Non-invasive Measurement of Cerebral Dynamic Autoregulation
Phase: NA
Conditions: Stroke
Sponsor: University of Pennsylvania

University of Pennsylvania    Institutional Review Board 
 
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Protocol Version dated March 17, 2016 
  
 
 
 
 Non-Invasive Measurement of Dynamic Autoregulation of Cerebral 
Blood Flow Using Diffuse Correlation Spectroscopy  
 
 
 
Principal Investigator:  
Michael Mullen, MD, MSCE  
3 W Gates Building  
3400 Spruce Street  
Philadelphia, PA 19104  
(215) 430-3466 
Michael.mullen@pennmedicine.upenn.edu 
 
IRB Number: 
 
821705 
 
NCT number: 
 
 
Date:                                           
NCT02442856 
 
March 17, 2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Version dated March 17, 2016 
  
 
 
 
 
 
 
 
 
 
 
Application for Review of Human Research: IRB Protocol Summary 
Biomedical Research 
Section II 
 
 
Principal Investigator:  
Mike Mullen, MD, MSCE 
 
 
 
 
3 W Gates Building 
 
 
 
 
 
 
 
3400 Spruce Street 
 
 
 
 
Philadelphia, PA 19104 
 
 
 
 
(215) 430-3466 
 
PROTOCOL # 821705 
Date: March 17, 2016 
 
PROTOCOL TITLE 
1.  Full Title: Non-Invasive Measurement of Dynamic Autoregulation of Cerebral Blood Flow Using Diffuse 
Correlation Spectroscopy 
 
2.  Brief Title: Non-invasive Measurement of Cerebral Dynamic Autoregulation 
 
STUDY SPONSORSHIP 
1.  Funding Sponsor: NIH R25 Research Grant 
 
 
PROTOCOL ABSTRACT 
 
List of Abbreviations 
dCA 
 
 
Dynamic Cerebral Autoregulation 
CA 
 
 
Cerebral Autoregulation 
CPP 
 
 
Cerebral perfusion pressure 
CBF 
 
 
Cerebral blood flow 
oCBF  
 
Optically measured Cerebral Blood Flow 
MAP 
 
 
Mean Arterial Pressure 
TCD 
 
 
Transcranial Doppler 
DCS 
 
 
Diffuse Correlation Spectroscopy 
ICP 
 
 
Intracranial Pressure 
CVR 
 
 
Cerebrovascular resistance 
CT 
 
 
Computed Tomography 
PET 
 
 
Positron emission tomography 
MRI 
 
 
Magnetic Resonance Imaging 
DRS 
 
 
Diffuse Reflective Spectroscopy 
VRF 
 
 
Vascular Risk Factors 
 
 

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OBJECTIVES 
1.  Overall Objectives 
The overall objective of this study is to evaluate the use of diffuse correlation spectroscopy (DCS) to non-invasively 
measure dynamic cerebral autoregulation (dCA).  Cerebral autoregulation (CA) refers to the process by which 
cerebral blood vessels change their caliber to ensure constant cerebral blood flow (CBF) in the face of changes in 
cerebral perfusion pressure (CPP).  Optical cerebral blood flow (oCBF) measurements will be correlated with 
changes in arterial blood pressure (ABP) to assess how CBF is maintained in response to changes in ABP.  CA 
measured by DCS will be compared with reference measurements using Transcranial Doppler (TCD). 
 
 
2.  Primary Objective 
The primary objective of this study is to validate the use of DCS to quantify dCA in healthy controls.  We will measure 
dCA with both TCD and DCS during acute changes in mean arterial pressure using thigh cuff deflation techniques 
in healthy subjects. Measurements will be compared between TCD and DCS in order to validate DCS as a tool to 
measure dCA.  We hypothesize that DCS based measurements will be tightly correlated to TCD based 
measurements. We hypothesize that continuous oCBF measurements will allow calculation of an autoregulation 
index that will correlate well with established methods for measuring CA using TCD.  The primary measured variable 
will be relative change in cerebral blood flow using DCS. 
 
BACKGROUND 
Cerebral Autoregulation 
CA allows blood flow to remain nearly constant during beat-to-beat changes in blood pressure, matching perfusion 
to metabolic demand. CA can be subdivided into dCA and static CA (sCA). dCA is the transient response of cerebral 
blood vessels to changes in blood pressure through changes in vessel resistance and arteriolar diameter, and is 
the strictest definition of CA. sCA refers to the control of blood flow during steady state conditions. Static 
autoregulation methods measure cerebral blood flow at two different steady state blood pressures and then 
calculate a static rate of regulation by calculating the percent change in CBF (or cerebrovascular resistance) divided 
by the change in arterial pressure.  While quantitative and relatively simple to interpret, static autoregulation 
measurements have multiple drawbacks.  First, static measures provide a single snapshot and do not allow dynamic 
measurements of how autoregulation changes over time.  In addition, these techniques require pharmacologic 
manipulations in blood pressure (such as infusion of a vasoconstricting agent to increase ABP), which may be 
contraindicated in critically ill patients and change other aspects of systemic physiology (such as vasomotor tone 
and cardiac output).  Dynamic measures of autoregulation assess time varying changes in CBF and 
cerebrovascular resistance (CVR) in response to an abrupt change in blood pressure (Aaslid, Lindegaard et al. 
1989) or in response to spontaneous fluctuations in ABP (Budohoski, Czosnyka et al. 2013). A standard method 
for calculating dynamic autoregulation is to measure the transient changes in cerebral blood flow that result from 
transient decreases in venous return and cardiac output following deflation of blood pressure cuffs applied to the 
thighs (Aaslid, Lindegaard et al. 1989). 
 
Prior human studies have documented that CA tightly controls flow over a range of mean arterial pressure from 60-
150mmHg (Paulson, Strandgaard et al. 1990). However, recent studies suggest that autoregulation may be 
impaired for up to 2 weeks following acute ischemic stroke (AIS), and that CA impairment may lead to poorer 
outcomes (Dawson, Blake et al. 2000, Dawson, Panerai et al. 2003, Reinhard, Roth et al. 2005, Atkins, Brodie et 
al. 2010, Aoi, Hu et al. 2012, Reinhard, Rutsch et al. 2012). The extent of CA impairment in acute stroke is likely 
highly variable. Early human studies determined that CA is impacted by age-related diseases, including 
hypertension and diabetes (McHenry, West et al. 1974, Dawson, Blake et al. 2000, Aries, Elting et al. 2010).  Animal 
models have also demonstrated impaired dCA in AIS and that the tissue becomes much more vulnerable to 
changes in blood pressure (Yang, Shah et al. , Smeda, VanVliet et al. 1999, Smeda 2003).  Based on the principle 
that CA is impaired following an acute ischemic event, current treatment recommendations revolve around tactics 
that increase cerebral perfusion (Goldstein 2000, Dawson, Panerai et al. 2003).  The American Heart 
Association/American Stroke Association guidelines recommend permissive hypertension to systolic of 220mmHg 
and diastolic to 120mmHg (Adams, del Zoppo et al. 2007). However, above the upper limit of CA blood vessels are 

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not able to adequately constrict to limit blood flow, which can lead to endothelial injury, breakdown of the blood-
brain barrier, and potentially cerebral edema (Nazir, Overell et al. 2004, Nazir, Overell et al. 2005). Data derived 
from this project will provide the groundwork for future projects using the DCS technique which may be able to 
establish a new bedside mechanism for identifying patients in whom dCA is impaired, allowing for more 
individualized use of permissive hypertension, intravenous fluids, and vasopressors. 
Limitations of existing autoregulation measurements 
 
Existing methods of measuring CBF include oxygen-15 positron emission tomography (PET), single-photon 
emission computed tomography (SPECT), arterial spin labeled MRI, and Xenon CT scanning, but these are not 
suitable for continuous or bedside monitoring (Chalela, Alsop et al. 2000, Baron 2001, Mahagne, David et al. 2004, 
Wintermark, Sesay et al. 2005). While transcranial doppler (TCD) ultrasound may be performed readily at the 
bedside, it does not directly measure CBF, but rather blood flow velocity (Bishop, Powell et al. 1986).  DCS is a 
novel method for non-invasively monitoring CBF developed at Penn by Yodh et al. and translated for bedside 
monitoring of acute stroke patients with support of an ongoing NINDS Bioengineering Research Partnership on this 
topic (Durduran, Zhou et al. 2009). In DCS, light scatter from flowing red blood cells in brain tissue is used to track 
rapid fluctuations and is used to derive the blood flow index (BFI), which has previously been shown to correlate 
with other blood flow measurements (Kim, Durduran et al. 2010, Mesquita, Schenkel et al. 2013). The BFI is derived 
from the DCS intensity auto-correlation function.  Current instrumentation allows for CBF calculations roughly every 
second (Durduran, Zhou et al. 2009). The benefit of this system is that it allows continuous bedside measurement 
of CBF and can be used in a variety of patient positions, such as supine compared to altered head-of-bed angles, 
as previously studied at our facility in brain injury patients, and in aging patients (Langewouters, Settels et al. 1998, 
Reinhard, Roth et al. 2005, Edlow, Kim et al. 2010, Kim, Durduran et al. 2010, Kim, Edlow et al. 2013).  Head of 
bed (HOB) manipulation has important limitations as a measure of cerebral autoregulation. HOB manipulation may 
alter intracranial pressure and vascular resistance in addition to blood pressure. Dynamic measures of 
autoregulation assess time varying changes in CBF and CVR in response to an abrupt change in blood pressure 
(Aaslid, Lindegaard et al. 1989) or in response to spontaneous fluctuations in ABP (Budohoski, Czosnyka et al. 
2013).  A standard method for calculating dynamic autoregulation is to measure the transient changes in cerebral 
blood flow that result from transient decreases in venous return and cardiac output following deflation of blood 
pressure cuffs applied to the thighs (Aaslid, Lindegaard et al. 1989, Newell, Aaslid et al. 1994, Tiecks, Lam et al. 
1995). To date, no evaluation of dCA with respect to acute blood pressure changes have been published using 
direct measurement of CBF via the DCS technique.  
 
Transcranial Doppler allows for the assessment of flow velocity in blood vessels.  It is based on the Doppler Effect, 
which results in sound being reﬂected at a higher or lower frequency depending on the velocity and direction of the 
reﬂector. The shift in frequency is directly related to the velocity of blood ﬂowing through an insonated vessel. 
Velocity is an indirect measure of cerebral blood flow (flow is equal to velocity times area).  TCD estimates of CBF 
may not be accurate if the area of the insonated vessel is variable.  A small study suggested that CBF, directly 
measured in the internal carotid artery during a surgical procedure, correlated with flow velocity measured by TCD 
(Newell, Aaslid et al. 1994).  As such, TCD has the potential to function as a useful surrogate for CBF; however, it 
is important to note that CBF at the tissue level often depends on blood supply from multiple vessels, not a single 
large artery.  Given that the ideal method for measuring autoregulation should assess CBF at the tissue level, TCD 
may not be a sufficiently accurate method to measure autoregulation.  In addition, TCD accuracy is operator 
dependent and requires an experienced technician.  Finally, while noninvasive, TCD measurements can be 
uncomfortable for patients since the ultrasound probe must be held in one position on the scalp with significant 
pressure.   
Dynamic cerebral autoregulation measurement using optics 
Under the direction of Dr. Arjun Yodh at the University of Pennsylvania Department of Physics and Astronomy, a 
versatile all-optical brain imaging probe has been constructed which has the ability to measure total hemoglobin 
concentration, blood oxygenation and blood flow non-invasively. This instrument combines two qualitatively different 
and complementary diffuse optical imaging modalities: (1) Diffuse Reflection Spectroscopy (DRS) for computation 
of blood oxygen saturation and total hemoglobin concentration, and (2) Diffuse Correlation Spectroscopy (DCS) for 

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measurement of blood flow.  These two diffuse optical imaging schemes hold a unique potential for continuous non-
invasive bedside imaging in humans (Hintz, Cheong et al. 1999, Benaron, Hintz et al. 2000). By allowing for 
accurate, real-time measurements of relative cerebral blood flow, non-invasive dynamic measures of cerebral 
autoregulation should be possible.  
 
The DCS device employed in this study uses diffuse light to probe tissue properties. Dynamic optical properties are 
monitored using diffuse correlation spectroscopy at 785 nm. Changes in the blood flow are obtained from the 
correlation decay times. Measurements are made from both the right and left frontal regions, with one rectangular 
probe on each side of the head.  Each probe has 1 source and 2 detector fibers.  The light from these probes 
penetrates about 0.5 cm into the brain. Each probe is covered with black padding (skin-compatible materials) in 
order to isolate the laser light and ensure good contact with the head.  The probes are held in place with medical 
adhesive tape and a padded Velcro band.  The input average power is 15 mW. Measurements are taken every 0.5 
seconds. 
  
Prior work from our group has validated DCS against other measures of CBF including Xenon CT and fluorescent 
microsphere measurements (Zhou, Eucker et al. 2009, Kim, Durduran et al. 2010). DCS has also been used in the 
laboratory to monitor changes during focal cerebral ischemia of rat brain (Zhou, Shimazu et al. 2008).  Finally, DCS 
has been successfully used in normal human subjects, and in patients with a variety of disease states including 
severe traumatic brain injury and ischemic (Durduran, Yu et al. 2004, Durduran, Zhou et al. 2009, Kim, Durduran 
et al. 2010). 
 
Optical CBF monitoring using DCS presents an exciting alternative to existing methods of measuring cerebral 
hemodynamics.  Compared to MRI, CT and PET, optical CBF monitoring is comparatively portable, inexpensive, 
non-invasive, and fast.  These unique attributes can be leveraged to study cerebral autoregulation in patients with 
brain injury and evaluate the impact of interventions in real-time. Optical measurements of cerebral blood flow do 
not require significant special technical expertise.  In addition, since the multiple optical probes can be placed in 
different locations on the head, spatial heterogeneities in cerebral autoregulation can be assessed.  Our goal is to 
measure dynamic autoregulation non-invasively using DCS.  We will induce a blood pressure change by rapidly 
deflating thigh blood pressure cuffs and measure changes in cerebral blood flow.  This will allow us to calculate 
changes in cerebrovascular resistance and provide a measure of cerebral autoregulation.   
 
Thigh Cuff Utilization 
 
Prior research evaluating dynamic cerebral autoregulation used thigh cuffs on healthy controls to artificially, but 
noninvasively and non-pharmacologically, induce brief changes in blood pressure. This study performed 6 episodes 
of 2 minute inflation in bilateral thigh cuffs to a pressure above the maximum systolic blood pressure of the awake, 
non-anesthetized subjects (Aaslid, Lindegaard et al. 1989). Other more recent studies have continued to use the 
thigh cuff technique in both healthy subjects (Tzeng, MacRae et al. 2014, Subudhi, Grajzel et al. 2015), as well as 
those with traumatic brain injury and stroke patients respectively (Bailey, Jones et al. 2013, Saeed, Panerai et al. 
2013). Of these studies using thigh cuff in healthy controls, traumatic brain injury, and stroke patients, only one 
subject (1.2%) out of) 83 total (49 healthy controls, 12 traumatic brain injury, 22 stroke) withdrew due to discomfort 
from the thigh cuffs.  None of these studies reported neurologic deterioration or any other adverse events secondary 
to thigh cuff utilization (Aaslid, Lindegaard et al. 1989, Bailey, Jones et al. 2013, Saeed, Panerai et al. 2013, Tzeng, 
MacRae et al. 2014, Subudhi, Grajzel et al. 2015). 
 
Surgical literature supports the safety of pneumatic tourniquet devices for bloodless field techniques. For upper limb 
bloodless field surgery using a tourniquet device, two hours of cuff inflation is considered safe (Noordin, McEwen 
et al. 2009). Although no prospective trials have been conducted to identify the maximum safe duration of lower leg 
ischemia using a pneumatic tourniquet device, trials have been done to evaluate the difference in recovery with and 
without tourniquet use.  One randomized controlled study demonstrated that for routine anterior cruciate ligament 
repair these devices are routinely used for a mean of 87 minutes with the cuff insufflated to an average of 269mmHg. 
This study was powered to determine if tourniquet use during surgery is associated with increased neuromuscular 
injury, strength deficits, or any impaired return of function.  The study showed that there was no evidence of injury 

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based on a wide range of tests (thigh girth, strength, functional testing, arthrometer evaluation, Lysholm knee scores 
and EMG) and 6-12 months (Arciero, Scoville et al. 1996).  In previous experiments and in our proposed 
experiments, the thigh cuffs are inflated for only 2-3 minutes. This brief period of ischemia is nearly 30 times less 
than what has been previously studied in the surgical literature.  Given the safety of prolonged thigh cuff inflation, 
the brief periods of arterial occlusion used in this study are expected to be safe and well tolerated.  
 
The tourniquet system that will be used in this study has been approved by the FDA as a Class-I medical devices, 
indicating that they present minimal harm to the user and do not present a reasonable source of injury through 
normal use (Noordin, McEwen et al. 2009). Development in tourniquet systems over the past 30 years make use 
much safer, including increased cuff width, micro-computer monitoring systems, auto-shut off in event of power 
failure, battery backup, and audio-visual alarms. Increased cuff width results in lower required tourniquet pressure 
to stop blood flow (McEwen, Kelly et al. 2002) and should further improve tolerability of cuff inflation. 
 
CHARACTERISTICS OF THE STUDY POPULATION 
1. Target Population 
Healthy adult volunteers with no history of prior brain ischemia. 
 
2.  Accrual 
20 subjects provides 90% power to detect a moderate correlation (rho=0.6), with alpha=0.05, based on a single 
sided test of correlation using Pearson’s correlation coefficient.  Because of a combination of technical and 
individual factors, it may be that not all enrolled subjects provide analyzable data.  The study will continue to enroll 
until we have complete, analyzable data on 20 subjects, or a maximum of 30 subjects will be enrolled.  We will 
evaluate the quality of obtained data on a rolling basis and halt study enrollment as soon as we have met our goal 
of 20 subjects with data for analysis.    
 
3.  Key Inclusion Criteria 
 
A.  Healthy Subjects 
1. Age ≥ 18 years  
4.  Key Exclusion Criteria 
 
A. Healthy Subjects 
1. Pregnant women are excluded 
2. Prisoners are excluded 
3. Prior history of vascular risk factors (hypertension, diabetes, hyperlipidemia, coronary artery 
disease, atrial fibrillation, prior myocardial infarct or stroke, transient ischemic attack, or 
history of smoking) 
4. Prior neurosurgical procedure or traumatic brain injury, including hemicraniectomy or other 
skull defect. 
5. Prior lower extremity amputation. 
 
5.  Vulnerable Populations 
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study. 
 
6.  Populations vulnerable to undue influence or coercion 
Penn employees and Penn students:  
Care will be taken during the consenting process to ensure that any Penn employee who meets the inclusion criteria 
for this study is not forced to participate on the basis of pay or the threat of loss of his or her position.  Care will be 
taken during the consenting process to ensure that any Penn student who meets the inclusion criteria for this study 
is not forced to participate on the basis of a grade. 
 
Educationally disadvantaged persons: 

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Care will be taken during the consenting process to fully explain the study in easily understood terms and to confirm 
the patient’s comprehension of the information put forward.  For specific information on how this will be 
accomplished, please see the “consent process” section. 
 
Economically disadvantaged persons:  
Subjects will not be paid in an amount that would encourage subjects to assume greater risks to participate in this 
study. 
 
7.  Subject Recruitment  
Volunteers will be recruited from the University of Pennsylvania community.  Advertisements will be placed across 
campus describing the research study and providing contact information.  In addition, volunteers from the 
surrounding community who are not affiliated with the University of Pennsylvania will be allowed to participate if 
they meet the inclusion criteria. Subjects will not be excluded on the basis of gender, economic status, or race.  
 
 
STUDY DESIGN 
1.  Phase 
Not applicable 
 
2. Design 
Observational study 
 
3. Study Duration  
Based upon the study design, 30 subjects will be enrolled over approximately 18 months. Each subject will be tested 
for approximately 1.5 hours with approximately a half hour for proper setup and removal of measuring instruments. 
 
DRUGS OR DEVICES 
 
The optical device used in this study was developed at the University of Pennsylvania in the Department of Physics 
and Astronomy under the direction of Dr. Arjun Yodh.  The instrument has been approved by the Environmental 
Health and Radiation Safety Department at the University of Pennsylvania for laser safety (B00050001).  It will be 
stored securely in a locked room in the ninth floor of the Silverstein building at HUP.  During monitoring sessions it 
will be brought to the Neurology clinic for healthy volunteers and to the patient’s bedside for inpatient subjects.  After 
the study session, it will be secured by study personnel.  
 
The Transcranial Doppler is standard equipment used in the neurodiagnostics lab at the University of Pennsylvania. 
It will be stored securely in a locked room in the 2nd floor of the Ravdin building at HUP.  During monitoring sessions 
it will be brought to the Neurology clinic for healthy volunteers and to the patient’s bedside for inpatient subjects.  
Following the study session, it will be secured by study personnel. 
 
The Finapres device allows for non-invasive continuous arterial blood pressure measurement. It will be stored 
securely in a locked room in the ninth floor of the Silverstein building at HUP.  During monitoring sessions it will be 
brought to the Neurology clinic for healthy volunteers and to the patient’s bedside for inpatient subjects.  After the 
study session, it will be secured by study personnel. 
 
The Thigh Cuff device allows for artificial elevation of blood pressure and artificial abrupt drop in blood pressure. It 
will be stored securely in a locked room in the ninth floor of the Silverstein building at HUP.  During monitoring 
sessions it will be brought to the Neurology clinic for healthy volunteers and to the patient’s bedside for inpatient 
subjects.  After the study session, it will be secured by study personnel. 
 
 
STUDY PROCEDURES 
1.  Procedures 

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After obtaining informed consent, all subjects will be placed supine with the head of bed flat.  A non-invasive 
Finapres blood pressure probe will be placed on a finger to continuously record arterial blood pressure.  Heart rate 
will be calculated by analyzing the frequency of pulsatile blood flow.  After the patient is comfortable optical probes 
will be attached to the patient’s forehead. The probes are embedded in foam pads that will be secured to each side 
of the forehead using a combination of medical adhesive tape and a padded Velcro strap.  The pads will be placed 
at the temporal margin of the forehead, superior to the frontal sinuses. A transcranial Doppler ultrasound probe will 
be placed on the scalp at the temporal bone to insonate the middle cerebral artery (MCA) and/or the anterior 
cerebral artery (ACA) bilaterally and secured in place using a commercial head frame The goal will be to insonate 
the MCA on one side and the ACA in the contralateral side.  Due to limitations of TCD insonation and variability in 
temporal bone windows, this may not be possible in all subjects.  In this way, optical blood flow from the right and 
left frontal cortex and blood flow velocity in the anterior cerebral circulation will be recorded simultaneously during 
the study session.  A large blood pressure cuff will be placed around each thigh.  Both cuffs will be connected 
together with a large bore Y-adapter that is connected to a bulb inflator.   
 
Once the patient is comfortable, optical blood flow and TCD blood flow velocity will be measured for 5 minutes to 
establish a baseline.  Both thigh cuffs will then be inflated to 20 mmHg above the patient’s systolic blood pressure 
so that blood flow to the legs is occluded.   Occlusion will be maintained for 4 minutes, followed by simultaneous 
deflation of bilateral cuffs and concurrent recording of blood pressure and CBF for an additional 4 minutes; 3 
measures will be obtained per subject and averaged to establish a curve. The rapid deflation of the thigh cuffs will 
induce a 5-10% step decrease in blood pressure that is expected to last for about 10 seconds before cardiovascular 
reflexes restore MAP to baseline levels.  During the thigh cuff deflation, changes in pulsatile blood pressure, and 
TCD blood flow velocity will be continuously recorded; oCBF will be recorded every 0.5 seconds. Intact 
autoregulation should cause a restoration of cerebral blood flow to pre-deflation values within 5-10 seconds in spite 
of the prolonged decrease in systemic blood pressure.  We expect to see a sudden drop in optical cerebral blood 
flow and MCA velocity followed by a quick increase in both of these parameters.  The change in cerebrovascular 
resistance (ΔCVR) can be calculated by dividing arterial blood pressure by cerebral blood flow.  ΔCVR will be 
calculated using both optical CBF values and MCA velocity.  The magnitude of ΔCVR over time gives a measure 
of dynamic cerebral autoregulation (see below for details regarding analysis). The thigh cuff occlusion will be 
repeated 4 times in each subject to establish a curve. A diagram of the study flow is shown below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Data Collected 
Subject preparation: supine 
position, attach Finapres, 
oCBF probe, TCD probe, thigh 
cuffs 
Establish CBF 
baseline 
Inflate thigh cuff 
Rapidly deflate thigh cuff while 
recording BP, oCBF and TCD, 
re-establish baseline 
Repeat thigh cuff 
inflation/deflation 
cycle x 2 
Disconnect  
30 min 
5 min 
4 min 
4 min 
… 
15 min 

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Information will be collected and stored securely from all study subjects. This information will include the following: 
age, sex, past medical history, current medications, non-prescription drug use. 
 
3.  Quantitative and Statistical Analysis 
 
dCA will be calculated as change in blood pressure from baseline (ΔBP) divided by change in cerebral blood flow 
from baseline (ΔCBF) at each time point, thus dCA = ΔBP/ΔCBF(Aaslid, Lindegaard et al. 1989); this data will be 
plotted against time in seconds.   
 
The data recorded from the TCD monitoring will be used to quantify the relation between changes in 
cerebrovascular resistance (ΔCVR) and blood pressure (ΔBP) as calculated by ROR = (ΔCVR/ΔT)/ΔBP and will be 
plotted along a curve for the first few seconds after cuff deflation (Aaslid, Lindegaard et al. 1989, Tiecks, Lam et al. 
1995, Panerai, White et al. 1998, Lang, Mehdorn et al. 2002).  The purpose of collecting TCD data is to show a 
correlation between the ROR calculated from TCD measures to that of dCA via DCS measurement, further 
validating our DCS measurements.   
 
The optical CBF output is directly recorded as relative CBF.  For blood flow velocity measured by TCD, relative CBF 
can be approximated by normalizing flow to baseline.  This is an approximation of CBF that assumes that the vessel 
diameter does not change over time.  Once the relative change in CVR over time is calculated, a dynamic rate of 
regulation index (dRoR) can be calculated by dividing the slope of the CVR over time curve by the maximum change 
in blood pressure (i.e. (ΔCVR/Δt)/ΔBP).  Intuitively, if autoregulation is intact, there should be a steep decrease in 
cerebrovascular resistance with a drop in blood pressure.  Perfect autoregulation would result in dRoR = 1.   
 
Baseline heart rate, MAP, and MCA velocity will be recorded for each subject and descriptive statistics including 
mean and standard deviation will be reported for these values.  For dRoR calculation, a mean dRoR will be 
calculated for each subject (from 5 trials) using both optical CBF and TCD.  The optical dRoR and TCD dRoR will 
be compared for each subject and significant differences will be evaluated using Student’s t-test or Wilcoxon rank-
sum as appropriate.   We will quantify the correlation between dRoR measured with TCD and DCS using Pearson 
or Spearman correlation coefficient as appropriate.  
 
4.  Confidentiality 
How will confidentiality of data be maintained?  Check all that apply. 
 
 Paper-based records will be kept in a secure location and only be accessible to personnel involved in the 
study. 
 Computer-based files will only be made available to personnel involved in the study through the use of 
access privileges and passwords. 
 Prior to access to any study-related information, personnel will be required to sign statements agreeing to 
protect the security and confidentiality of identifiable information. 
 Whenever feasible, identifiers will be removed from study-related information.  
 
 A Certificate of Confidentiality will be obtained, because the research could place the subject at risk of 
criminal or civil liability or cause damage to the subject’s financial standing, employability, or liability. 
 A waiver of documentation of consent is being requested, because the only link between the subject and the 
study would be the consent document and the primary risk is a breach of confidentiality.  (This is not an option 
for FDA-regulated research.)  
 Precautions are in place to ensure the data is secure by using passwords and encryption, because the 
research involves web-based surveys.   
 Audio and/or video recordings will be transcribed and then destroyed to eliminate audible identification of 
subjects.  
 Other (specify):  
 
 

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5. Privacy 
Subject confidentiality will be maintained at all times and study information will be protected against release to 
unauthorized people. Subjects will be assigned study numbers for entry into the protocol; this number alone will 
identify them. Subjects are free to refuse participation in the study and can withdraw at anytime without 
compromising care. 
 
All data obtained in this study will be entered into a secure password protected database and de-identified. 
 
HIPAA  
The following protected health information (PHI) will be collected: 
• 
Name 
• 
Date of birth 
• 
Social Security Number 
 
Collected PHI will be recorded on the case report form, which will be secured as detailed above.  This data may be 
disclosed to the medical monitor in the event of a potential adverse event.  It will otherwise not be disclosed to anyone 
not listed on Section I of this application.   
 
The HIPPA authorization for this study will be incorporated into the informed consent form.  In the event that a subject 
revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to use all information 
collected prior to the revocation of subject authorization.   
 
6.  Tissue Specimens 
Not applicable 
 
7.  Genetic Testing 
Not applicable 
 
RISK/BENEFIT ASSESSMENT 
1.  Potential Study Risks 
 
Pregnancy risks 
There is not enough information about the effect of infrared light to pregnant women, or their fetus.  Female 
participants will be screened and excluded for pregnancy by clinical history.  There is not a risk of pregnancy during 
the study as patients will be continuously monitored during the study period.  
 
Risks of DCS/Optical Blood Flow Monitoring: There is a risk of damage to the eye if the eye is exposed directly 
to the infrared light coming from the DCS patches.  Damage could include retinal (light sensitive tissue at the back 
of the eye) burn.  In order to prevent such an injury we will put optical fibers in a foam pad where they will be away 
from the surface of the skin.  Therefore the light will be concentrated on the top of the head.  The probes will be 
secured by a lightly wrapped bandage which will ensure that the light pads remain secure, covered,  and away from 
the eyes.  In addition the patient can elect to wear safety goggles that will reduce the risk of retinal damage if probes 
and protective foam become dislodged.   
 
A research staff member will be continuously monitoring the subject while on the study and will be able to cycle the 
light off in less than three seconds.  The instrument has passed clinical engineering safety inspection.   
 
A member of the study team will be present at all times and will assist in the placement of the probe(s) and the 
collection of the data. No discomfort should be associated with the procedure. 
 
Risks of Transcranial Doppler Monitoring: 
 

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There is no known risk of the use of ultrasound equipment for transcranial doppler monitoring.  It is non-ionizing 
radiation, and therefore does not have the same risk as x-rays or other types of radiation.  
 
A member of the study team will be present at all times and will assist in the placement of the probe(s) and the 
collection of the data. At times the TCD probes can cause mild discomfort.  If the subject feels uncomfortable study 
personnel will attempt to reposition the probes to maximize comfort.  If at any point the discomfort becomes 
significant, the study will be terminated.  
 
Risks of non-invasive blood pressure monitoring: 
 
There is no known risk of the use of non-invasive blood pressure monitoring via the Finapress system.  
 
A member of the study team will be present at all times and will assist in the placement of the probe and the 
collection of the data. No discomfort should be associated with the procedure. 
 
Risks of Thigh Cuff Manipulation of Blood pressure 
 
There is a risk of discomfort during the thigh cuff inflation. This discomfort will be related to the inflation of the cuff 
around the thigh and is expected to be the same amount of discomfort as experienced during routine brachial blood 
pressure measurement, only sustained for 3 minutes. A member of the study team will be present at all times. If the 
subject feels uncomfortable study personnel will attempt to reposition the cuffs around the thigh.  If at any point the 
discomfort becomes significant, the study will be terminated. 
 
2.  Potential Study Benefits 
There will be no direct benefit to subjects as a result of their participation in this study; however, information gained 
from this research will lead to a better understanding of cerebrovascular physiology.  
 
3.  Alternatives to Participation 
Participation in this research study is voluntary.  Subjects who do not wish to participate in the study will not be 
coerced into participating.  
 
4.  Data and Safety Monitoring 
Who will monitor this study? Check all that apply. 
 Principal Investigator 
 Sponsor or contract research organization 
 NCI sponsored cooperative group 
 Cancer Center (if mandated by CTSMRC) 
 Medical monitor 
 Safety monitoring committee 
 Data and safety monitoring board 
 
5. Management of Information for Multi-center Research where a Penn Investigator is the Lead 
Investigator of a multi- center study, or Penn is the lead site in a multi-site study. 
Not applicable 
 
6.  Risk/Benefit Assessment 
Low Risk:  This study represents a minor increase over minimal risk.  There is a small risk in retinal damage from 
infrared laser radiation from the optical blood flow monitor; however, the exposure of infrared light to the patient’s eye 
is minimal to zero. Information gained from this study may be foundational for future use of DCS technology and 
ultimately help take care of patients with many types of brain injury.  In light of the anticipated benefits to others, the 
risks, which are quite modest, are reasonable.  
 
SUBJECT COMPENSATION 

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Subjects will be compensated with $25. 
 
INFORMED CONSENT 
1. Consent Process 
Informed consent is an ongoing process that takes place between the investigator/study staff and study participants.  
Informed consent for this research study will be obtained by the Principal Investigator or her designee (co-
investigators or a research nurse/research coordinator from the Neurosurgery Clinical Research Division).  It is the 
responsibility of the Principal Investigator (PI) to ensure that informed consent has been properly obtained.   
During the consent process, the person obtaining consent will 
1. Approach the prospective subject to introduce the research team and the project.  
o 
The discussions will take place in an area where privacy and confidentiality can be 
respected.  
o 
Subject must be given sufficient time to comprehend the research.  
2. Review the research study and the informed consent form with the subject.  
o 
The researcher should clearly explain the background/purpose, voluntary nature, 
commitment, risks, benefits, alternatives, and other elements making sure to include 
all the necessary elements of informed consent.   
3. Answer any preliminary questions.  
4. Allow the subject time to review the informed consent form independently.  
o 
Provide the subject with a sample consent form to review prior to the consenting 
process and study appointment.  
o 
Subjects will be given time to discuss participation with family or friends if they so 
desire. 
5. Evaluate the subject's understanding by asking open-ended questions about the study and 
addressing any misperceptions or unanswered questions. Possible questions include:  
 
Can you describe the study in your own words? 
 
What more would you like to know? 
 
Would you please explain to me what we are asking you to do? 
 
What are your concerns? 
6. If willing, ask the subject to sign and date the consent document.  
o 
Subjects must sign and date the most recent IRB-approved version of the informed 
consent form. 
o 
The consent form must contain an approval stamp from the IRB.  
o 
The person obtaining consent should also sign and date the informed consent form.  
7. Give the subject a copy of the signed and dated informed consent form.  
8. Document the informed consent process. A note in the research records may include:  
 
Name of study and subject 
 
Date and time of consent 
 
Statement that the benefits, risks, commitment and alternatives were 
discussed 
 
Presence of any family members, friends, or witnesses  
 
Description of subject's level of understanding 
 
Specific, relevant criteria not otherwise captured (e.g. time frames of 
screening tests that are not apparent in records) 
 
2.  Waiver of Authorization 
Not applicable 
 
RESOURCES NECESSARY FOR HUMAN RESEARCH PROTECTION 

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All research staff have completed their Patient Oriented Research Training (POR) and/or Collaborative Institutional 
Training Initiative (CITI).   There will be study-specific “Team Meetings” to train and review study processes ensuring 
compliance, patient safety and confidentiality. Study-specific monitoring will be conducted by the study sponsor as 
well UPHS regulatory committees responsible for review of patient oriented research. 
 
Neither Dr. Detre nor Dr. Yodh will consent study subjects. Dr. Detre and Dr. Yodh will not personally acquire the 
primary data nor personally calculate the results of the primary data.  In those cases where TCD data may be 
generated, to the extent (if any) Dr. Detre oversees analysis of any TCD data, he will do so without knowledge of 
the optical device findings.  
 
 
 

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