Effect of Transcranial Magnetic Stimulation to the Frontoparietal Attention Network on Anxiety Potentiated Startle

Objective: To determine the effect of non-invasive brain stimulation on anxiety and
anxiety-cognition interactions in healthy subjects. Toward this aim we will test the effect
of transcranial magnetic stimulation (TMS) on two outcome measures: 1) Fear and anxiety
during the threat of predictable and unpredictable shock (NPU threat test), and 2) Working
memory (WM) related anxiety downregulation while performing the Sternberg WM task under
threat of shock.

Study population: The study population will consist of up to 184 healthy volunteers between
the ages of 18-50.

Design: This study will consists of two (sub-studies 1 and 2) or three (sub-study 3)
outpatient visits (1 MRI, 1 or 2 TMS visits [2 for sub-study 3]). In this protocol we will
explore the effect of TMS in three sub-studies in the TMS study visit. The sub-studies will
contain either the NPU or the Sternberg task during the TMS visits. The first visit (MRI)
will consist of the same procedures for all sub-studies. Each subject will be assigned to
only one of the sub-studies.

Sternberg Task: Expose subjects to active or sham TMS to a region of the frontoparietal
attention network during the Sternberg WM task. Subjects will have to maintain a series of
letters in WM for a brief interval during blocks of safety and threat of shock.

NPU Task: Expose subjects to active or sham TMS to a region of the frontoparietal attention
network during the NPU threat test. Subjects will be exposed to blocks in which they are
either 1) safe from shock (neutral), 2) at risk of shock delivered only during a cue
(predictable), or 3) at risk of shock presented randomly (unpredictable).

Outcome measures: In both studies the primary outcome measure will be anxietypotentiated
startle (APS), which is the increase in startle magnitude during periods of threat compared
to periods of safety. We expect active, but not sham TMS to increase activity in the dlPFC,
and therefore reduce APS in both studies

- INCLUSION CRITERIA:

- Ages 18-50

- Subjects able to give their consent

- Right handed

EXCLUSION CRITERIA:

- Non-English speaking individual

- Any significant medical or neurological problems (e.g. cardiovascular illness,
respiratory illness, neurological illness, seizure, etc.)

- Current or past Axis I psychiatric disorder(s) as identified with the Structured
Clinical Interview for DSM-IV, non-patient edition (SCID-np)

- Active or history of active suicidal ideation.

- Evidence of a first-degree relative with history of psychosis or bipolar disorder;
specifically, participant will know diagnosis or treatment in order to confirm
presence of disorder.

- Alcohol/drug problems in the past year or lifetime alcohol or drug dependence
according to the Structured Clinical Interview for DSM-IV.

- Current use of medications that act on histamine (i.e. diphenhydramine), dopamine
(methylphenidate), norepinephrine (buproprion), serotonin (sertraline), or
acetylcholine (amitryptiline) receptors. Subjects will be excluded on this basis if
they either 1) take these medications on a chronic basis, or 2) if they have taken the
drug within 5 half-lives of the drug metabolism, determined by the medical
professional at the time of screening.

- History of seizure (childhood febrile seizures are acceptable and these subjects may
be included in the study),

- History of epilepsy in self or first degree relatives, stroke, brain surgery, head
injury, cranial metal implants, known structural brain lesion.

- Increased risk of seizure for any reason, including prior diagnosis of increased
intracranial pressure (such as after large infarctions or trauma), or currently taking
medication that lowers the seizure threshold (table below).

- Pregnancy, or positive pregnancy test.

- Neurological syndrome of the arm (e.g., carpal tunnel syndrome, cubital tunnel
syndrome, etc.)

- Positive urine toxicology screen during the screening visit.

- IQ <80

- Employee or staff of NIMH or are an immediate family member of a NIMH employee, staff,
or NIMH contractors.

- Allergy to lidocaine or topical anesthetics (participants in sub-study 3 only).

- Any medical condition that increases risk for fMRI or TMS:

- Any metal in their body which would make having an MRI scan unsafe, such as
pacemakers, stimulators, pumps, aneurysm clips, metallic prostheses, artificial
heart valves, cochlear implants or shrapnel fragments, or if you were a welder or
metal worker, since you may small metal fragments in the eye.

- Participants who are uncomfortable in small closed spaces (have claustrophobia)
and would feel uncomfortable in the MRI machine

- Patients who have difficulty lying flat on their back for up to 60 min in the
scanner

- History of hearing loss