1,  or 2,  and  4.  
 
5) Study Drug  
 
DOSING:  The study drug will be methylphenidate which you take by mouth. You will take methylphenidate 60 mg or 
placebo on visit 2 before the TMS sessions.. You will take methylphenidate 60 mg or placebo on visit 3 before PET scans. 
You will not know when you will be taking the active drug and when you are taking the placebo. In addition, on visit 3, 
we will give you the study drug for  4 weeks. You will take 5 mg pill two times a day for 3 days and then 10 mg daily for 
the next 3 days. This is a gradual increase in dose over about a week’s time. We will call you one week after visit 3 and 
will ask if you have had any side effects after taking the drug.  If you get: a) allergic reactions, heart attack, stroke, 
stomach pain, psychosis, get uncontrolled movements in your body, hair loss or mood change, we will ask you to stop the 
drug. If you get: b) headache, changes in blood pressure or heart rate, or trouble sleeping the doctor will tell you how to 
lower the dose of the drug. If you do not have any side effects, you will take 30 mg of the drug two times a day. You will 
take this dose daily until the study is finished. We will call you two more times when you will be on this dose. If you have 
side effects mentioned earlier as a) from the drug, you will stop the drug. If you get side effects as b), we will ask you to 
lower the dose. The doctor will tell you how to lower the dose. .  You will take this lower dose until the end of the study 
and not go back up.  .. You will take on the day of visit 4. You will return all unused pills. We will count them on visit 4. 
You will stop taking the drug after visit 4 is completed.  
 
 
6) TMS  
 
We will do this twice, once before and once after you take the study drug.  Each of the 2 sessions is about 80 minutes. 
For TMS, a wire coil is held on the scalp. A brief electrical current is passed through the coil and creates a magnetic pulse 
that stimulates the brain. You will hear a click and may feel a pulling sensation on the skin under the coil. There may be a 
twitch in the muscles of your face, arm or leg. During the stimulation, we may ask you to tense certain muscles slightly or 
perform other simple actions. We will make some marks on your scalp. The marks will be removed at the end of the 
session.  
 
At the beginning of each experiment, we will put metal electrodes on one of your hands with tape. We will ask you to 
relax your arms and hands. We will find the correct stimulation strength needed to activate your hand muscles and then 
give you about 40 TMS pulses, some of which will actually be pairs of pulses very close together.  You can expect to 
receive about 60 TMS pulses in each session. These will be so close to each other that you will feel just one movement. 
We will use these measurements of the movements as a baseline for your brain. We will compare them with the 
movements that are made during the main part of the experiments. TMS with and without the study drug can be done on 
separate visits (visits #1, #2 or #3).    


 
  
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•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 6  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
7) Effort task 
 
You will do this task twice, once before and once after you take the study drug. You will sit in front of a computer screen, 
which will give you the task instructions.  It will ask you to make a movement, which activates a hand muscle a lot or a 
little. The computer screen will show you how much you are activating it.  Sometimes we will give you the choice of how 
much to activate it. We will pay you different amounts of money to make the different activations.  However, you will not 
be paid every time you activate the muscle. The task takes about 40 minutes. The tasks without and with the study drug 
can be done on separate visits (visits #1, #2 or #3).   
 
8) PET Procedure  
 
Before performing the PET scan, you will take one dose of methylphenidate 60 mg or placebo by mouth.  You will have 
an intravenous catheter placed in your arm. This is done by using a needle to guide a thin plastic tube (catheter) into 
your elbow crease area. The needle will be removed, leaving only the catheter in the vein. The catheter will be taped to 
the skin to hold it in place. The intravenous catheter will be used for the injection of a small amount of the radioactive 
substance [11C]raclopride. This substance travels to the brain and tells us where a chemical called dopamine is acting. 
  
During the time the catheter is in place, you need to keep your arm still. The catheter should not move. Once the 
catheter is in place, a swimming cap with small light reflectors will be put on your head. It is used to monitor the position 
of your head during the scan. You will be scanned for approximately 2 hours after the injection. During the scan you have 
to lie quietly on the scanner bed. While you are inside the PET scanner, we will be able to hear you speak. After the scan 
is completed, we will ask you to go to the bathroom to urinate.  
 
Take one dose of methylphenidate 60 mg or placebo by mouth. Take a break for about 1 hour. Have another infusion of 
raclopride through the catheter in your arm, and repeat the 2-hour PET scan. We will ask you to urinate again after the 
second PET scan. The scans with placebo and the study drug can be done on the same day or on different days (visits 
#1, #2 or #3).  
 
The study procedures are described below visit-by-visit.  All visits will be done at the NIH Clinical Center. 
 
Visit 1 (will take approximately to 3 hours).  During your first visit, you will have the following procedures as 
described above: 
1) Study explanation and sign informed consent 
2) Blood draw 
3) Urine collection for pregnancy testing (if applicable)  
4) TBI history, surveys and medical history 
5) Neurological examination 
6) MRI  
 
Visit 2 (will take about 5 hours). You will return to the NIH Neurology Clinic within 2 weeks after Visit 1. You will 
have the following:  
1) Urine collection for pregnancy testing, (if applicable) 
2) Neuropsychological testing  
3) You will have TMS and effort task without and with methylphenidate  


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
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STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 7  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
Visits 3 (will take about 4.5  hours). You will return to the NIH Neurology Clinic within 2 weeks after Visit 2. You will 
have the following: 
1) Urine collection for pregnancy testing, (if applicable) 
2) An intravenous catheter will be placed in your arm to administer the radio dye. 
3) You will have PET scan twice once with either placebo or methylphenidate; another time you will take either 
methylphenidate or placebo.  You will not know which one you are taking.   
4) We will give you the study drug to take home and give you instructions on how to take it. 
Phone calls (will take about 15 min).  We will call you three times. The first phone call will be one week after visit 3. 
The second phone call will be two weeks after visit 3.  The last phone call will be 3-4 weeks after visit 3. ou will have the 
following: 
1. We will find out if you have side effects or allergic reactions. 
2. We will tell if you need to change your drug dosage.  
 
Visit 4 (will take up to 3 hours).  You will return to the NIH Neurology Clinic 4 weeks after visit 3. You will repeat the 
following:  
 
1) Blood draw  
2) Urine collection for pregnancy testing (if applicable) 
3) The research assistant will review a list of symptoms with you.   
4) You will have an interview with one of the study doctors to discuss any symptoms you may have experienced.  
5) Neuropsychological testing 
6) MRI  
7) You will return unused pills. 
 
Risks, Inconveniences and Discomforts    
 
1) Blood Drawing:  You may have some discomfort and bruising at the site of needle entry. There is a very small risk 
of fainting. Infection in the area of the needle insertion is rare. 
 
2) Risks associated with MRI:  People are at risk for injury from the MRI magnet if they have pacemakers or other 
implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a 
large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent 
eyeliner, implanted delivery pump, or shrapnel fragments. Welders and metal workers are also at risk for injury.  They 
may have small metal fragments in their eye without knowing it. You will be screened for these conditions before having 
any scan, and if you have any, you will not receive an MRI scan.  If you have a question about any metal objects being 
present in your body, you should inform the staff.  In addition, all magnetic objects (for example, watches, coins, jewelry, 
and credit cards) must be removed before entering the MRI scan room. 
 
It is not known if MRI is completely safe for a developing fetus. Therefore, all women of  able to become pregnant will 
have a pregnancy test performed no more than 24 hours before each MRI scan. The scan will not be done if the 
pregnancy test is positive.  
 
People with fear of confined spaces may become anxious during an MRI. Those with back problems may have back pain 
or discomfort from lying in the scanner.  The noise from the scanner is loud enough to damage hearing, especially in 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 8  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
people who already have hearing loss. Everyone having a research MRI scan will be fitted with hearing protection. If the 
hearing protection comes loose during the scan, you should let us know right away. Please notify the investigators if you 
have hearing or ear problems. You will be asked to complete an MRI screening form for each MRI scan you have. There 
are no known long-term risks of MRI scans. 
3) Risks associated with PET: Radiation exposure during the PET scan: This research study involves exposure to 
radiation from 2 PET scans that use a total of 24 millicuries of the [11C]raclopride, plus a small amount of radiation from 
the transmission scan done to calibrate the scanner. This radiation exposure is not required for your medical care and is 
for research purposes only. The amount of radiation you will receive in this study is 0.6 rem which is below the guideline 
of 5 rem per year allowed for research subjects by the NIH Radiation Safety Committee. The average person in the 
United States receives a radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and 
the earth's air and soil.  
If you would like more information about radiation, please ask the investigator for a copy of the pamphlet, An 
Introduction to Radiation for NIH Research Subjects. 
While there is no direct evidence that the amount of exposure received from participating in this study is harmful, there is 
indirect evidence it may not be completely safe. There may be a very slight increase in the risk of cancer.  
Please tell us if you have had any radiation exposure in the past year, either from other research studies or from medical 
tests or care, so we can make sure that you will not receive too much radiation. Radiation exposure includes x-rays taken 
in radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive 
materials were injected into your body.  
If you are pregnant, you will not be permitted to participate in this research study. If you are breast feeding, you will not 
be permitted to participate. It is best to avoid radiation exposure to unborn or nursing infants since they are more 
sensitive to radiation than adults are. 
The radiopharmaceutical used, carbon-11 labeled raclopride, is being administered under an investigational new drug 
(IND) approval from the Food and Drug Administration (FDA). Peter Herscovitch, M.D. is the sponsor. The sponsor and 
the FDA have access to the medical records of the research subjects.  
4) Risks associated with methylphenidate:   
Side effects of methylphenidate may include nervousness, trouble sleeping, loss of appetite, weight loss, dizziness, 
nausea, vomiting, headache, or blurred vision. Side effects may include allergic reactions, heart attack, abnormal heart 
rate, stomach pain, stroke, mood changes, loss of hair.  If any of these effects persist or worsen, tell your study 
coordinator or study doctor promptly. You do not have to wait until a planned visit to report adverse events.  You can call 
1-855-2-OnPage (or +1 (855) 266-7243 24/7 hours/day.   You can the nearest emergency room in the event of life- 
threatening emergency. 
 
Pregnancy:  Methylphenidate has not been studied in pregnant women.  We will give a pregnancy test to any woman 
who is able to become pregnant before enrolling her into the study.  We will repeat the urine pregnancy test before  MRI, 
PET or TMS. You will not be able to enroll in the study if you are pregnant.  You are not able to have any more 
methylphenidate, PTEs, TMSs or MRIs if the pregnancy test becomes positive during the study. 
 
Statement on contraception: 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 9  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
We do not know if the study drug affects pregnancy or fetal development. Therefore, sexually active women who are 
able to get pregnant must agree to use an effective method of contraception (birth control) from the time you enroll in 
the study until 2 weeks after you completed the study drug.  
 
Effective methods of contraception for this study include:  
1. hormonal contraception (birth control pills, injected hormones or vaginal ring),  
2. intrauterine device 
3. barrier methods (condom or diaphragm) combined with spermicide 
4. surgical sterilization (hysterectomy, tubal ligation), or vasectomy in a partner. 
 
It is important for you to know that no method of birth control is totally effective in preventing pregnancy except for 
surgical sterilization (hysterectomy or tubal ligation for women and vasectomy for men) and total abstinence from sexual 
relations. 
Nursing mothers: It is not known whether methylphenidate goes into breast milk. As a precaution, nursing mothers 
cannot be in this study. 
5)  Neuropsychological testing: The neuropsychological tests are not harmful, but may be frustrating or stressful. 
We only ask that you try your best. No one performs perfectly on these tasks. You may refuse to answer any question 
or to stop a test at any time and for any reason.  
 
6) Risks associated with loss of confidentiality: Any time we collect information, there is a potential risk for loss of 
confidentiality.  We will try to keep your information confidential, but this cannot be guaranteed. If we learn that you are 
a danger to yourself or to others, we will have to report this to the appropriate authorities for your and others’ protection. 
 
Risks associated with TMS: TMS is a safe procedure that has been used on thousands of patients throughout the 
world. Most people do not find the stimulation painful, but sometimes strong contractions of scalp muscles can cause 
some discomfort or headache. If you find the procedure too uncomfortable, you may stop it at any time. Headaches 
usually go away promptly with nonprescription medication. The noise of the TMS magnet may affect hearing, so you will 
be fitted with earplugs to wear during TMS. Magnetic stimulation will not be done in people who have pacemakers, 
implanted pumps or stimulators, or who have metal objects inside the eye or skull. Please tell the investigators if you 
have any of these or known hearing loss.  If your pregnancy test is positive, you will not have TMS.  We do not know if 
there is any risk to you or your fetus, but we want to be careful to promote your safety.  
 
Risks associated with computer tasks (effort task): There are no risks from the effort tasks in this study except 
fatigue or boredom. 
 
Anticipated Benefits: There will be no direct benefit to you from participating in this study. However, we hope to learn 
more about TBI.  
 
Right of Withdrawal and Conditions for Early Withdrawal   
You may withdraw from the study at any time and for any reason without loss of benefits or privileges to which you are 
otherwise entitled. The investigator can remove you from the study at any time if she or he believes that continuation is 
not in your best medical interest or if you are unable to comply with the requirements of the study. 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
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•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 10  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
We will send your blood samples to a repository without any information that could be used to identify you.  We will not 
be able to destroy your samples if you choose to withdraw from this study because all identifiable information has been 
removed and will we not be able to tell who provided the sample.    
You might be able to stay in the study even if you find out that you cannot take methylphenidate or do any of the 
procedures.    
You can talk with or write to the study doctor if you wish to stop participating in the study. 
Results from this Study The researchers will not give you the results of any research tests or evaluations. However, if 
information is developed from this study that may be important for your health, you will be informed when it becomes 
available. We will share it with your doctors at your written request.  
Genetic (DNA) Testing: The genetic testing is done for research purposes only.  It will not provide any information about 
your health or ancestry. It is our policy not to give you results of any genetic testing.  
 
Incidental findings   We will inform you about any finding that may require further evaluation or care. We are not able 
to provide evaluation or treatment for these conditions at NIH. If needed, we will refer you to a health care provider. We 
may not inform you about minor abnormalities that do not have importance for your health or well-being.  
 
Alternatives to Participation or Treatment  This study is for research only and does not replace any therapy that 
your own doctor is giving you.  You will remain under the care of your own doctors while you are in this study.  The 
alternative to participating in this study is not to participate.  
Confidentiality To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. With this Certificate, the researchers cannot be forced to give out information that may identify you, 
even by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings. 
The researchers will use the Certificate to resist any demands for information that would identify you, except as explained 
below. 
The Certificate cannot be used to resist a demand for information from personnel of the United States Government that is 
used for auditing or evaluation of federally funded projects or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA). 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your family from 
voluntarily releasing information about yourself or your involvement in this research. If an insurer, employer, or other 
person obtains your written consent to receive research information, then the researchers may not use the Certificate to 
withhold that information.The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, 
without your consent, information that would identify you as a participant in the research project if they discover child, 
spousal, or elder abuse or that you have an intent to hurt oneself or others which is also mandatory MD Department of 
Health reporting. 
In addition to the voluntary disclosures listed above, if you are an active member of the military, you will not have 
guarantees that your information will be kept completely confidential. Typically, this refers to HIV, illicit drug use, alcohol 
abuse, sexual misconduct or abuse, as well as serious criminal behavior, may also be reportable. 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 11  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
Your study information will be kept confidential to the extent possible under existing regulations and laws, but absolute 
confidentiality cannot be guaranteed. Complete confidentiality cannot be promised, especially to military personnel, 
because information bearing on their health may be required to be reported to appropriate medical or command 
authorities. Future research that uses your data may lead to new commercial products, but you will not receive payment 
for these products. Some future studies may need your health information (such as updated information on your health) 
that we do not already have.  
 
Paper records will be kept in locked rooms, or in computer files protected by computer passwords.  The collected data 
will be accessible only by research personnel.  When research results are presented, no information will be given that 
may reveal your identity.   
 
This study is part of the Center for Neuroscience and Regenerative Medicine (CNRM), a joint federal program involving 
the United States (US) Department of Defense (DoD) and the National Institutes of Health (NIH) joining physicians and 
scientists from different specialties to study new approaches to traumatic brain injury (TBI) research.  The CNRM 
network will collect de-identified clinical data, imaging data, and blood samples contributed from us and other 
participating centers. Members of the CNRM, Uniformed Services University, Henry M Jackson Foundation, US 
Department of Defense and NIH, may have access to the study data for auditing purposes. 
 
If you choose to participate in this protocol, identifiable data collected for this study will be shared with Eric 
Wassermann, MD and other IRB-approved study investigators who are working on this study.  
 
We may share your data with outside investigators or collaborators but only after all information that can identify you has 
been removed.  This data may be used for a variety of research purposes that we may not be able to specify at this time.  
 
Data and samples may be shared with other researchers by the sponsor (CNRM).  All data and samples will have 
personally-identifying information removed and will be coded. The same code will be used for your data and samples 
whenever you participate in a CNRM study.  If you participate in a CNRM study with researchers outside of NIH, those 
researchers may therefore be able to identify samples and data from NIH as yours.  Your samples and data may also be 
sent to other repositories for storage or additional use.  It will not be possible for other repositories to identify the 
samples or data as yours. 
 
Your blood samples will be stored in secured freezers at the CNRM Biorepository.  Your name and identifying information 
will not be on the samples; we will assign them a code. The key to the code will be kept in a separate, secure area. Once 
the samples and the code arrive at the CNRM Biorepository, a repository manager will be responsible for maintaining the 
samples and sending them to others who may use the samples for research. The samples will be stored for up to 20 
years. The purpose of the repository is to store a large number of samples and related data so that we can learn more 
about traumatic brain injury and how to rehabilitate people who may have it. The CNRM is a federal medical research 
program of the U.S. Department of Defense (DOD), and DOD is the custodian of the samples. The Uniformed Services 
University (USU) operates the CNRM and the USU IRB reviews the repository for patient protection and receives reports 
from a Biorepository Steering Committee on the operations of the repository. 
 
Dr. Wassermann is responsible for your samples here at NIH and until they are received at Dr. Diaz-Arrastia’s laboratory 
at his CNRM laboratory for analysis pertaining to this study.  Dr. Diaz-Arrastia is an outside  study doctor on this study. 
The remainder of blood not needed for Dr. Diaz-Arrastia’s analysis will be taken to the CNRM Biorepository. Your blood 
samples will only be accessible by current and future CNRM Investigators after approval by all relevant IRBs. Your sample 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 12  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
may be used for other research projects if you agree.  If you do not want your sample used for other studies, please 
initial on the line below 
 
__________I do not want my samples used for other research projects. Please destroy my samples once this project is 
complete. 
 
If you withdraw from this research project before it is complete, any remaining samples you have contributed will be 
discarded. Results obtained before you withdraw will be kept and your privacy will be protected. 
 
 
We may share your data, including imaging data, with outside investigators or collaborators but only after all information 
that can identify you has been removed.  Your data, including imaging data, will be stored either at the study origination 
site or at the CNRM Image Processing Core database at NIH. This data may be used for a variety of research purposes 
including genetic research that we may not be able to specify at this time. The Henry M. Jackson Foundation for the 
Advancement for Military Medicine (HJF) may also access samples and data for audit purposes. 
 
_____  I give my permission to Dr. Wassermann and the Investigators in this study to store and share my data, including 
imaging data, with other researchers after it has been de-identified. 
 
_____  I do not give my permission to Dr. Wassermann and the Investigators in this study to store and share my data, 
including imaging data, with other researchers after it has been de-identified. 
Future Contact   We will send your research results without identifying information to the CNRM Informatics Repository. 
Your data may be used for other research projects. If you do not want your data used for other projects, please note this 
by initialing the appropriate space below.  Your data will only be shared with approved Investigators.  Any future use of 
the data must be approved by CNRM Repository and NIH review committees. Future research that uses your data may 
lead to new commercial products, but you will not receive payment for these products. Some future studies may need for 
health information (such as updated information on your health) that we do not already have. If so, we may contact you 
to obtain this information.  You are not obligated to provide any additional information.     
______ I do not want my de-identified data from this study used for other projects. 
______ I am willing to share de-identified data learned about me in this study with researchers working on other studies 
that Drs. Wassermann and Diaz-Arrastia think are important and that my information will help. 
Compensation and Travel costs   You will be compensated for research-related discomfort and inconveniences in 
accord with NIH guidelines. If you are unable to finish the study, you will be paid for those parts completed. 
 
Blood collection: $20.00, Neuropsychological testing including attention tests: $75.00, MRI: $50.00, each PET $50.00 
($100 for PET with placebo and with methylphenidate). TMS for both placebo and methylphenidate will be $75.  
Study participants may also be reimbursed for travel expenses. 
$20.00 for completing or attempting to complete the blood draw 
$75.00 for completing or attempting neuropsychological testing including attention tests 
$50 for completing or attempting the MRI 
$50 for completing or attempting the each PET ($100 for PET with placebo and methylphenidate).  
$75 for completing or attempting the TMS  (with placebo and methylphenidate)  


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 13  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
Visit 1 will be compensated $70, Visit 2 $150, Visit 3 $100 and Visit 4 $145. Maximal possible compensation will be $465 
for all completed 4 visits. Study participants may also be reimbursed for travel expenses. 
 
Posting of Research Results on www.ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required by U.S. Law.  This web site 
will not include information that can identify you.  At most the Web site will include a summary of the results.  You can 
search this Web site at any time. 
 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital 
accreditation organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health.  Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4.    Problems or Questions.  If you have any problems or questions about this study, or about your rights as a 
research participant, or about any research-related injury, contact the Principal Investigator, Building, Room, Telephone. 
Dr Eric Wassermann, Building 10, Room 7D43, 10 Center Drive,  Bethesda, MD 20814, tel 301-496-0151 
 
You may also call the Clinical Center Patient Representative at (301) 496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again.   
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: T-N-2856 
 
CONTINUATION: page 14  of  13  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have 
been given the opportunity to discuss it and to ask 
questions.  I hereby consent to take part in this study. 
I have read the explanation about this study and have 
been given the opportunity to discuss it and to ask 
questions.  I hereby give permission for my child to take 
part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM THROUGH.  
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name