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