Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness - A Phase 1 Study
Phase: PHASE1
Conditions: Brain Injury Traumatic Severe (Diagnosis), Coma, Consciousness, Level Altered, Anoxic Brain Injury
Sponsor: Massachusetts General Hospital

 
 
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PROTOCOL 
 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 
812)  
• 
ICH E6  
 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Subjects Protection Training. 
 
1 PROTOCOL SUMMARY 
Title: 
 
STIMPACT: Stimulant Therapy Targeted to Individualized 
Connectivity Maps to Promote ReACTivation of Consciousness 
 
 
 
 
 
 
 
 
 
 
Précis: 
 
 
 
 
 
 
 
 
 
 
 
Phase 1 of the STIMPACT trial is an open label, dose-escalation, safety 
study of intravenous (IV) methylphenidate (MPH) therapy in patients 
with disorders of consciousness (DoC) caused by severe brain injuries.  
To be classified as having a DoC, a patient must be in a coma, 
vegetative state (VS), or minimally conscious state (MCS),1 as 
determined by behavioral assessment using the Coma Recovery Scale-
Revised (CRS-R).2  Patients with DoC admitted to the intensive care 
unit (ICU) will be eligible for the study. 
 
A total of 22 patients with DoC will be enrolled in the Phase 1 study.  
Patients will receive escalating daily doses of IV MPH starting at 0.5 
mg/kg, increasing stepwise to 1.0 mg/kg and 2.0 mg/kg unless an 
adverse event (AE) necessitates dose de-escalation or a serious 
adverse event (SAE) necessitates that the patient stop participation in 
the study.  Pharmacokinetics will be evaluated in selected patients with 
indwelling venous catheters or arterial catheters via serial serum 
measurements of MPH at each dose.  The pharmacodynamic 
properties of IV MPH at each dose will be assessed by comparison of 
pre- versus post-dose EEG-based measures.  The pharmacodynamic 
properties of the maximum tolerated dose will also be assessed by 
comparison of pre- versus post-dose resting state functional MRI (rs-

 
 
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Objectives: 
fMRI) connectivity measures.  Finally, we will test the association 
between structural connectivity of the ventral tegmental area (VTA), a 
dopaminergic brainstem nucleus that is believed to mediate MPH 
activation of the cerebral cortex, and EEG and rs-fMRI 
pharmacodynamic measures. 
 
The primary objectives of the STIMPACT Phase 1 study are: 
 
1) To determine the maximum tolerated dose of IV MPH in patients 
with DoC caused by severe brain injuries. 
 
2) To define the pharmacokinetics of IV MPH in patients with DoC 
caused by severe brain injuries. 
 
The secondary objectives of the STIMPACT Phase 1 study are: 
 
1) To explore the effect of IV MPH on an EEG pharmacodynamic 
biomarker of cerebral cortical connectivity in patients with DoC 
caused by severe brain injuries. 
 
2) To explore the effect of IV MPH on a rs-fMRI pharmacodynamic 
biomarker of brain connectivity in patients with DoC caused by 
severe brain injuries. 
 
3) To explore the relationship between structural VTA connectivity 
and each pharmacodynamic biomarker in patients with DoC 
caused by severe brain injuries. 
Endpoints: 
The outcome variables for the primary outcomes are: 
 
1) The number of AEs and SAEs at each dose. 
 
2) The time to maximal serum concentration (TMAX) and the serum 
half-life (T1/2) of IV MPH at each dose. 
 
The outcome variables for the secondary outcomes are: 
 
1) The effect of each stimulant dose on cerebral cortical 
connectivity, as measured by EEG.3 
 

 
 
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2) The effect of the maximum tolerated stimulant dose on brain 
connectivity, as measured by rs-fMRI.4 
 
3) The association between VTA connectivity, as measured by high 
angular resolution diffusion imaging (HARDI),5 and the 
pharmacodynamic biomarkers, as measured by EEG and rs-
fMRI. 
Population: 
Patients with DoC caused by severe brain injuries. 
Phase: 
Phase 1 
Number of Sites: 
1 
Description of 
Study Agent: 
IV MPH, administered as a bolus, at escalating doses of 0.5 mg/kg, 1.0 
mg/kg, and 2.0 mg/kg 
Study Duration: 
2 Years (including data analysis) 
Participant 
Duration: 
5 days 
1.1 DESCRIPTION OF STUDY DESIGN 
 
In this Phase I open label, dose-escalation, safety study, we will test a novel stimulant therapy, IV 
MPH, which we believe has potential to promote recovery of consciousness in patients with DoC 
caused by severe brain injuries.  The trial will begin with a HARDI MRI scan to generate 
individualized connectivity maps of the subcortical ascending arousal network (AAN) that is critical 
to human consciousness.5 On the day of the MRI (Day 0), patients will also undergo continuous 
EEG and serial behavioral assessments to determine the patient’s baseline variation in the EEG 
pharmacodynamic biomarker and the level of consciousness, respectively. Starting the next day 
(Day 1), each patient will receive escalating doses of IV MPH for four days (Days 1-4). Dosing 
will start at 0.5 mg/kg, and then increase to 1.0 mg/kg and 2.0 mg/kg.  Blood pressure (BP) and 
heart rate (HR) will be monitored continuously, given that elevated BP and HR are the most 
common side effects associated with IV MPH according to prior human studies.  In the case of an 
AE that is deemed to be possibly related to IV MPH administration, the patient will either 1) be 
discontinued from the study if the AE occurred at the lowest dose (0.5 mg/kg); or 2) be continued 
in the study at the previously tolerated dose if the AE occurred at a dose of 1.0 mg/kg or 2.0 
mg/kg.  If there is an SAE that is deemed to be possibly related to IV MPH administration, the 
patient will be discontinued from the study. All AE’s and SAE’s will be reported to the Independent 
Medical Monitor, Institutional Review Board (IRB), and FDA in compliance with published 
guidelines. If the patient emerges from DoC during the trial, the patient will be discontinued from 
the study. Serum levels of IV MPH will be measured at each dose to assess pharmacokinetics.  
Continuous EEG data will be acquired to assess the EEG pharmacodynamic biomarker. A follow-
up MRI will be conducted on the last day of the study (Day 4) to assess the rs-fMRI 
pharmacodynamic biomarker.  

 
 
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1.2 SCHEMATIC OF STUDY DESIGN 
 
 
 
 
2 BACKGROUND AND SIGNIFICANCE 
More than a million civilians worldwide experience an acute DoC caused by a severe brain 
injury each year.6-9  In addition, thousands of military personnel have experienced an acute DoC 
caused by severe brain injury since 2001.10  These patients typically arrive at the hospital in a 
coma, unable to open their eyes or respond purposefully to any stimulus.  Some civilians and 
veterans remain in VS or MCS after emergence from coma.11, 12  Although the precise 
prevalence is unknown, it is estimated that thousands of people are currently living in the United 
States and Europe with persistent DoC.13, 14   
Nevertheless, recovery of consciousness, communication, and functional independence are 
possible after severe brain injury.11, 12, 15-18 Indeed, recent evidence suggests that recovery of 
consciousness is possible even for patients who have persistent DoC in the subacute and 
chronic stages of severe brain injury.15, 19, 20 Emerging evidence suggests that specific patterns 
of brain network connectivity are necessary to enable this recovery.21-23  Given the profound 

 
 
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implications of recovering consciousness for the individual, the family, and society, it is essential 
that patients whose brain network connectivity is capable of supporting recovery are identified 
and that stimulant therapies are developed to promote this recovery. 
Currently, no stimulant therapy has been shown to promote recovery of consciousness in patients 
with DoC in the ICU.  The treatments available for patients with subacute and chronic DoC are 
limited,24-27 with amantadine hydrochloride being the only therapy to show efficacy in a 
randomized controlled trial.25  A key lesson from the amantadine trial and other proof-of-principle 
studies is that therapeutic modulation of injured brain networks is feasible and may improve 
the level of consciousness in selected patients with DoC.  Moreover, since patients with DoC 
have heterogeneous patterns of brain network disruption, and since not all patients respond to 
therapy, these studies suggest that specific nodes and/or connections within brain networks must 
be preserved for stimulant therapies to promote consciousness.  Currently, there is a critical gap 
in knowledge about which brain network connectivity properties enable a response to stimulant 
therapy. 
Recent advances in the field of brain imaging now make it possible to map the connectivity of 
brain networks that mediate consciousness.4, 5, 28-30  These advanced imaging techniques provide 
personalized connectivity maps for individual patients,21 which creates a new opportunity to target 
therapies to specific brain network connectivity patterns.  These brain network mapping tools have 
recently been applied to the brainstem connections that are the target of IV MPH.  Specifically, it 
is now possible to map the connections of the VTA in the human brain5, 31 – a key methodological 
advance that will allow us to assess whether DoC patients with partially preserved VTA 
connections respond to IV MPH.  
2.1 RATIONALE  
The pathophysiological basis of altered arousal in patients with DoC is disruption of brainstem 
monoaminergic, cholinergic, and glutamatergic pathways that project to the thalamus, 
hypothalamus, basal forebrain, and cerebral cortex.5, 32  Histopathological studies show that the 
brainstem is invariably injured in patients with traumatic DoC.31, 33, 34  For patients with DoC caused 
by other types of brain injuries (e.g. hypoxic-ischemic injury), the brainstem itself may be spared 
but its connections with the thalamus, hypothalamus, basal forebrain or cerebral cortex are at 
least partially disrupted.35-37  However, regardless of the type of brain injury causing the DoC, not 
all brainstem arousal nuclei are lesioned and not all axons are disrupted.37, 38  Rather, 
histopathological data in trauma patients indicate that the ventral brainstem, where VTA neurons 
reside, is often spared.33, 34, 39-46 MRI studies by our group and others similarly reveal that 
brainstem lesions often spare the ventral brainstem.47, 48 There is thus a strong scientific rationale 
for our central hypothesis that preserved dopaminergic VTA neurons are a target for stimulant 
therapy to promote restoration of consciousness in patients with DoC.   
MPH acts by blocking the dopamine transporter protein, thereby enhancing dopaminergic 
neurotransmission at synapses throughout the brain.49, 50  There is also evidence that MPH may 
block reuptake of norepinephrine and histamine as well.51  Today, oral MPH is widely prescribed 
to treat attention deficit hyperactivity disorder (ADHD), which has an incidence of 6-9% in 

 
 
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children.52 Swanson and Volkow reported that MPH levels reach their peak concentration (TMAX) 
in the brain rapidly after IV administration in healthy humans, as evidenced by 11C-MPH PET 
scans showing peak levels in the striatum within 8-10 minutes.53  MPH levels in the striatum 
remain at approximately 70% of peak concentration one hour after IV administration in healthy 
humans, indicating that MPH clearance is slow.53  The half-life (T1/2) in the brain, per 11C-MPH 
PET scans, is approximately 90 minutes.  These pharmacokinetic data acquired in healthy human 
subjects indicate that if IV MPH does promote recovery of consciousness, this effect should be 
rapid in onset and should be sustained for a period of several hours after administration. 
 
A response to IV MPH could change the course of a patient’s recovery in multiple ways.  For 
patients with DoC in the ICU, the emergence of consciousness in response to IV MPH could 
reduce the likelihood of withdrawal of life-sustaining therapy, enable self-expression and 
autonomous decision-making, shorten ICU length-of-stay, decrease complications associated 
with immobility, and increase access to rehabilitative care.  
 
 
3 SUBJECT RECRUITMENT, SELECTION, AND ENROLLMENT 
 
3.1 SUBJECT RECRUITMENT 
 
This study will take place at Massachusetts General Hospital (MGH) in the ICU at Lunder 6 and 
Ellison 4.  For Phase 1, we will aim to enroll 22 patients aged > 18 years who have sustained a 
severe brain injury and are in coma, VS, or MCS.  
 
3.2 SUBJECT SELECTION 
 
Only those patients who have a surrogate available to provide consent will be considered for this 
study.  
 
Inclusion Criteria:  
1) Age ≥ 18 years 
2) Severe TBI (post- resuscitations Glasgow Coma Scale score ≤ 8) within the past 28 days  
3) Disorder of Consciousness (DoC), defined as coma, vegetative state (VS) or minimally 
conscious state (MCS)  
 
Exclusion Criteria:  
1) Metallic foreign body contraindicating a 3T MRI for any participant undergoing a MRI 
scan 
2) Prisoner or ward of the state 
3) Neurological 
a. Bilateral dilated unresponsive pupils 
b. Intracranial hypertension (Intracranial Pressure [ICP] > 20 mmHg  for > 5 min within 
past 24 hours with head of-bed at standard clinical angle of 30-45o) 

 
 
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c. Intracranial bolt 
d. Status epilepticus or concern for post-ictal state 
4) Cardiovascular 
a. Poorly controlled hypertension (SBP sustained > 200 mmHg or DBP > 120 mmHg for 
30 minutes, despite anti-hypertensive therapy, within the past 24 hours) 
b. Coronary artery disease 
c. ST elevation myocardial infarction 
d. Acute coronary syndrome  
e. Hemodynamically significant dysrhythmia 
f. Congestive heart failure 
g. Cardiomyopathy (including Takotsubo cardiomyopathy) 
h. Other severe structural cardiac abnormalities 
5) Renal 
a.  Renal failure requiring renal replacement therapy (e.g. CVVH or HD) 
6) Endocrine 
a. History of or clinical suspicion for thyrotoxicosis 
7) Reproductive 
a. Pregnancy 
8) Ophthalmologic 
a. History of glaucoma  
9) Pharmacologic 
a. Monoamine oxidase inhibitor therapy within past 14 days 
10) Other 
a. Any condition or finding that in the judgment of the PI or treating clinical team 
significantly increases the risk or significantly decreases the likelihood of a response 
to IV MPH 
3.3 SUBJECT ENROLLMENT 
 
If a patient is deemed eligible for the study, study staff will approach the surrogate to explain the 
study and answer any questions. A consent form will be presented for review and each section of 
the consent form explained. Surrogates will have as much time as needed to review the consent 
form and make a decision regarding participation. This will allow adequate time for the surrogate 
to review the consent form in detail, have any questions answered and consider enrollment. 
 
If the surrogate chooses to enroll the patient in the study, the surrogate and study investigator will 
sign the consent form. We will make clear to the surrogate that he/she may withdraw from the 
study at any time prior to the start of the study or once the study has begun and that participation 
and/or withdrawal will not affect the patient’s clinical care.  
 
Remote Consent: 
 
We will attempt to obtain informed consent for study participation from a surrogate in person. 
However, if the surrogate (LAR) is not available to meet with the research team in person (e.g., 

 
 
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due to being out of town, COVID restrictions, etc.), a remote (phone) consent will be obtained 
from their LAR according to the remote consent policy and guidelines defined by PHS (Partners 
HealthCare System) Human Research Affairs Department. In such a situation, a member of the 
research team will call the surrogate and send them the consent form electronically through the 
FDA COVID MyStudies App, REDcap or via  email or facsimile; if by email, the email will be sent 
securely per Partners IS guidelines. The surrogate will review the consent form, discuss 
participation in the study with the physician investigator, sign and date (including time) the consent 
form agreeing to the patient's participation in the research and return the signed (handwritten or 
digital) and dated consent form electronically (via email, facsimile or the FDA COVID MyStudies 
App). The consent discussion that takes place by phone will include a healthcare worker 
(physician, patient’s nurse or other floor nursing staff) not associated with the study as a witness 
to the consent process. The investigator and the witness will sign and date (including time) the 
consent form to indicate that phone consent has been granted by the LAR. 
 
Additionally, if the surrogate/LAR resides within two hours of drive of the Study site (MGH), then 
remote, off-site, in-person consent may be obtained. A meeting will be held with the Investigator 
and the patient’s legal representative/surrogate that is authorized to sign for the patient.  
Additionally, during this meeting, an impartial third-party witness will also be present (in-person 
or virtually by phone/videocall). 
 
4. STUDY PROCEDURE 
 
4.1 PROTOCOL DETAILS 
As this is a Phase I study, all eligible subjects will be enrolled without randomization to study 
arms.  
 
Subjects enrolled in this study will undergo behavioral, EEG, and MRI assessments on Study Day 
0 before receiving IV MPH.  The goals of these Day 0 assessments are 1) to establish a baseline 
diagnosis regarding the patient’s level of consciousness; 2) establish the baseline variance in 
EEG measures of cortical connectivity that will subsequently be used as pharmacodynamic 
biomarkers; and 3) acquire the structural HARDI MRI data needed to generate the VTA 
connectivity biomarker.  Subjects will also undergo hemodynamic monitoring on Day 0 to assess 
BP and HR.  The cerebral perfusion pressure (CPP) will also be monitored if ICP is being 
measured via an external ventricular drain (EVD).  The purpose of these Day 0 hemodynamic 
assessments is to determine if there is a baseline correspondence between any hemodynamic 
parameter (BP, HR, or CPP) and any behavioral assessment (e.g. CRS-R score) or EEG 
biomarker (e.g. cortical connectivity).  These Day 0 assessments will thus allow us to 
subsequently account for the possibility that IV MPH may affect behavioral and/or EEG measures 
because of a hemodynamic change related to IV MPH rather than because of a change in 
dopaminergic neurotransmission. 
 
Throughout the 5-day study (from Day 0 to Day 4), each subject will be monitored for 
hemodynamic and behavioral changes.  IV MPH is known to increase BP and HR, but these 

 
 
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predictable changes should be easily manageable in the ICU environment, where subjects will be 
appropriately monitored and a full armamentarium of vasoactive drugs will be immediately 
available.  
 
On Day 1, each subject will receive an IV bolus of 0.5 mg/kg MPH, using the actual body weight 
to calculate the dose.  Serum levels of MPH will be measured in subjects with indwelling catheters 
(e.g. central venous catheter or arterial catheter) at baseline immediately pre-dose and post dose 
at 5 min, 15 min, 30 min, 1 hour, 1.5 hours, 2 hours, 4 hours, 8 hours, 12 hours, and 16 hours 
after each dose. Serum collection for pharmacokinetic analysis will continue from Day 1 to Day 4 
as per Table 1 below, where 1mL serum samples will be collected at each time point.  Patients 
without these indwelling catheters will not undergo the pharmacokinetic part of the study, given 
the potential discomfort associated with multiple needle sticks. Any patient whose hematocrit is 
<21 g/dl, who is actively bleeding, or whose clinical team does not approve the blood draws will 
not undergo the pharmacokinetic part of the study. Serum creatinine and liver function tests will 
be assessed on each study day to assess daily renal and liver function. All participants will have 
a single baseline blood draw (~ 3 mL) collected for genetic analysis of dopamine transmission 
genes such as DAT1 and SLC6A3. No other genetic testing is part of this protocol. The results of 
the blood assays and genotyping will be used for research purposes only and will not be entered 
into the medical record.  
 
Table 1. Serum Specimen Collection Schedule and Intended Analyses 
Study  
Days  
 
       Timepoint 
Day 0 
Day 1 
Day 2 
Day 3 
Day 4 
Intended Analysis 
Baseline 
X 
- 
- 
- 
- 
Dopamine Genes  
Pre-Dose 
- 
X 
X 
X 
X 
Pk3 and Genetic4 
Post- Dose1  
- 
X 
X 
X 
X2 
Pk 
 
1. Post-Dose Serum samples will be collected as follows: 5 mins (+/- 5 mins) , 15 mins (+/- 
5mins) , 30 mins (+/- 15 min), 1 hour (+/- 15 min), 1.5 hours (+/- 15 min), 2 hours (+/- 15 
min), 4 hours (+/- 15 min), 8 hours (+/- 15 min), 12 hours (+/- 15 min) and 16 hours (+/- 15 
min ) post infusion.  
2. Day 4 post infusion blood draw at 5 mins, 15 mins, 30 mins may not always be possible 
as the participant will be in the scanner 
3. Pk = Pharmacokinetic analysis; serum concentration assays performed at Worldwide 
Clinical Trials (WCT), data analysis performed at MGH  
4. Genetic analysis for presence of dopamine transmission genes conducted at MGH 
Center for Genomic Medicine 
 
Serum samples collected for genetic analysis will be processed and stored at MGH in the lab of 
Dr. W. Taylor Kimberly. Plasma samples will be stored at -80°C and analysed for MPH 
enantiomers (ng/mL) and for total ritalinic acid (metabolite, ng/mL) concentrations using an achiral 
LC-MS/MS assay. Sample analysis will be performed at Worldwide Clinical Trials (Austin, TX).  
 

 
 
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In compliance with the Partners Healthcare Blood Sampling Guidelines, the total amount of blood 
drawn for research will not exceed the lesser of 50 ml or 3 ml/kg in 8 weeks 
(https://partnershealthcare.sharepoint.com/sites/phrmApply/aieipa/irb/Documents/IRB%20Clinic
al%20Research%20Documents/BLOOD_SAMPLING_GUIDELINES.pdf). 
 
EEG will be performed continuously from Day 0 to Day 4, and the EEG pharmacodynamic 
biomarker will be assessed from one hour before to one hour after the bolus is administered on 
Days 1-4.  MRI will be performed on Day 0 and Day 4.  The rs-fMRI connectivity biomarker will 
be assessed on Day 4 over a 40-minute continuous scanning period beginning 10 minutes before 
and ending 30 minutes after administration of the IV MPH bolus. 
 
If the 0.5 mg/kg dose of IV MPH does not cause an AE or SAE on Day 1, then the next day (Day 
2) the subject will receive 1.0 mg/kg IV MPH.  If there is no AE or SAE at this dose, the subject 
will receive 2.0 mg/kg IV MPH on Day 3.  The maximum tolerated dose, as defined below, will 
then be administered on Day 4 while the subject is in the MRI scanner.   
 
Participating in this research study will in no way change the standard care or clinical protocols 
that guide the management of patients with severe brain injuries at MGH.  
 
Changes in HR and BP are common in patients with severe brain injuries, and increases in both 
are more likely in the patients who receive MPH.54, 55 Therefore, MPH will not be administered if 
the patient’s systolic BP is greater than 180 mmHg, if the diastolic BP is greater than 100 mmHg, 
or HR is greater than 120 bpm. A study protocol checklist will be used by the study team to ensure 
that the patient’s BP and HR do not surpass these prespecified thresholds.  
 
If a patient experiences a significant neurologic or cardiovascular AE, the patient will be treated 
immediately, and continuous hemodynamic monitoring will continue per ICU protocols.  Any 
patient with a life-threatening myocardial infarction or cardiac dysrhythmia will be treated 
according to Advanced Cardiac Life Support protocols, and a cardiologist will be promptly 
consulted for management recommendations.  Acute hemodynamic changes that are not life-
threatening will be managed at the discretion of the clinical care team assigned to the patient, not 
the study staff.  We expect that all patients in this study will be under the care of a neurologist, 
but if that is not the case and a neurologic adverse event occurs, then a neurologist will be 
promptly consulted to guide further management.  
 
It is possible that a subject may emerge from DoC during the 5-day study period, as defined by 
the behavioral criteria for emergence from MCS on the CRS-R assessment (i.e. functional object 
use or functionally accurate communication).  If this occurs, then the subject will remain in the 
study to undergo the behavioral, EEG, and rs-fMRI assessments on the remaining study days, 
but the subject will not receive another dose of IV MPH.  The reason that another dose of IV MPH 
will not be administered is that the purpose of the study drug is to promote recovery of 
consciousness, and once a subject emerges from MCS to a higher level of consciousness, the 
potential benefits of the therapy may no longer outweigh the risks.  
 

 
 
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If a subject emerges from DoC, a board-certified neurologist on the study staff will assess the 
subject’s decision-making capacity to determine if the subject is capable of providing assent or 
consent.  If the subject is deemed to have capacity to provide assent or consent, the study 
investigator will ask the subject is he/she wishes to remain in the study to undergo additional study 
procedures. The additional procedures would include safety assessments (e.g. BP and HR 
monitoring), serum measurements of IV MPH (if the subject emerged from DoC within hours of 
receiving a dose of IV MPH while the pharmacokinetic measurements were still being performed), 
behavioral assessments, EEG and MRI.  The subject will be informed about the risks and benefits 
of the study, will be given the opportunity to ask questions (if capable of doing so), and will be 
notified that he/she may withdraw participation from the study at any time.  The subject will be 
asked to provide written or verbal assent or consent, according to his/her capacity to do so.   
 
If a subject emerges from DoC during the study, but then has a subsequent decline in level of 
consciousness such that the subject returns to a DoC (e.g. a subject could emerge from MCS but 
then go back into MCS), the subject will resume dosing of IV MPH according to the study protocol. 
 
Video recording of participants will be obtained pre-dose, during dose administration and post 
dose using an Apple iPhone 12 set upon a gorilla stand. The recording apparatus will not have 
direct contact to the participant and will be set up out of the way of clinical care. Further 
functionalities of the recording device (Apple iPhone 12) will be disabled such as voice recognition 
through Siri and calling services. The iPhone will be encrypted using the Partners research 
computing security system: mobileiron.  The recording will allow us to detect discreet changes in 
level of consciousness (if any) in response to IV Methylphenidate and may be correlated to the 
CRSR-R exam. Data will be recorded to the iPhone’s memory and uploaded to Partner’s Dropbox. 
The iPhone will be assigned an ID number and labeled with the PI name and IRB number. We 
will ensure data is linked to its respective participant by linking the data with each subject 
identification number (SID).  The iPhone will be disinfected and stored, all participant data will be 
copied from the device and erased from iPhone storage to allow sufficient memory and the device 
to be reused for other participants. 
 
At the time of study consent, participants will be notified that video recordings will take place 
before, during and after drug administration.  
 
4.2 DOSING CONSIDERATIONS  
 
There is extensive literature on the use of oral MPH.   
 
There is also literature on the use of IV MPH, which has been shown to be safe at doses ranging 
from 0.5 mg/kg to 0.88 mg/kg in healthy human subjects (see Section 7, Previous Human 
Experience).  Thus, our proposed starting dose of 0.5 mg/kg of IV MPH has, in effect, already 
been shown to be safe for administration to humans.  Notably, doses far higher than our maximum 
dose of 2.0 mg/kg have also been shown to be tolerated in human patients, albeit in a smaller 
number of studies.  Specifically, one study of 11 patients who had overdosed on barbiturates 
found that these patients tolerated IV MPH doses of 30 mg to 1400 mg without harmful side effects 

 
 
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(representing an estimated ~0.5 mg/kg to ~20 mg/kg, although exact patient weights were not 
reported in this study).54  Another study of 26 patients with barbiturate intoxication found that 
patients tolerated IV MPH doses of 60 mg to 1100 mg without harmful side effects (representing 
an estimated ~0.9 mg/kg to ~15.7 mg/kg, although exact patient weights were not reported in this 
study either).56  All doses of IV MPH that we propose in the STIMPACT trial – 0.5 mg/kg, 1.0 
mg/kg and 2.0 mg/kg – have thus been shown to be safe for administration to humans.   
 
In Section 7 (Previous Human Experience) we provide a comprehensive literature review on 
previous experience with IV MPH in human subjects.  In it we cite numerous papers that reported 
an MPH dose of 0.5 mg/kg IV or greater in healthy human subjects, with no serious adverse 
reactions.  We also cite several papers that detail the use of IV MPH in humans receiving sedation, 
which are relevant to our proposed study of patients with DoC, because both types of patients 
have depressed levels of consciousness that may have similar underlying neurobiological 
mechanisms.   
 
After carefully reviewing the literature, we concluded that 0.5 mg/kg IV MPH is a safe starting 
dose for this patient population in the ICU setting.  We believe that stepwise escalation of the 
dose to 1.0 mg/kg and 2.0 mg/kg on subsequent days is also likely to be safe, based upon the 
absence of SAEs at doses up to approximately 20 mg/kg in humans,54 as described above.  As 
in previous studies, MPH will be administered as an IV bolus.  All of the previous human studies 
cited in our IND application administered MPH as an IV bolus, indicating that this is safe.   
 
We selected a maximum dose of 2.0 mg/kg for our population of patients with DoC caused by 
severe brain injuries.  In doing so, we carefully considered the possibility that this dose of IV MPH, 
or even the 0.5 mg/kg or 1.0 mg/kg doses, could cause AEs in patients with brain injuries who 
may have hyperactivity of the sympathetic nervous system and elevated levels of serum 
catecholamines.57  Indeed, it is possible that serum catecholamine levels may be higher in the 
brain-injured population than in the populations of healthy human controls or patients with 
barbiturate overdoses who have been studies previously.  Nevertheless, we believe that dose 
escalation to a maximum of 2.0 mg/kg is clinically and ethically appropriate for the following 
reasons:  
 
1) Patients with severe brain injuries are likely to have at least partial disruptions to their VTA 
dopaminergic pathways, with consequent decreased production of dopamine.  Thus, a larger 
dose of IV MPH may be needed to generate adequate dopaminergic activity in VTA synapses to 
restore consciousness. 
 
2) If we proceed to Phase 2 and Phase 3 without establishing the maximum tolerated dose of IV 
MPH in the population of patients with DoC caused by severe brain injuries, we run the risk of an 
ethically unjustifiable enrollment of future patients in trials whose study design has not been 
optimized because the maximum tolerated dose was never appropriately identified in Phase 1.  
 
Given the need to establish the maximum tolerated dose, we considered the possibility of 
administering IV MPH at a dose higher than 2.0 mg/kg, especially since doses up to approximately 

 
 
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20 mg/kg were well tolerated, with non-harmful increases in HR and BP, in the 11-patient 
barbiturate overdose study.54  However, after carefully balancing the potential clinical benefits of 
higher doses of IV MPH with the potential risks, our judgment is that a dose of 2.0 mg/kg is the 
maximum dose at which the potential benefits continue to outweigh the potential risks.  Although 
doses far higher than 2.0 mg/kg were tolerated in the barbiturate overdose study, these patients 
likely were not experiencing the higher levels of catecholamines that may be present in patients 
with acute brain injuries caused by trauma, hypoxic-ischemic injury, or other mechanisms.  Thus, 
we believe that a maximum dose of 2.0 mg/kg minimizes the potential risk of a harmful increase 
in HR or BP, while still optimizing the chances that a subject will have an increase in level of 
consciousness due to IV MPH-mediated stimulation of partially preserved dopaminergic VTA 
neurons.   
 
 
4.2.1 ROUTE OF ADMINISTRATION 
Intravenous. 
4.2.2 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Day 0: no study drug administered 
Day 1: 0.5 mg/kg 
Day 2: 1.0 mg/kg 
Day 3: 2.0 mg/kg 
Day 4: 2.0 mg/kg 
 
4.2.3 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
If the subject experiences an AE at the lowest dose, then the subject will stop participation in the 
study.  If there is an AE at a higher dose, then the subject will receive the previously tolerated 
dose on subsequent days.  If there is an SAE at any dose, the subject will be withdrawn from 
the study. 
Prior to each administration of the study drug, the clinical team will be asked to approve 
administration of the drug.  If the clinical team states that the next dose should not be 
administered because of a clinical concern about the risk of IV MPH administration, then the 
dose will not be administered and the patient’s surrogate will be informed of the reason provided 
by the clinical team.  The subject would remain in the study to complete the observational 
components of the study (e.g. EEG, behavioral assessments, and rs-fMRI).  If this were to occur 
before the last day of the study, then the subject would have the opportunity to receive the drug 
on the next day if the clinical team approves of the next dose.  Importantly, the patient would not 

 
 
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skip a dose in the escalation protocol.  For example, if the patient has received the 0.5 mg/kg 
dose on Day 1 and the clinical team states that the 1.0 mg/kg dose should not be administered 
on Day 2 but can be administered on Day 3, then the subject would receive the 1.0 mg/kg dose 
on Day 3 and Day 4 and would not receive the 2.0 mg/kg dose.   
 
4.2.4 DURATION OF THERAPY 
4 days (Days 1-4).  No IV MPH is administered on Day 0. 
4.2.5 TRACKING OF DOSE 
Not applicable, given that each dose will be administered as an IV bolus in the ICU, directly 
observed by study staff.  
4.3 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
4.3.2 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
Not applicable. 
4.4 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
Monoamine oxidase inhibitors are contraindicated during the study.  
4.5 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
 
HR (bpm) 
< 120 
≥ 120 
SBP * 
(mmHg) 
< 180 
None 
5-10 mg IV 
metoprolol 
≥ 180 
5-20 mg IV 
hydralazine 
5-50 mg IV 
labetalol 
Prior to administration of each dose of IV MPH, the SBP must be < 180 mmHg and HR must be 
< 120 bpm.  If these goals are not met, prophylactic medications should be administered, as 
detailed in the table above.  The clinical team may decide to administer a different medication, 
or a different dose, per its clinical judgment, to meet these hemodynamic goals.  
* SBP > 180 mmHg is an exclusion criteria for enrollment in STIMPACT.  However, a subject’s 
SBP could rise above 180 mmHg after enrollment, prior to administration of IV MPH.  The 
prophylactic medication plan for SBP > 180 mmHg pertains to this type of subject. 
4.6 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
 

 
 
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HR (bpm) 
< 120 
≥ 120 
SBP 
(mmHg) 
< 180 
None 
5-10 mg IV 
metoprolol 
≥ 180 
5-20 mg IV 
hydralazine 
5-50 mg IV 
labetalol 
 
After administration of each dose of IV MPH, the SBP goal is < 180 mmHg and HR goal is < 120 
bpm.  If these goals are not met, rescue medications should be administered, as detailed in the 
above table. The clinical team may decide to administer a different medication, or a different dose, 
per its clinical judgment, to meet these hemodynamic goals.  
 
4.7 REASONS FOR WITHDRAWAL OR TERMINATION 
 
Participants are free to withdraw from participation in the study at any time upon 
request of their surrogate. Given that participants will only be enrolled if they have a 
DoC, no participant will have the decision-making capacity to withdraw 
himself/herself at the beginning of the study.  However, a participant may emerge 
from DoC and regain the capacity for assent or consent during the 5-day study (as 
detailed above), in which case the participant will be notified that he/she is free to 
withdraw from participation at any time.   
An investigator may terminate participation in the study if:  
• 
Any clinical AE, laboratory abnormality, or other medical condition or situation  
occurs such that continued participation in the study would not be in the best interest of 
the participant.  
• 
The participant meets an exclusion criterion (either newly developed or not previously  
recognized) that precludes further study participation. 
 
4.8 BIOSTATISTICAL ANALYSIS 
 
Sample Size Calculation 
22 subjects will be enrolled in this Phase 1, open label, dose-escalation, safety trial.  
Safety Analysis 
The incidence of AEs and SAEs will be calculated as the ratio of the number of events divided by 
the number of administrations of IV MPH at each dose. The percentage of subjects experiencing 
each documented AE and SAE will be reported for each dose.  
 
Pharmacokinetic Analysis 

 
 
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The T1/2 and TMax of IV MPH will be determined by analyzing the concentration of serum-level 
MPH over a time frame of 5 minutes to 16 hours. 
 
As pharmacokinetic and pharmacodynamic potency may differ between MPH enantiomers [73], 
serum samples will also be analyzed for d-threo-MPH and l-threo-MPH enantiomer 
concentrations (ng/mL). Non-compartmental analysis will be used to calculate pharmacokinetic 
parameters using Pheonix WinNonLin (Version 8.1; Certara, L.P; Princeton, NJ) to determine time 
to maximum concentration (Tmax) and elimination half-life (T½), as well as maximum concentration 
(Cmax) and area under the concentration-time curve (AUCinf). Pharmacokinetic data will be 
summarized using descriptive statistics.   
 
MRI Predictive Biomarker Analysis  
An MRI scan will be performed at the beginning of the study to measure the structural connectivity 
of the VTA using HARDI.  We will focus on VTA connectivity because the VTA is a dopaminergic 
arousal nucleus upon which IV MPH acts.  Graph theoretical analysis will be used to measure the 
connectivity of the VTA within the AAN.58  We hypothesize that higher VTA connectivity is 
associated with larger stimulant-based improvements in the EEG and rs-fMRI pharmacodynamic 
biomarkers.  
 
EEG Pharmacodynamic Biomarker Analysis  
Patients will be monitored with continuous EEG throughout the study. Functional connections 
between cortical regions will be measured for each pair of EEG electrodes.3  EEG-based 
functional connections will be quantified for the hour prior to and following the intervention.  We 
will measure the pre- vs. post-dose change in EEG connectivity.  We hypothesize that stimulant 
therapy is associated with an increase in EEG-based connectivity. 
 
Pharmacodynamic rs-fMRI Analysis 
On the last day of the study, all patients will receive IV MPH during an MRI scan.  A rs-fMRI 
sequence will be performed to measure brain network connectivity.4  The rs-fMRI sequence will 
be continuously acquired from 10 minutes before to 30 minutes after IV MPH administration.  We 
will measure the pre- vs. post-dose change in brain network connectivity.  We hypothesize that 
stimulant therapy is associated with an increase in brain network connections. 
 
 
5 RISK AND DISCOMFORT 
5.1 KNOWN POTENTIAL RISKS  
 
Overall, MPH has a long history of safe use in patients over the age of 6.  The FDA product 
description for oral MPH59 includes a comprehensive discussion of its side effects.  
 
Because it is a stimulant medication, MPH carries the risk of sudden death in certain high-risk 
patients with pre-existing cardiac disease.  It may also lower the seizure threshold in certain 
susceptible patients. Cardiac disease and status epilepticus or post-ictal state are thus 

 
 
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exclusion criteria for our study.  Because MPH is a pregnancy Category C drug, expectant 
mothers will also be excluded from our study.  There are also some concerns regarding 
carcinogenicity, as well as reproductive and developmental toxicities of MPH, but these are 
related to long-term use and therefore are less of a concern for our study.  A recently 
completed, unpublished study (Clinical Trials Identifier: NCT02051452), in which IV MPH was 
administered to patients undergoing general anesthesia, showed there were no SAEs over 
n=10 Phase I and n=32 Phase II patients (42 patients total). 
 
The risks of MPH fall in two categories: cardiovascular and non-cardiovascular.  
 
Cardiovascular Risks:  
The expected cardiovascular side effects of IV MPH are increases in HR, systolic BP, and diastolic 
BP.55, 60 Because the cardiovascular side effects occur within 4 to 10 minutes of the drug’s 
administration, and because these cardiovascular parameters will be continuously monitored in 
our study subjects, the ICU care team can readily treat these side effects with standard agents 
as soon as they appear.  Medications to treat these side effects will be prepared in advance and 
will be ready to administer prior to administering MPH.  Because of general concerns that the 
FDA has recently expressed regarding the effects of brain stimulants on the cardiovascular 
system and possible increased risk of sudden death and stroke,61 we will exclude any potential 
subjects with known structural cardiac abnormalities, cardiomyopathies, serious dysrhythmias, 
coronary artery disease, or other serious cardiac problems.  
 
Non-Cardiovascular Risks:  
In a subset of patients nausea, anxiety, euphoria or insomnia may occur.59 We will treat 
nausea/emesis, if necessary, by administering an anti-nausea/anti-emetic agent. Anxiety, 
euphoria and insomnia are potential side effects in healthy subjects that we do not expect to 
observe in patients with DoC.  
 
Neurological Risks: 
According to the FDA product description of oral MPH, there is some clinical evidence that 
stimulants may lower the seizure threshold in patients with a prior history of seizures, in patients 
with prior EEG abnormalities in absence of seizures, and, very rarely, in patients without a 
history of seizures and no prior EEG evidence of seizures.59  If seizures occur, they will be 
treated by the clinical team with anti-seizure therapy, per routine ICU care.  If seizures occur 
and the PI or Independent Medical Monitor believe that the seizure is related to IV MPH, then 
this will be considered a drug-related SAE and the subject will stop participation in the study.  
 
EEG Risk 
EEG is a well-established and safe clinical diagnostic tool. Using standard EEG equipment poses 
no significant risks to subjects and this component of the study will not interfere with other 
standard tests and procedures.  Minor discomfort such as irritation of the scalp may occur.  If a 
subject has an external ventricular drain in place during the study, the EEG leads will be placed 
in a way that does not interfere with the functioning or safety of the external ventricular drain, as 
has been previously reported.62 

 
 
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MRI Risk 
MRI is a well-established and safe clinical diagnostic tool. Using standard MRI equipment poses 
no significant risks to subjects and this component of the study will not interfere with other 
standard ICU tests and procedures. Some people become nervous or restless while in the MRI 
scanner or feel claustrophobic. Should this occur, the scan can be terminated. The MRI scanner 
emits loud sounds during image acquisition. Hearing protection is provided to all subjects via 
headphones or earbuds.  If the clinical team states that it is not safe for a subject to lie supine for 
an MRI scan due to concerns for increased ICP, then the subject will not undergo MRI.   
 
5.2 POTENTIAL BENEFITS  
Early recovery of consciousness would benefit patients by decreasing the risk of withdrawal of 
life-sustaining therapy, facilitating self-expression, enabling autonomous decision-making, 
decreasing ICU complications associated with immobility, and increasing access to post-ICU 
rehabilitative care. 
 
 
 6 ASSESSMENT OF SAFETY 
 
6.1 DEFINITION OF ADVERSE EVENTS (AES) 
An AE is defined as any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention-related (21 CFR 312.32 (a)).  In the current 
IND an AE may include, but is not limited to: 
• 
Sustained hypertension = SBP > 200 mmHg or DBP > 120 mmHg for > 30 min, refractory 
to medical therapy, or 
• 
Sustained tachycardia = HR > 120 bpm for > 30 min, refractory to medical therapy, or 
• 
Sustained intracranial hypertension = ICP > 25 mmHg for > 5 min, refractory to medical 
therapy  
6.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An AE or suspected adverse reaction is considered "serious" if, in the view of the investigator or 
the Independent Medical Monitor, it results in any of the following outcomes: 
• 
Death not related to withdrawal of life-sustaining therapy 
• 
A life-threatening adverse event  
• 
Prolongation of existing hospitalization  
• 
Persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
 
Important medical events that may not result in death, be life-threatening, or require prolonged 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include:  

 
 
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Neurologic 
• 
Seizure  
• 
Neuro-worsening = decline in Glasgow Coma Scale (GCS) score of ≥ 
2 points and/or loss of pupillary reactivity and/or deterioration in 
neurological or CT status sufficient to warrant immediate medical or 
surgical intervention 
Cardiovascular 
• 
Acute coronary syndrome 
Renal  
• 
Acute renal failure 
Pulmonary 
• 
Acute respiratory distress syndrome (ARDS) 
 
Any event that the Principal Investigator or the Independent Medical Monitor judges to 
impose a significant hazard, contraindication, side effect or precaution.  
 
Of note, the clinical criteria for the aforementioned events will be based upon event 
definitions published in a recent study of medical and neurological ICU complications by 
Muehlschlegel and colleagues.63  Also of note, all AEs and SAEs will be classified 
according to the SNOMED Clinical Trials criteria (https://browser.ihtsdotools.org/?) 
 
 
 
6.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
6.3.1 SEVERITY OF EVENT 
The Principal Investigator and Independent Medical Monitor will classify each AE using the following 
grading system:  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
6.3.2 RELATIONSHIP TO STUDY AGENT 
All AE’s will have their relationship to IV MPH intervention assessed by the Principal Investigator 
and Independent Medical Monitor based on temporal relationship and clinical judgment. The 
degree of certainty about causality will be graded using the categories below: 

 
 
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• 
Related – The AE is known to occur with IV MPH, there is a reasonable possibility that 
IV MPH caused the AE, or there is a temporal relationship between IV MPH 
administration and the event. Reasonable possibility means that there is evidence to 
suggest a causal relationship between IV MPH administration and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of IV MPH 
caused the event, there is no temporal relationship between administration of IV MPH 
and event onset, or an alternate etiology has been established. 
6.3.3 EXPECTEDNESS  
 
Expectedness will be determined by the Principal Investigator and Independent Medical Monitor 
with reference to the package insert for oral Ritalin (see IND #113736).  An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention. 
 
6.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by 
those with the training and authority to make a diagnosis), and time of resolution/stabilization of 
the event. All AEs occurring while on study will be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution, discharge from the hospital or death.  
 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. Documentation of onset and duration of each 
episode will be provided for AEs characterized as intermittent. 
The Principal Investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until for 7.5 hours (approximately five half-lives of IV MPH) after the 
last dose is administered. AE’s will be followed until resolution or stabilization. 
Any Clinical Oversight Committee member shall have the discretion and responsibility to 
recommend that the study be terminated.   
6.5 
REPORTING PROCEDURES 
 
6.5.1 ADVERSE EVENT REPORTING  

 
 
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All anticipated and unanticipated AE’s will be recorded in the REDCap data collection system 
throughout the study.  
The Clinical Oversight Committee, including the Independent Medical monitor will meet quarterly 
(four times per year) unless no patients are enrolled in a prior quarter.  
In accordance with IND, IRB and FDA requirements, AE’s will be reported on an annual basis 
by way of inclusion in the annual report and in the annual AE summary, which will be provided 
to the Independent Medical Monitor. The Clinical Oversight Committee will review all AEs. 
 
The following disease-related events common to patients with DoC caused by severe brain 
injuries (e.g. expected), will not be reported per the standard process for reporting, unless the 
Principal Investigator or the Independent Medical Monitor believes that the event is related to 
the study drug: hyperglycemia, fever, systemic inflammatory response syndrome, hypotension, 
pneumonia, anemia, hyponatremia, urinary tract infection, pulmonary edema, and venous 
thromboembolism.  Clinical criteria for these events are defined in a recent paper by 
Muehlschlegel and colleagues.63 Events that are part of the natural history of recovery from TBI 
and are key features of the post-traumatic confusional state (PTCS)65, such as agitation, 
insomnia and restlessness, will be recorded as events of clinical interest. Consistent with the 
operational definition of insomnia66, insomnia will only be reported as an adverse event if it is 
self-reported by the pariticpant. When a patient emerges from MCS into a confusional state, 
basic communication abilities often return, making it possible to assess for insomnia based on 
self-report.  
 
6.5.2 SERIOUS ADVERSE EVENT REPORTING  
 
SAEs that are unanticipated and possibly related to the study intervention (i.e. a single occurrence 
of an event that is uncommon and known to be strongly associated with IV MPH exposure or one 
or more occurrences of an event that is not commonly associated with IV MPH, but is otherwise 
uncommon in patients diagnosed with DoC caused by severe brain injuries) will be reported to 
the Independent Medical Monitor, IRB, and FDA in accordance with published guidelines.   
 
IND Safety reports will be submitted electronically in the common technical document (eCTD) 
format based on the following time-table:  
• 
7-day IND Safety Report (unexpected fatal or life-threatening AEs related to the 
intervention); a copy of the report sent to the Independent Medical Monitor within 24 
hours of FDA notification.  
• 
15-day IND Safety Report (any other serious and unexpected AE related to the 
intervention); a copy of the report submitted to the FDA will be submitted to the 
Independent Medical Monitor within 24 hours of FDA notification.  
All SAEs will be followed until satisfactory resolution or until the Principal Investigator deems the 
event to be chronic or the participant is stable. 

 
 
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The following disease-related medical events common to patients with DoC caused by severe 
brain injuries (e.g. expected), will not be reported per the standard process for reporting, unless 
the Principal Investigator or the Independent Medical Monitor believes that the event is related 
to the study drug: sepsis, acute respiratory distress syndrome, disseminated intravascular 
coagulation, acute renal failure, acute liver failure, and rhabdomyolysis.   
 
Similarly, the following disease-related neurological events common to patients with DoC 
caused by severe brain injuries (e.g. expected), will not be reported per the standard process for 
reporting, unless the PI or the Independent Medical Monitor believes that the event is related to 
the study drug: ICP crisis, herniation, rebleed (e.g. contusion expansion or subdural 
hemorrhage expansion), brain edema requiring osmotherapy, seizure, ischemic stroke, CNS 
infection.  Clinical criteria for these medical and neurological events are defined in a recent 
paper by Muehlschlegel and colleagues.63 
 
6.5.3 REPORTING EVENTS TO PARTICIPANTS  
 
The Principal Investigator will inform the participant’s clinical team on all AE’s and incidental 
findings. The clinical team and/or Principal Investigator will discuss findings with the participant’s 
surrogate (and the participant if he/she has regained the capacity for assent or consent) and 
recommend follow-up as needed.  
 
6.5.4 REPORTING OF PREGNANCY  
Females who are pregnant will not be enrolled in this study.  
 
7 UNANTICIPATED PROBLEMS 
 
7.1 DEFINITION OF UNANTICIPATED PROBLEMS 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research protocol 
and informed consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized.  

 
 
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The Principal Investigator and Independent Medical Monitor will be responsible for determining 
whether an AE is anticipated or unanticipated.  
 
7.1.1 UNANTICIPATED PROBLEM REPORTING 
The Principal Investigator will report unanticipated problems to the reviewing IRB, the 
Independent Medical Monitor, and the FDA via MedWatch 
(https://www.fda.gov/safety/medwatch/). The unanticipated problems report will include the 
following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an unanticipated problem;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the unanticipated problem. 
To satisfy the requirement for prompt reporting, unanticipated problems will be reported using 
the following timeline:   
• 
Unanticipated problems that are SAEs will be reported to the IRB and to the 
Independent Medical Monitor within 7 days of the investigator becoming aware of the 
event.  
• 
Any other unanticipated problems will be reported to the IRB and to the Independent 
Medical Monitor within 7 days of the investigator becoming aware of the problem.  
• 
All unanticipated problems will be reported to appropriate institutional officials (as 
required by Partners Human Research Committee written reporting procedures) and the 
OHRP within 7 days of the IRB’s receipt of the report of the problem from the 
investigator, in accordance with IRB policy. 
• 
Unanticipated problems will be reported to the FDA via MedWatch in a time frame 
consistent with FDA requirements. 
7.1.2 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
The Principal Investigator will inform the participant’s surrogate (and the participant if he/she 
has regained the capacity for assent or consent) of all unanticipated problems related to 
increased risk to subjects.  
 
8 MONITORING AND QUALITY ASSURANCE 
 
Safety oversight will be under the direction of the Clinical Oversight Committee composed of 
individuals with the appropriate expertise.  The Principal Investigator and Independent Medical 

 
 
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Monitor are both board-certified neurointensivist physicians.  The Clinical Oversight Committee 
also includes a neuro-ethicist with extensive experience working with patients with DoC caused 
by severe brain injuries.64  There are also experts in electrophysiology, neuroimaging, behavioral 
assessment, and statistics. The members of the Clinical Oversight Committee are free from 
conflict of interest. The Clinical Oversight Committee will meet at least quarterly (four times per 
year) to assess safety and biomarker data, unless no data are acquired in the prior quarter.  
 
Monitoring the validity and integrity of the data and adherence to the IRB-approved protocol will 
be the primary responsibility of the Principal Investigator. For each subject, he will confirm that 
written informed consent has been properly obtained, and that all data are appropriately recorded 
and maintained. The Principal Investigator will guarantee strict adherence to the IRB-approved 
protocol, and will monitor the integrity of the data collected. Should an AE need to be reported, 
the Principal Investigator will be responsible for reporting it in a timely manner according to the 
IRB regulations. All data collected during the study will be recorded and stored in a de-identified 
form for offline analysis.  
 
8.1 DATA AND SAFETY MONITORING PLAN 
 
The Data and Safety Monitoring Plan will be executed by the Independent Medical Monitor who 
will, on a quarterly basis, review all AEs and unanticipated problems, distinguish SAEs from non-
serious AEs, and provide attributions regarding causality and severity. Parameters for AEs and 
SAEs and subsequent action are described above.   
 
This study will be stopped prior to its completion if: (1) the intervention is associated with 
adverse effects that call into question the safety of the intervention; (2) difficulty in study 
recruitment or retention will significantly impact the ability to evaluate the study endpoints; (3) 
any new information becomes available during the trial that necessitates stopping the trial; or (4) 
other situations occur that might warrant stopping the trial. If the Independent Medical Monitor 
judges that risks to subjects outweighs the potential benefits, the Independent Medical Monitor 
shall have the discretion and responsibility to recommend that the study be terminated.  
 
 
9 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
9.1 
INSTITUTIONAL REVIEW BOARD  
This protocol and the informed consent document (see section 4a) and any subsequent 
modifications will be reviewed and approved by the IRB responsible for oversight of the study.   
9.2 
INFORMED CONSENT PROCESS  
 
9.2.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 

 
 
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A signed consent form will be obtained from the patient’s surrogate.  A copy of the consent form 
will be given to the surrogate. 
9.2.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent will be obtained from the patient’s surrogate.  The investigator obtaining 
consent will explain in detail the protocol of the study, its purpose and potential benefits to 
society.  The surrogate will be informed of all risks related to IV MPH and about the minimal 
risks of routine EEG and MRI. The surrogate will also be informed about the small space within 
the MRI scanner and noises made by switching gradients. The surrogate will be informed that 
his/her refusal to consent to the study or choosing to terminate it at some point will have no 
effect on care and treatment received by the participant at any Partners institution now or in 
future. The surrogate will be informed that the participant’s personal information will be 
protected as per the HIPAA guidelines. Surrogates will have as much time as they wish to 
consider consenting to the study. 
 
The surrogate will also provide screening information about the subject for MRI compatibility.  
Informed consent clearly states that the subject and surrogate may choose to terminate the 
study at any time. 
 
 
 
 
9.3 
PARTICIPANT AND DATA CONFIDENTIALITY  
Participant and data confidentiality will be maintained through routine precautions.  We assign a 
series of letters and numbers to the research data preventing the identity of the subject to be 
viewed. We keep any paper records of procedures and scans in a locked closet. In addition, all 
electronic clinical and imaging datasets will be de-identified using a code whose translation key 
will be stored on a password-protected network drive that is behind the institutional firewall and 
is securely backed up nightly.  Electronic data will be stored in one of two secured locations: 1) 
on a password-protected network drive that is behind the institutional firewall and is securely 
backed up nightly; or 2) in a secured, password-protected, web-based REDCap database.  Of 
note, REDCap was designed to comply with HIPAA regulations.  It utilizes “Secure Sockets 
Layer (SSL)” encryption, and it is the database tool that is currently recommended by Harvard 
Catalyst (see http://catalyst.harvard.edu/services/redcap/).  
Only authorized personnel will have access to these data.  The Principal Investigator shall be 
responsible for the confidentiality of the data and access to the data. We will take every 
precaution to preserve the rights of the research subject. 
9.3.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified only by the Study Identification Number (SID) to maintain subject confidentiality.  All 
records will be kept in a locked file cabinet.  All computer entry and networking programs will be 

 
 
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done using SIDs only.  Clinical information will not be released without written permission of the 
subject, except as necessary for monitoring by IRB, the FDA, the NINDS, or the OHRP. 
 
10 DATA HANDLING AND RECORD KEEPING  
 
10.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection and accurate documentation will be the responsibility of CITI-certified study staff 
under the supervision of the Principal Investigator.  All source documents and reports will be 
reviewed by the study team and data entry staff, who will ensure that they are accurate and 
complete.  Unanticipated problems and AE’s will be reviewed by the Principal Investigator. 
10.2 STUDY RECORDS RETENTION  
In compliance with local IRB policies, all study records will be maintained in an electronic 
regulatory REDCap binder. All individual subject-specific data will be stored in a separate file. 
Access to study documents will be restricted to study staff. Physical (paper) records will be 
stored in a secure locked office. Electronic records will be stored on Partners HealthCare 
compliant computers or mobile devices or other internally hosted services. Research records 
will be retained for at least seven years from the time the study is completed.  
10.3 PROTOCOL DEVIATIONS  
All protocol deviations will be reported to the local IRB in accordance with institutional policies. 
Minor protocol deviations, which do not have the potential to negatively impact subject safety or 
integrity of study data, or affect the subject’s willingness to participate will be recorded in a log 
and submitted with the annual IRB Continuing Review application. Major protocol deviations, 
alterations, or modification to the IRB-approved research that has the potential to negatively 
impact subject safety or integrity of study data, or subject willingness to participate, will be 
reported to the IRB within five working days of the date the investigator becomes aware of the 
unapproved deviation. 
 
 

 
 
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11 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Independent Medical Monitor 
Brian L. Edlow, M.D. 
Thomas P. Bleck, M.D. 
Massachusetts General Hospital 
Rush University  
 
 
 

 
 
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12 LIST OF ABBREVIATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AAN 
Ascending Arousal network 
AE 
Adverse Event 
BP 
Blood Pressure 
CRF 
Case Report Form 
CRS-R 
Coma Recovery Scale- Revised 
DMN 
Default Mode Network 
DoC 
Disorders of Consciousness 
EEG 
Electroencephalography 
EVD 
External Ventricular Drain 
FDA 
Food and Drug Administration 
GCS 
Glasgow Coma Scale 
HARDI 
High Angular Resolution Diffusion Imaging 
HR 
Heart Rate 
IRB 
Institutional Review Board 
ICP 
Intracranial Pressure 
ICU 
Intensive Care Unit 
IV 
Intravenous 
MCS 
Minimally Conscious State 
MGH 
Massachusetts General Hospital 
MPH 
Methylphenidate 
MRI 
Magnetic Resonance Imaging 
OHRP 
Office for Human Research Protections 
PTCS 
Post-traumatic Confusional State 
Rs-fMRI 
Resting State Functional Magnetic Resonance Imaging 
SAE 
Serious Adverse Event 
T1/2 
Half life 
TBI 
Traumatic Brain Injury 
TMAX 
Time to Maximum Concentration 
VS 
Vegetative State 
VTA 
Ventral Tegmental Area 

 
 
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13 
REFERNCES 
1. 
Giacino JT, Fins JJ, Laureys S, Schiff ND. Disorders of consciousness after acquired brain 
injury: the state of the science. Nature reviews Neurology 2014;10:99-114. 
2. 
Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement 
characteristics and diagnostic utility. Arch Phys Med Rehabil 2004;85:2020-2029. 
3. 
Chu CJ, Kramer MA, Pathmanathan J, et al. Emergence of stable functional networks in 
long-term human electroencephalography. J Neurosci 2012;32:2703-2713. 
4. 
Threlkeld ZD, Bodien YG, Rosenthal ES, et al. Functional networks reemerge during 
recovery of consciousness after acute severe traumatic brain injury. Cortex 2018:in press. 
5. 
Edlow BL, Takahashi E, Wu O, et al. Neuroanatomic connectivity of the human ascending 
arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol 2012;71:531-
546. 
6. 
Faul M, Xu L, Wald MM, Coronado VG. Traumatic brain injury in the United States: 
emergency department visits, hospitalizations and deaths 2002-2006. Atlanta (GA): Centers for 
Disease Control and Prevention, National Center for Injury Prevention and Control; 2010. 
7. 
Perel P, Arango M, Clayton T, et al. Predicting outcome after traumatic brain injury: 
practical prognostic models based on large cohort of international patients. BMJ 2008;336:425-
429. 
8. 
Kitamura T, Kiyohara K, Sakai T, et al. Public-Access Defibrillation and Out-of-Hospital 
Cardiac Arrest in Japan. N Engl J Med 2016;375:1649-1659. 
9. 
Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of-hospital 
cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation 
2010;81:1479-1487. 
10. 
Armed Forces Health Surveillance Center. Defense Medical Surveillance System (DMSS) 
and Theater Medical Data Store (TMDS). (Numbers for 2000 - 2017). http://www.dvbic.org/TBI-
Numbers.aspx 2017. 
11. 
Katz DI, Polyak M, Coughlan D, Nichols M, Roche A. Natural history of recovery from 
brain injury after prolonged disorders of consciousness: outcome of patients admitted to inpatient 
rehabilitation with 1-4 year follow-up. Prog Brain Res 2009;177:73-88. 
12. 
Gray M, Lai S, Wells R, et al. A systematic review of an emerging consciousness 
population: focus on program evolution. J Trauma 2011;71:1465-1474. 
13. 
Pisa FE, Biasutti E, Drigo D, Barbone F. The prevalence of vegetative and minimally 
conscious states: a systematic review and methodological appraisal. J Head Trauma Rehabil 
2014;29:E23-30. 

 
 
30 
 
 
 
 
 
 
                         Protocol Version 12/16/2021 
 
14. 
van Erp WS, Lavrijsen JC, van de Laar FA, Vos PE, Laureys S, Koopmans RT. The 
vegetative state/unresponsive wakefulness syndrome: a systematic review of prevalence studies. 
European journal of neurology 2014;21:1361-1368. 
15. 
Nakase-Richardson R, Whyte J, Giacino JT, et al. Longitudinal outcome of patients with 
disordered consciousness in the NIDRR TBI Model Systems Programs. J Neurotrauma 
2012;29:59-65. 
16. 
Edlow BL, Giacino JT, Hirschberg RE, Gerrard J, Wu O, Hochberg LR. Unexpected 
recovery of function after severe traumatic brain injury: the limits of early neuroimaging-based 
outcome prediction. Neurocritical care 2013;19:364-375. 
17. 
Lo C, Shifteh K, Gold T, Bello JA, Lipton ML. Diffusion tensor imaging abnormalities in 
patients with mild traumatic brain injury and neurocognitive impairment. Journal of computer 
assisted tomography 2009;33:293-297. 
18. 
McNamee S, Howe L, Nakase-Richardson R, Peterson M. Treatment of disorders of 
consciousness in the Veterans Health Administration polytrauma centers. J Head Trauma Rehabil 
2012;27:244-252. 
19. 
Estraneo A, Moretta P, Loreto V, Lanzillo B, Santoro L, Trojano L. Late recovery after 
traumatic, anoxic, or hemorrhagic long-lasting vegetative state. Neurology 2010;75:239-245. 
20. 
Whyte J, Nakase-Richardson R, Hammond FM, et al. Functional outcomes in traumatic 
disorders of consciousness: 5-year outcomes from the National Institute on Disability and 
Rehabilitation Research Traumatic Brain Injury Model Systems. Arch Phys Med Rehabil 
2013;94:1855-1860. 
21. 
McNab JA, Edlow BL, Witzel T, et al. The Human Connectome Project and beyond: Initial 
applications of 300mT/m gradients. Neuroimage 2013;80:234-245. 
22. 
Fernandez-Espejo D, Soddu A, Cruse D, et al. A role for the default mode network in the 
bases of disorders of consciousness. Ann Neurol 2012;72:335-343. 
23. 
Thengone DJ, Voss HU, Fridman EA, Schiff ND. Local changes in network structure 
contribute to late communication recovery after severe brain injury. Science translational medicine 
2016;8:368re365. 
24. 
Schiff ND, Giacino JT, Kalmar K, et al. Behavioural improvements with thalamic 
stimulation after severe traumatic brain injury. Nature 2007;448:600-603. 
25. 
Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe 
traumatic brain injury. N Engl J Med 2012;366:819-826. 
26. 
Whyte J, Rajan R, Rosenbaum A, et al. Zolpidem and restoration of consciousness. Am J 
Phys Med Rehabil 2014;93:101-113. 
27. 
Thibaut A, Bruno MA, Ledoux D, Demertzi A, Laureys S. tDCS in patients with disorders 
of consciousness: sham-controlled randomized double-blind study. Neurology 2014;82:1112-
1118. 

 
 
31 
 
 
 
 
 
 
                         Protocol Version 12/16/2021 
 
28. 
Bodien YG, Chatelle C, Edlow BL. Functional Networks in Disorders of Consciousness. 
Semin Neurol 2017;37:485-502. 
29. 
Sharp DJ, Scott G, Leech R. Network dysfunction after traumatic brain injury. Nature 
reviews Neurology 2014;10:156-166. 
30. 
Edlow BL, Wu O. Advanced neuroimaging in traumatic brain injury. Seminars in 
Neurology 2012;32:372-398. 
31. 
Edlow BL, Haynes RL, Takahashi E, et al. Disconnection of the ascending arousal system 
in traumatic coma. J Neuropathol Exp Neurol 2013;72:505-523. 
32. 
Parvizi J, Damasio A. Consciousness and the brainstem. Cognition 2001;79:135-160. 
33. 
Strich SJ. Shearing of Nerve Fibers as a Cause of Brain Damage due to Head Injury: A 
Pathological Study of Twenty Cases. Lancet 1961;2:443-448. 
34. 
Rosenblum WI, Greenberg RP, Seelig JM, Becker DP. Midbrain lesions: frequent and 
significant prognostic feature in closed head injury. Neurosurgery 1981;9:613-620. 
35. 
Kinney HC, Korein J, Panigrahy A, Dikkes P, Goode R. Neuropathological findings in the 
brain of Karen Ann Quinlan. The role of the thalamus in the persistent vegetative state. N Engl J 
Med 1994;330:1469-1475. 
36. 
Kinney HC, Samuels MA. Neuropathology of the persistent vegetative state. A review. J 
Neuropathol Exp Neurol 1994;53:548-558. 
37. 
Newcombe VF, Williams GB, Scoffings D, et al. Aetiological differences in neuroanatomy 
of the vegetative state: insights from diffusion tensor imaging and functional implications. J Neurol 
Neurosurg Psychiatry 2010;81:552-561. 
38. 
Rosenblum WI. Immediate, irreversible, posttraumatic coma: a review indicating that 
bilateral brainstem injury rather than widespread hemispheric damage is essential for its 
production. J Neuropathol Exp Neurol 2015;74:198-202. 
39. 
Adams JH, Graham DI, Jennett B. The neuropathology of the vegetative state after an acute 
brain insult. Brain 2000;123 ( Pt 7):1327-1338. 
40. 
Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI, McLellan DR. Diffuse axonal 
injury in head injury: definition, diagnosis and grading. Histopathology 1989;15:49-59. 
41. 
Abou-Hamden A, Blumbergs PC, Scott G, et al. Axonal injury in falls. J Neurotrauma 
1997;14:699-713. 
42. 
Adams JH, Mitchell DE, Graham DI, Doyle D. Diffuse brain damage of immediate impact 
type. Its relationship to 'primary brain-stem damage' in head injury. Brain 1977;100:489-502. 
43. 
Tomlinson BE. Brain-stem lesions after head injury. J Clin Pathol Suppl (R Coll Pathol) 
1970;4:154-165. 

 
 
32 
 
 
 
 
 
 
                         Protocol Version 12/16/2021 
 
44. 
Gibson PH. A quantitative method for comparing the distribution of cerebral trauma in 
closed-head injuries with and without tentorial herniation. Neuropathol Appl Neurobiol 
1983;9:135-148. 
45. 
Crompton MR. Brainstem lesions due to closed head injury. Lancet 1971;1:669-673. 
46. 
Peerless SJ, Rewcastle NB. Shear injuries of the brain. Can Med Assoc J 1967;96:577-582. 
47. 
Izzy S, Mazwi NL, Martinez S, et al. Revisiting Grade 3 Diffuse Axonal Injury: Not All 
Brainstem Microbleeds are Prognostically Equal. Neurocritical care 2017. 
48. 
Gentry LR, Godersky JC, Thompson BH. Traumatic brain stem injury: MR imaging. 
Radiology 1989;171:177-187. 
49. 
Schweri MM, Skolnick P, Rafferty MF, Rice KC, Janowsky AJ, Paul SM. [3H]Threo-(+/-
)-methylphenidate binding to 3,4-dihydroxyphenylethylamine uptake sites in corpus striatum: 
correlation with the stimulant properties of ritalinic acid esters. Journal of neurochemistry 
1985;45:1062-1070. 
50. 
Volkow ND, Wang GJ, Fowler JS, et al. Dopamine transporter occupancies in the human 
brain induced by therapeutic doses of oral methylphenidate. The American journal of psychiatry 
1998;155:1325-1331. 
51. 
Heal DJ, Cheetham SC, Smith SL. The neuropharmacology of ADHD drugs in vivo: 
insights on efficacy and safety. Neuropharmacology 2009;57:608-618. 
52. 
Dopheide JA, Pliszka SR. Attention-deficit-hyperactivity disorder: an update. 
Pharmacotherapy 2009;29:656-679. 
53. 
Swanson JM, Volkow ND. Serum and brain concentrations of methylphenidate: 
implications for use and abuse. Neurosci Biobehav Rev 2003;27:615-621. 
54. 
Ticktin H, Epstein J, Shea JG, Fazekas JF. Effect of methylphenidate hydrochloride in 
antagonizing barbiturate-induced depression. Neurology 1958;8:267-271. 
55. 
Volkow ND, Wang GJ, Gatley SJ, et al. Temporal relationships between the 
pharmacokinetics of methylphenidate in the human brain and its behavioral and cardiovascular 
effects. Psychopharmacology 1996;123:26-33. 
56. 
Smith B, Adriani J. Studies on Newer Analeptics and the Comparison of Their Action with 
Pentylenetetrazole, Nikethamide and Picrotoxin. Anesthesiology 1958;19:115. 
57. 
Meyfroidt G, Baguley IJ, Menon DK. Paroxysmal sympathetic hyperactivity: the storm 
after acute brain injury. Lancet Neurol 2017;16:721-729. 
58. 
Crossley NA, Mechelli A, Scott J, et al. The hubs of the human connectome are generally 
implicated in the anatomy of brain disorders. Brain 2014;137:2382-2395. 
59. 
FDA. 
Oral 
Ritalin 
Product 
Description 
[online]. 
Available 
at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021284s020lbl.pdf. Accessed July 
23, 2018. 

 
 
33 
 
 
 
 
 
 
                         Protocol Version 12/16/2021 
 
 
60. 
Volkow ND, Wang GJ, Fowler JS, et al. Cardiovascular effects of methylphenidate in 
humans are associated with increases of dopamine in brain and of epinephrine in plasma. 
Psychopharmacology 2003;166:264-270. 
61. 
Adverse Effects of Psychostimulant Medications Working Group. ADHD Medications 
and Risk of Stroke In Young and Middle-Aged Adults; 2011. 
https://www.fda.gov/downloads/Drugs/DrugSafety/UCM279877.pdf. Accessed July 23, 2018. 
62. 
Chatelle C, Spencer CA, Cash SS, Hochberg LR, Edlow BL. Feasibility of an EEG-based 
brain-computer interface in the intensive care unit. Clin Neurophysiol 2018;129:1519-1525. 
 
63. 
Muehlschlegel S, Carandang R, Ouillette C, Hall W, Anderson F, Goldberg R. Frequency 
and impact of intensive care unit complications on moderate-severe traumatic brain injury: early 
results of the Outcome Prognostication in Traumatic Brain Injury (OPTIMISM) Study. 
Neurocritical care 2013;18:318-331. 
 
64. 
Fins JJ. Rights come to mind: Brain injury, ethics, and the struggle for consciousness. New 
York, NY: Cambridge University Press, 2015. 
 
65.  
Sherer M, Katz DI, Bodien YG, et al. Post-traumatic Confusional State: A Case Definition 
and Diagnostic Criteria. Archives of Physical Medicine and Rehabilitation. 101, 2041-2050, 
(2020). doi:10.1016/j.apmr.2020.06.021 
 
66.  
Edinger JD, Bonnet MH, Bootzin RR. Derivation of Research Diagnostic Criteria for 
Insomnia: Report of an American Academy of Sleep Medicine Work Group. Sleep. 27 (8), 1567-
1596, (2004). doi: 10.1093/sleep/27.8.1567.