Establishing Functional Biomarkers for Spaced Theta-Burst Stimulation

Overall study design:

The investigators propose a functional MRI study of 10 healthy participants recruited from
the community using a cross-over design over two days. On day 1, half of the participants
will be randomized to receive iTBS and half will receive cTBS. On scan day 2 the alternate
form of TBS will be applied such that all participants will have completed iTBS and cTBS
sessions at the end of the two study days.

MRI scan days 1 and 2 will be identical except that iTBS will be applied on one day and cTBS
on the other. The duration of the MRI scan session will be approximately 120 minutes each
day. The iTBS and cTBS scans sessions will be separated by at least 3 days to ensure that the
effects of scan day 1 are not carried over to scan day 2.

Each scan day will consist of the following sessions:

1. Pre-scan session

2. Baseline scan

3. TBS (individually targeted to M1)

4. Post-TBS scan

Participants and Screening:

10 healthy individuals from the community will be recruited. Potential participants will be
screened using the MRI Safety Screening Questionnaire, the Transcranial Magnetic Stimulation
Adult Safety Screen (TASS), and the Mini Mental State Examination (MMSE) to exclude
individuals with contraindications to MRI, TMS, or with cognitive impairments, respectively.
Eligible participants will provide written informed consent.

Experimental Design:

Participants will be asked to refrain from taking any analgesic medication for 24 hours prior
to scan days. At the start of each scan day, participants will first undergo a Pre-scan
session outside of the scanner. In this session, baseline resting motor thresholds and pain
thresholds to laser stimuli will be obtained. Participants will also have the opportunity to
practice the motor and pain tasks that they will perform in the MRI sessions during this
time. For the motor task participants will be asked to tap their finger when a verbal and/or
auditory cue is provided. For the pain task, participants will passively experience and rate
laser stimuli applied to different regions of the dorsum of their fingers/hands using a 0-10
numerical rating scale (NRS). Ratings will be made for both pain intensity and pain
unpleasantness.

On both scan days (iTBS and cTBS) baseline MRI scans will be acquired. These scans will
include the following: a high-resolution anatomical scan, a resting-state scan, a motor task
scan, a pain task scan, cerebral blood flow imaging, and an interleaved TMS-fMRI scan.

Participants will then be removed from the scanner and receive a spaced TBS session (either
iTBS or cTBS depending on the day) whereby 2 TBS protocols are applied with a 15 minute break
in between. TBS will be applied at The stimulation will be delivered at 90% of the resting
motor threshold. The brain region that will be targeted is the M1 region with the highest
activity from the fMRI motor task that occurred in the baseline scan. In this way, each
participant will receive TBS that is individually targeted based on their brain function.

Following TBS, participants will then receive their post-TBS MRI scans as described in the
baseline scan session.

Study Specifics:

rTMS administration: Using single pulse TMS the scalp position of lowest motor threshold for
the right first dorsal interosseous or abductor pollicis brevis muscles will be determined.
Resting motor threshold (rMT) will be defined by the lowest power setting producing a visible
muscle contraction in 50% trials utilizing PEST software. The investigators will then perform
40 seconds of cTBS or iTBS (depending on the session), which will be followed by 15 minutes
of spacing, and then an additional 40 seconds of cTBS or iTBS as has been previously
described. The individualized TBS target location for the left M1 will be determined by using
each participants' functional motor task MRI scan and Localite Neuronavigation. The baseline
structural scan obtained during scan 1 will also be utilized for this localization process.

Pain induction assessment procedures: On the scanning days, baseline warmth sensation
threshold, heat-pain threshold (HPTpre) and suprathreshold stimulus intensities and maximum
heat tolerance temperature (HTTpre) will be determined for each volunteer using an MRI-safe
infrared diode laser stimulator. A 1.5 s, heating ramp up to 20 °C/s will be applied to 10-20
spots (40 mm2) on the hairy skin of the hand and fingers (but not the thumb) of participants.

Pain threshold will be determined using a random staircase method of assessment. The average
laser power necessary to produce a rating of "1" will be used to establish the pain
threshold. To determine an intensity-effect relationship, pulses will then applied with
increasing stimulus intensities to different areas of the dorsum of the hand/fingers with at
least 30 s between stimuli. Subjects will be asked to rate the pain intensity and
unpleasantness immediately after each stimulus (0 to 10, NRS).

Stimulus intensities will be increased in 300 mW increments. Intensity increases will be
continued until a given subject reports a level of moderate pain intensity (5 out of 10,
NRS). This intensity will be considered "suprathreshold" for the scan studies. In order to
train volunteers in rating their pain with an 11-point numerical rating scale (0 to 10, NRS),
the temperature of the laser will then be set to evoke random skin temperatures for 5 s
between the individual HPTpre and HTTpre separated by 30-s intervals, and the volunteers were
asked to rate their pain. For scans after rTMS-augmented hypnotic analgesia or hypnotic
analgesia alone (sham rTMS + hypnotic analgesia), heat pain scores evoked by the
pre-established threshold and suprathreshold laser powers will be assessed following each
scan. Decreased pain ratings will determine the strength of any analgesic effect TBS.
Subjects will be asked to rate their laser-evoked pain following each stimulus during each
scan.

Physiologic data acquisition: Throughout the scanning procedure we will monitor peripheral
autonomic physiology using MRI compatible EKG leads and a chest belt that monitors
respiration. This will allow us to compute respiratory sinus arrhythmia, which provides a
good estimate of vagal tone, which, in turn, is associated with better cardiac health and
self-soothing. Customized algorithms developed here at Stanford for simultaneous fMRI/EEG to
remove MRI scanner artifact from the EKG tracing will be applied.

Brain Imaging Scans:

1. T1-weighted scan (high-resolution anatomical image)

2. Resting-state scan

3. BOLD motor-tapping task scan

4. Pain task scan

5. Arterial-spin labeling scan (cerebral blood flow)

6. Interleaved TMS-fMRI scan

Inclusion Criteria:

- Age 18 or older

- Right-handed

- Agree to having fMRI scan

- Willingness to suspend use of analgesic drugs or cough suppressants for 24 hours prior
to the scans

- Proficiency in English sufficient to complete questionnaires/follow instructions
during fMRI assessments

- US Citizen or resident able to receive payment legally

Exclusion Criteria:

- A medical condition that would contraindicate the use of rTMS

- Any condition that would contraindicate MRI (like ferromagnetic metal in the body)

- Pregnancy or breast feeding

- Any significant neurologic disease, including dementia, multi-infarct dementia,
Parkinson's or Huntington's disease, brain tumor, progressive supranuclear palsy,
seizure disorder, subdural hematoma, multiple sclerosis, history of significant head
trauma

- Current antidepressant use (must be washed out for two weeks prior to starting
protocol)

- Inability to stop taking medication contraindicated with treatment