Imaging Biomarker for Addiction Treatment Outcome

Objective:

Despite recent advance in addiction neuroscience, achieving a breakthrough in predicting
addiction treatment outcome has been difficult and long-term abstinence success unacceptably
low. The aim of this study is to create a biomarker using various neuroimaging metrics that
can predict treatment outcome in opioid and alcohol use disorder patients.

Study Population:

The study population will include three hundred fifty (350) participants (50 per group) based
on their addiction status (1) healthy, non-drug using control participants (CON) (2)
Early-in-treatment, healthy prescription opioid use disorder participants currently enrolled
in physician health program (PHP) within 2 month of starting treatment (POUD-E), (3)
Long-term-in-treatment, healthy prescription opioid use disorder participants currently
enrolled in PHP more than 2 months and less than 5 years (POUD-L), (4) Early-in-treatment,
healthy alcohol use disorder participants currently enrolled in PHP within 2 month of
starting treatment (AUD-E), (5) Long-term-in-treatment, healthy alcohol use disorder
participants currently enrolled in PHP more than 2 months and less than 5 years (AUD-L), (6)
Early-in-treatment, healthy dual prescription opioid and alcohol and use disorder
participants currently enrolled in PHP within 2 month of starting treatment (POAUD-E), (7)
Long-term-in-treatment, healthy dual prescription opioid and alcohol use disorder
participants currently enrolled in PHP more than 2 months and less than 5 years (POAUD-L).

Design: Two studies will run simultaneously:

1. Cross-sectional study that will include all participants enrolled at a PHP over the past
5 years and have been in treatment for more than 2 months. Three target groups, in
addition to the control group, will be included in this study [POUD-L, AUD-L, and
POAUD-L]. Each participant will complete a screening evaluation session (approximately
3-4 hours) at the PHP through secure communication. The screening visit will include the
consenting process and the administration of questionnaires to characterize clinical
phenotype, and physical condition. Participants enrolled in the cross-sectional study
will be invited to come to NIDA IRP for one imaging visit that will take approximately
6-8 hours.

The aim of the cross-sectional study is to identify imaging based brain differences
between control group and drug using groups and to examine correlations between brain
imaging markers at different stages of recovery and (1) severity of drug use (duration
and quantity), (2) duration of abstinence, and (3) number of relapses in drug using
groups.

The primary outcome measure for the cross-sectional study will be differences in
functional connectivity and BOLD signal activation in executive and impulsive
neurobehavioral decision systems at various stages of sobriety in relation to controls.

2. Longitudinal study that will include all participants enrolled at PHP within two months
of starting treatment. Three groups, in addition to the control group, will be included
in this study [POUD-E, AUDE, and POAUD-E]. Each participant will complete the screening
evaluation session as described in the cross-sectional study and three imaging visits at
NIDA; 1) baseline visit within 2 months from enrolling in the study, (2) mid-year visit
within 4-8 months from baseline visit and (3) one-year visit within 10-14 months from
baseline visit. Each imaging visit will take approximately 6-8 hours.

The aim of the longitudinal study is to measure brain imaging changes over time in
abstinent and relapsing addicts and to identify brain imaging markers that differentiate
between abstinent and relapsing participants at 6 months and at 1 year. The rationale
behind the mid-year visit is that most relapses take place early (within the first 6
months) during treatment and by one year some of those who relapsed earlier achieve
abstinence and by including this visit, we will preclude a contaminated sample of both
abstinent without early relapse and abstinent with early relapse which could confound
our results.

The primary outcome measure for the longitudinal study will be differences in baseline
and changes over time in functional connectivity circuits, BOLD signal activation in
executive and impulsive neurobehavioral decision systems between abstinent and relapsing
addicts that can predict treatment response at 6 and 12 months.

3. Secondary outcome measures for both studies will be phenotypic (performance on
behavioral tasks, self-reported measures of cravings, impulsivity and personality
traits), genotypic and imaging (structural and spectroscopy) differences between
different addiction groups.

- INCLUSION CRITERIA:

All participants: (CON), (POUD-E), (POUD-L), (AUD-E), (AUD-L), (POAUD-E), (POAUD-L):

-Males and females between 25-65 years of age will be enrolled in the study. Justification:
The lower age cut off is chosen because the sample consists of addicted physicians who are
all above 25 years of age. The upper age cut off is chosen because of aging-related brain
changes that could confound the results. Assessment tool: Participants will provide an
identification card like driver license that

contains their date of birth.

- Able and willing to provide written informed consent. Justification: It is important
for subjects to understand and agree to all the procedures, time-commitments and
expectations entailed in this study. Assessment tool: Verbal confirmation of
willingness to consent and a score of 80% or more on consent quiz.

- Must be right-handed. Justification: Some of the neural processes assessed in this
protocol may be lateralized in the brain. In order to reduce potential variance,
participants will be required to be righthanded. Assessment tool: Edinburgh Handedness
Inventory.

- Participants must be in good health. Justification: Many illnesses may alter fMRI
signals as well as neural functioning. Assessment tool(s): Control participants will
undergo a medical history and physical examination. Experimental group participants
will provide a brief health history during phone/internet screening. Written physician
health records will also be obtained to verify health status of the experimental
groups.

HEALTHY CONTROL PARTICIPANTS (CON) IN ADDITION TO ALL PARTICIPANTS' INCLUSION CRITIERIA:

- Free of lifetime DSM-5 substance use disorders except for tobacco use disorder.
Justification: the presence of substance use disorder in the control group will
confound the results. Please note we exempted tobacco use disorder in order to match
the experimental group participants. Assessment tool(s): The MINI, the lifetime
alcohol and substance use modules of the MINI-Plus, Addiction Severity

Index (ASI) and clinical assessment.

-16 years of education or more Justification: To match the educational status of the
experimental group. Assessment tool: Participant will provide educational history.

Early-in-treatment, prescription opioid use disorder (POUD-E) participants- in addition to
all participants inclusion criteria:

1. Recently (within about 2 months) enrolled in a physician health program (PHP) or
equivalent at time of enrollment in the study Justification: The two months interval
was chosen because we wish to longitudinally follow participants from very early
abstinence to long-term abstinence/relapse at one year. Importantly, participants are
allowed to leave residential treatment centers and go home for weekends or short
holidays after two months of starting treatment, so inviting enrolled participants to
travel to NIDA IRP for one-day visit after two months of treatment is not expected to
increase their risk of relapse. Assessment tool: addiction treatment records.

2. Meet a minimum of 6/11 DSM-5 criteria for severe opioid use disorder (OUD) for at
least 2 years prior to enrollment and in full remission for at least 2 months at time
of imaging. Justification: The hypothesized differences in measured brain imaging
parameters are more likely to be detected in severe OUDs compared to mild or moderate
OUDs. Assessment tool: DSM 5 Opioid Use Disorder

Checklist.

Early-in-treatment, alcohol use disorder (AUD-E) participants- in addition to all
participants inclusion criteria:

1. Recently (within about 2 months) enrolled in a physician health program (PHP) or
equivalent at time of enrollment in the study Justification: The two months interval was
chosen because we wish to follow longitudinally participants from very early abstinence to
long-term abstinence/ relapse at one year. Importantly, participants are allowed to leave
residential treatment centers and go home for weekends or short holidays after two months
of starting treatment, therefore, inviting enrolled participants to travel to NIDA IRP for
one-day visit after two months of treatment is not expected to increase their risk of
relapse. Assessment tool: addiction treatment records.

2. Meet a minimum of 6/11 DSM-5 criteria for severe alcohol use disorder (AUD) for at least
2 years prior to enrollment and in full remission for at least 2 months at time of imaging.
Justification: The hypothesized differences in measured brain imaging parameters are more
likely to be detected in severe AUDs compared to mild or moderate AUDs. Assessment tool:
DSM 5 Alcohol Use Disorder

Checklist.

Early-in-treatment, dual prescription opioid and alcohol use disorder (POAUD-E)
participants- in addition to all participants inclusion criteria:

1. Recently (within about 2 months) enrolled in a physician health program (PHP) or
equivalent at time of enrollment in the study Justification: The two months interval
was chosen because we wish to follow longitudinally participants from very early
abstinence to long-term abstinence/ relapse at one year. Importantly, participants are
allowed to leave residential treatment centers and go home for weekends or short
holidays after two months of starting treatment, therefore, inviting enrolled
participants to travel to NIDA IRP for one-day visit after two months of treatment is
not expected to increase their risk of relapse. Assessment tool: addiction treatment
records.

2. Meet a minimum of 6/11 DSM-5 criteria for either severe opioid or severe alcohol use
disorders and a minimum of 4/11 DSM-5 for either moderate opioid or moderate alcohol
use disorder at least 2 years for each substance prior to enrollment and in full
remission for at least 2 months at time of imaging. Justification: The hypothesized
differences in measured brain imaging parameters are more likely to be detected in
severe SUDs compared to mild or moderate SUDs, so at least one of the two dual
addictions should be severe and the second one can be moderate. Assessment tool: DSM 5
Opioid Use Disorder and Alcohol Use Disorder Checklists.

Long-term-in-treatment, prescription opioid use disorder (POUD-L) participants- in addition
to all participants inclusion criteria:

1. Enrolled in a physician health program (PHP) or equivalent for more than 2 months and
less than 5 years at time of enrollment in the study Justification: The more than two
months and less than 5 years interval was chosen because we wish to study brain
changes (compared to non-drug using controls) at different stages of abstinence.
Assessment tool: addiction treatment records.

2. Meet a minimum of 6/11 DSM-5 criteria for severe opioid use disorder for at least 2
years prior to starting treatment and in full remission for at least 2 months at time
of imaging. Justification: The hypothesized differences in measured brain imaging
parameters are more likely to be detected in severe OUD compared to mild or moderate
OUDs. Assessment tool: DSM 5 Opioid Use Disorder Checklist.

Long-term-in-treatment, alcohol use disorder (AUD-L) participants- in addition to all
participants inclusion criteria:

1. Enrolled in a physician health program (PHP) or equivalent for more than 2 months and
less than 5 years at time of enrollment in the study and in full remission for at
least 2 months at time of imaging. Justification: The more than two months and less
than 5 years interval was chosen because we wish to study brain changes (compared to
non-drug using controls) at different stages of abstinence. Assessment tool: addiction
treatment records.

2. Meet a minimum of 6/11 DSM-5 criteria for severe alcohol use disorder for at least 2
years prior to starting treatment. Justification: The hypothesized differences in
measured brain imaging parameters are more likely to be detected in severe AUD
compared to mild or moderate AUDs. Assessment tool: DSM 5 Alcohol Use Disorder
Checklist.

Long-term-in-treatment, dual prescription opioid and alcohol use disorder (POAUD-L)
participants - in addition to all participants inclusion criteria:

1. Enrolled in a physician health program (PHP) or equivalent for more than 2 months and
less than 5 years at time of enrollment in the study Justification: The more than two
months and less than 5 years interval was chosen because we wish to study brain
changes (compared to non-drug using controls) at different stages of abstinence.
Assessment tool: addiction treatment records.

2. Meet a minimum of 6/11 DSM-5 criteria for either severe opioid or severe alcohol use
disorder and a minimum of 4/11 DSM-5 for either moderate opioid or moderate alcohol
use disorder at least 2 years for each substance prior to enrollment and in full
remission for at least 2 months at time of imaging. Justification: The hypothesized
differences in measured brain imaging parameters are more likely to be detected in
severe SUDs compared to mild or moderate SUDs, so at least one of the two dual
addictions should be severe and the second one can be moderate. Assessment tool: DSM 5
Opioid Use Disorder and Alcohol Use Disorder Checklists.

EXCLUSION CRITIERIA:

All participants: (CON), (POUD-E), (POUD-L), (AUD-E), (AUD-L), (POAUD-E), (POAUD-L):

1. Females must not be pregnant or lactating. Justification: The impact of exposing
pregnant females to MRI and stress paradigms is unknown. Including lactating females
will confound the results because of the effect of lactation-associated hormonal
changes on the brain. Assessment: medical history and negative urine pregnancy test
prior to each MRI visit (and at screening for control participants).

2. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the
head (e.g. pacemakers or other implanted electrical devices, brain stimulators, some
types of dental implants, aneurysm clips, metallic prostheses, permanent eyeliner,
implanted delivery pump, or shrapnel fragments) or fear of enclosed spaces.
Justification: The presence of ferromagnetic objects poses risk of injury during MRI.
Assessment tool: medical history and MRI screening form.

3. Noise-induced hearing loss or tinnitus. Justification: individuals with noise-induced
hearing problems may be particularly vulnerable to the acoustic noise generated by MRI
scanner. Assessment tool: medical history and MRI safety screening. 4. Head trauma
with loss of consciousness or significant sequelae for more than 30 minutes.
Justification: The presence of head injury could result in subtle alterations in brain
structure or function and could confound the results. Assessment tool: medical history
and physical exam (controls).

5. Current or past DSM-5 diagnosis of any psychiatric disorder that required
hospitalization other than detoxification (any length), or chronic medication management
for more than three months, (except for stable doses of antidepressants) and that could
impact brain

function at the time of the study based on study MAI s discretion. Current or past tobacco
use disorder or nicotine use, opioid use disorder in opioid use disorder participants,
alcohol use disorder in alcohol use disorder participants, and both opioid and alcohol use
disorders in the dual opioid and alcohol use disorder group is not exclusionary.
Justification: The presence of severe or unstable comorbid psychiatric conditions could be
associated with brain alterations that could confound the results. Assessment tool:
history, MINI, the lifetime alcohol and substance use modules of the MINI-Plus, ASI and
clinical assessment, as well as review of medical records, including clinical exam, for
experimental group.

6. Currently (at time of imaging sessions) using any medications that are known to alter
BOLD signal such as stimulant or stimulant-like medications (amphetamine, methylphenidate,
modafinil); anorexics (sibuteramine); antianginal agents; antiarrhythmics; antiasthma
agents that are systemic corticosteroids; anticholinergics; anticonvulsants;
antineoplastics; antiobesity; antipsychotics; hormones (exceptions: thyroid hormone
replacement, oral contraceptives, and estrogen replacement therapy); insulin; lithium;
herbal products with

known psychotropic effects (e.g. Gingko biloba, or St. John s Wort) and other medications
based on study MAI s discretion. Justification: Concomitant intake of medications that
could alter BOLD signal could confound the results. Assessment tool: medical history for
experimental groups; controls will also have a comprehensive urine toxicology screen.

7. Currently (at time of imaging sessions) taking methadone opioid replacement therapy.
Please note that experimental group participants taking disulfiram, acamprosate,
naltrexone, or long acting naltrexone treatment or those at a stable dose (for at least 2
weeks) of buprenorphine containing medications will be allowed to participate in the study.
Justification: Opioid agonists or partial agonists are known to alter BOLD signal and could
confound the results. However, about 60%-80% of opiate use disorder patients in PHP
treatment programs receive buprenorphine. Excluding these participants could significantly
decrease the chance for meeting our enrollment target. In addition, including these
participants will result in better representation of the target population and enhance the
generalizability of any findings. Assessment tool: medical history for experimental groups;
controls will also have a comprehensive urine toxicology screen.

8. Medical conditions that can impact brain function such as seizure disorder, diabetes
mellitus, renal insufficiency (e.g. Creatinine > 2.5), uncontrolled hypertension (BP>
160/100 on screening), uncontrolled or severe coronary artery disease, clinically
significant heart disease, HIV, syphilis, or autoimmune disorders. Justificati...