Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study

Objective: To establish an effective repetitive transcranial magnetic stimulation (rTMS)
protocol for stimulating circuits relevant for addiction. Specifically, we will develop
stimulation parameters and outcome measures for rTMS of the anterior cingulate cortex (ACC)
with a specialized TMS coil: the HAC coil (Brainsway Ltd.). Various parameters of rTMS
stimulation (frequency and intensity) will be varied, and the sensitivity of behavioral tasks
and MRI measures to this stimulation will be determined. The objective of this protocol is
therefore to allow for the development, assessment and refinement of rTMS parameters for
stimulating ACC targets. In addition, outcome measures will be developed to capture the
effects of this stimulation. Results from this development protocol will be applied to
subsequent cognitive imaging protocols.

Study population: Up to 50 healthy, non-smoking adults will be tested in several conditions
over up to two weeks. Subjects must fit exclusion/inclusion criteria for TMS and MRI. We
expect 140 subjects to be enrolled to arrive at a number of 50 who complete the protocol.

Design: Within-subject design with each subject completing up to 10 rTMS sessions.

Outcome measures: In a first phase, the outcome measure will be the behavioral response on a
task that relies on the ACC. In a second phase, outcome measures will be the effects on MR
measures. These will include task-related blood oxygen level-dependent (BOLD) responses, as
well as resting state BOLD fMRI. Other MR measures, such as magnetic resonance spectroscopy
(MRS) and arterial spin labeling (ASL), will also be explored as potential biomarkers.

- INCLUSION CRITERIA:

Subjects must:

1. Be able to give valid informed consent

2. Be 18 55 years of age.

1. 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 increases with age.

2. Screening tool: 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.

3. Be in good health.

1. Justification: Many illnesses may alter neural functioning as well as fMRI
signals.

2. Screening 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 >250 mg/dl, Hemoglobin < 10.5
g/dl, WBC < 2400/microl, LFTs > 3Xnormal, HCG positive, Casual serum glucose >
200 mg/dl, Urine protein > 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.) MAI will make the final judgment on any
questionable lab results.

4. Right-handed.

1. Justification: Using right-handed individuals will reduce variability in BOLD MRI
data.

2. Screening tool: Edinburgh Handedness Inventory.

5. Estimated IQ greater than or equal to 85

1. Justification: Subjects must be able to perform a cognitively challenging task to
a high standard.

2. Screening tool: Wechsler Abbreviated Scale of Intelligence.

EXCLUSION CRITERIA:

1. Personal history of stroke, brain lesions, previous neurosurgery, any personal 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 two days.

Justification: Stroke or head trauma can lower the seizure threshold, and are
therefore contra-indications for TMS. Fainting episodes or syncope of unknown cause
could indicate an undiagnosed condition associated with seizures.

Screening tool: TMS adult safety questionnaire, Medical History.

2. First-degree family history of any neurological disorder with a potentially hereditary
basis, including migraines, epilepsy, or multiple sclerosis.

1. Justification: Neurological disorders can lower the seizure threshold, and are
therefore contra-indications for TMS. First-degree family history of certain
neurological disorders with a hereditary component increases the risk of the
subject having an undiagnosed condition that is associated with lowered seizure
threshold.

2. Screening tool: TMS adult safety screening, Medical History.

3. Cardiac pacemakers, neural stimulators, implantable defibrillator, implanted
medication pumps, intracardiac lines, or acute, unstable cardiac disease, with
intracranial implants (e.g. aneurysm clips, shunts, stimulators, cochlear implants, or
electrodes) or any other metal object within or near the head that precludes MRI
scanning.

1. Justification: Any metal around the head is a contraindication for both MRI and
TMS, as both methods involve exposure to a relatively strong magnetic field.

2. Screening tool: TMS adult safety screening, MRI safety screening, Medical
History.

4. Noise-induced hearing loss or tinnitus.

1. Justification: individuals with noise-induced hearing problems may be
particularly vulnerable to the acoustic noise generated by TMS and MRI equipment.

2. Screening tools: TMS adult safety screening.

5. Current use (any use in the past 4 weeks, chronic use within 6 past six months) of any
investigational drug or of any medications with psychotropic, anti or pro-convulsive
action.

1. Justification: The use of certain medications or drugs can lower seizure
threshold and is therefore contra-indicated for TMS.

2. Screening tools: MRI safety screening questionnaire, Medical history, Medical
Assessments: Urine toxicology analyzes for presence of a broad range of
prescription and nonprescription drugs.

6. Lifetime history of major depressive disorder, schizophrenia, bipolar disorder, mania,
or hypomania.

1. Justification: The population of interest here is a healthy control population
with no psychiatric disorders. In subjects with depression, bipolar disorder,
mania or hypomania, there is a small chance that TMS can trigger (hypo)manic
symptoms.

2. Screening tools: SCID Screen Patient Questionnaire. Potential diagnoses will be
further evaluated by a counsellor.

7. Meet current DSM V criteria for moderate to severe substance use disorder (excluding
nicotine), smoke daily, or urine toxicology positive for any illicit substance
inconsistent with history given.

1. Justification: The population of interest here is a healthy control population
with no substance use disorder. Current use of illicit substances could impact on
seizure threshold and is therefore contra-indicated for TMS.

2. Screening tools: SCID Screen Patient Questionnaire. Potential diagnoses will be
further evaluated by a counsellor, Drug Use Survey (DUS), Substance Use Disorder
Evaluation, Medical Assessments: urine qualitative drug screen is performed for
methadone, benzodiazepines, cocaine, amphetamine/methamphetamine, opiates,
barbiturates, and tetrahydrocannabinol.

8. Have met DSM V criteria for moderate to severe substance use disorder (excluding
nicotine, alcohol and cannabis) in the past, or have met DSM V criteria for moderate
to severe substance use disorder for cannabis or alcohol in the past 5 years.

1. Justification: the population of interest here is a healthy control population
with no present or past substance use disorder.

2. Screening tools: SCID Screen Patient Questionnaire. Potential diagnoses will be
further evaluated by a counselor. Drug Use Survey (DUS), Substance Use Disorder
Evaluation.

9. History of myocardial infarction, angina, congestive heart failure, cardiomyopathy,
stroke or transient ischemic attack, or any heart condition currently under medical
care.

1. Justifications: the risk of TMS for individuals with a heart condition is
unknown.

2. Screening tool: physical assessment (EKG), medical history.

10. Pregnant women or women with reproductive potential who are sexually active and not
using an acceptable form of contraception.

1. Justification: it is unknown whether TMS poses a risk to fetuses.

2. Screening tool: Medical assessments (urine pregnancy test) at the beginning of
each visit that involves TMS or MRI.

11. History of learning disability or current ADHD

1. Justification: Subjects should be able to perform cognitive tasks to a high
degree of accuracy, both in the MRI scanner and outside the scanner. Subjects
with ADHD/LD may engage different neural circuitry even if they can perform the
tasks.

2. Screening tool: Wechsler Abbreviated Scale of Intelligence, Medical history,
Adult ADHD Self-Report Scale.

12. Participation in an rTMS session less than two weeks ago.

1. Justification: in order to limit exposure to TMS, we will not enroll subjects who
have received TMS less than two weeks ago.

2. Screening tool: TMS safety screening questionnaire.