Probing Homeostatic Plasticity With Priming Theta-burst Stimulation of the Dorsolateral Prefrontal Cortex
Phase: NA
Conditions: Depression Minor
Sponsor: Dr Georg Kranz

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Interventional Study Protocol 
 
Official Title: 
Probing homeostatic plasticity with priming theta-burst stimulation of the 
dorsolateral prefrontal cortex 
 
Date: 
15. Mar. 2022 
 
 
Principal Investigator: 
Georg S. Kranz 
 
 
 

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2) Brief Summary: 
Priming stimulation is a highly promising tool to boost the beneficial effects of therapeutic 
repetitive transcranial magnetic stimulation (rTMS) in psychiatry. The potentiating effects of 
priming stimulation, however, depend on the time interval between the priming and the test 
stimulation. Although it is known that too short and too long intervals have no effects, systematic 
studies that identify the time needed to maximize efficacy have not yet been done. Thus, there is a 
need for studies to investigate the effects of priming stimulation in order to fully utilize the 
potential benefits and advantages of this promising new rTMS protocol. Here we propose a 
research program that will systematically investigate the neuromodulatory process underlying 
priming stimulation to enhance metaplasticity in the left dorsolateral prefrontal cortex (DLPFC) – 
one of the main targets for therapeutic rTMS – in individuals with subclinical depression. 
The brain is a highly plastic organ and its activity can be influenced using rTMS. At the same time, 
the brain also has a mechanism – called homeostatic metaplasticity – which counteracts extreme 
plastic changes. Homeostatic metaplasticity therefore can limit the beneficial effects of brain 
stimulation interventions. However, priming stimulation protocols that include both a priming and 
a test stimulation session may utilize homeostatic metaplasticity to increase the beneficial effects 
of brain stimulation, although the optimal treatment parameters for priming are not known. 
Moreover, little is known about homeostatic metaplasticity in the DLPFC, an area that is 
particularly relevant for psychiatric conditions given its role in the top-down control of emotions. 
Here, we will systematically study metaplasticity using priming theta-burst stimulation (TBS), a 
potent form of rTMS in the left DLPFC. The optimized stimulation intensity will be investigated 
by a pilot study. Changes in blood oxygenation that signal brain activity changes will be assessed 
using functional near-infrared spectroscopy (fNIRS) at rest and during engagement in several 
cognitive tasks. The findings from this study will (1) elucidate the optimal time interval between 
priming and test stimulation; (2) elucidate the influence of priming TBS on emotion discrimination 
as well as executive function and its underlying brain activity in subclinical depression; and (3) 
validate homeostatic metaplasticity in the left DLPFC. 
Subclinical depression has serious consequences for the quality of life and is associated with 
considerable economic costs but adequate treatments are poorly explored. Therefore, by 
systematically testing priming stimulation and investigating its underlying neural processes, this 
study will pave the way towards developing adequate antidepressant treatments that will reduce 
personal suffering, reduce costs and occupational disability. 
3) Detailed Description: Please refer to the ECS proposal 
4) Primary Disease or Condition being studied in the trial, or the focus of the study: 
Subclinical Depression 
5) Keywords: Priming Stimulation, Theta-Burst Stimulation, Functional NIRS, Emotion 
Discrimination, Subclinical depression 
6) Primary Purpose: Optimization of stimulation parameters for a priming stimulation protocol 

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7) Study Phase: N/A 
8) Intervention Study Model: Parallel, sham-control 
9) Model Description: (Objectives) 
The proposed research has two primary objectives. 
The first objective is to understand the effects of priming stimulation timing of the left DLPFC 
using fNIRS at rest. The time window between priming cTBS and test iTBS will be either 0, 10, 
or 20 minutes. We hypothesize that 0 minutes will eliminate the effect of the test iTBS, whereas 
10 minutes will potentiate it; 20 minutes will have no effect (i.e., result in no difference, relative 
to sham priming). 
The second objective is to evaluate the effects of priming stimulation in the context of facial 
emotion processing and executive function in subclinical depression. Previous evidence indicates 
that DLPFC stimulation modulates affective processing on the neural and behavioral level. We 
hypothesize that optimal priming stimulation will affect reaction times in an emotion-specific way 
and will reduce the negative bias observed in subclinical depression. 
10) Interventions: 
Number of Arms: 4 
Allocation: Randomized 
Enrollment Type: Anticipated 
Number of Subjects: 80 participants with subclinical depression 
Arm 1: Control 
 
Arm Title: Priming sham TBS – followed by iTBS after an ISI of 0 minutes 
 
Arm Description: self-explanatory, see Arm Title 
Arm 2: Experimental 
 
Arm Title: Priming cTBS – followed by iTBS after an ISI of 0 minutes 
 
Arm Description: self-explanatory, see Arm Title 
Arm 3: Experimental 
 
Arm Title: Priming cTBS – followed by iTBS after an ISI of 10 minutes 
 
Arm Description: self-explanatory, see Arm Title 
Arm 4: Experimental 
 
Arm Title: Priming cTBS – followed by iTBS after an ISI of 20 minutes 
 
Arm Description: self-explanatory, see Arm Title 

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11) Outcome Measures: 
Outcome 1: Primary Outcome Measure 
Title: HbO during rest before and after stimulation (raw values and change scores) 
Description: Prefrontal neural activity will be measured using fNIRS before 
(baseline) and about 10-15 minutes after the stimulation (delay will be recorded). 
TBS-induced blood oxygen changes (HbO) at rest will be evaluated in the frontal 
cortex 
Time Frame: baseline, post intervention 
Outcome 2: Secondary Outcome Measure 
Title: HbO during which participants perform cognitive tasks (e.g., emotional 
stroop task, verbal fluency task, emotion discrimination task ) 
Description: Prefrontal neural activity will be measured using fNIRS before 
(baseline) and about 10-15 minutes after the stimulation (delay will be recorded). 
TBS-induced blood oxygen changes (HbO) during participants perform the 
cognitive tasks will be evaluated in the frontal cortex 
Outcome 3: Secondary Outcome Measure 
 
Title: Behavioral measures including reaction times and recognition accuracy 
Description: Reaction times and accuracy during the cognitive tasks will be 
evaluated before and after stimulation 
12) Eligibility: 
Sex (all) 
Eligibility Criteria: 
Inclusion: : (1) age 18-35, (2) education level of primary six or above, (3) right-handedness, 
(4) normal or corrected-to-normal vision, (5) being able to understand the verbal 
instructions, (6) willingness to sign the informed consent form. 
Exclusion: (1) a history of seizures, (2) current or past psychiatric disorders, (3) current or 
past severe internal or neurological illness, (4) ferromagnetic implants <20cm from the 
head, cardiac pacemaker, deep brain stimulation and other common TMS exclusion criteria, 
(5) history of substance dependence or abuse within the last 3 months, (6) intake of any 
medication known to affect the excitation threshold (i.e., benzodiazepines, 
anticonvulsants). 
 
13) Statistical Analysis Plan: 
fNIRS data analysis will follow the standard processing steps. This includes spatial 
registration (recording of standard cranial landmarks nasion, inion, left and right ear, and 
the 3D locations of the fNIRS probes); transformation to MNI space [39]; band-pass 

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filtering for motion artifact removal; and estimation of the hemodynamic response function 
using GLM, as implemented in the NIRS Toolbox for MATLAB. Comparisons between 
baseline and task HbO will reveal task-related de/activations, corrected for multiple 
comparisons (52 channels). Average HbO changes will then be determined for each 
channel and each measurement and entered into second-level analysis. Similarly, means of 
HbO for pre and post-stimulation will be entered into second-level analysis. 
A t-test between pre- and post-stimulation in condition 1 will be performed to test 
hypothesis 1. Hypothesis 1 will be supported if there is a significant increase in prefrontal 
HbO after stimulation. 
A t-test between condition 2 and 1 using change scores will be performed to test hypothesis 
2. Hypothesis 2 will be supported if there is a significant stronger change in HbO in 
condition 1 compared to condition 2 
A t-test between condition 3 and 1 using change scores will be performed to test hypothesis 
3. Hypothesis 3 will be supported if there is a significant stronger change in HbO in 
condition 3 compared to condition 1. 
A t-test between pre- and post-stimulation in condition 4 and between change scores of 
condition 1 and 4 will be performed to test hypothesis 4. Hypothesis 4 will be supported if 
there is a significant increase in prefrontal HbO after stimulation, but no significant 
difference in change scores between condition 1 and 4. 
 
Regarding the three exploratory hypotheses about participants’ behavior (reaction times, 
hits and misses) and HbO changes during cognitive tasks , linear mixed models will be 
conducted to determine differences between conditions, followed by post-hoc pairwise 
comparisons. Here, a three-way interaction between time, condition and emotion will be 
evaluated and followed by post-hoc two-way interactions and pairwise comparisons. 
Hypothesis E1 will be supported if there is a significant change in HbO and/or behavioral 
measures in condition 1 in some (e.g. sad) but not other emotions (e.g. happy) after 
stimulation (following a post-hoc 2-way interaction between time and emotion). 
Hypothesis E2 will be supported if there is a significant interaction between time, emotion 
and conditions 2 and 1. 
Hypothesis E3 will be supported if there is a significant interaction between time, emotion 
and conditions 3 and 1. 
Hypothesis E4 will be supported if there is a significant change in condition 4 in some (e.g. 
sad) but not other emotions (e.g. happy) after stimulation (following a post-hoc 2- way 
interaction between time and emotion). 
Finally, two t-tests comparing ERA- recognition accuracies between subclinically 
depressed and control participants and between pre and post stimulation in the sample of 
subclinically depressed participants will be performed in order to test hypotheses E5 and 
E6, respectively. 
Hypothesis E5 will be supported if recognition accuracy is reduced in participants with 
subclinical depression compared to the control sample. 
Hypothesis E6 will be supported if recognition accuracy will be increased after stimulation 
compared to baseline in participants with subclinical depression. 

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Behavioral data will be analyzed using the IBM SPSS software (http://www- 
01.ibm.com/software/analytics/spss/). The alpha level will be set at 0.05, adjusted for 
multiple comparisons using the Bonferroni-Holm procedure. For GLM, post-hoc pairwise 
comparisons will be corrected using Fisher least significant difference procedure in 
accordance with the closed test principle, i.e., post hoc comparisons will be declared 
nonsignificant if the global p value of the main- or interaction effect is nonsignificant, but 
carried out without further correction in case of a significant global effect.