Estimating the Sensitivity of a Mobile Neuro-cognitive Platform ("BrainE") to Detect Neural Plasticity and Cognitive Enhancements Following Theta-burst Stimulation to Superior Frontal/dACC TMS Stimulation.
Phase: NA
Conditions: Cognitive Control
Sponsor: University of California, San Diego

Official title: Estimating the Sensitivity of a Mobile Neuro-cognitive Platform ("BrainE") to Detect Neural 
Plasticity and Cognitive Enhancements Following Theta-burst Stimulation to Superior 
Frontal/dACC TMS Stimulation.   
 
NCT number: NCT03946059 
 
Document Date: February 16th 2021 
 
 
 

Study Protocol: Participants provided written informed consent for the TMS study protocol approved by the 
UCSD IRB (#190059). Participants were screened for this study prior to enrollment. Any individuals with a history 
of seizure disorder; vascular, traumatic, tumoral, infectious or metabolic lesion of the brain; administration of 
drugs that lower the seizure threshold; implanted or non-removable metallic objects above the neck; implanted 
devices with electrical circuits (pace-makers, cochlear implants) were excluded from enrollment. In addition, 
subjects were excluded if they had chronic sleep deprivation or confirmed heavy alcohol use (defined as greater 
than 5 episodes of binge drinking in the past month with >5 alcohol drink-equivalents per sitting for men (or >4 
drink-equivalents per sitting for women). Subjects were also excluded if they reported the use of stimulant drugs 
in the past month (cocaine, methamphetamines), or if they were pregnant, or had any history of severe 
cardiovascular disease (i.e. history of transient ischemic attack, heart attack or stroke). 
 
Repetitive Transcranial Magnetic Stimulation (rTMS). We used the FDA-approved Magventure stimulator 
(MagPro R30) for rTMS delivery. Each participant made two visits for this study, separated by a one-week 
interval, and each visit lasted up to 2 hours. Participants were provided either the continuous theta burst 
stimulation (cTBS) or intermittent TBS (iTBS) TMS protocol at each visit. Participants were blinded to the 
stimulation type, and stimulation order in week 1 or 2 was counterbalanced across subjects. The research staff 
who performed stimulation were blind to the effects of the cTBS or iTBS protocol, and the data analytics lead 
and study principal investigator were blind to the identity of the protocol i.e. all data were analyzed with cTBS 
blinded as stim A and iTBS as stim B. TBS stimulation was delivered to the midline at FCz target location, 
consistent with the pre-supplementary motor area site for rTMS in superior frontal cortex, which was active in 
most of our cognitive tasks (Verbruggen et al., 2010). A train of 3 pulses, spaced 20 msec apart (50 Hz 
stimulation), followed by an inter-train interval of at least 200 msec (5 Hz) was applied either continuously (cTBS), 
or intermittently (iTBS) with a jitter between trains as has been tested in prior research (Rossi, Hallett, Rossini, 
Pascual-Leone, et al., 2009; Oberman et al., 2011). In cTBS, bursts of 3 pulses at 50 Hz were applied at a 
frequency of 5 Hz for 20 sec, total 100 bursts. In iTBS, ten 2 sec periods (10 bursts) of TBS were applied at a 
rate of 0.1 Hz for a total 100 bursts. Stimulation amplitude was set at 80% of motor threshold individually 
determined in each participant.  
 
At each rTMS study visit, participants first performed a set of neuro-cognitive assessments (pre-stim), then 
immediately received either cTBS or iTBS TMS stimulation, then performed the neuro-cognitive assessments 
again (post-stim). We investigated the sensitivity of the neuro-cognitive assessments to measure brain plasticity 
in pre-stim versus post-stim comparisons, as a function of the rTMS protocols. Details of the neuro-cognitive 
assessments are provided in Balasubramani, et al., Mapping Cognitive Brain Functions at Scale. Neuroimage 
2021 in Press https://doi.org/10.1016/j.neuroimage.2020.117641 
 
Statistical Analysis Plan: 
For neural analyses for the primary outcome, we applied a uniform processing pipeline to all EEG data acquired 
simultaneous to the cognitive tasks. This included: 1) data pre-processing, and 2) cortical source localization of 
the EEG data filtered within the relevant theta frequency bands. 
 
For the secondary outcome, behavioral data for cognitive assessments were analyzed for signal detection 
sensitivity, d’, computed as z(Hits)-z(False Alarms) (Heeger and Landy, 2009). Task speeds were calculated as 
log(1/RT); RT is response time acquired in milliseconds then converted to RT in seconds to be used in the log 
speed calculation.  Then, task efficiency was calculated as a product of d’ and speed (Barlow et al., 1980; 
Vandierendonck, 2017), and global task efficiency was the average efficiency across all cognitive tasks.  
 
Both for the primary (neural) and secondary (behavioral) outcome, data were compared across stimulation type 
(iTBS vs cTBS) using repeated measures analyses of variance (rm-ANOVA) with a within-subject factor of task-
type; the Tukey-Kramer method was used for post-hoc testing.