Pilot Study of Transcranial Magnetic Stimulation (TMS) in Nicotine Addiction

Primary objective: Transcranial magnetic stimulation (TMS) provides a non-invasive means of
inhibiting brain neural activity. This pilot study will test whether 5 days of single pulse
(sp) TMS reduces cue-induced nicotine craving and use in cigarette smokers.

Hypothesis: We predict that active spTMS will significantly lower craving for nicotine
compared with sham spTMS.

Study population: Subjects will be up to 73 adult cigarette smokers (averaging greater than
or equal to 10 cigarettes daily for greater than or equal to one year) with current nicotine
dependence (based on DSM-IV criteria or Faerstrom Test for Nicotine Dependence score greater
than or equal to 3). Subjects will not have other current major psychiatric disorders or
substance abuse. Subjects in the pilot phase (one fMRI and one TMS session to valid brain
mapping procedures) will be up to 25 healthy non-smokers.

Design: Following a baseline day to evaluate subject characteristics, subjects will be
randomly assigned to receive 5 days of active or sham spTMS session. spTMS at strength 120
percent of the motor threshold will be applied to the prefrontal cortex (PFC) using a
figure-eight coil. Magnetic pulses will be triggered by cigarette-related pictorial cues and
delivered at varying intervals prior to presentation of a cigarette-related picture. TMS
pulses will not be delivered during emotionally salient images unrelated to nicotine or
emotionally neutral images. Brain site localization will use a computerized navigation system
based on functional and structural MRI scans obtained before the first session. Each session
(lasting around 20 minutes) will consist of 108 trials (cue presentations): 72 with
nicotine-associated cues and 18 each with non-drug-associated positive or neutral cues.
Subjects return for follow-up fMRI and behavioral assessments one and two weeks after the
final TMS session.

Outcome measures: The primary outcome measure will be nicotine craving assessed with the
Tobacco Craving Questionnaire and visual analog scales before and after every TMS session and
at one- and two-week follow-up. Secondary outcome measures will include cigarette smoking
over the test period and at follow-up assessed by self-report, salivary cotinine levels, and
expired breath CO levels. A follow-up fMRI will evaluate changes in regional brain activity
associated with changes in craving and TMS treatments.

Benefits: Participants will not directly benefit from this study. This study may contribute
to better scientific understanding of nicotine addiction and development of better treatment
methods.

Risks: The primary risks from TMS are transient headache, scalp discomfort, and hearing loss
(minimized by wearing ear plugs). Seizures are very rare when spTMS is administered within
accepted safety guidelines and individuals at increased risk of seizures are excluded. By
excluding individuals with a history of non-drug-induced mania/ hypomania we minimize the
risk of inducing a manic episode.

-INCLUSION CRITERIA:

i) Eighteen years of age or older

ii) Current nicotine dependence (by DSM-IV criteria or Fagerstrom Test for Nicotine
Dependence score greater than or equal to 3) and averaging smoking 10 or more cigarettes
per day for at least one year.

iii) Reading level of at least 6th grade, based on the Wide Range Achievement Test (WRAT)

iv) Ability to give valid informed consent

v) Right-handed

vi) If the subject is female, of childbearing potential, and sexually active, she agrees to
use a medically acceptable contraception, and not become pregnant for the duration of the
study. A woman is considered of childbearing potential unless post-menopausal or surgically
sterilized. Female patients of childbearing potential who are or who anticipate the
possibility of becoming sexually active with a male partner must use either: (1)
contraceptive pill or IUD or depot hormonal preparation (ring, injection implant); and/or
(2) a barrier method of contraception such as diaphragm, sponge with spermicide, or condom.
Women who are not sexually active do not have to agree to use one of the acceptable
contraception methods. Contraceptive measures will be reviewed with female subjects at each
visit prior to the TMS session.

vii) Self-report experiencing nicotine craving when exposed to nicotine-associated cues

EXCLUSION CRITERIA:

i) Personal or first-degree family history of any clinically defined neurological disorder,
including organic brain disease, epilepsy, stroke, brain lesions, multiple sclerosis,
previous neurosurgery, or personal history of head trauma that resulted in loss of
consciousness.

ii) 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 cannot be safely removed.

iii) Metal shrapnel or bullet in the head or body including metal shavings.

iv) Current use of any investigational drug or of any medications with anti or
pro-convulsive action

v) Increased intracranial pressure (lowers seizure threshold)

vi) Lifetime history of major depressive disorder, schizophrenia, bipolar disorder, mania,
or hypomania

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

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

ix) Any history of seizure

x) Current dependence (DSM-IV criteria) on substances other than nicotine.