State and Trait Mediated Response to TMS in Substance Use Disorder

OBJECTIVES: The current protocol seeks to develop brain-based intermediate phenotypes of
response to transcranial magnetic stimulation (TMS) in chronic substance use disorder (SUD).
To date the field has relied on subjective reports, behavioral performance, and long-term
clinical outcomes as primary measures of TMS efficacy. While certainly ecologically valid,
these observable behaviors lack the sensitivity necessary to fully quantify the effects (or
lack thereof) across both individual participants and TMS intervention protocols.

This proposed within-subjects design seeks to leverage differences in metaplasticity that is,
the context in which stimulation occurs-by studying the response to stimulation in both sated
and abstinent states. It is predicted these state manipulations will potentiate response to
TMS. When a disruptive allostatic load like chronic nicotine exposure or acute abstinence is
placed on the brain, the underlying network becomes less stable and thus more susceptible to
TMS intervention. For SUD in general and tobacco use disorder (TUD) in particular, this state
dependence of TMS response is a potentially valuable tool to improve a given intervention s
clinical efficacy.

STUDY POPULATION: Physically and psychiatrically healthy smokers will be recruited. A
comparison group of non-smokers will be concurrently enrolled. We estimate we will require
n=51/group of completers to have sufficient power to develop the intermediate phenotypes of
TMS.

DESIGN: The protocol is a two group, between/within subject, fully counterbalanced design.
The between-subjects factor is GROUP (smoker/non-smoker) and the within-subjects factor for
each GROUP is TMS CONDITION (active/sham). Additionally, and for the smoker group, nicotine
STATE (sated/abstinent) is a nested within-subjects factor. Each group will receive single
sessions of active and sham intermittent theta burst stimulation to left dorsal lateral
prefrontal cortex, followed immediately by an MRI scan to characterize the acute
neurobiological response to stimulation. Smokers will repeat these procedures both during
smoking satiety and following an ~48-hour period nicotine abstinence.

OUTCOMES PARAMETERS: In addition to subjective and behavioral task performance changes
associated with TMS intervention, changes in MRI BOLD signal will be used to characterize the
neurobiological response to TMS intervention across groups and states. Taken together, the
development of brain-based markers of TMS response may thus improve both our mechanistic
understanding of the causal dysfunctions of TUD as well as the potential efficacy of these
interventions longer term to address the relevant clinical characteristics of the disease and
ultimately improve treatment outcomes.

- INCLUSION CRITERIA (MAIN STUDY):

All participants must:

- Be between the ages of 18-60. Justification: Many neural processes change with age,
and these changes could introduce unwanted variability in both behavioral and MRI
signals. In addition, the risk of difficult-to-detect medical abnormalities such as
silent cerebral infarcts increase with age. Assessment tools: History. Government-
issued forms of identification (e.g. driver s license, birth certificate) will be
required when participant appears to be out of age range.

- Be in good health. Justification: Many illnesses may alter fMRI signals as well as
cognitive processes and neural functioning. Assessment tools: Medical Assessment,
Medical History and Physical Examination. Medical assessments include: Vital Signs,
EKG, oral HIV test, height/weight measurements, urinalysis and blood sample. Tests on
the blood sample include CBC, complete metabolic profile, TSH, ESR, STS and HIV (if
needed to confirm a positive salivary test for HIV). The following individual
laboratory results will independently disqualify individuals: Cholesterol greater than
250 mg/dl, Hemoglobin less than 10.5 g/dl, WBC less than 2400/ (Micro)l, LFTs less
than 3 times upper normal, HCG positive, Casual serum glucose less than 200 mg/dl,
Urine protein less than 1+. The MAI will retain discretion to exclude at less extreme
values, depending on the clinical presentation. (Serum glucose over 140 mg/dl will be
followed up with a fasting serum glucose assessment. Those with fasting glucose below
100 mg/dl may be considered for the protocol. Others will be rejected and referred for
work-up.) Liver function will be evaluated with aspartate aminotransferase (AST) and
alanine transaminase (ALT). A greater than 3 times upper normal limit for AST or ALT
will disqualify individuals. MAI will make the final judgment on any questionable lab
results.

- Be right-handed. Justification: Using right-handed individuals will reduce variability
in BOLD MRI data. Assessment tool: Edinburgh Handedness Inventory.

- Be able to abstain from alcohol and other substances 24hrs and caffeine for 12 hours
before each of the imaging sessions. Justification: Alcohol and caffeine (among other
substances) modulate neural functioning in a way that would complicate data
interpretation. Assessment tools: Self-report, urine drug screen and breathalyzer.

- For smoker group, must have a urine cotinine level of greater than 4 as measured by a
semi-quantitative in vitro diagnostic (e.g., NicAlert) and have been smoking a regular
combustible tobacco product consistently for at least one year. Based on the
correlation between self-reported cpd/FTND and urine cotinine levels, a single
inclusion criterion will be easier to manage and provide adequate characterization of
dependent smokers. Urine cotinine level provides a biomarker that does not rely on
self-report/memory. Quit attempts will be assessed via clinical interview and
judgment. Justification: The present protocol is interested in neurobiological
mechanisms that underlie nicotine dependence-induced plasticity, and is thus
contingent on the presence of nicotine dependence. Assessment tools: Self-report,
NicAlert of 4 or higher (or other nicotine/cotinine lab test equivalent to 200ng/ml
cotinine concentration)

- For the smoker group, must be willing to attempt an acute abstinence period lasting
approximately 48 hours on 2 separate occasions. Justification: We aim to look at the
response to stimulation in both drug sated and abstinent states in smokers. Assessment
tool: Self-report.

- For the non-smoking control group, less than 20 cigarettes lifetime, no cigarette or
other nicotine product in past year and no history of daily use of any other nicotine
products for > 2 weeks. Justification: Minimal cigarette exposure in the control group
is required to assess differences between healthy control and the smoker groups.
Assessment tools: Self-report, NicAlert of less than or equal 2, CO less than 6 or MAI
discretion if there is a reasonable planation for high CO exposure.

EXCLUSION CRITERIA (MAIN STUDY):

- Current or personal history of cerebrovascular or neurological illnesses including,
but not limited to, seizure disorders, frequent migraines or on prophylaxis, multiple
sclerosis, movement disorders, history of significant head trauma, or CNS tumor.
Current or personal history of any neurological disorders that would increase seizure
risk from iTBS such as stroke, brain lesions, previous neurosurgery, any history of
seizure or fainting episode of unknown cause, or head trauma resulting in loss of
consciousness, lasting over 30 minutes or with sequela lasting longer than three
months, regardless of loss of consciousness. Justification: Cerebrovascular and
neurological conditions may alter blood flow, CNS function, the fMRI signal and other
autonomic signals. Additionally, neurological disorders such as stroke, vascular
lesions or head trauma can lower the seizure threshold and are therefore
contra-indications for iTBS. Fainting episodes or syncope of unknown cause could
indicate an undiagnosed condition associated with seizures. Assessment tools: TMS
Safety Screen and Medical History and Physical Exam. The MAI who will also retain
discretion to exclude based on a history of neurological illness that may compromise
data integrity.

- First-degree family history of any neurological disorder with a potentially hereditary
basis, including migraines, epilepsy, or multiple sclerosis. Justification:
Neurological disorders can lower the seizure threshold and are therefore
contra-indications for iTBS. First -degree family history of certain neurological
disorder with a hereditary component increases the risk of the participant having an
undiagnosed conditi n that is associated with lowered seizure threshold. Assessment
tools: TMS Safety Screen and Medical History.

- Implantable defibrillator, implanted medication pumps, cardiac pacemaker,
neurostimulator, some artificial joints, metal pins, surgical clips, intracardiac
lines, or acute unstable cardiac disease with intracranial implants (e.g. aneurysm
clips, shunts, stimulators, cochlear implants or electrodes) or any other implant or
metal object in the body that precludes MRI scanning or iTBS administrations.
Justification: certain metal in the body is a contra-indication for MRI scanning and
iTBS administration, which involves exposure to a relatively strong static magnetic
field that can move magnetic material not securely bound and rapidly alternating
magnetic fields that can generate heat and current in metal contained in the body.
Assessment tools: TMS Safety Screen, MRI Safety Screen and Medical History.

- Are not suitable to undergo an fMRI experiment due to body morphology or
claustrophobia. Justification: MR scanning is one of the primary measurement tools
used in the protocol. Assessment tools: MRI Safety Screen, Medical History.
Prospective participants will be questioned about symptoms of claustrophobia and may
be placed in the mock scanner during screening to assess for possible difficulty
tolerating the confinement of the scanner and for ability to fit into the scanner.
Noise-induced hearing loss or tinnitus. Justification: individuals with noise-induced
hearing problems may be particularly vulnerable to the acoustic noise generated by
iTBS equipment and MRI (even with the use of sound attenuation ear plugs). Assessment
tools: TMS Safety Screen, MRI Safety Screen, Medical History.

- Current use (any use in the past 4 weeks, daily use for more than a week within the
past 6 months) of any substances (excluding alcohol, see criteria 9), investigational
drug or of any medications with psychotropic, anti- or pro-convulsive action, or anti
coagulants. This will be determined at the discretion of the MAI. Justification: the
use of certain medications or drugs can lower seizure threshold during use or
withdrawal and is therefore contra-indicated for iTBS. Assessment tools: Medical
History, urine toxicology analysis for the presence of a broad range of prescription
and non-prescription drugs. Lifetime history of schizophrenia, bipolar disorder,
mania, or hypomania. Justification: The population of interest here is a healthy
population with no psychiatric disorders other than tobacco use disorders. In
participants with bipolar disorder, mania or hypomania, there is a small chance that
iTBS can trigger (hypo)manic symptoms. Assessment tools: M.I.N.I. Potential diagnoses
will be further evaluated by a counselor.

- Current major psychiatric disorders to include, but not limited to, mood, anxiety,
psychotic disorders, or substance-induced psychiatric disorders, or any current
suicidal ideations or currently under antidepressant or antipsychotic medication
treatment. The MAI will reserve the right to exclude on the basis of psychiatric
history not explicitly described in this criterion. Justification: Psychiatric
disorders involve the central neural system (CNS) and, therefore, can be expected to
alter the fMRI measures being used in this study. Assessment tools: M.I.N.I., Beck
Depression Inventory, Beck Anxiety Inventory, Adult ADHD Self-Report Scales and
clinical terview confirmation by clinician.

- Meet current DSM-5 criteria for moderate to severe substance use disorder, for alcohol
or any drug (except nicotine for the smoker group). Past substance use disorder (SUD)
is acceptable based on MAI determination. Those with past SUD of substances other than
alcohol or marijuana may not have any current use (past 6 months) of the substance on
which they were dependent. Individuals with past SUD of either alcohol or marijuana
who report current use of the previously dependent substance may be included provided
they do not currently meet withdrawal criteria. Justification: SUD of other substances
(drugs or alcohol) may result in unique CNS deficits that could confound results and
introduce excessive variance. Assessment tools: The Mini International
Neuropsychiatric Interview (M.I.N.I) and clinical SUD assessment, Drug Use Survey,
Addiction Severity Index. A positive drug test for marijuana will not be exclusionary
as long as participants, based on self- report, have not used in the 24hrs preceding
the imaging visits. In the event of a positive drug test for marijuana, self-reports
of current marijuana use will be used to differentiate intermittent/infrequent from
chronic/frequent users.

- History of myocardial infarction, angina, congestive heart failure, cardiomyopathy,
stroke or transient ischemic attack, mitral valve prolapse, or any heart condition
currently under medical care. Justification: the risk of iTBS for individuals with a
heart condition is unknown, further such conditions may alter blood flow, the fMRI
signal and other autonomic signals. These conditions are also likely to add
considerable additional variability to the data. Assessment tools: physical
assessment, EKG, medical history.

- Women who are pregnant, sexually active and not using an acceptable form of birth
control. Justification: study procedures used in the current protocol (MRI, iTBS) may
complicate pregnancy. Assessment tools: Urine and/or serum pregnancy tests, and
clinical interview. Urine pregnancy tests will also be conducted at the beginning of
each imaging visit.

- Participation in any NIBS session (excluding the current protocol) less than two weeks
ago. No NIBS exposure for treatment purposes in the last 6 months. Justification: in
order to avoid possible carry-over effects from previous exposure to NIBS prior to
participation in the proposed intervention, we will not enroll participants who have
received any NIBS in the two weeks preceding enrollment or treatment with NIBS
modality with the last 6 months preceding enrollment. Assessment tools: TMS safety
screen.

- Cognitively impaired or learning disabled. Justification: Cognitive impairment and
learning disabilities may be associated with altered brain functioning in regions
recruited during laboratory task performance. Cognitive impairment may affect one s
ability to give informed consent. Assessment tool: Medical History and Wechsler
Abbreviated Scale of Intelligence (WASI). IQ estimate must be 80 or over.

- Have coagulopathies, history of, current superficial, or deep vein thrombosis,
musculoskeletal abnormalities restricting an individual s ability to lie flat for
extended periods of time. Justification: MR scanning sessions require participants to
lie flat on their backs and remain perfectly still for approximately two hours.
Therefore, conditions that would make that difficult (e.g. chronic back pain,
significant scoliosis) or dangerous (e.g. familial hypercoagulability syndrome,
history of thrombosis) will be exclusionary. Assessment tools: History and physical
examination by a qualified IRP clinician, supplemented with a trial of lying in the
mock scanner to ssess comfort issues.

- Regularly use any prescription (e.g., antidepressants, benzodiazepines,
antipsychotics, anticonvulsants, barbiturates), over-the-counter (e.g., cold medicine)
or herbal medication (e.g., Kava, Gingko biloba, St. John s wort) that may alter CNS
function, cardiovascular function, or neuronal-vascular coupling. Justification: The
use of these substances may alter the fMRI signal and/or neural functions of interest
in the current study. Assessment tools: History and comprehensive urine drug screening
to detect antidepressants, benzodiazepines, antipsychotics, anticonvulsants, and
barbiturates.

INCLUSION CRITERIA (PROTOCOL TRIANING):

Participants must:

- Be Right-handed.

- Justification: Differences in hemispheric dominance could confound iTBS
administration and MRI measurements.

- Screening tool: Self-report.

- Be in good health.

- Justification: Many illnesses may increase likelihood of TMS ...