Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04846829 |
| Other study ID # |
16-002086 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
Early Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
April 24, 2017 |
| Est. completion date |
April 24, 2026 |
Study information
| Verified date |
August 2023 |
| Source |
University of California, Los Angeles |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This study will recruit 30 subjects diagnosed with Major Depressive Disorder (MDD). Subjects
will be recieve one infusion treatment of citalopram or placebo and 10 treatments of a form
of transcranial magnetic stimulation, theta burst stimulation (TBS). Subjects will also
undergo brain scans, quantitative electroencephalography (qEEG) brain activity recordings,
and mood surveys. Study activities will be performed over the course of 4 weeks.
Description:
Repetitive Transcranial Magnetic Stimulation (rTMS) is an increasingly common treatment for
Major Depressive Disorder (MDD). rTMS applied to dorsolateral prefrontal cortex (DLPFC), the
most common treatment target, appears to change neuronal excitability in this region. rTMS
also changes function of brain circuits connected to DLPFC. This application proposes an
innovative approach to elucidating the mechanism of action (MOA) underlying these circuit
changes, using MDD as a significant translational model.
One form of rTMS, theta burst stimulation (TBS), has particularly strong effects on cortical
excitability: intermittent pulsing over left DLPFC (iTBS) increases excitability, while
continuous pulsing over right DLPFC (cTBS) reduces excitability. TBS applied to DLPFC alters
functional connectivity with the anterior cingulate, medial frontal, and orbitofrontal
cortices (ACC, MFC, and OFC); however, the MOA underlying these changes in connectivity is
incompletely understood. Pilot data will be obtained for a larger grant application that will
test the hypothesis that changes in local excitability underlie the changes in functional
connectivity and the therapeutic efficacy of TBS for MDD.
TBS modulation of cortical excitability may be modulated in turn by the serotonergic (5HT)
neurotransmitter system, which is also a key target of classical antidepressant medications.
The investigators will use the 5HT transport inhibitor citalopram (CIT), a widely-used
clinical antidepressant agent, to investigate the serotonergic modulation of functional
connectivity and neurophysiologic measures of excitability.
Intravenous citalopram hydrochloride has been available for prescription to patients with
treatment-refractory major depression and anxiety disorders in most of continental Europe for
more than 30 years. In the U.S., it has been used extensively as an investigational drug to
study human neurochemistry and in clinical trials for depressive disorders. An IND for the
University of Pittsburgh has utilized this compound safely as a research tool for more than
10 years (Smith et al., 2009).
This double-blinded study will recruit 30 subjects diagnosed with Major Depressive Disorder
(MDD). Subjects will be randomized to acute (single-dose) citalopram (CIT) 40 mg iv treatment
or placebo, counterbalanced and combined with one of two forms of unblinded Transcranial
Magnetic Stimulation, i.e., either intermittent Theta Burst Stimulation or continuous Theta
Burst Stimulation. Assessments for this study include brain scans, qEEG recordings, and
cognitive and mood scales. One citalopram/placebo infusion and 10 TBS treatments will be
administered over the course of approximately two weeks.
Thirty subjects ages 21-55 with a DSM-V diagnosis of MDD will be enrolled in a two-week
treatment study. After a baseline diagnostic assessment, all subjects will undergo
pretreatment assessment of brain functional connectivity (qEEG and fMRI) and structural
connectivity (DTI). They then will be randomized 1:1 to treatment with an intravenous dose of
CIT or placebo (PBO), followed by 1:1 randomized assignment to two weeks (10 sessions) of
treatment with either iTBS to left or cTBS to right DLPFC (four treatment conditions). The
end of Week 2 will constitute the primary endpoint.
High-density qEEG will be recorded throughout the initial CIT-TBS treatment session using
TMS-compatible qEEG. These recordings will be used to assess changes in excitability with
CIT/PBO and iTBS/cTBS treatment (i.e., TMS evoked Local Mean Field Power, or LMFP). The
investigators will determine whether changes in cortical excitability in DLPFC are modulated
by 5HT neurotransmission.
Next, changes in neuroplasticity in limbic circuits involving DLPFC will be examined, from
pretreatment baseline to after the first treatment, and from baseline to the primary
endpoint, using functional connectivity measures. qEEG will be used to measure changes in
signal synchronization and information flow (i.e., lagged coherence, Granger Causality), as
well as location and spread of current sources (LORETA source localization). fMRI will be
used to examine resting state network function (BOLD signal). The investigators will test
whether changes in excitability measured in the first treatment are correlated with changes
in connectivity with the first treatment, as well as over the full course of treatment.
Correlation would suggest that excitability may exert a metaplastic effect on functional
connectivity in limbic circuits involving DLPFC.
Finally, the investigators will examine symptom change at the primary endpoint, and determine
whether excitability and connectivity changes correlate with symptom improvement. Integrated
examination of changes in excitability, immediate and longer-term connectivity, and symptom
improvement, will elucidate the MOA of TBS and could lead to strategies to enhance treatment
outcomes.
Clinical diagnosis and assessment. Thirty subjects with a DSM-V diagnosis of MDD established
using the Mini International Neuropsychiatric Interview (MINI, version 7.0)
(http://www.medical-outcomes.com/index/mini7fororganizations) will be enrolled, with all
subjects having depressive symptoms of at least moderate severity as indicated by a 17-item
Hamilton Depression Rating Scale [Ham-D17] score > 17 (23 below) will be enrolled. Subjects
will undergo clinical assessment using methods similar to those employed in our previous
treatment studies using TMS (Leuchter et al., 2015). Subjects will have failed to enter
remission with at least two prior antidepressant medications (Sackeim et al., 1990; Vasavada
et al., 2016) and must have been free of any medications known to significantly affect brain
function for at least ten days prior to enrollment (except fluoxetine, which will require a
five-week washout) (Vasavada et al., 2016). Subjects will be excluded if they meet DSM-V
criteria for any other current primary Axis I mood, anxiety, or psychotic disorder,
depression secondary to a general medical condition, or substance-induced illness. Subjects
also will be excluded if they have current suicidal intent or plan, a history of substance
abuse or dependence within the past six months (except nicotine and caffeine), Bipolar
Disorder or psychotic disorder (lifetime), eating disorder (current or within the past year),
Obsessive Compulsive Disorder (lifetime), Post-Traumatic Stress Disorder (PTSD, current or
within the past year), medical or neurologic illness that would contraindicate administration
of study interventions or complicate interpretation of study results, or have an implanted
medical device or metal in their body that would contraindicate an MRI or TMS treatment
(Leuchter et al., 2015). Subjects also will be excluded if they have had prior history with
IV citalopram. Women who are currently pregnant, not using a medically acceptable means of
birth control, or are breastfeeding will be excluded. A urine drug screen will be performed,
and subjects with a positive screen for illicit substances will be excluded.
Mood symptoms will be examined after the first, second, and 10th treatment sessions using the
Clinician Global Impressions-Severity of Illness (CGI-S) and Improvement (CGI-I) (Cohen et
al., 2014), and the subject-rated Inventory of Depressive Symptomatology-Self Report (IDS-SR)
(Connolly et al., 2012), with symptoms of suicidal ideation assessed using the Columbia-
Suicide Severity Rating Scale (C-SSRS) (Cornwell et al., 2012). Assessments at time of entry
and exit from the study will include symptom ratings with the Ham-D17 and quality of life and
functional status ratings with the Quality of Life Inventory (QOLI) (Dandash et al., 2015).
Treatment response at the primary endpoint is defined as a 50% or greater improvement from
baseline on the Ham-D17 and remission as a final Ham-D17 score < 7.
Treatment procedures Citalopram (CIT) and placebo (PBO) infusion. CIT and saline PBO will be
administered intravenously using established clinical procedures. A single dose of citalopram
40 mg in 60 cc normal saline, or saline PBO, will be delivered intravenously under
double-blind conditions via pump over a 40-minute period. Blood will be drawn at the
conclusion of infusion to obtain a plasma sample for CIT levels. Subjects will be fasting
after midnight or for a minimum of 8 hours prior to undergoing infusion. Vital sign
monitoring will include blood pressure, pulse oximetry, and respiratory rate recording every
3 minutes and a continuous cardiac rhythm strip. A change of greater than 25% increase in
heart rate or blood pressure from baseline or absolute increase in heart rate above 120 bpm
or systolic blood pressure ≥ 180 mm Hg or diastolic blood pressure ≥ 105 mm Hg sustained from
more than 2 minutes will prompt the immediate discontinuation of double-blind infusion and
evaluation for intervention. Similarly, a drop of O2 saturation via pulse oximetry to less
than 92% will prompt evaluation of subject, initiate use of nasal cannula O2 at 2 liters/min
or rate necessary to return O2 saturation to baseline at room air or greater than 95%. A
physician investigator will administer the CIT or PBO infusion, perform subject assessment
and direct nursing staff. Mental status monitoring will also occur during double-blind
infusion to assess for any untoward behavioral or psychological effects. Subjects will be
instructed not to drive for up to 24 hours after infusion and will need to be driven to and
from UCLA for the procedure.
Theta burst transcranial magnetic stimulation (TBS). Stimulation will be performed using a
Magstim Rapid2 biphasic stimulator with a figure-8 coil (14 cm width) and 2 T peak field
strength. Stimulation percentages are expressed as a proportion of this individual unit's
Maximum Stimulator Output (MSO). This unit can generate the theta-burst stimulation patterns
at intensities of 45% MSO or below, well within range of most participant's individual motor
threshold (MT). To determine MT, the coil will be held mediolaterally over the region of the
left motor cortex with the handle pointing backwards and 45° from sagittal midline. This
technique induces current roughly perpendicular to the central sulcus. The right first dorsal
interosseus muscle (FDI) will be monitored with surface electromyography (5000 Hz). TMS
pulses will be delivered in a grid at suprathreshold intensities in order to identify the
location which produces the largest, most consistent motor evoked potential (MEP) recorded
from the FDI. Intensities at this hotspot will then be lowered 1% with each stimulation. The
lowest intensity stimulation that produces peak-to-peak MEP amplitudes >100 μV on at least 5
of 10 trials under conditions of gentle activation of the FDI is defined as the active motor
threshold (AMT). TBS intensity is then set at 120% AMT.
TBS consists of three TMS pulses given at 50 Hz, with this triplet repeated at a frequency of
5 Hz (every 200 ms) (Huang et al., 2005). 1800 pulses of cTBS will be delivered to the right
DLPFC, and an equal number to left DLPFC following the iTBS paradigm of a 2 s train of
repeated every 10 s. This number of pulses has been shown to have antidepressant efficacy
after two weeks of treatment (Li et al., 2014). Left and right DLPFC will be targeted using
the F3 and F4 EEG electrode locations, respectively. This method for magnet placement bears a
close relationship to placing the magnet over radiographically defined Broadmann areas (BAs)
in DLPFC (i.e., BA46) (Ahdab et al., 2010; Fitzgerald et al., 2009). This approach, widely
used in clinical practice, will allow us to easily relate the findings of this project to
clinical use. The investigators recognize that this probabilistic method for defining DLPFC
may result in some variability of magnet placement relative to underlying neuroanatomy. Given
interindividual variability in sulcal and gyral anatomy, however, it may not be possible to
reliably identify a specific BA in all subjects, and there is no "gold-standard" method for
standardizing neuroanatomic targeting across subjects. The investigators will have digitized
surface electrode locations from all subjects, and these locations will be fused with the
structural MRI images obtained from each subject at baseline and after the 10th iTBS
treatment. This will allow us to utilize neuroanatomic coil placement data as a post-hoc
covariate in data analyses (see MRI-EEG image integration below).
Neurophysiologic recording and analyses. EEG recording. Data will be recorded using the "eego
mylab" TMS-compatible EEG system at a sampling rate of 1000 Hz (Advanced Neuro Technology
[ANT]; Enschede, Netherlands). Electrodes will be applied using the 64-electrode "WaveGuard"
system with sintered Ag/AgCl electrodes mounted in an elastic cap and positioned according to
the Extended 10-20 System. The material and shape of the electrodes prevents current loops is
designed for minimal DC shifts and optimal stability of the incoming signal during TMS. The
cap utilizes active shielding of each lead to limit electric noise. Data are recorded using
full-band EEG DC amplifiers that return to physiologic baseline signal level within 10 ms
after the end of the TMS pulse. Filters will not be applied during data acquisition, and
recording will be performed using a common average reference with impedance kept below 5 kΩ.
EOG will be recorded by placing two electrodes above and below the left eye. EEG will be
processed off-line in BrainVisionAnalyzer2 (BVA2) (BrainProducts GmbH; Gilching, Germany)
with a digital band-pass filter (Butterworth zero-phase shift, 0.5-70 Hz, 12 dB/oct; plus 60
Hz notch) before segmenting into 2 s epochs (100 ms pre-stimulus period), detrending, and
baseline correction. Data initially will be processed using semi-automated artifact rejection
methods previously described including ±100 μV peak-to-peak voltage step gradient or
persistent low activity (Leuchter et al., 2012), followed by visual inspection by two
independent technicians to eliminate data contaminated by muscle, head, or eye movement
artifacts. Adaptive Mixture ICA (AMICA) also will be used to separate out non-brain source
processes including eye blinks and saccades, scalp muscle, electrocardiographic artifact, and
line noise, increasing signal-to-noise (artifact) ratio and increasing reliability of high
frequency (beta and gamma) frequency analyses as well as brain source localization
(Bigdely-Shamlo et al., 2013; Delorme et al., 2011).
Excitability measures. Excitability will be measured using the Local Mean Field Power (LMFP)
and Global Mean Field Power (GMFP) methods. Oscillatory voltage amplitude is the principal
measurement that directly reflects cortical excitability, and therefore changes in EEG field
power are used as the principal indicator of changes in excitability. LMFP can be used as a
measure of excitability at the site of TMS stimulation in any region of cortex; GMFP is a
measure of global excitability that has been used to study a number of non-invasive
neuromodulation treatments (Casarotto et al., 2013; Chung et al., 2015; Huber et al., 2008;
Pellicciari et al., 2013; Romero Lauro et al., 2014). After administration of a local
stimulus, a focal change in excitability may come to elicit a global change; as a result,
GMFP can be used to interpret LMFP and determine whether a local change in excitability
remains focal, or becomes part of a global change in excitability. For the excitability
determinations, single TMS pulses will delivered to left or right DLPFC (F3 or F4 electrode
location, coinciding with the treatment site) 10 minutes before and after treatment sessions.
Given the number of TBS pulses delivered in the protocol, changes in excitability can be
expected to remain stable for at least one hour following TBS treatment (Huang et al., 2005).
Pulses will be administered at a frequency of 0.25 Hz so that they are sufficiently
infrequent so as not affect excitability. During excitability determination, subjects will
wear earplugs and a masking noise will be played to reproduce the TMS "click" in time-varying
frequency components in order to suppress auditory evoked potentials. TEPs will be computed
by averaging valid artifact-free single trials, filtering between 2 and 40 Hz, and performing
baseline correction before and after the TMS pulse. LMFP will be calculated from the
amplitudes of the TEPs averaged from F3 or F4 and their respective four surrounding
electrodes, while GMFP will be calculated from all 64 electrodes. GMFP and LMFP will be
calculated in 30 ms time windows following the TMS pulse ranging from the end of the pulse to
400 ms (i.e., 0-30 ms, 30-60 ms, 60-90 ms, etc.) so that early and later changes in
excitability can be detected. Early time points (< 90 ms) will be used to assess LMFP, and
later time points will be used to assess GMFP and spread altered excitability to other
cortical regions.
Regional measures of neurophysiologic activity. Current source density (CSD) in gray matter
structures will be calculated using the eLORETA (exact Low Resolution Brain Electromagnetic
TomogrAphy) method (http://www.uzh.ch/keyinst/loreta.htm) (Lehmann et al., 2014). eLORETA
computes local neurophysiologic activity (Current Source Density, or CSD) as a linear
weighted sum of scalp electrical potentials. CSD measurements using eLORETA have been
validated as cortical sources of neurophysiologic activity, and obviate the the ambiguity of
source localization and the reference-dependence that are inherent in scalp EEG measurements
(Lehmann et al., 2014; Pascual-Marqui et al., 2011). The method identifies the smoothest
possible distribution of sources in a three-shell spherical head model, consisting of CSD at
each of 6239 cortical voxels (plus hippocampus and amygdala) (5 mm spatial resolution) in
Montreal Neurological Institute (MNI) space with electrode coordinates assigned according to
cross-registration between spherical and realistic head geometry (Towle et al., 1993).
Reported Brodmann areas utilize MNI space corrected to coincide with Talairach space (Brett
et al., 2002). Regions of interest (ROIs) will be created for subregions of the ACC, OFC,
hippocampus, insula, and other cortical ROIs in the limbic system based upon our prior work
and the broader literature (Arns et al., 2015; Korb et al., 2008; Korb et al., 2009; Korb et
al., 2011; Whitton et al., 2016).
Neurophysiologic connectivity measures. The investigators will use one primary
neurophysiologic measure and several complementary techniques as secondary (exploratory)
measures in order to examine baseline and changes in neurophysiologic connectivity. Our
primary connectivity measure based upon CSD data will be examined using "lagged" coherence
(omitting zero phase angle) based on intracortical source modeling techniques (Lehmann et
al., 2014; Pasi et al., 1989). The investigators will identify cortical ROIs throughout the
PFC, hippocampus, and amygdala based upon BAs and subcortical probabilistic atlases, and will
apply the eLORETA option "all nearest voxels" to assigned voxels to the ROIs. The
investigators will use the ROIs identified by eLORETA as showing high activity to seed the
connectivity analyses; The investigators anticipate that the primary ROIs of interest will be
those with strong connections to DLPFC in the limbic system, including OFC, MFC, ACC,
hippocampus, and insula. Lagged coherence represents one of the two main components of
neurophysiologic connectivity: instantaneous and lagged. The lagged component is mediated by
physiological time delays, with the instantaneous contribution to the connectivity is
eliminated. This method selectively retains connectivity due to physiologic processes (for
any non-zero, measurable time delay) that is not confounded by low resolution and volume
conduction effects (Lehmann et al., 2014).
Secondary measures also will examine connectivity and cross-frequency coupling in the
electrode space using the Source Information Flow Toolbox (SIFT) (Delorme et al., 2011). This
method uses time-varying (adaptive) multivariate autoregressive modeling to detect and
measure fluctuations in effective connectivity between sources of neural activity. this
method is complementary to the lagged coherence method in using advanced multivariate
measures of directed information flow (e.g., Granger Causality Modeling and Directed Transfer
Function modeling). SIFT functions will be used to examine changes in effective connectivity
among the different experimental conditions and between treatment groups, using
bootstrap/resampling techniques to correct for multiple comparisons. 'Network Projection',
which is an extension of Measure Projection (Bigdely-Shamlo et al., 2013) will be performed
using pairwise connectivity to measure input, which is computed by blurring the dipole
locations and loading them with connectivity measures. The brain space will then be segmented
into 88 pre-defined anatomical ROIs provided by automated anatomical labeling (AAL) obtained
from WFU Pick Atlas (which is a SPM plugin). At this point, all the subjects have 88x88
matrix of connectivity values, therefore every subject has 7744 (88x88=7744) possible
combinations of directed causal flows. Diagnostic condition differences will be computed and
bootstrap statistics will be performed for each condition to control for type 1 error.
MRI scanning and analyses. Structural and functional MRIs including DTI will be acquired
using a head-only Siemens Prisma-FIT 3 Tesla scanner at the UCLA Ahmanson-Lovelace Brain
Mapping Center. This scanner is the latest Siemens 3T product modeled after the custom made
Skyra system originally developed for the Human Connectome Project (HCP). The investigators
will utilize the optimized HCP protocols (http://www.humanconnectome.org/) to ensure that the
connectivity data are collected and processed with state-of-the-art methods that will be
interpretable in the context of other ongoing NIH research. Total scanning time will about
one hour.
Structural MRI (sMRI). A whole brain structural scan will be obtained for registration with
EEG data and evaluating morphology (MPRAGE, TR=2300 ms, TE=3 ms, FOV=256 mm, 208 slices, .8 x
.8 x .8 mm voxels). The standardized HCP sMRI protocols include both 3D T1- and T2-weighted
(T1w and T2w) high resolution scans. Analyzed together, these sequences improve the automated
extraction of brain features, though both T1 and T2 scans may also be examined separately.
Diffusion tensor MRI (DTI). The acquisition of DTI data will be used to measure the
structural connectivity of white matter. DTI will be acquired with two diffusion-weighted
gradients of b=0 and 1000 s/mm2 in 98 orthogonal directions (TE = 89.2 ms, TR = 3222 ms,
FOV=210mm, 92 slices, 1.5 x 1.5 x 1.5 mm voxels). The HCP also uses HARDI (High Angular
Resolution Diffusion Imaging) that provides greater precision for mapping the direction of
fibers in regions where fibers are crossing and allows for probabilistic tractography to
estimate fiber trajectories from ROIs defined with other imaging modalities (sMRI, fMRI, or
EEG). These same acquisition protocols will be used for this project.
Resting-state fMRI (fMRI). fMRI will be used to characterize resting state network function
in a manner complementary to EEG. The investigators will use an echo-planar sequence (72
axial slices per volume, 104×90 matrix [2.0×2.0×2.0mm3], FOV=208mm, TE = 33.1ms, TR = 720ms,
FA = 52°, 420 volumes) to gauge resting-state BOLD signals. The HCP fMRI multiband EPI
sequence offers excellent spatial and temporal resolution and contain anterior-posterior and
posterior-anterior phase encoding to correct for anatomic distortions.
MRI image processing. The investigators already have installed the HCP pipeline developed by
the Washington University group and have processed HCP-compliant data collected at UCLA using
this pipeline, achieving high quality tissue segmentation on the T1w MRI, white matter
tractography using HARDI, and resting brain networks based on fMRI. Each pipeline is
described separately below.
Structural MRI. Three HCP pipelines are applied to sMRI (T1w & T2w) data. The PreFreeSurfer
pipeline registers T1w and T2w images, performs bias-field correction, and normalizes these
images to MNI space. The FreeSurfer pipeline recreates FreeSurfer's reconall pipeline, which
segments tissue, reconstructs cortical surfaces, and aligns images to standard volume and
surface atlases.
DTI. The Diffusion Preprocessing pipeline performs standard preprocessing steps using FSL,
including equalizing intensity of b0s across runs, removing EPI and eddy-current distortions,
correcting for motion and gradient nonlinearities, and registration to T1w images. The
investigators perform postprocessing using BrainSuite and its BrainSuite Diffusion Pipeline
(BDP) (http://brainsuite.org), which enables us to compute deterministic tractography using
the ODF data to generate whole-brain diffusion tracts. The investigators will then compute
the average fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and
number of tracts along the white matter pathways connecting the anatomical ROIs (specific
circuits associated with depression, including tracts originating from the subgenual ACC and
DLPFC).
Resting state fMRI. Preprocessing protocols for functional data include two pipelines. The
first, fMRIVolume, corrects images for spatial distortions and motion, registers to T1w
images, corrects for subject motion, among other standard steps. The fMRISurface pipeline
aligns the output of fMRIVolume to cortical surfaces, including mapping onto a "grayordinate"
system to facilitate comparison and analyses across subjects. The investigators perform
resting state fMRI postprocessing using a novel method that is sensitive to spatial
differences between subjects. For graph theoretic analysis of brain networks, The
investigators will use independent components computed by ICA as well as structural ROIs
based on the Destrieux atlas as nodes, and the connectional relationships between each pair
of components will be evaluated by partial correlation analysis. The brain networks will be
characterized by network parameters computed from their adjacency matrixes to quantitatively
describe topology of networks, including 1) node degree, degree distribution and
assortativity; 2) clustering coefficient and motifs; 3) path length and efficiency; 4)
connection density or cost; 5) hubs, centrality and robustness; and 5) modularity.
MRI-EEG image integration. In order to identify the location of the F3 electrode scalp site
at which TBS is being delivered into the MRI space, as well as fully integrate the EEG and
MRI datasets, The investigators will employ the Advanced Neuro Technology Xensor 3D electrode
digitizer system (ANT Neuro; Enschede, Netherlands). This system uses a digitizing wand with
reflective markers and an infrared camera to identify the 3D locations of all 64 EEG
electrodes and three major fiducials (nasion, left and right preauricular points) for each
participant in less than 10 minutes. The 3D digitized locations then are coregistered to the
Montreal Neurological Institute (MNI-Colin27) template brain (Montreal Neurological
Institute, Montreal, Canada. URL www.bic.mni.mcgill.ca/brainweb). Electrode locations can be
used in the Visor 2.0 neuronavigation system (ANT Neuro; Enschede, Netherlands) to visualize
the stimulation target and associated scalp site that was actually used during TBS in each
individual. After loading each subject's raw MRI images into the Visor software, the
relationship of the F3 stimulation site to the DLPFC target, as well as any individual
electrode to underlying neuroanatomy, can be identified using the MNI coordinates.
