research thesis proposal written and oral.

Breathing Patterns to Minimize Cardiovascular Disease Risk in Major Depressive Disorder

Introduction

Cardiovascular disease (CVD) is the leading cause of death within the United States (Kochanek et al., 2019). Importantly,

there is strong epidemiological and experimental evidence to suggest those with a large-magnitude of stressor-evoked

cardiovascular reactions (i.e. heart rate, blood pressure) are at an elevated risk for CVD (Carroll, Ginty et al., 2012;

Carroll, Phillips et al., 2011; Allen et al., 1997). Epidemiological studies have also linked major depressive disorder

(MDD) to CVD and all-cause mortality, independent of socioeconomic status and traditional CVD risk factors (Kozela et

al., 2016). Depression is linked to autonomic dysfunction, specifically sympathetic overactivity (Scalco et al., 2009;

Koschke et al., 2009), which contributes to the development of hypertension, heart failure, arrhythmias, and

atherosclerosis (Grassi et al., 2004; Erami et al., 2002). Furthermore, MDD is the leading cause of disability worldwide

(WHO, 2017) with an economic burden of $210.5 billion in the United States in 2010 (Hasin et al., 2018) and at least one

third of patients are resistant to current treatment practices (Rush & Jain, 2018). Altogether, these findings warrant the

discovery of novel therapies targeting autonomic function in depressed adults.

Device-guided slow breathing (DGSB) has emerged as a potential therapy to lower blood pressure and sympathetic

nervous system activity in disorders characterized by sympathetic overactivity (Oneda et al., 2010; Fonkoue, Marvar et

al., 2018). Although DGSB is effective at acutely lowering blood pressure and muscle sympathetic nerve activity (MSNA),

long-term cardiovascular benefits may not be seen (Fonkoue, Yingtian et al., 2020) due to a lack of psychobehavioral

effects of the therapy. Alternatively, mindful-based meditation results in similar breathing patterns (<10 breaths/min) as

DGSB (Peng et al., 2003) while encouraging the individual to be present in the moment and to acknowledge and accept

their thoughts without judgement. Indeed, mindful meditation has been shown decrease in anxiety, depression, blood

pressure and MSNA in young adults and those with disorders characterized by sympathetic overactivity (Bell, 2015; Park

et al., 2014). Furthermore, mindful meditation may target brain processing alterations present within depression (Fales

et al., 2008) resulting in greater reductions of cardiovascular reactivity compared to device-guided slow breathing during

stress-evoking situations.

Given these findings, we hypothesize that depressed young adults will show attenuated cardiovascular reactivity during

a stress-evoking situation while practicing device-guided slow breathing or mindful meditation. Furthermore, depressed

young adults will show greater attenuations in cardiovascular reactivity during mindful meditation compared to device-

guided slow breathing.

Methods

The proposed study will evaluate the effects of 15 minutes of device-guided slow breathing and 15 minutes of mindful

meditation (MM) (independent variables) on respiratory rate (breaths/min), MSNA burst frequency (bursts/min) and

incidence (bursts/100 heart beats), blood pressure (mmHg), and heart rate (beats/min) (dependent variables) during the

cold pressor test (CPT). The primary outcome of this project is MSNA burst frequency (bursts/min).

A total of 25 young adults (18-35 years old) with depressive symptoms will be recruited for this study. Participants will

be recruited from the University of Texas at Arlington and the surrounding area through the use of flyers, email, social

media, class presentations, and radio ads. Inclusion criteria consists of those 18-35 years old and confirmation of

depressive symptoms with a diagnostic interview. Exclusion criteria consists of a mental illness aside from depression,

any use of depression mediation, active suicidal/homicidal intent, active alcohol or drug dependence, an eating disorder,

use of medication that could alter how the brain or cardiovascular system functions, cardiovascular, kidney, lung or

metabolic disease, tobacco use, pregnancy, or amenorrhea (women).

Sample size was calculated a priori using G-power. MSNA measurement in young adults with MDD has not been studied

to our knowledge; therefore, due to the similarities between posttraumatic stress disorder (PTSD) and MDD, MSNA

values were estimated from studies involving young adults with PTSD (Fonkoue, Marvar et al., 2018). Estimates of MSNA

values during the DGSB+CPT and MM+CPT conditions were derived from both previous studies of MSNA recordings

during both breathing patterns, and clinically significant MSNA values (Park et al., 2014; Fonkoue, Marvar et al., 2018).

Means were estimated as the change score between a cold-pressor test and the DGSB+CPT condition, and the change

score between a cold-pressor test and the MM+CPT condition. Accounting for a 70% success rate on peroneal nerve

innervation and MSNA recording, a total of 25 subjects are needed to detect a 3 burst/min difference between DGSP

and MM conditions with 80% power and an alpha level of 0.05.

Experimental Approach

Participants will arrive to the laboratory for one screening visit and two experimental visits. Each participant will be

randomly allocated to the device-guided slow breathing or mindful meditation intervention for Experimental Day 1 using

a random number generator. Each participant will participate in the opposite intervention for Experimental Day 2, and

each experimental visit will be separated by at least 24 hours. Participants will be instructed to avoid exercise and

alcohol consumption for 24 hours prior to the experimental visits, and abstain from food and caffeine 12 hours prior to

the experimental visits.

The screening visit will consist of basic health assessments and take about one hour. First, height weight, 7-site skinfold

(body fat percent), blood pressure, heart rate and temperature will be taken. Then, the participant will complete a

medical health history form to confirm the absence of any exclusion criteria. Women will also complete a urine

pregnancy test to confirm absence of pregnancy. Last, the MINI international neuropsychiatric interview will be

administered by a trained research member to determine the presence of depressive symptoms and absence of other

mental illnesses. Lastly, a blood draw will be taken for assessment of a complete metabolic panel, lipid profile, and

hemoglobin A1c.

Both experimental visits are identical with only the intervention (device-guided slow breathing vs mindful meditation)

during the cold pressor test varying. All participants will arrive to the laboratory in the morning having avoided exercise,

alcohol, food, and caffeine as outlined above. After using the restroom, participants will lay supine and be instrumented

with a tungsten microneurography electrode in the peroneal nerve for MSNA, the Finapres for beat-to-beat blood

pressure, electrocardiograph electrodes for continuous heart rate and sinoatrial rhythms, and a respiratory belt to

measure respiration rate. After instrumentation, 15 minutes of baseline MSNA, BP, HR, and respiration data will be

collected. Following baseline, a “baseline” cold pressor test will be performed for 2 minutes to obtain baseline

cardiovascular reactivity. Next, there will be 15 minutes of rest to ensure MSNA, BP, and HR return to resting levels.

Lastly, participants will perform 15 minutes of device-guided slow breathing or guided mindful meditation. During the

last 2 minutes of device guided slow breathing and mindful meditation, the participant will perform another CPT.

Participants will be asked to measure their perceived stress on a scale of 1-10, with 1 being “not stressed at all”, to 10

being the “most stressed they’ve ever been”, after each CPT. MSNA, blood pressure, heart rate, respiratory rate, and

ECG will be collected for the duration of the visit. A study schematic of the experimental visit can be found below in

Figure 1.

Figure 1. Schematic of the experimental visit. Abbreviations: electrocardiogram (ECG), blood pressure (BP), muscle sympathetic nerve activity

(MSNA), heart rate (HR), cold pressor test (CPT), slow breathing (SB).

7-site skinfold is a validated measure of total body fat percentage. The method consists of gathering subcutaneous fat

into a “pinch” and measuring the thickness (mm) of the pinch with calipers across 7 standardized sites of the body

(chest, triceps, subscapular, superiliac, thigh, midaxillary, and abdominal). Each site is measured 2-3 times in a rotating

fashion. The measures are then inserted into an algorithm established by the American College of Sports Medicine to

produce a body fat percentage. Since the reliability of this method is dependent upon the individual performing the

measure, one trained research personnel will complete the body composition portion of the experiment for all subjects.

The MINI international neuropsychiatric interview is a short, structured interview (~15 minutes) with 16 modules

assessing DSM-IV and ICD-10 psychiatric disorders. It has been validated in many clinical populations including those

with MDD (Fantino & Moore, 2009; Sheehan et al., 1998). The MINI will be administered by a research team member

who has received extensive training in the administration of this interview by a psychiatrist. The results from the MINI

will be used to document MDD severity and determine depressive symptoms for the purpose of this study.

A small amount of blood (~10 mL or ~2 teaspoons) will be drawn by a certified phlebotomist at the end of the screening

visit. The blood specimens will then be sent to LabCorp to assess a complete metabolic panel (glucose, BUN, Chloride,

Calcium, Albumin, Bilirubin, AST, Potassium, Alkaline Phosphatase, Sodium, Protein, Creatinine, BUN/Creatinine Ratio,

Globulin, A/G ratio), lipid panel (total cholesterol, triglycerides, HDL cholesterol, Cholesterol/HDL ratio, LDL cholesterol,

VLDL cholesterol), and hemoglobin A1c. All blood test results will be provided to the participant.

Microneurography allows for the direct recording of efferent sympathetic nervous system activity in humans. Multiunit

postganglionic MSNA will be recorded using standard techniques described within previous literature (Sundlof & Wallin,

1978; Vallbo et al., 1979). A wand-like device is used for external electrical stimulation to track the anatomy of the

peroneal nerve. An active tungsten microelectrode and grounding reference electrode are inserted through the skin into

the peroneal nerve and surround tissue, respectively, to directly measure sympathetic activity. The nerve signal will be

amplified (70,000-fold), bandpass filtered (700-2,000 Hz), rectified, and integrated (time constant 0.1s) using a nerve

traffic analyzer. Nerve signal of MSNA will be confirmed by lack of increase in afferent activity during light stroking of the

skin and a confirmed increase in efferent burst frequency and spontaneous cardiac synchronous efferent bursts during

voluntary end-expiratory apnea.

The cold pressor test is an acute stress-evoking situation that accesses cardiovascular disease risk by measuring the

amplitude of cardiovascular reactivity during the two minutes that the participants hand is submerged in the ice water.

Carroll et al. (2012) showed the greater the amplitude of cardiovascular reactivity to an acute stressor, the lower the

survival rates over the span of 20 years. Beat-to-beat blood pressure derived from finger plethysmography, continuous

ECG derived heart rate, and MSNA activity will be recorded as cardiovascular reactivity for the duration of the cold

pressor test. The greatest change in MSNA burst frequency, heart rate, and blood pressure from baseline measures will

be used for data analysis. Water temperature will be between 0 and 4 degrees Celsius at the time of hand submersion.

Device-guided slow breathing will be completed using the RESPeRATE system set to a respiration rate of 8 breaths/min

for 15 minutes. Participants will be equipped with headphones in which the RESPeRATE system will instruct the

Experimental Visit

participant to inhale and exhale at a time interval congruous with 8 breaths/min. Respiration rate, blood pressure, heart

rate, and MSNA will be recorded for the last 5 minutes of the intervention to ensure compliance and evaluate its

cardiovascular effects. The cold pressor test will be employed during the last 2 minutes of device-guided slow breathing

to assess its effects on cardiovascular reactivity. Data used for analysis will be derived similarly to the “baseline” cold

pressor test. The change score between the “baseline” cold pressor test and the cold pressor test + device-guided slow

breathing will be used for data comparisons.

Mindful meditation will be completed using a pre-recorded 15-minute video. Participants will be equipped with

headphones in which the mindful meditation video will instruct the participant to focus on sensations in the present

moment while accepting their thoughts without judgement. Similar to the device-guided slow breathing intervention,

respiration rate, blood pressure, heart rate, and MSNA will be recorded for the last 5 minutes of the intervention to

ensure compliance and evaluate its cardiovascular effects. The cold pressor test will be employed during the last 2

minutes of mindful meditation to assess its effects on cardiovascular reactivity. Data used for analysis will be derived

similarly to the “baseline” cold pressor test. The change score between the “baseline” cold pressor test and the cold

pressor test + mindful meditation will be used for data comparisons.

Scientific rigor will be upheld by implementing a series of practices in this within-subject design. First, random allocation

of participants into interventions for Experimental Day 1 eliminates an “order effect”. MSNA is the gold-standard for

measuring sympathetic nervous system activity as it is a direct measure of the sympathetic nervous system activity via

the peroneal nerve. Beat-to-beat blood pressure via finger plethysmography is a validated and reliable measure (Schutte

et al., 2004). In addition to its validity and reliability, the Finapres will be re-calibrated to two brachial artery pressures

before each recording period ensuring appropriate calibration before recording data. Data analysts will be blinded as to

which intervention group the data contains. Statistical analyses and sample size has been chosen a priori. Since

participants are not able to be blinded as to which treatment they are receiving, this awareness is an inherit bias that

will be acknowledged within the study findings.

Statistical Analyses

A sample size of 19 will detect a 3 bursts/min difference in MSNA burst frequency with 80% power and a significance

level of 0.05. An additional 6 subjects will be recruited for a total sample size of 25 subjects to account for the 70%

success rate of obtaining an MSNA reading.

The statistical approach for data analysis will use a matched pairs t-test to assess differences in the change score of

MSNA burst frequency from the “baseline” CPT and CPT paired with each breathing intervention. Matched pairs t-tests

will also be used for comparing differences in change scores of respiratory rate, heart rate, blood pressure, and MSNA

burst incidence. Data distributions will be assessed for symmetry; if distributions of variables are not symmetrical, then

data will be compared using non-parametric statistical tests. Data will be reported as means ± standard deviation and

significance will be set at an alpha of 0.05. Lastly, data will be presented as both change scores and absolute values for

transparency.

Anticipated Findings and Interpretation

We anticipate that depressed young adults will have attenuated MSNA burst frequency during the cold pressor test

while practicing device-guided slow breathing or mindful meditation compared to the cold pressor test without a

breathing or meditation intervention. Further, depressed young adults will show greater attenuations in MSNA burst

frequency during mindful meditation compared to device-guided slow breathing.

Regardless of the experimental outcomes, information gained from this study is essential to understanding increased

cardiovascular disease risk and neurovascular dysfunction in adults with major depressive disorder. MDD is a pervasive

disease in which 2/3 of its population is currently treatment resistant. If the anticipated findings within this study are

confirmed, then mindful meditation may be useful to decrease cardiovascular reactivity during stressful situations for

depressed young adults. These attenuations in cardiovascular reactivity may establish mindful meditation as a useful

therapy to reduce CVD risk in those with depression, especially in those that are treatment resistant.

Protection of Human Subjects Document

Inclusion Criteria

Inclusion criteria consists of those 18-35 years old and confirmation of depressive symptoms with a diagnostic interview.

Exclusion Criteria

Exclusion criteria consists of a mental illness aside from depression, any use of depression mediation, active

suicidal/homicidal intent, active alcohol or drug dependence, an eating disorder, use of medication that could alter how

the brain or cardiovascular system functions, cardiovascular, kidney, lung or metabolic disease, tobacco use, pregnancy,

or amenorrhea (women).

Those with any illnesses related to cardiovascular disease (i.e. high blood pressure, heart disease, or heart arrhythmias),

history of frostbite, history of seizures, or history of Reynaud’s phenomenon are contraindicated for cold pressor test.

Number of Subjects

A total of 25 subjects will be recruited for this study. Sample size was calculated a priori using G-power. MSNA

measurement in young adults with MDD has not been studied to our knowledge; therefore, due to the similarities

between posttraumatic stress disorder (PTSD) and MDD, MSNA values were estimated from studies involving young

adults with PTSD (Fonkoue, Marvar et al., 2018). Estimates of MSNA values during the DGSB+CPT and MM+CPT

conditions were derived from both previous studies of MSNA recordings during both breathing patterns, and clinically

significant MSNA values (Park et al., 2014; Fonkoue, Marvar et al., 2018). Means were estimated as the change score

between a cold-pressor test and the DGSB+CPT condition, and the change score between a cold-pressor test and the

MM+CPT condition. Accounting for a 70% success rate on peroneal nerve innervation and MSNA recording, a total of 25

subjects are needed to detect a 3 burst/min difference between DGSP and MM conditions with 80% power and an alpha

level of 0.05.

The recruitment of 25 subjects ensures adequate power for scientific data analysis while minimizing unnecessary and

excessive recruitment. This prevents putting participants at unnecessary, although minimal, risk.

Recruitment

Participants will be recruited from the University of Texas at Arlington and the surrounding area through the use of

flyers, email, social media, class presentations, and radio ads. Participation within the study is voluntary and participants

are able to withdraw at any point. All information collected during recruitment will be confidential and discarded after

their participation in the research study.

Compensation and costs

Participants will be compensated $25 per experimental visit for a total of $50 if both experimental visits are completed.

This compensation amount adequately compensates for their time at a rate of about $15 /hour which is slightly higher

than an hourly rate of a part-time job. The screening and experimental visits will be of no costs to participants, and

participants will receive a copy of all laboratory results.

Risks to subjects

Microneurography: Microneurography is an accepted and safe research technique. The use of the wand-like device for

external electrical stimulation to assess nerve anatomic tracking may cause minor discomfort. An active microelectrode

and a grounding reference electrode will be inserted into the skin. There may be mild discomfort when the fine wire

needle is inserted through the skin; however, the needle is very small. Brief sensations of pins and needles and/or

cramping are likely to be felt during the nerve search. This needle will be left in place for the duration of the

experimental visit (approximately 1.5 hours). There is also a small risk of infection at the site where the fine wire needle

is inserted. While unlikely, there’s a risk of nerve damage from the procedure.

Mini-International Neuropsychiatric Interview (M.I.N.I.): The MINI has been validated in many clinical populations

including those with MDD. The MINI is a short, structured clinical interview (~15 minutes) that is used as a tool to

identify people who may have particular experiences or forms of psychological distress useful for the purposes of this

study. Subjects may feel uncomfortable about answering the questions. They are reminded that they may decline to

answer the questions and leave the study at any time. Some subjects may be disturbed if the test recommends their

inclusion in the depression group. They are reminded that the test is not intended to be a diagnosis or healthcare

recommendation.

Blood draw: There is a small risk of infection at the site where the needle is inserted. There may be some bruising and

mild discomfort at the site where blood was drawn.

Electrocardiogram: We attach three electrodes to the subject’s chest and attach electrode wires to a standard ECG

machine. There have been no adverse effects from this measure. Participants may be shy with having the electrodes

placed on their chest. The tape from the electrodes may temporarily redden or irritate the skin. Sensitivity to the tape is

unlikely to produce long-term effects.

Cold pressor test: The participants hand is placed in ice water (0-4 degrees Celsius) for 2 minutes. Their hand is likely to

feel cold during the time it’s submerged. It’s unlikely to have any long-lasting effects from this test. The participant is

reminded they may stop the test at any time.

Medical Screening: This includes a typical medical exam (blood sample, height, weight, 7-site skinfold, blood pressure,

heart rate) and medical health history performed by research personnel. Subjects may be uncomfortable with giving

medical information or being measured. They will be reminded that their participation is voluntary and they may decline

any measures.

7-Site Skinfold: 7 sites on the body are pinched and measured with calipers twice. The pinch may cause minor

discomfort for 1-2 seconds and redness. Participants may be shy about having sites pinched and adipose tissue

measured.

Blood Pressure: Blood pressure is measured in accordance to the American Heart Association guidelines. During the

short time the cuff is inflated, the participants arm may feel numb or tingly. The finapres finger cuff may cause their

finger to become number or tingly over time. The cuff can be moved to a different finger to minimize this feeling.

Confidentiality: There is a risk of loss of confidentiality if the subjects information or identity is obtained by someone

other than the investigators, but precautions will be taken to prevent this from happening. The confidentiality of

electronic data created by the participant or researchers will be maintained to the degree permitted by the technology

used. Absolute confidentiality cannot be guaranteed.

Strategies to minimize risks

Microneurography: The microneurography procedure will be immediately discontinued if the subject experiences

excessive discomfort. The nerve search will be limited to 45 minutes as the risk of symptoms during or after

microneurography are minimized when the search is not over 60 minutes; therefore, the nerve search will never be over

60 minutes.

Mini-International Neuropsychiatric Interview (M.I.N.I.): Participants are reminded that they may decline to answer the

questions and leave the study at any time. We remind participants that the test is not intended to be a diagnosis or

healthcare recommendation. A protocol is implemented to adequately respond to those who are in distress by creating

walk-in appointments with the Counseling and Psychological Services at the University of Texas at Arlington. Lastly, a list

of local mental healthcare providers will be provided to all participants in the study, regardless of their MINI results.

Blood Draw: Participants may decline a blood draw. All blood draws will be completed by phlebotomy certified

personnel. Sterile supplies and techniques are used to minimize infection risks, and participants will be in a semi-

recumbent position when blood is drawn.

Electrocardiogram: Electrocardiogram leads are carefully removed after the experiment. The test is conducted

professionally and privately, and the participant may request that the research personnel performing the test be of the

same gender.

Cold Pressor Test: The cold pressor test will be immediately discontinued if the subject experiences excessive

discomfort. The participant’s hand is dried and warmed immediately after the end of the test.

Medical Screening: All medical information will be collected in a private and professional manner, and participants may

decline to answer questions or participate in measures. Research personnel will ensure subjects meet all inclusion and

exclusion criteria to minimize risk to participants. The participant may request someone of the same gender to conduct

parts of the screening.

7-Site Skinfold: The measurement will be taken efficiently to minimize the amount of time the participant is “pinched”.

The participant may decline the 7-site skinfold measure, or request someone of the same gender to conduct the

measure.

Blood Pressure: The measurement will be taken efficiently to minimize that amount of time the cuff is inflated on the

arm. Finapres finger cuffs will be alternated between two fingers every 20 minutes to give the other finger a rest.

Confidentiality: All paper and electronic data collected from this study will be stored in the investigator’s lab for at least

three years after the end of this research. Participants will be provided with a unique subject code identifier that does

not contain any personal information. All measures will be labeled with this unique code identifier. Paper data collected

from this study is stored in a locked file cabinet behind two locked entrances, and only research personnel will have

access to the data. Additionally, we have obtained a Certificate of Confidentiality from the National Institutes of Health.

With this certificate, we can’t be forced by a court order or subpoena to disclose information that could identify the

participant in any civil, criminal, administrative, legislative or other proceeding.

Possibility for coercion or undue influence

Participants will be compensated $25 per experimental visit for a total of $50 if both experimental visits are completed.

This amount adequately compensates for their time at a rate of about $15 /hour which is slightly higher than an hourly

rate of a part-time job without coercion or undue influence.

EH&S considerations

All research personnel are up to date on trainings in Biomedical Human Subjects Research (CITI), Good Clinical Practice

(CITI), Bloodborne Pathogens, Biosafety Level 2, and Hazard Communication and Waste Management. All materials used

for blood draws and blood processing will be immediately and properly disposed of in biohazard reciprocal bins. All

research personnel involved with the blood draw and blood processing will be dressed in long pants, closed toed shoes,

lab coat, and latex gloves. Needles involved with the blood draw and microneurography measures will be disposed of

within sharps disposal containers.

Direct benefits to subjects

Participants will receive financial compensation and the medical screening provides information about their physical

well-being. They receive a complete metabolic panel, lipid panel, and hemoglobin A1c levels in addition to their blood

pressure and heart rate. This is important health information to use as a “baseline” measure for participants, or the

knowledge of high blood pressure and cholesterol levels is important as they contribute to many health problems.

Participants are also educated on the connection between MDD and CVD, and whether mindful meditation or slow

breathing will be beneficial techniques to use for their own physical or mental health.

Overall benefits

Overall, this project will provide direct benefits to the subjects, undergraduate and graduate students, and will

contribute to the field of neurovascular dysfunction in regards to those with major depressive disorder. Further, the

study may provide insight into alternative therapies for reducing cardiovascular disease risk in those with MDD. In

regards to undergraduate and graduate students, the study provides valuable experience, education, and partial

fulfillment of degree-work at the University of Texas at Arlington.

Subject Privacy

All subject data will remain anonymous as all measures will be labeled with a random, unique code identifier assigned to

them. All information collected during recruitment will be confidential and discarded after their participation in the

research study. Participants are able to decline any measures or not answer questions regarding their medical or mental

health history. Participants are also able to request that a research member of the same gender perform measures at

the screening or experimental visits.

Confidentiality and Data Security

There is a risk of loss of confidentiality if the subjects information or identity is obtained by someone other than the

investigators, but precautions will be taken to prevent this from happening. The confidentiality of electronic data

created by the participant or researchers will be maintained to the degree permitted by the technology used. Absolute

confidentiality cannot be guaranteed. All paper and electronic data collected from this study will be stored in the

investigator’s lab for at least three years after the end of this research. Participants will be provided with a unique

subject code identifier that does not contain any personal information; therefore, all data collected will be deidentified.

All measures will be labeled with this unique code identifier. Paper data collected from this study is stored in a locked

file cabinet behind two locked entrances, and only advised research personnel will have access to the data. Additionally,

we have obtained a Certificate of Confidentiality from the National Institutes of Health. With this certificate, we can’t be

forced by a court order or subpoena to disclose information that could identify the participant in any civil, criminal,

administrative, legislative or other proceeding.

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