Mechanism of Non-invasive Magnetic Stimulation

Objectives: The goal of the protocol is to investigate acute modulations of brain activity by
transcranial magnetic stimulation (TMS). Using simultaneous TMS and functional magnetic
resonance imaging (fMRI), we will evaluate TMS induced changes in brain activity, including
regional brain activation and inter-regional functional connectivity. Repetitive TMS will be
applied over the dorsolateral prefrontal cortex (DLPFC) with different frequencies and
interleaved with fMRI acquisition to provide online monitoring of brain activity.
Furthermore, we will assess the relationship between the TMS induced brain activity and the
anatomical connection obtained from diffusion tensor imaging (DTI), using individual
variations in these imaging measures. Results from this study will help to understand the
underling mechanism of TMS and will provide insights for interpretation of TMS and fMRI data.

Study population: Up to 70 healthy, adults will be tested. Subjects must fit
exclusion/inclusion criteria for both TMS and MRI. We expect to enroll 70 subjects to arrive
at 50 who complete the protocol.

Design: The study is a within-subject design with each subject completing up to 4 TMS-fMRI
sessions in two days (2 sessions per day)

Outcome measures: The outcome measures will be the effects of TMS on fMRI blood oxygen
level-dependent (BOLD) responses, TMS induced changes on resting state functional
connectivity, and their associations with relevant structural connectivity revealed by DTI.

- INCLUSION CRITERIA:

Subjects must:

- Be able to give valid informed consent

- Be 18 60 years of age.

- 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.

- 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.

- Be in good health.

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

- 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/ (Micro)l, 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.

- Right-handed.

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

- Screening tool: Edinburgh Handedness Inventory.

EXCLUSION CRITERIA:

- 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 safety questionnaire, Medical History.

- 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 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.

- Screening tool: TMS safety screening, Medical History.

- 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.

- 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.

- Screening tool: TMS safety screening, MRI safety screening, Medical History.

- Noise-induced hearing loss or tinnitus.

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

- Screening tools: TMS safety screening.

- 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.

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

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

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

- 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.

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

- Current use of nicotine or history more than 20 cigarettes lifetime or history of
daily smoking.

- Justification: The population of interest here is a healthy control population
with no substance use disorder and therefore a minimal cigarette exposure history
in the control group is required.

- Screening tools: Self-report, urine cotinine (e.g. NicAlert) level of 2, CO < 6.

- Meet current DSM-5 criteria for any substance use disorder, smoke daily, or urine
toxicology positive for any illicit substance inconsistent with history given.

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

- Screening tools: MINI 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. Participants who test positive at
screening (under protocol 06-DA-N415) will be evaluated with a neuromotor exam to
further assess for current intoxication. For participants who are not found to be
currently intoxicated, screening staff will assess for SUD and coherence of their
drug use history and toxicology, with particular attention to substances for
which they are positive and may require a return screening visit to demonstrate
ability to produce a negative urine before allowing them to proceed to clearance
for this study.

- Have met DSM-5 criteria for any substance use disorder in the past.

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

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

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

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

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

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

- Justification: it is unknown whether TMS or MRI poses a risk to fetuses.

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

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

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

- Screening tool: TMS safety screening questionnaire.

- Learning disability, ADHD or cognitive impairment

- Justification: Cognitive impairment and learning disabilities are associated with
alterations in brain regions and may introduce significant variably into the
data.

- Screening tool: self-report of special education classes, history of specific
learning disability or mental retardation, Wechsler Abbreviated Scale of
Intelligence (WASI), Medical history and Adult ADHD Self-Report Scale with follow
up clinical interview.