Modulating Default Mode Network Function: A Transcranial Direct Current Stimulation (TDCS) Pilot Study
Phase: NA
Conditions: Depression, Anxiety
Sponsor: Jay Fournier

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Study Protocol  
 
 
 
 
 
 
Official Title: Modulating Default Mode Function: A Transcranial 
Direct Current Stimulation (TDCS) Pilot Study 
 
 
 
ClinicalTrials.gov ID (NCT number): NCT04598152 
 
 
 
Protocol Date:11/24/2020 
 
 
 
 
 

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Scientific Background 
Several theories about depression and anxiety suggest that a broad dimension of negative 
affectivity is shared by the disorders.1,3,10,11,15 This dimension represents the tendency to 
experience negative emotions and to cope inadequately with emotional distress.16 Recent work 
in our laboratory has begun to identify and describe one specific component of the broad 
dimension of negative affectivity, Excessive Self-Consciousness (ESC), that holds promise as a 
specific phenotype underlying depression and anxiety in adults. This dimension reflects the 
tendency to feel shame, embarrassment, humiliation, and inadequacy around others. 
Preliminary work suggests that it is uniquely associated with impairments in interpersonal 
functioning over and above psychiatric symptoms, and it is associated with a specific pattern of 
disruption in the functioning of neural systems during emotional regulation. Specifically, among 
adults with depression, we have observed that higher levels of ESC are associated with: 1) 
decreased top-down control from the dorso-  and ventrolateral prefrontal cortex (DLPFC, 
VLPFC; portions of the cognitive control network)17,18 during regulation of an initial emotional 
response in the amygdala; 2) heightened activity during emotion regulation in the precuneus 
and posterior parietal cortex, regions typically active when thinking about on oneself;19-21 and 3) 
an abnormal pattern of interference by which the abnormally elevated activity in parietal regions 
alters the patterns of connectivity in the cognitive control network – specifically, decreasing the 
communication between the DLPFC and the dorsal Anterior Cingulate Cortex (ACC), a region 
critical for the adaptive regulation of emotional experience.17,22 The goal of the proposed project 
is to determine whether direct, temporary hyperpolarization of portions of the posterior parietal 
cortex associated with self-referential processing can alter the patterns of abnormal functioning 
described above and provide a more effective and targeted treatment option for individuals with 
high levels of ESC, regardless of diagnosis.   
Transcranial direct current stimulation (tDCS) provides a safe method for intervening directly 
on the functioning of brain regions. The technique involves passing a weak current through the 
brain using a montage of electrodes, pre-selected to target a specific location.  Anodal tDCS 
results in depolarization of cortical pyramidal cells, increasing neuronal excitability and 
neuronal-neuronal connections. Cathodal stimulation, by contrast, results in hyperpolarization, 
decreasing neuronal excitability and reducing neuronal-neuronal connections.23 tDCS has been 
tested as a potential treatment for both major depressive disorder24-27 and anxiety disorders.28 
Approximately half of the randomized controlled trials of tDCS have observed significant effects, 
and half have not.24 When studies are meta-analytically combined, the efficacy of tDCS as a 
treatment for depression is similar to that observed for standard treatments whereby effect-sizes 
are small24,27  and only 1/3rd of patients respond to the treatment.27  We believe that outcomes 
from direct interventions like tDCS can be dramatically improved by individualizing them to 
target the specific pathophysiological mechanisms associated with a particular individual’s 
illness.  As such, we hypothesize that by combining our initial results demonstrating that the 
ESC phenotype is associated with specific patterns of cortical network dysfunction with the 
targeted intervention capability of tDCS, we will be in a position to develop and test a truly 
personalized, circuit-based intervention that has the capability of improving treatment outcomes.  
 
Study Objectives 
There is growing recognition that strict distinctions between clinical psychiatric disorders such 
as anxiety and depression, on the one hand, and trait-like dispositions to experience negative 
emotions, on the other, fail to capture the true nature of psychopathology and are ultimately 
unhelpful.1-3 We contend that by examining specific dimensional phenotypes that are associated 
with the experience of negative emotions and that cut across depression and anxiety disorders, 
we will be better able to identify the neurobiological processes associated with an individual’s 

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distress and to develop better, individually targeted interventions. Recent work in our laboratory 
has identified one such phenotype, Excessive Self-Consciousness (ESC), that cuts across 
depression and anxiety disorder presentations, predicts specific impairments in real-world 
interpersonal functioning, and correlates with a particular pattern of dysfunction in neural 
systems.  In this study, we propose to test whether the ESC phenotype can be used to guide a 
novel, transcranial direct current stimulation (tDCS) intervention to target specific abnormalities 
in cortical network functioning. 
 
ESC has long been recognized as one component of the general trait-like disposition to 
experience negative emotions. It describes the tendency to feel shame, humiliation, and 
inadequacy around others. In our work with depressed adults, we observed that higher levels of 
ESC were associated with the following neurofunctional abnormalities during emotion 
regulation: 1) inefficient functioning of the top-down, cognitive control network necessary to 
regulate negative emotions; 2) abnormally increased activity in regions of the parietal cortex that 
are typically active during self-reflection; and 3) a pattern of network interference by which the 
elevated activity in the parietal regions interfered with communication in the cognitive control 
network.  
 
In this study, we propose to test whether the ESC dimensional phenotype can be used to 
guide a novel  tDCS intervention to target the network-based abnormalities described above. 
tDCS involves passing a weak current through the brain. One variant, cathodal tDCS, can be 
used to temporarily hyperpolarize cortical pyramidal cells, thereby decreasing neuronal 
connections. tDCS has been explored as a possible treatment for depression, but results to date 
are mixed. No work has examined whether tDCS can be used in an individually guided manner 
to target locations in the parietal cortex and alter the patterns of circuitry dysfunction described 
above.  The aims of this study were designed to provide pilot data for a competitive future 
funding proposal:  
 
1) Determine the impact of acute cathodal tDCS to regions of the left posterior parietal 
cortex associated with self-reflection on the patterns of abnormal neural activity and connectivity 
described above. We will compare this to a sham condition whereby no active tDCS will be 
applied.  
 
2) Determine if the impact of the intervention is greater for those with higher vs. lower levels 
of ESC, controlling for symptoms of depression and anxiety. 
 
3) Document the feasibility and acceptability of the intervention, and explore whether the 
tolerability or efficacy of the intervention differs as a function of demographic variables or 
psychiatric symptoms. 
 
Study Design & Methods 
Sample: In order to demonstrate that the patterns of functional neural abnormalities associated 
with ESC can be specifically altered by cathodal tDCS, we will recruit a sample of 44 adults (18-
30 years old, 50% male/female), all of whom will have clinically significant levels of depression 
(> 10 on the Quick Inventory of Depressive Symptoms29,30) or anxiety (> 60 on the PROMIS 
Anxiety Short-form31). We are selecting a sample of depressed and anxious adults so that we 
can confirm that it is the ESC dimensional phenotype, and not psychiatric symptom severity, 
that is associated with the patterns of cortical functioning abnormalities described above. To 
ensure an adequate range of ESC scores, the sample will be stratified to require that half 
(N=22) fall in the upper tertile of ESC scores expected among adults with depression or anxiety2  
and half (n=22) fall in the bottom tertile.  
 
Procedures: The proposed study will be carried out at the University of Pittsburgh, Magnetic 
Resonance Research Center (MRRC). Participation will occur over three assessment periods. If 
participants appear eligible after a telephone screen, they will be scheduled for Visit 1 (which 
may be virtual or in-person), during which a more thorough set of screening procedures will 

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determine full eligibility and demographic, symptom, trait, functioning, and life history information 
will be collected. If participants continue to be eligible following Visit 1, they will be scheduled for 
two scan visits (Visits 2 and 3) to be held on separate days, approximately one week apart. The 
following  data will be collected:  
 
Initial Eligibility Screening (Visit 1). To determine eligibility, participants will complete the 
Quick Inventory of Depressive Symptoms (QIDS30) and the Patient Reported Outcomes 
Measurement Information System Anxiety 7-item short form (PROMIS-A31). The QIDS is a 16-
item, self-report measure of depression symptoms.29,30 Item-response theory analyses suggest 
cut-offs for moderate depression severity at total scores of 10.29,30 The PROMIS-A is an 7-item, 
self-report tool assessing anxiety. Instrument developers recommend a cutoff for clinical 
significance at T scores of 60.32  To determine scores on the ESC phenotype, participants will 
complete the NEO-PI-R,16 a 240-item inventory that measures the constructs associated with 
the Five Factor Model of personality, along with the facets of each broad domain. We will use 
scoring algorithms developed in our laboratory and validated in three separate samples to 
determine ESC scores.   
 
fMRI Protocol (Visits 2 and 3):  At each scanning visit, symptoms (i.e., QIDS, PROMIS-A) 
will be reassessed. During fMRI at each visit, participants will complete the Cognitive 
Reappraisal Task. This widely used task examines the functioning of the neural circuitry 
associated with exerting cognitive control over the response to emotionally salient stimuli.34,35 
Each trial begins with an instruction cue (2s) to either “attend” or “reappraise” the image that will 
follow. Next, a negatively or neutrally valenced interpersonally relevant picture is presented (8s) 
during which participants follow the instructions given for that trial. The task consists of three 
trial types: attend neutral, attend negative, and reappraise negative. During attend trials, 
participants view the scene and experience their natural emotional response. During the 
reappraise trials, participants are asked to reframe the meaning of the scene so as to diminish 
the negative emotional impact.36 Participants practice the task prior to the scan, and they are 
provided feedback on their reappraisals of practice items. The stimulus display is followed by an 
emotional rating probe (4s) and finally a fixation cross (4s) to mark the end of the trial. Twenty 
trials of each type are presented in a pseudorandom order over two 10 minute, 20 second runs. 
Two versions of the task have been developed to facilitate repeated testing. These will be 
counterbalanced across subjects and visits. This task has been used in several studies of 
healthy adults,37-39 and Dr. Fournier has successfully used the task in a sample of depressed 
individuals. Prior to fMRI scanning, structural brain data will be collected for all participants. 
Following the final visit, participants will complete a short, self-report questionnaire regarding 
their experience of the intervention and will be debriefed by study personnel.  
 
tDCS Protocol (Visits 2 and 3): TDCS will be administered concurrently with the emotion 
regulation paradigm in the scanner using procedures already in place at the MRRC. TDCS is 
applied to the scalp, typically providing the equivalent of what a 6V battery would produce (and 
providing no more than 15V). The TDCS sponge electrodes and connecting wires are non-
ferromagnetic and thus can be used safely within the MRI facility. These will be connected to 
the main apparatus situated outside of the facility. Investigators have determined the optimal 
placement of wires in the scanning environment to reduce occurrence of scanning artifacts.  The 
montage for left posterior parietal cortex stimulation and the sham will be based on our prior 
work, the published literature26, and neurotargeting software. We will employ left posterior 
parietal cortex cathodal stimulation and anodal stimulation on the shoulder. Cathodal stimulation 
of -1mA will be used, as this produces neural inhibition41, and because higher cathodal 
stimulation currents can yield paradoxical excitation42. Voltage is controlled by the device to 
maintain a constant electrode -1mA current. Cathodal stimulation will be applied for the duration 
of the emotion regulation task (approx. 20 minutes), and it will be slowly ramped up to start and 
ramped down to end. Previous findings indicate that effects of acute TDCS can last about 2 
hours after the procedure but not into the next day42. Side effects: mild skin sensations under 

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the electrode (itching, prickling), dizziness, visual flickering; much less frequently, nausea, 
headache and more serious atopic skin reactions. There is a built-in safety mechanism to 
prevent shorting and discomfort. Participants indicate, using a squeeze ball, if they feel scalp 
warmth. Sham stimulation will be slowly ramped up and down to a nominal low level (1ua). 
 
 
Eligibility Criteria  
Inclusion Criteria:  
1) Between 18-30years old 
2) Score > 10 on the QIDS or > 60 on the PROMIS-A 
3) We will use a flexible extreme groups recruitment strategy to ensure an adequate 
distribution of ESC scores. We will ensure that at least 62% of the sample will be composed 
of those scoring .5 SD above or below the mean, as measured by the NEO-PI-R. This value 
corresponds to the expected values assuming a normal distribution of the trait. 
4) Normal or corrected to normal vision 
5) Able to provide informed consent in English 
6) Right-handed (Annett criteria)  
Exclusion Criteria:  
1) Have a history of head trauma with loss of consciousness. 
2) Have a systemic medical illness that may impact fMRI measures of cerebral blood flow. 
3) Meet standard exclusion criteria for fMRI scanning (e.g. claustrophobia, cardiac 
pacemakers, neural pacemakers, surgically implanted metal devices, cochlear implants, 
metal braces, or other MRI non-safe metal objects in the body). 
4) Are pregnant (self-report and tested for as part of any scan by the scanning center) 
5) Not native English speaking or not fluent 
6) Premorbid NAART IQ estimate<85;  
7) Visual disturbance (<20/40 Snellen visual acuity) with correction 
8) Left/mixed handedness (Annett criteria), to ensure a uniform hemispheric dominance for 
interpretation of neuroimaging data  
9) Active suicidal ideation in need of immediate treatment 
10) Scoring below the cutoffs on both the QIDS and the PROMIS-A 
11) History of alcohol/substance use disorder (including nicotine) and/or illicit substance use 
(except cannabis) over the last 3 months, determined by the MINI. Lifetime/present cannabis 
use (non-disordered levels) will be allowed, given its common usage in individuals in this age 
range.  
13) Current or past psychotic-spectrum disorder 
14) History of seizures 
 
Statistical Considerations 
A1: Repeated-measures ANOVA models will be used to determine whether acute cathodal 
tDCS to the left posterior parietal cortex, compared to the sham condition, alters patterns of 
neural activity in and connectivity with the posterior parietal cortex and corresponding patterns 
of activity and connectivity within the cognitive control network during emotion regulation. A2: 
Repeated measures ANCOVA models will determine whether the impact of tDCS is stronger for 
those with higher ESC scores, controlling for concurrent depression and anxiety symptoms. A3: 
Feasibility and tolerability of the intervention will be assessed by examining attrition rates 
between the fMRI/tDCS visits and by examining responses on the self-report questionnaire 
regarding the acceptability of the intervention. Differences in acceptance, tolerability, and 
efficacy will be explored as a function of demographic variables and psychiatric symptoms.