Accelerated Intermittent Theta Burst Stimulation for Depressive Symptoms
Phase: NA
Conditions: Depression and Suicide
Sponsor: Stanford University

 
 
 
Accelerated Intermittent Theta-Burst Stimulation for 
Depressive Symptoms   
 
 
NCT03601117 
 
December 13 2018 
 
Nolan Williams, Principal Investigator  
Stanford University  
Stanford, California 94305 
 

 
 
1) Name of Study: Accelerated Intermittent Theta Burst Stimulation for Depressive 
Symptoms 
 
 
2) PI and other key investigators or key study personnel:  
 
Nolan Williams 
Alan Schatzberg 
Charles DeBattista 
Kristin Raj 
Jessica Hawkins 
Eleanor Cole 
Merve Gulser  
Jaspreet Pannu 
Brandon Bentzley 
Romina Nejad 
 
 
3) Specific source of institutional funding (account number): 
 
Account 1198181 
Account EHBGN 
Account GHFES 
Account 1189192-121-DHCMV 
 
 
4) List of sources from whom you are seeking funds (or have sought funding) for this 
project: 
 
National Institutes of Health, MQ Foundation, IMHRO One Mind 
 
 
5) Specific aims and basic hypothesis including an explicit primary hypothesis or goal: 
 
SPECIFIC AIMS 
 
The overarching aim of this proposal is to test the preliminary efficacy of a highly efficient version 
of an established non-invasive neuromodulation technique, termed repetitive transcranial magnetic 
stimulation (rTMS). This novel technique, called accelerated intermittent theta-burst stimulation 
(aiTBS), is to be utilized as a rapid-acting intervention for depressive symptoms and suicidality. 
Excitatory rTMS over L LDPFC is FDA-approved for treatment-resistant depression (TRD). The 
onset of antidepressant response ranges between two to four weeks, which is not an optimal strategy 
for rapidly affecting acute depressive and suicidal thinking and behaviors. The aiTBS protocol 
suggested here may induce a faster onset of antidepressant effect by employing 10 sessions/day for 
5 consecutive days (90,000 total pulses). This application is motivated by two recent findings in 
the neuromodulation field.  

 
 
 
First, multiple sham-controlled investigations, evaluating an accelerated rTMS protocol, where 
multiple stimulation sessions were safely delivered across 2-5 days, demonstrate safety, 
tolerability, and efficacy of such stimulation. Importantly, this verifies that rTMS cannot only be 
‘accelerated,’ safely and effectively, but it has demonstrated efficacy for depressive symptoms 
among both inpatient and outpatient samples. Relevant to the proposed study, and to high-risk 
target samples, these studies demonstrated significant post-stimulation reductions in acute 
depressive and suicidal symptoms.  
 
Second, two landmark sham-controlled trials using a new, more powerful type of rTMS, 
intermittent theta-burst stimulation (iTBS), applied to the left dorsolateral prefrontal cortex (L-
DLPFC), demonstrate strong efficacy (with large observed effects) among those with treatment-
resistant depression (TRD), a condition where risk for suicide is considerably heightened. A single 
application of iTBS is shown to have 5X the potency of traditional high frequency rTMS, allowing 
for a much-reduced stimulation time in comparison to traditional rTMS, therefore making multiple 
stimulation sessions per day feasible. We thus propose novel evaluation of this low-risk brain 
stimulation intervention (i.e., capable of modulating neural circuitry that underlies self-
preservation, cognitive control, and affective regulation), as an innovative approach for acute 
suicidal symptoms. This intervention will be investigated in the context of a randomized, two-site 
trial for indication as a rapid-acting rTMS intervention for acute depression and suicidal behaviors 
among high-risk psychiatric inpatients. 
 
 
Taken from Dayan, Eran, et al. "Noninvasive brain stimulation: from physiology to network 
dynamics and back." Nature neuroscience 16.7 (2013): 838-844) 
 
RAPID (5 DAY) TBS FOR ACUTE DEPRESSIVE AND SUICIDAL SYMPTOMS: A 
RANDOMIZED CONTROLLED TRIAL (N=200) 
 
Within a two-site trial, we propose development and testing of an accelerated intermittent theta-
burst stimulation (aiTBS) according to primary, secondary, and exploratory outcomes. Psychiatric 
inpatients will be randomized to one of two stimulation arms: (1) L DLPFC aiTBS –or- (2) ACC 
aiTBS. 
 

 
 
Primary Aims Primary Outcome: Suicide Ideation (SI) Symptoms, Suicide Attempts (SA). 
 
Aim 1.1: To develop and test the feasibility of a standardized L DLPFC and ACC aiTBS protocol 
for acute depressive and suicidal symptoms. 
 
Aim 1.2: To examine the preliminary efficacy of aiTBS (both L DLPFC and ACC) in lowering 
suicidal ideation symptoms. 
 
Hypothesis 1: Both L DLPFC and ACC aiTBS will result in significant reductions in SI symptoms 
and incident SA, but each target will produce a novel pattern of suicide symptom reductions. 
 
Secondary Aims Secondary Outcome: Mood Indices (Depressive Symptoms, Emotion 
Regulation (ER) Deficits) 
 
Aim 2: To examine indications of aiTBS (both L DLPFC and ACC) response in reducing targeted 
mood indices. 
 
Hypothesis 2: Both L DLPFC and ACC aiTBS will result in significantly reduced depressive 
symptoms and ER deficits. 
 
Exploratory Aims Exploratory Outcome: Symptoms specific to the patient’s primary diagnosis 
 
Aim 3: To explore whether symptoms associated with patients’ primary diagnoses are also 
reduced as a consequence of aiTBS. 
 
Hypothesis 3: In addition to the anti-depressant effects, both L DLPFC and ACC aiTBS will 
result in significant improvements in symptoms associated with primary diagnoses. Each 
stimulation site will result in a different pattern of symptom improvement. 
 
 
 
 

 
 
BACKGROUND AND SIGNIFICANCE 
 
Suicide represents a preventable problem, accounting for 57% of all violent deaths annually (Krug, 
Mercy, Dahlberg, & Zwi, 2002; Wong, 2003). In addition, an estimated 10 to 25 nonlethal attempts 
(100-200 for youth) occur for every death by suicide. Given its overwhelming public health 
significance, the prevention of suicide has been deemed a National Imperative (Wong, 2003). 
Despite high treatment demand among those at risk for suicide (i.e., half will refuse treatment, and 
75% will drop out <1 year; Krulee & Hales, 1988; Rudd et al., 1996), the time required for 
therapeutic response to standard pharmacologic and psychotherapy treatments (i.e., weeks, months) 
is mismatched to the acute nature of a suicidal crisis. This highlights the alarming urgency and need 
for development of rapid-action therapeutic agents for suicidal behaviors. 
 
At the level of the neural network, suicidality is theorized as a state of emotional dysregulation 
coupled with suboptimal cognitive control (Tracy et al., 2015). Dysfunctional neural circuits 
underlying cognitive control and affect regulation are proposed to underlie suicidal ideation and 
behavior. A non-invasive brain stimulation technique, termed rTMS, has been demonstrated to 
modulate the neural networks underlying cognitive control and affect regulation (Fox, Halko, 
Eldaief, & Pascual-Leone, 2012; Liston et al., 2014). By applying brief, high-intensity magnetic 
fields to the scalp (George, Taylor, & Short, 2013a), rTMS enables investigation and 
neuromodulation of the neural networks underlying specific subregions of interest (George et al., 
2015). Two rTMS strategies have thus been suggested; turn down dysfunctional affective 
regulation or turn up cognitive control (Tracy et al., 2015). Both approaches may, however, be 
required to effectively modulate all neural networks involved in self-preservation and mood 
regulation processes (Nahas et al., 2010; Williams et al., 2016). The dorsolateral prefrontal cortex 
(DLPFC) is a core component of the cognitive control circuit (Lesh et al., 2013; MacDonald, 2000), 
this area is hypoactive in depressed patients (Grimm et al., 2008; Koenigs & Grafman, 2009) and 
DLPFC stimulation has been shown to reduce suicidal ideation (Desmyter et al., 2016; George et 
al., 2014). The anterior cingulate cortex (ACC) is an area associated with both cognitive control 
and affect regulation circuits. Reduced activity in ACC has been found in depressed patients during 
cognitive control tasks (Halari et al., 2009) and reduced ACC volume has also been reported in 
depressed patients (Ballmaier et al., 2004; Botteron, Raichle, Drevets, Heath, & Todd, 2002; 
Caetano et al., 2006). Suicidal ideation and behavior have been associated with differences in ACC 
functional connectivity (Chase et al., 2017; Du et al., 2017; Minzenberg et al., 2015). Therefore, 
both the DLPFC and the ACC are promising stimulation targets when probing the neurocircuitry 
underlying depressive symptoms. 
 
Suicidal ideation and major depressive episodes are not symptoms which are restricted to clinical 
diagnoses of MDD; depressive symptoms and suicidal thoughts are experienced by patients with a 
range of psychiatric conditions.  For example, individuals with diagnoses of bipolar disorder, 
schizophrenia, anorexia nervosa, opioid use and alcohol use disorder have been reported to have 
greater than 10 times higher risk of suicide than the general population (Chesney et al., 2014). 
rTMS has successfully induced antidepressant effects in individuals with a range of psychiatric 
diagnoses (J. C. Cole, Bernacki, Helmer, Pinninti, & O’Reardon, 2015; Desmyter et al., 2016; 
George et al., 2014; McClelland et al., 2013; Rosenberg et al., 2002). The proposed aiTBS protocol 

 
 
could therefore potentially be effective at reducing depressive symptoms and suicidal ideation in 
patients with a range of primary psychiatric diagnoses. 
 
Using a systems neuroscience approach (Williams et al., 2016a; 2016b), the current study thus 
proposes novel testing of an rTMS approach for its efficacy, while enabling study of transdiagnostic 
targets for suicide prevention. Recently, a specialized form of rTMS was developed, termed theta 
burst stimulation (TBS), which uses short, higher-frequency stimulation pulses (i.e., 50 Hz, every 
200 ms; Huang, Edwards, Rounis, Bhatia, & Rothwell, 2005) to produce more robust effects on the 
brain region of interest. In the case of neuropsychiatric conditions, TBS has been demonstrated to 
modulate clinical mood assessments(Li et al., 2014) as well as neurocognitive performance 
(Demeter, Mirdamadi, Meehan, & Taylor, 2016). This approach is thought to more directly mimic 
the natural rhythms of the brain (Huang et al., 2005) and is unique insofar as the stimulation 
sessions required are significantly reduced (Daskalakis, 2014; George et al., 2010). For example, 
studies demonstrate equivalent antidepressant efficacy for 3 mins of TBS versus 37 mins of rTMS 
(Blumberger et al., 2015). Using an accelerated rTMS approach (i.e., stacking ten, 10-min sessions 
into 1 day, with spaced sessions), this method enables a reduction from 4-6 weeks of stimulation 
to only 5 days (i.e., or 500 total mins; Holtzheimer et al., 2010).  
Important to the present study, the antidepressant effect of rTMS has been demonstrated across 
diverse populations (George et al., 2014; Li et al., 2014), samples (clinical, nonclinical; (Demeter 
et al., 2016), and psychiatric conditions (George et al., 2014; Hadley et al., 2011; Isserles et al., 
2013; Li et al., 2014; Mallet et al., 2008), highlighting its trans-diagnostic utility and effectiveness. 
Findings furthermore suggest that rTMS/TBS is a safe(Hong et al., 2015) and efficacious, non-
invasive treatment for depression (Li et al., 2014), which, likewise, produces minimal side effects 
in comparison with standard pharmacotherapies. Next, an accelerated rTMS approach, recently 
tested among psychiatric inpatients referred for imminent suicide risk, demonstrates its safety, 
feasibility, and preliminary efficacy for the proposed trial (George et al., 2014). Combined with a 
comprehensive assessment battery of proposed warning signs and biomarkers, this 
neuromodulatory approach has the ability to reveal testable hypotheses (Tracy et al., 2015) about 
suicidal behaviors, and their underlying neural circuitry, to inform mechanistic understanding of 
rTMS. 
 
 

 
 
Innovation.  
 
Suicide may be considered the tragic outcome of psychiatric illness and interacting risk factors. 
Our proposal aims are in accordance with the NIMH mission to advance understanding of the 
causes and prevention of suicide, particularly those, which promote evidence based prevention and 
treatment strategies. Commensurate with this goal, the current project aims to develop and test a 
new approach to the prevention of suicidal behaviors among psychiatric inpatients, utilizing a 
rapid-acting brain stimulation technique aimed at modulating the neurocircuitry underlying suicidal 
ideation. This goal is furthermore aligned with the Research Domain Criteria (RDoC) NIMH 
strategic aims (Insel et al., 2010) to examine mechanisms of psychopathology using a broad-based, 
multi-dimensional approach, emphasizing neurobiological assessment and developmental 
trajectories. Using a systems neuroscience approach  (Williams et al., 2016a; 2016b), novel testing 
of a rapid-action intervention for suicidal behaviors enables theoretically-driven study of neural 
networks underlying antidepressant responses. The proposed study may also represent an 
innovative approach clinically.  
 
First, we are proposing a low-risk intervention (Hong et al., 2015) that targets a high-risk sample 
for which retention in treatment is alarmingly poor. Testing use of non-invasive brain stimulation 
may be an effective strategy to enhance access to care. Second, suicide risk is a clinically-distinct 
taxon (Witte, Holm-Denoma, Zuromski, Gauthier, & Ruscio, 2017), which exists across diverse 
medical conditions. An intervention that targets neural circuitry underlying neurocognitive and 
affective deficits, that lie at the intersection of suicidal behaviors, promises insights into the 
pathogenesis of risk. Third, the proposed project allows us to evaluate whether a non-suicide 
focused intervention, targeting dysfunctional brain circuits, is more acceptable to participants. In 
this way, the proposed intervention may be valuable as a stand-alone or adjunctive to standard 
treatment, or as a means to improve retention. Fourth, brain-based interventions may be less 
stigmatizing compared to suicide-focused interventions. Testing use of a non-mental health 
intervention may be an effective tactic to enhance acceptance of care. Fifth, the time to 
psychotherapy and pharmacological treatment response remains mismatched to the acute nature of 
a suicidal crisis. By comparison, the brevity of aiTBS may increase accessibility and ease of 
intervention among an otherwise low-treatment seeking, high-need group (Nock et al., 2013). Sixth, 
suicide is preventable, yet research-tested interventions are scarce (Christensen, Cuijpers, & 
Reynolds, 2016; Mann et al., 2005).  
 
The proposed study thus has public health significance and addresses a gap in the literature wherein 
efficacious interventions are either few in number, unacceptable to patients (i.e., based on retention 
rates), or inaccessible to those most in need. 
 
 
 

 
 
Preliminary Studies.  
 
The preliminary studies below support feasibility of the proposed trial. 
 
 
George et al. (2014).Brain stimul; 7(3):421-431. 
Conducted randomized, sham controlled trial of N=42 suicidal inpatients (n=17 post traumatic 
stress disorder (PTSD), n=23 mild traumatic brain injury (mTBI) and PTSD) of 10 Hz rTMS 
targeting the L-DLPFC (3x/day across 3days, 9 total sessions), supporting safety and feasibility of 
rTMS. SSI-C scores declined (by 75%) significantly for both groups. 
 
Hadley et al. (2011). JofECT; 27:18-25 
Among N=19 patients with treatment-resistant bipolar or unipolar depression in an uncontrolled 
trial, 10 Hz rTMS over the DLPFC was associated with significant posttreatment reductions in BDI 
(66%) and SSI-C (84.2%). Higher levels of rTMS were well-tolerated, safe, and effective. 
 
Li et al. (2014). Brain; 137(7): 2088-2098. 
In a randomized sham-controlled trial, researchers compared continuous and intermittent pulsed 
TBS treatments, and their combination (cTBS, iTBS, cTBS+iTBS). Compared to control, TBS over 
DLPFC among those with TRD (N = 200) resulted in significant post-treatment reductions in 
HAM-D. Large effects were observed for iTBS and cTBS+iTBS relative to control. 
 
Cheng et al. (2016). Prog neuropsychoph; 66:35- 40. 
Among N=60, a sham-controlled trial compared cTBS, iTBS, cTBS+iTBS (1x/day for 2 weeks) 
over DLPFC among those with TRD. Compared to control, iTBS showed superior improvements 
in HAM-D and on the WCST. Large effects were observed for iTBS compared to control. 
 
Salomons et al. (2014). Neuropsychopharmacol; 39(2):488-498. 
Among N=25 patients with unipolar and bipolar TRD, conducted 10 Hz rTMS (1x/day for 4 wks) 
with MRI neuronavigation. Treatment resulted in significant (45%) HAM-D reductions. Based on 
MRI, pretreatment sub-region connectivity (DMPFC, SGACC) predicts treatment response. 
 
Bakker et al. (2014). Brain stimul; 8(2):208- 215. 
Compared effects of 10 Hz rTMS (N = 98) and iTBS group (N=87; total N=185) on targeting the 
DMPFC (1x/day for 4 weeks). iTBS matched or exceeded the effectiveness of the 10Hz rTMS 
comparison on clinician and self-rated measures, and supporting safety and tolerability. 
 
Downar et al. (2014). Biol psychiat; 76(3):176- 185. 
Conducted DMPFC-rTMS using 10 Hz (1x/day for 4 wks) for unipolar or bipolar disorder patients 
with current treatment resistant depression (N=47). Patients showed statistically significant 
improvements on the HAM-D (51.1%) and the BDI-II (48.9%) from pre-treatment to post-
treatment. 
 
Clark et al. (2015). Curr Psychiatry Rep; 17:83 

 
 
Based on review of rTMS use in PTSD (n=10 papers), with a focus on inpatient applications, both 
DLPFC and mPFC are implicated as an efficacious treatment target. rTMS proposed as a safe and 
well tolerated non-pharmacological intervention, warranting further investigation. In a sham-
controlled trial conducted by George et al,26 rTMS was administered to the L-DLPFC for 30 mins 
(3 x/daily) to N=42 psychiatric inpatients. Results revealed that rTMS produced rapid declines in 
SSI-assessed suicidal ideation. Compared to sham control, subjective ratings of ‘being bothered by 
thoughts of suicide’ likewise declined more with active versus sham rTMS. Findings were 
furthermore maintained at 3 and 6 months follow up. Comorbid conditions (PTSD, mTBI) were 
not excluded, and treatment was offered as an addition to TAU. Next, Li et al (Li et al., 2014) 
conducted a randomized, sham-controlled trial of intermittent theta-burst stimulation (iTBS) over 
DLPFC among N=60 participants with TRD. Relative to control, 2 weeks of daily TBS resulted in 
post-treatment reductions in depressive symptoms. Concurrently, rTMS has been demonstrated as 
efficacious when ‘accelerated.’  
 
Studies conducted by Hadley and colleagues (Hadley et al., 2011) and Holtzheimer and colleagues 
(Holtzheimer et al., 2010) support the safety, tolerability, and effectiveness of high dose rTMS 
antidepressant treatment protocols across treatment refractory samples, predicting post-treatment 
improvements in suicidal ideation and depression. Such studies support feasibility of the proposed 
trial. 
 
Duprat et al. (2016) J Affect Disord; 200: 6-14 
Randomized sham-controlled study investigating the effectiveness of aiTBS in patients (N=47) 
with treatment-resistant depression. Stimulation was applied to the left DLPFC at 110% resting 
motor threshold 5 times daily (1620 pulses per session) for 4 days. aiTBS to DLPFC was associated 
with significant reductions in the HAM-D compared to sham stimulation. aiTBS was well tolerated 
and safe, supporting the potential of aiTBS to DLPFC for quick and effective treatment of 
depressive symptoms in treatment-resistant depression. 
 
Desmyter et al. (2016) Front Hum Neurosci; 10: 480 
The effect of aiTBS on suicidal ideation was investigated in a subsample of patients from the trial 
presented by Duprat and colleagues above. aiTBS reduced the risk of suicide (BSI score) in 
previously treatment-resistant patients with depression who reported suicidal ideation prior to 
treatment (N=32). Reduced suicidal ideation was still present 1 month after baseline, 2 weeks after 
treatment had finished. 
 
 

 
 
SIGNIFICANCE 
 
Development of a rapid-acting stimulation protocol for psychiatric inpatients is motivated by 
scientific, clinical, and theoretical rationale.  The crucial need for greater testing of interventions, 
likewise, remains mismatched to a dearth of trialists in suicide prevention. Indeed, clinicaltrials.gov 
search reveals that less than 10 clinical trials have been conducted, worldwide, evaluating suicide 
ideation and depressive symptoms as primary outcomes. In this way, investigation of a rapid, non-
invasive neuromodulation intervention, among psychiatric inpatients, will address an important gap 
wherein few clinical trials exist, in particular those utilizing a biologically-based approach. 
 
 
Rationale for Efficacy Testing Among Psychiatric Inpatients. Rationale for the use of a non-mental 
health intervention targeting high suicide risk psychiatric inpatients, is motivated by: (1) the high 
sustained rates of suicide across psychiatric inpatients, (2) the perceived stigma associated with 
mental health care treatment observed, (3) the correspondingly low rates of reported treatment 
seeking and retention, (4) the mismatch between the time course of therapeutic response to standard 
pharmacolocic and psychotherapy treatments and the imminent risk to suicidal patients, [5] 
preliminary data from rTMS and aiTBS trials (Cheng et al., 2016; George et al., 2014; Hadley et 
al., 2011; Li et al., 2014), conducted among psychiatric inpatients, demonstrating the safety, 
feasibility, and efficacy for depression, and (based on an rTMS pilot) suicidal symptoms 
specifically, (6) the planned use and integration of a transdiagnostic RDoC data sharing platform, 
with potential to synchronize NIH efforts to enhance prediction science by large-scale data capture 
and comparisons. Based on all such rationale, we propose study of an intervention targeting neural 
networks associated with depression and acute suicidal risk using a safe, low risk approach, with 
broad scientific and clinical impact. Finally, the proposed trial offers long-term application to 
prevention, with potential adaptation to military preventive strategies. Taken together, we propose 
testing of aiTBS as an innovative and low-risk intervention strategy to enhance suicide prevention 
among psychiatric inpatients. 
 
Hypotheses and Technical Objectives. We aim to test the preliminary efficacy of a novel rapid-
acting transdiagnostic brain-stimulation technique for acute depression and suicidal behaviors. The 
proposed study will combine two efficacious rTMS paradigms, accelerated rTMS (Baeken et al., 
2015; Holtzheimer et al., 2010) and intermittent TBS (Chistyakov, Rubicsek, Kaplan, Zaaroor, & 
Klein, 2010; Daskalakis, 2014; Li et al., 2014) for initial testing, which we term accelerated theta-
burst stimulation (aiTBS). We hypothesize that, aiTBS (both L DLPFC and ACC) will produce 
significant reductions in: (1) suicidal ideation and risk for suicide attempts (primary hypothesis), 
and (2) change in depressive symptomatology and emotion regulation function (Becker, Strohbach, 
& Rinck, 1999; Cha, Najmi, Park, Finn, & Nock, 2010; R. et al., 2013) (secondary hypothesis). We 
will also explore (3) change in symptomology associated with patient’s primary diagnosis in 
patients who have a psychiatric diagnosis other than MDD and (4) mechanisms and moderators of 
antidepressant responses, including known behavioral, neurocognitive, and psychosocial variables 
for suicidal behaviors, based on past reports and NIH-funded research (Turvey et al., 2002). 
Technical Objectives 1-2: Develop and Test an aiTBS Protocol for Suicidal Ideation Symptoms 
 

 
 
1) Manualize a novel neuromodulation strategy for suicidal behaviors among psychiatric inpatients. 
 
2) Examine aiTBS (both L DLPFC and ACC) efficacy in lowering suicidal ideation  
 
Hypothesis 1: Both L DLPFC and ACC aiTBS will result in significantly lower SI symptoms and 
risk for SA. 
 
Technical Objective 3: Evaluate Impact of Protocol on Targeted Secondary Measures of Mood 
 
3) Examine aiTBS effects on reducing affective dysregulation indices. 
 
Hypothesis 2: Both ACC and L DLPFC aiTBS will result in significant improvement in mood 
function, including depressive symptoms and affective regulation. 
 
Technical Objective 4: Evaluate Impact of Protocol on Symptomology Associated with Patients’ 
Primary Psychiatric Diagnosis 
 
4) Examine aiTBS effects on reducing symptomology associated with patient’s primary diagnosis. 
 
Hypothesis 3: Both ACC and L DLPFC aiTBS will result in significant improvement in primary 
diagnosis symptomology. 
 
Technical Objectives 5-6: Explore Mechanisms and Moderators of Antidepressant Response 
 
5) Explore mechanisms and moderators of antidepressant responses, based on candidate risk factors 
and biomarkers. 
 
6) Explore L DLPFC and ACC aiTBS effects on reducing objective measures of the neural network 
that underlies cognitive control and affective regulation. 
 
Hypothesis 4: Genetic, microbiome and EEG biomarkers will be identified which significantly 
predict response to aiTBS. 
 
Hypothesis 5: Both L DLPFC and ACC aiTBS will increase measures of cognitive control circuit 
and affective regulation circuit connectivity. 
 

 
 
RESEARCH DESIGN AND METHODS 
 
Participants. We propose preliminary testing of an aiTBS protocol for suicidal behaviors among 
psychiatric 
inpatients. 
Participants 
(N=200) 
will 
be 
recruited 
according 
to 
study 
inclusion/exclusion criteria using an established, in-use protocol of high suicide risk psychiatric 
inpatients (NCT01958541). To protect the safety of the target sample, this intervention will 
augment TAU by providing evidence-based suicide risk assessment and safety planning (Mann et 
al., 2005). The stimulation protocol will consist of 5 days of intensive (500 mins) TBS.  
 
Targeted Brain and Affective Circuits. Two primary circuits are proposed as targets for stimulation 
to inform the pathophysiology of effect on primary, secondary, and exploratory outcomes. This 
includes: (1) The “Negative Affect” circuit, and (2) the “Cognitive Control” circuit. The negative 
affect circuit is engaged by negatively-valenced stimuli and comprises subcortical nodes in the 
amygdala, brainstem, hippocampus and insula, and prefrontal nodes. This includes the dorsal 
medial prefrontal cortex (DMPFC) and dorsal ACC connections, as well as ventral mPFC (vMPFC) 
and ventral-rostral ACC connections (Kober et al., 2008; Robinson et al., 2014). Whereas 
dorsal/rostral nodes have been preferentially implicated in appraisal, in which expression of 
emotion may be considered an “aversive amplification” sub-network (Robinson et al., 2014); 
ventral nodes are implicated in automatic regulation of negative emotion (Etkin, Prater, Hoeft, 
Menon, & Schatzberg, 2010; Kober et al., 2008). These sub-networks may be engaged, even in the 
absence of conscious sensory awareness, via direct brainstem inputs (Kober et al., 2008; Williams, 
2006). Given their commonly observed co-activation (Kober et al., 2008), the negative affect circuit 
could subserve the perception of negative emotion, and arousal aspects of feeling these emotions. 
The cognitive control circuit comprises the dorsolateral prefrontal cortex (DLPFC), anterior 
cingulate cortex (ACC), dorsal parietal cortex (DPC) and pre-central gyrus (Williams et al., 2016). 
Together, these regions, and their interconnectivity, are implicated in working memory and 
selective attention (Niendam et al., 2012), (evidenced by convergent neuroimaging methods; Cole 
& Schneider, 2007). Under task-specific demands, the cognitive control circuit is implicated in 
cognitive flexibility (Roalf et al., 2014). In the proposed study, we treat such circuits as independent 
(vs. dependent) variables to parse out neural factors in a trans-diagnostic manner, conceptualizing 
extremes along dimensions of dysfunction and underlying brain circuits. 
 
Neuromodulation. The proposed intervention will target the left dorsolateral prefrontal cortex (L-
DLPFC) and the bilateral anterior cingulate cortices (bil ACC). The DLPFC (BA 9 and 46; (Cieslik 
et al., 2013)) is a critical node in the mesocortical system (central to the proposed Cognitive Control 
circuit), a dopaminergic tract that modulates anticipation, goal selection, planning monitoring, and 
the use of feedback in task performance (Bonelli & Cummings, 2007). The DLPFC is also critical 
for working memory of spatial and non-spatial information (Fuster, 2015). There has been some 
suggestion that direct stimulation (activation) of the cognitive control network (CCN) modulates 
the connected parietal attentional networks involved in the automatic processing of environmental 
stimuli. According to recent meta-analysis (of 162 imaging studies), coactivation of BA 9 (which 
spans dorsolateral and medial prefrontal cortices) and midbrain regions (e.g., periaqueductal gray 
or PAG) is essential for assigning emotional valence (Kober et al., 2008). These results underscore 
the critical role of this region in mood regulation (Lévesque et al., 2003). In depressed patients, the 

 
 
L-DLPFC is hypoactive and thought to be associated with negative emotional judgment; as a result, 
it has constituted a primary rTMS target for depression (George, Taylor, & Short, 2013). Previous 
studies of rTMS for suicidality have likewise targeted L-DLPFC, showing safety, feasibility, and 
therapeutic benefit (Desmyter, Duprat, Baeken, Bijttebier, & Van Heeringen, 2014; George et al., 
2014). The ACC is involved in emotion regulation and has also been found to be hypoactive in 
depressed patients (Halari et al., 2009). rTMS has been applied to ACC in patients with OCD and 
MDD, producing reduced depressive symptoms and highlighting safety and tolerability of the 
technique (Kreuzer et al., 2015; Vanneste, Ost, Langguth, & de Ridder, 2014; Zangen et al., 2016). 
Cognitive Control and Negative Affect circuits have been shown to interact in the explicit/implicit 
regulation of emotion (Bernert et al., 2013; Lee & Siegle, 2012; Ochsner & Gross, 2005) . 
Additionally, following rTMS to the DLPFC, ACC grey matter has been shown to increase and the 
degree to which this occurs, correlates with improved depressive symptoms (Lan, Chhetry, Liston, 
Mann, & Dubin, 2016). This highlights the rationale for testing a brain stimulation protocol which 
targets both circuits implicated, to optimize antidepressant responses (Bakker et al., 2015; Downar, 
Blumberger, & Daskalakis, 2016; George et al., 2010). The protocol will be standardized, and 
tested at two stimulation sites for efficacy in the prevention of suicidal behaviors. Eligible 
psychiatric inpatients will be randomized to one of two conditions, (1) L DLPFC aiTBS or (2) ACC 
aiTBS. 
 
Eligibility. Screening will use a structured diagnostic interview [Mini International 
Neuropsychiatric Interview; MINI], self-report inventories, and clinician-administered scales to 
determine study eligibility. Rather than occurring exclusively in the context of depression, suicidal 
symptoms exist across Axis I psychiatric diagnoses; therefore, we will include patients with 
primary diagnoses other than major depressive disorder (MDD) if they display suicidal ideation or 
are experiencing a major depressive episode. Previous rTMS and TBS trials, which have evaluated 
benefit to suicidal ideation and depressive symptoms, have been conducted among those with 
diverse comorbid psychiatric and medical conditions (e.g., PTSD(Berlim & Van Den Eynde, 2014) 
OCD (Dunlop et al., 2016), TBI (George et al., 2014), etc.), and among those on concurrent 
medications(George et al., 2014; Levkovitz et al., 2015). Participants will not be asked to change 
or discontinue medications as a condition for participation in this study, and current 
pharmacotherapy or psychotherapy will not be a basis for exclusion provided that changes do not 
immediately precede enrollment.  
 
Inclusion criteria:  
1. Over 18 at the time of screening 
 
2. Able to read, understand, and provide written, dated informed consent prior to screening. 
Participants will be deemed likely to comply with study protocol and communicate with study 
personnel about adverse events and other clinically important information. 
 
3. Currently diagnosed with Major Depressive Disorder (MDD), according to the criteria defined 
in the Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-
IV-TR) 
 

 
 
4. Display suicidal ideation (score >6 on the SSI). 
 
5. Meet the threshold on the total HAMD17 score of >/=20 at baseline. 
 
6. Meet the threshold on the BDI-II score of >/=17 at baseline. 
 
7. Not in a current state of mania (Young Mania Rating Scale) or psychosis (MINI) 
 
8. In good general health, as ascertained by medical history. 
 
9. Access to clinical rTMS after hospital discharge 
 
Exclusion criteria: 
 
1. Any structural lesion e.g. structural neurological condition, more subcortical lesions than 
would be expected for age, stroke effecting stimulated area or connected areas or any other 
clinically significant abnormality that might affect safety, study participation, or confound 
interpretation of study results. 
 
2. Metal implant in brain (e.g. deep brain stimulation), cardiac pacemaker, or cochlear 
 
3. History of epilepsy/ seizures (including history of withdrawal/ provoked seizures) 
 
4. Shrapnel or any ferromagnetic item in the head 
 
5. Pregnancy 
 
6. Autism Spectrum disorder 
 
7. Any current or past history of any physical condition which in the investigator's opinion might 
put the subject at risk or interfere with study results interpretation 
 
8. Active substance use (<1 week) or intoxication verified by toxicology screen--of cocaine, 
amphetamines, benzodiazepines 
 
9. Cognitive impairment (including dementia) 
 
10. Current severe insomnia (must sleep a minimum of 5 hours the night before stimulation) 
 
11. Current mania or psychosis 
 
12. Showing symptoms of withdrawal from alcohol or benzodiazepines 
 
13. IQ<70 
 
14. Parkinsonism or other movement d/o determined by PI to interfere with treatment 
 
15. Desirous of getting ECT and previous tolerant exposure to ECT 
 

 
 
16. Any other indication the PI feels would comprise data. 
 
17. No access to clinical rTMS after discharge 
 
STIMULATION 
 
Accelerated theta-burst stimulation (aiTBS) Brainsway TMS Platform. The TMS stimulator 
(Brainsway H-Coil, Israel) will be used to generate repetitive biphasic magnetic pulses. Both 
stimulation groups (ACC aiTBS and DLPFC aiTBS) will receive simulation from specially-
designed coils (Brainsway H-Coil, Israel). The ACC stimulation utilizes the H7 coil and the L 
DLPFC stimulation utilizes the H1 coil. We will employ a spaced intermittent theta-burst technique 
(Goldsworthy, Pitcher, & Ridding, 2012) capable of modulating targeted brain region of interest, 
L-DLPFC (Duprat et al., 2016) and ACC. 
 
Stimulation Timing, Dose and Spacing: This study will utilize a total of 50 applications of 1800 
pulses of iTBS at 90% of the resting MT; proven effective in producing a prolonged change in 
cortical excitability(Huang et al., 2005). The (50-min) spaced application of TBS was chosen as 
the stimulation strategy given its ability to produce sustained effects to the targeted neural network. 
By comparison, research suggests that continuous stimulation approaches (without spacing) can 
minimize or reverse intended effect (Gamboa, Antal, Moliadze, & Paulus, 2010). Such spacing has 
been tested for safety and specificity of achieved stimulation targets in animal and human models 
(Larson & Munkácsy, 2015). This TBS approach will be applied to L-DLPFC or ACC 
(randomized). Dosing of aiTBS will = 90% of the active MT adjusted to the skull to cortex distance, 
as this is documented to modulate the desired cortical target (Huang et al., 2005; Li et al., 2014). 
1800 pulses of iTBS at 50 Hz will be utilized, consistent with standard parameters. There will be 
10 trains of 3 pulses at 50Hz every 200ms (50Hz over 5Hz), which is 30 pulses per theta burst train. 
60 trains will be delivered to achieve 1800 pulses.  This will utilize 10 stimulation sessions of 1800 
pulses (with 50-min spacing between each iTBS session; Duprat et al., 2016)). This will generate 
a 10 total stimulation sessions/day, 50 sessions total over the 5 days with a total of 90,000 pulses. 
 
 
Motor Threshold (MT) Elicitation: Inherent to the safe and accurate dosing of TBS stimulation, 
active MT elicitation will be performed according to established protocols, which have been in use 
since 1994 (George et al., 2010; Pascual-Leone, Valls-Solé, Wassermann, & Hallett, 1994). This 
protocol is well-established as an effective method for MT Elicitation (Borckardt, Nahas, Koola, 
& George, 2006), widely implemented within both sham-controlled rTMS and TBS trials with 
demonstrated safety (Borckardt et al., 2006; George et al., 2013b). 
 
 
Potential Risks: rTMS is FDA approved as a non-invasive treatment modality for depression 
(George et al., 2013b). There is no known risk of seizure for the above-stated brain stimulation 
parameters (Huang et al., 2005; L. Oberman, Edwards, Eldaief, & Pascual-Leone, 2011). The MT 
is reflective of stimulation output necessary to cause neuronal depolarization. Since its first use in 
2005 (Huang et al., 2005), only one case of TBS has resulted in seizure, which occurred for 
stimulation at >100% resting MT (120% of aMT) and this was cTBS not iTBS (L. Oberman et al., 

 
 
2011; L. M. Oberman & Pascual-Leone, 2009).  Finally, the proposed stimulation parameters 
mirror those used in Stanford IRB-approved TBS protocols underway (Protocol Director Williams 
N; ID 33797, ID 38138), which have received a “minimal risk” designation. Further, studies 
utilizing 90% rMT are shown to modulate a deep target as has been validated in the motor system 
(Mori et al., 2010), suggesting that past parameters are safe (Nathan Bakker et al., 2015), yet may 
be further optimized (Mori et al., 2010). 
 
STIMULATION RESPONSE, INTEGRITY, AND TRAINING 
 
Evaluation of Response. Response to aiTBS will be quantified by the reduction in score on SSI-C 
from baseline to post-aiTBS. The primary clinical endpoint for outcome will occur at Day 6 (after 
the aiTBS course, after the participant has slept). 
Responders will be defined as individuals who show 50% decrease in SSI-C as the result of 5 days 
of aiTBS. The effect of aiTBS on depressive symptoms (HAMD-24) and symptoms associated with 
patients’ primary diagnosis will be quantified in the same way. 
 
Participant Acceptance and Focus Groups. Dropout following baseline assessment will 
operationally define acceptance. This definition will be used to guide intent-to-treat analyses. Study 
completers and non-completers will be invited to focus groups to elicit feedback about: (a) reaction 
to aiTBS format/timing, (b) attitudes/ expectations toward aiTBS, (c) ease of participation, (d) 
perceived barriers, and (e) aiTBS satisfaction. With consent, these will be recorded and transcribed 
for review. All data will be reviewed and applied to protocol refinements. 
 
NIH toolbox: Cognitive abilities will be tested before and after the aiTBS course using a number 
of neurocognitive assessments that are accessed through the NIH toolbox ipad app. The 
assessments will provide measures of executive function, attention, working memory, episodic 
memory and processing speed. Measuring cognitive abilities of participants before and after aiTBS 
will allow us to demonstrate the safety of the technique in terms of cognitive effects as well as 
identify potential cognitive improvements associated with antidepressant responses. 
 
EEG measures: 
Resting-state electroencephalography (EEG) will be recorded before the first aiTBS session and 
after the final session, to monitor changes in brain activity and functional connectivity as a result 
of aiTBS. Baseline EEG recordings will also be used to identify potential indicators of aiTBS 
response. EEG measures will also be taken during stimulation sessions to identify aiTBS-induced 
changes in brain activity.  
 
MEASURES AND MATERIALS 
 
Eligibility and Screening Measures 
 
Antidepressant Treatment History Form [ATHF; Fava, 2003)]: This is an established, clinician-
administered tool to assess history of treatment non-response according to standard criteria within 
clinical trials.  

 
 
 
Maudsley Refractoriness Measure [MRM; Fekadu, Wooderson, Markopoulo, et al., 2009a; 
2009b)]: This uses a staging model to provide a continuous index of treatment refractoriness, found 
to have strong predictive utility and sensitivity to treatment response. 
 
TMS Adult Safety Screen [TASS]: This self-report instrument assesses risk of seizure related to 
TMS. Any identified risk will disqualify the participant to minimize risk and ensure safety. 
 
 
Mini International Neuropsychiatric Interview  [MINI; Lecrubier et al., 1997; Sheehan et al., 1998]: 
The MINI is a structured diagnostic interview which is used to screen for a number of psychiatric 
disorders. This tool will be used to identify any potential comorbid conditions.  
 
Demographic Overview: A brief demographic overview will be administered at baseline to assess 
basic demographic and medical history characteristics. Mini-Mental State Examination [MMSE; 
Folstein, Folstein, & McHugh, 1975]. This is a brief, mental status examination, widely-used in 
research and past trials. Scores > 24 are generally indicative of normal mental status function.  
 
Medication Monitoring Form [MMF]: A medication monitoring survey will be administered at the 
start of each day of aiTBS to closely monitor medication use and changes throughout enrollment.  
 
Young Mania Rating Scale [YMRS; Young et al., 2004]: This is an 11-item clinician-administered 
scale used to measure symptoms of mania. Each item is scored from 0-4 with scores of 4 indicating 
the presence of more severe mania. Participants who are currently experiencing a manic episode 
will not be enrolled in the study. This scale will be used to monitor symptoms of mania each day 
they receive aiTBS to make sure manic symptoms have not arisen during study enrollment.  
 
Scale for Suicide Ideation—Current [SSI-C; Beck, Kovacs, & Weissman, 1979]: This is a clinician-
administered questionnaire used to assess the severity of suicidal ideation, with higher scores 
indicative of greater symptom severity. Patients must display elevated scores (>5) to be enrolled in 
the study. The scale has strong psychometric properties, and is widely used in randomized suicide 
prevention trials. 
 
Scale for Suicide Ideation—Worst Point [SSI-W; Beck, Brown, Steer, Dahlsgaard, & Grisham, 
1999]: This is a 19-item clinician-administered scale to assess worst point symptoms in a 
participant’s life (0-38). The SSI-W predicts up to a 13-fold increased risk for suicide, and is thus 
widely-used in intervention research to identify a subgroup of at-risk patients. 
 
 

 
 
 
Suicidality Outcome Measures 
 
Scale for Suicide Ideation—Current [SSI-C]: This is a 19-item clinician-administered rating scale 
to assess the severity of suicidal ideation, with higher scores (0-38) indicative of greater symptom 
severity. The scale has strong psychometric properties, and is widely used in randomized suicide 
prevention trials. 
Columbia-Suicide Severity Rating Scale [C-SRS; Posner et al., 2011]: Clinician administered 
questionnaire identifying the presence or absence of six suicidal thoughts or behaviors in the past 
month or since the last visit. Each ‘yes’ answer is scored as 1, meaning the maximum total score 
is 6. 
 
Depression Outcome Measures 
 
Quick Inventory Depressive Scale-Self Reported [QIDS-SR; Rush et al., 2003]: The QIDS-SR is a 
16-item validated self-report instrument, designed to measure the severity of depressive symptoms 
for one week. Items are rated on a 0-3 scale, with higher scores (0-27) indicating greater severity. 
 
Hamilton Depression Rating Scale 24-Item [HAMD-21; Hamilton, 1960]: This is a clinician rated 
scale which assesses 21 symptoms from either 0-2 or 0-4. Total scores are between 0 and 76, higher 
scores on this scale indicate greater severity of depression  
 
Montgomery-Asberg Depression Scale [MADRS; (Montgomery & Asberg, 1979)]This is a ten-
item clinician rated questionnaire in which the clinician rates each item from 0-6. Scores of 6 
indicate more severe depressive symptoms. Total scores are between 0 and 60 with scores>35 
indicating severe depression. 
 
Emotional Conflict Task [ECT; (Etkin, Egner, Peraza, Kandel, & Hirsch, 2006)]: This is a brief, 
computerized task of implicit emotion regulation (ER). It consists of 148 presentations of happy or 
fearful facial expression photographs, overlaid with words “FEAR” or “HAPPY.” Stimuli are 
presented (Neurobehavioral Systems, http://nbs.neuro-bs.com), and counterbalanced across trials 
for expression, word, response button, and gender. Subjects indicate facial affect with button press 
response. Deficits predict behavioral and neural correlates of psychopathology. 
 
Difficulties in Emotion Regulation Scale [DERS; (Gratz, Roemer, Cameron, & Payne, 2011)]: This 
is a 36-item self-report instrument of explicit emotion regulation that has well-established 
reliability and validity, including in comparison with ECT. 
 
Pittsburgh Insomnia Rating Scale-20 Item Version [PIRS-20; (Veqar, Moiz, & Hussain, 2014)]: 
A 20-item, self-report scale used to measure the quality of sleep an individual is getting. Total 
scores range from 0-60 with higher scores indicating a greater degree of sleep difficulty. 
 

 
 
NIH toolbox (Weintraub et al., 2013): A number of neurocognitive assessments that are accessed 
through an ipad app. The assessments have been created by a team of 300 scientists from 100 
academic institutions and have shown good psychometric properties (Heaton et al., 2014; Zelazo 
et al., 2014). The assessments provide measures of executive function, attention, working memory, 
episodic memory and processing speed. 
 
Heart Rate Variability [HRV]: Individuals with depression tend to display lower levels of heart 
rate variability, reflecting atypical parasympathetic activity (Kemp et al., 2010). Heart rate 
variability will be measured each day during the aiTBS course to monitor changes. 
 
Cortisol Levels: Individuals with depression tend to display elevated levels of cortisol; a hormone 
which is released in response to stress (Herbert, 2013; Lindqvist, Isaksson, Lil-Träskman-Bendz, 
& Brundin, 2008). Salvia samples will be taken at baseline and post aiTBS to record changes in 
cortisol levels as a result of aiTBS. 
 
Primary Diagnosis Outcome Measures 
 
Clinical Monitoring Form [CMT; (Sachs, Guille, & McMurrich, 2002)]: This is a clinician filled 
form used to assess both depressive symptoms and symptoms of mania associated with bipolar 
disorder. Robust correlations have been found between CMT assessments and well-established 
mood scales such as HAMD, YMRS and MADRS (Sachs et al., 2002). 
 
The Positive and Negative Syndrome Scale [PANSS]: The presence of positive and negative 
symptoms of schizophrenia are rated on a scale from 1 (absent) to 7 (extreme). Seven negative 
symptoms, seven positive symptoms and 16 general symptoms of schizophrenia are assessed. Total 
scores for positive and negative scales range from 7 to 49. 
 
The Calgary Depression Scale for Schizophrenia [CDSS; Addington, Addington, & Maticka-
Tyndale, 1993)]:  
A nine-item questionnaire designed to assess depressive symptoms in patients with 
Schizophrenia. Each item is rated from 0 (absent) to 3 (severe), resulting in total scores ranging 
from 0 to 27. 
 
Alcohol Craving Questionnaire, short form [ACQ-SF-NOW; (Singleton, 2000)]: This is a 12-item 
self-report questionnaire. For each question, a statement is given and the participant indicates how 
strongly they agree or disagree to each statement across a 7-point scale. This questionnaire will 
also be sufficiently adapted so that we have version for patients with opioid use disorders and 
psycho-active drug use disorders. 
 
Obsessive Compulsive Drinking Scale [OCDS; (Anton, 2000)]: This is a 14-item multiple choice 
self-report questionnaire. Each question has 5 possible responses rated from 0-5, scores of 5 
indicate more prominent obsessions and compulsions regarding alcohol intake. This questionnaire 
will also be adapted so it can be applied to other substance misuse disorders (opioids, psycho-active 
drugs etc.) according to the patient’s primary diagnosis.  

 
 
 
Young-Brown Obsessive Compulsive Scale Modified for Binge Eating [YBOCS-BE; (Deal, 
Wirth, Gasior, Herman, & McElroy, 2015)]: This is a clinician-administered assessment which 
assesses five core dimensions: time spent on symptoms, interference due to symptoms, distress 
due to symptoms, resistance against symptoms, and degree of control over symptoms across 10 
questions. For each question a score is given between 0 and 4 with 4 indicating severe 
obsessions/compulsions associated with bingeing behavior.  
 
Yale-Brown-Cornell Eating Disorder Scale [YBC-EDS; (Mazure, Halmi, & Sunday, 1994)]: A 
clinician-administered scale that is not restricted to questions regarding a particular eating 
disorder. The YBC-EDS consists of 19 items assessing severity of preoccupations, rituals, and 
motivation for change. Each item is scored from 0 to 4 with 4 indicating more severe symptoms.  
 
 
Eating Disorder Examination Questionnaire [EDE-Q; (Berg, Peterson, Frazier, & Crow, 2012)]: 
This is a 28-item self-report questionnaire in which participants rate the number of times certain 
events have occurred or how severe eating disorder related thoughts have been over the last 28 
days. Each response is scored from 0 to 6 with 6 indicating a greater number of occurrences or 
more protruding thoughts in the last 28 days.  
 
Post-traumatic Stress Disorder Checklist-Civilian Version [PCL-C; (Wilkins, Lang, & Norman, 
2011)]: This is a 17-item self-report questionnaire assessing the key symptoms associated with 
PTSD. For each question, the amount each symptom has effected the individual in the month is 
rated from 1-5, 5 being extremely effected.   
 
Hamilton Anxiety Rating Scale (HAM-A; (Hamilton, 1959)): A clinician rated scale which assesses 
14 symptoms of anxiety on a scale of 0-4, with 4 indicating more severe levels of anxiety. 
 
Generalized Anxiety Disorder 7-item (GAD-7; (Terrill, Hartoonian, Beier, Salem, & Alschuler, 
2015)) scale: A 7 item self-report questionnaire, rating how often symptoms of anxiety occur. 
Each question is rated from 0-4 with scores of 4 indicating anxiety symptoms occur more 
frequently.  
 
Numeric Rating Scale (NRS) for Chronic Pain (National Institute of Clinical Studies, 2011): Self-
reported pain scale where pain experienced in the last 24 hours (average & worst) and current 
pain are rated from 1-10. Scores of 10 indicating the worst possible pain imaginable. 
 
Panic Disorder Severity Scale (PDSS; (Houck, Spiegel, Shear, & Rucci, 2002)): A 7-item self-
report questionnaire in which the frequency and severity of panic attacks are measured. Each item 
is rated from 0 to 4 with 4 indicating severe impairment caused by panic attacks. 
 
The Somatic Symptom Scale (SSS-8; (Gierk et al., 2014)): A self-report questionnaire in which 
the severity of eight symptoms over the last 7 days are rated. Each item is rated from 0-4 with a 
score of 4 indicating more severe symptoms. This tool has been shown to have good validity and 
reliability (Gierk et al., 2014) 

 
 
 
EEG Outcome Measures 
 
Resting-state EEG recordings will be made both before and after aiTBS in order to examine 
potential EEG biomarkers for antidepressant response as well as identify aiTBS-induced changes 
in EEG recordings. Oscillations in the theta and alpha frequency bands over frontal areas are of 
particular interest as these waveforms have been identified as possible biomarkers for suicidal 
ideation. 
 
Sequence of Investigation: Patients will first consent to be screened for eligibility to take part in 
the study, potential participants will be screened for inclusion based on central eligibility and 
screening measures. If patients are eligible, they will provide informed consent before participating 
in the study. Participants will complete 5 days of aiTBS as well as follow-up assessments (1 day 
after aiTBS). Data will be collected according to clinician administered, computerized, and self-
report measures.  
 
Clinician administered: SSI-C assessments will be conducted by a clinician. Suicide risk will be 
evaluated, with on-call DSMP IRB-approved procedures in place.  
 
MRI Outcome Measures  
 
Magnetic Resonance imaging will be made both before the first treatment (baseline) and after 50 
aiTBS treatments (post-treatment discharge). The baseline MRI scan is required to determine the 
cortical depth measurement which is used to determine the strength of the aiTBS treatment 
administered. The immediate post-treatment scan is conducted to examine potential MRI 
biomarkers for antidepressant response as well as identify aiTBS-induced changes in MRI 
imaging.  
 
 
DESIGN AND PROCEDURES USED TO ACCOMPLISH SPECIFIC AIMS 
 
 
Suicidality Aim 1.1: To develop and test an integrated aiTBS intervention protocol for suicidal 
behaviors. 
 
Analyses: Descriptive-level analyses will be conducted to evaluate feasibility, acceptance, residual 
symptom change, adherence and retention rates, in addition to data collected from focus groups 
(i.e., assessing palatability of individual protocol modules, ease of participation, protocol 
compliance etc.), to inform future adaptation and refinements to the protocol. In addition, 
quantitative analyses will be used to assess the average length of stay of patients undergoing aiTBS 
in comparison to TAU to observe whether aiTBS results in reduced lengths of stay. 
 
Suicidality Aim 1.2: To examine aiTBS response in lowering suicidal symptoms. 
 

 
 
Hypothesis 1: Both L DLPFC and ACC aiTBS will significantly lower suicidal ideation.  
 
Analyses: Continuous data will be analyzed using standard linear mixed-effects modeling in line 
with intent to treat analysis principles. A mixed-effects linear model with auto-regressive error 
structure will examine differences between stimulation sites with respect to rate of change (the 
slope of individual regression lines) in: (a) SSI-C scores, (b) SIS scores. Though SSI-C will serve 
as the primary outcome, self-reported 
indices of response (BSS, VAS-SI) will also be examined. For the primary analysis, we will use a 
random slope model and estimate the group differences (ACC aiTBS vs. L DLPFC aiTBS) across 
3 points (baseline; day 1, post aiTBS). To test Hypothesis 1, growth parameter estimates will be 
converted to antidepressant effect estimates for our clinical endpoint (i.e., Day 1 post aiTBS). 
 
Depression Aim 1: To examine aiTBS response in reducing targeted mood indices post- aiTBS 
 
Hypothesis 1: aiTBS will result in significant reductions in mood dysfunction. 
 
Analyses: The same analytic strategy above will be used to examine differences between 
stimulation sites (L DLPFC aiTBS vs. ACC aiTBS) with respect to rate of change in: (a) QIDS-
SR, (b) DERS, (c) ECT. Though these will serve as main outcomes, self-reported indices of 
response (BDI, VAS-MI) will also be examined. The model will estimate fixed effects to compare 
stimulation effects across the same 3 assessment points. To test Hypothesis 2, growth parameter 
estimates will be converted to effect estimates for our primary clinical endpoint (i.e., day 1 post-
aiTBS). 
 
Exploratory Aim 1: To explore the effect of aiTBS on symptoms associated with participant’s 
primary diagnoses. 
 
Analyses: The same analytic strategy above will be used to examine differences between 
stimulation sites (L DLPFC aiTBS vs. ACC aiTBS) with respect to rate of change in symptoms 
associated with primary diagnoses (OCDS, EDE-Q, PANSS, PDSS etc.) 
 
Exploratory Aim 2: To explore mechanisms and moderators of aiTBS outcome.  
 
Analyses: In the mixed effects modeling framework, we will explore a comprehensive battery of 
proposed risk factors, candidate biomarkers, and underlying neural circuitry in the prediction of 
antidepressant response. The rate of change (slope of individual regression lines) in indicated risk 
factors will be tested as potential mediators of proposed effect on SSI-C scores. The model will 
estimate fixed effects to compare stimulation effects across the same 3 assessment points. This 
will include all exploratory and proposed biomarkers. For testing candidate moderators, baseline 
symptoms, genetic factors, microbiome and potential EEG biomarkers will be entered into the 
model. For testing candidate mediators, intermediate variables (using the MacArthur Model) will 
be used. 
 
SAMPLE SIZE AND POWER 

 
 
 
For power estimation, we consistently used an alpha of .05, and two-tailed tests. Post-aiTBS (Day 
1, post- aiTBS) assessment will represent the primary clinical endpoint for all power calculations. 
Our longitudinal analyses will be conducted fully utilizing data that will be collected across all time 
points (baseline, aiTBS (days 1-5), and post-aiTBS, which will inform clinical and exploratory 
analyses. Power estimation was conducted focusing on our primary end point at the end of aiTBS. 
Feasibility analyses (e.g., acceptance, adherence, focus group data) will be conducted based on 
descriptive-level statistics to guide future adaptations and refinements of the proposed aiTBS 
protocol. 
 
Power to detect preliminary symptom change (depression symptom reduction) for 
Hypothesis 1 is based on ES estimates observed in (1) a previous RCT pilot rTMS for pre-
treatment to post-treatment symptom change in HAMD, and (2) two sham-controlled TBS 
trials, utilizing a similar treatment approach, which demonstrated large effects for 
depressive symptoms (>d=1). Given this information, we used a somewhat conservative 
effect size of d=0.8 for our power estimation. Based on our prior studies, we assumed about 
10% attrition by 1 mos post-treatment. Under this setting, with an n=200, the estimated 
power to detect between-subjects effects on SI (hypothetical---L DLPFC aiTBS vs. Sham) 
would be 0.82 (alpha=.05, two-sided). We are not powered to test non-inferiority between 
the two stimulation sites, but believe that an n=200 would provide the appropriate amount 
of data for a future blinded study power calculation. 
 
Data and Safety Monitoring Plan (DSMP) and Risk Assessment Framework 
 
All procedures will be closely supervised by this study’s PIs and on-site Medical Monitor, 
Dr. Schatzberg.  
 
 
 

 
 
DISSEMINATION AND IMPLEMENTATION PLAN 
 
The findings in this study have strong potential to impact psychiatric inpatient care by providing 
the first rapid acting intervention for acute depressive symptoms and suicidal risk. As of now, there 
are no low-risk, non-invasive interventions that remedy the urgency of an acute suicidal crisis to 
achieve therapeutic benefit; the proposed randomized controlled trial would be the first in the world 
to apply aiTBS to combat depression and suicidal ideation in psychiatric inpatients. Given data 
sharing aspects of an RDoC approach, study findings promise insights into risk on a large-scale, 
offering unique, long-term, transdiagnostic comparisons that extend beyond efficacy findings of 
the proposed trial. Data will be analyzed for its feasibility, efficacy, and according to mechanisms 
of antidepressant response. Given translational benefit, and oversampling of underrepresented 
groups (e.g., women) at elevated suicide risk, this aims to maximize relevance of our findings to 
relevant groups. PI will work with Brainsway to further the knowledge of and access to aiTBS and 
studied effects. To accomplish this end, information about aiTBS study results will be presented to 
stakeholders based on their guidance, for broad impact and implementation.  
 
 
 

 
 
PROCEDURES AND PRECAUTIONS IN THE PROTECTION OF HUMAN SUBJECTS 
 
 
Data and Safety Monitoring Plan (DSMP) and Risk Assessment Framework 
 
All procedures will be closely supervised by this study’s PIs. Suicide risk assessment will be 
conducted using empirically-established risk categorizations (minimal, mild, moderate, severe, 
imminent) to routinize clinical decision-making and emergency referral procedures for suicidal 
behaviors. This study will utilize a comprehensive, in-built infrastructure and set of standard 
operating procedures that support safe conduct of the current trial. Clinical staff will be notified of 
inpatients that are believed to be at imminent risk of suicide.  
 
 
Data and Safety Monitoring Board (DSMB) 
 
As a further protection against risk, a DSMB will be formally constituted to: independently review, 
oversee, and monitor risk procedures for the proposed study. DSMB construction will be closely 
guided by the PI’s supervision, and consultation with Investigators and Consultants. This DSMB 
will report to Stanford University IRB regarding study recruitment and adverse event (AE) 
reporting on a monthly basis. The DSMB will consist of individuals with the following expertise, 
nonaffiliated with the study: (1) An expert in suicidology, (2) A biostatistician with expertise in 
clinical trials, and (3) A patient advocate. During the proposed intervention, participants and their 
physicians will be instructed to report any intervention-emergent AEs or symptoms to study 
Personnel. Adverse events will be closely monitored and assessed. DSMB and Stanford IRB will 
be immediately advised if a participant reports a serious emerging condition or AE—independent 
of cause or relation to the intervention. In the rare case that an AE warrants evaluation by the 
ombuds/patient advocate, DSMB consensus will have power to determine appropriateness of a 
participant’s continuing participation. Such decisions will be binding. 
 
 
 

 
 
DATA AND SAFETY MONITORING PLAN (DSMP) 
 
Training of Personnel in Suicide Risk Assessment: 
 
1. All study personnel will complete extensive clinical training in suicide risk assessment practices, 
led by the PIs, safety monitor, and planned consultants. This team will meet regularly to discuss 
suicide risk assessment, DSMP procedures, adequacy and assessment of training. Although all 
personnel will receive training, the SSI-C will only be administered only by trained clinicians 
(PIs/CoIs, Study Clinicians). 
 
Primary Assessment Measure 
 
2. A score > 6 on the SSI-C will prompt standardized suicide risk assessment and administration of 
The Suicide Checklist and Suicide Assessment Decision Tree (See Below). 
 
a. If risk is elevated but not imminent, established behavioral methods will be used to effectively 
manage risk. The PI will closely monitor decision-making and assessment, and action taken will 
be clearly documented. 
 
b. Imminent risk would usually result in participants being referred for immediate hospitalization 
and emergency mental health services. As the participants involved in this project will already be 
on the inpatient unit, the clinical staff will be notified and the PI/Co-Is will closely monitor 
decision-making and assessment, and action taken will be documented. 
 
 
 
 

 
 
OVERVIEW OF SUICIDE RISK CATEGORIZATIONS 
 
 
I. Previous Suicidal Behavior: Previous suicidal behavior represents the single most important 
factor in risk assessment, distinguishing 3 clinically distinct groups: 
 
a. Suicide ideators 
b. Single attempter 
c. Multiple attempters 
 
II. The Nature of Current Suicidal Symptoms: 2 Factors 
a. Resolved Plans and Preparation. Symptoms (8): A sense of courage to make an attempt, 
A sense of competence to make an attempt, Availability of means for attempt, 
 
Opportunity for attempt, Specificity of plan for attempt, Preparations for attempt,  Duration of 
suicidal ideation, Intensity of suicidal ideation 
 
b. Suicidal Desire and Ideation. Symptoms (9): Reasons for living, Wish to die,  
 
Frequency of ideation, Wish not to live, Passive attempt, Desire for attempt, Expectancy of attempt, 
Lack of deterrents, Talk of death 
 
III. Precipitant Stressors: Interpersonal losses (e.g., separations from loved ones), Interpersonal 
discord, Legal troubles, Physical or emotional abuse 
 
IV. General Symptomatic Presentation, Including the Presence of Hopelessness: Axis I and II 
diagnostic comorbidity in MDD, Alcohol use, Hopelessness 
 
V. Other Predispositions to Suicidal Behavior: Person-centered and background (internal static risk 
factors) examples: history of prior attempt (especially multiple attempts); past and current 
psychiatric history; chaotic family history, recent separation or divorce; history of physical or 
sexual abuse; family history of suicide and mental illness. Demographic variables examples: 
ethnicity (Caucasian or American Indian), age (elderly), gender (male), marital status (widowed or 
divorced). Behavioral factors: impulsivity or low impulse control 
 
 
 

 
 
RISK CATEGORIZATIONS 
 
Nonexistent or Minimal Suicide Risk 
1. No identifiable suicidal symptoms, no past of suicide attempts or intentional self-harm, 
and no identifiable suicide risk factors present 
 
Mild Suicide Risk 
1. A multiple attempter with: no other risk factors 
2. A nonmultiple attempter with: 
a. Suicidal “Desire and Ideation” of limited intensity and duration, 
b. No or only mild symptoms of the “resolved plans and preparation” factor 
c. No, or few other risk factors present 
 
Moderate Suicide Risk 
1. A multiple attempter with: any other notable finding 
2. A nonmultiple attempter with moderate-severe symptoms of the “resolved plans and 
preparation factor” 
3. A nonmultiple attempter with: 
a. No or mild symptoms of the “resolved plans and preparation” factor 
b. Moderate-to-severe symptoms of the suicidal desire and ideation factor 
c. At least 2 other risk factors present 
 
Severe Suicide Risk 
1. A multiple attempter with: any two or more other notable findings 
2. A nonmultiple attempter with: 
a. Moderate/severe symptoms of “resolved plans and preparation” factor and 
b. At least 1 other risk factor present 
 
Extreme or Imminent Suicide Risk 
1. A multiple attempter with: severe symptoms of the “resolved plans and preparation” 
2. A nonmultiple attempter with: 
a. Severe symptoms of “the resolved plans and preparation factor” and 
b. At least 2 or more other risk factors present 
 
 
 

 
 
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