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. Author manuscript; available in PMC: 2024 Nov 1.
Published in final edited form as: Neurobiol Learn Mem. 2023 Sep 10;205:107825. doi: 10.1016/j.nlm.2023.107825

Frontopolar multifocal transcranial direct current stimulation reduces conditioned fear reactivity during extinction training: A pilot randomized controlled trial

Thomas G Adams 1,2, Benjamin Kelmendi 2,5, Jamilah R George 2,6, Jennifer Forte 2,7, Troy Hubert 1, Hannah Wild 1, Colton Rippey 1, Christopher Pittenger 2,3,4
PMCID: PMC10872945  NIHMSID: NIHMS1933412  PMID: 37699439

Abstract

Exposure-based therapies for anxiety and related disorders are believed to depend on fear extinction learning and corresponding changes in extinction circuitry. Frontopolar multifocal transcranial direct current stimulation (tDCS) has been shown to improve therapeutic safety learning during in vivo exposure and may modulate functional connectivity of networks implicated in fear processing and inhibition. A pilot randomized controlled trial was completed to determine the effects of frontopolar tDCS on extinction learning and memory. Community volunteers (n=35) completed a 3-day fear extinction paradigm with measurement of electrodermal activity. Participants were randomized (single-blind) to 20-min of sham (n=17, 30s. ramp in/out) or active (n=18) frontopolar (anode over Fpz, 10–10 EEG) multifocal tDCS (20-min, 1.5mA) prior to extinction training. Mixed ANOVAs revealed a significant group*trial effect on skin conductance response (SCR) to the conditioned stimulus (CS+) during extinction training (p=.007, Cohen’s d=.55). The effects of frontopolar tDCS were greatest during the first two extinction trials, suggesting that tDCS may have promoted fear inhibition prior to safety learning. Return of fear to the CS+ during tests were comparable across conditions (ps>.50). These findings suggest that frontopolar tDCS may modulate the processing of threat cues and associated circuitry or promote the inhibition of fear. This has clear implications for the treatment of anxiety and related disorders with therapeutic exposure.

Keywords: transcranial direct current stimulation, medial prefrontal cortex, frontal pole, fear conditioning, fear extinction, anxiety

1.1. Introduction

Exposure-based cognitive-behavioral therapies (CBTs) are among the most efficacious treatments for patients with anxiety and related disorders: obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and anxiety disorders (Adams et al., 2015; Tuerk, 2014). Despite robust effect sizes (Adams et al., 2015; Parker et al., 2018), return of fear and incomplete response to exposure-based treatments are common, and up to 30% of patients do not significantly benefit from exposure-based CBT (Craske, 1999; Hofmann & Smits, 2008; McNally, 2007).

Exposure therapies are believed to promote the inhibition of fear and anxiety through the acquisition and recall of new safety learning (Craske et al., 2014; Peters et al., 2009). More specifically, exposure therapy is believed to depend on fear extinction learning. Extinction learning is commonly studied in laboratory settings by first conditioning fear to a neutral stimulus (CS+ [e.g., red light]) through repeated pairings of the CS+ with an aversive unconditioned stimulus (US [e.g., a shock]). Most paradigms also include a second neutral stimulus (CS− [e.g., yellow light]) that is never paired with the US. To study the acquisition of fear extinction learning, the CS+ is repeatedly presented in the absence of the US. This promotes the creation of new safety memories (e.g., CS+ ≠ US) that compete with previously learned fear-related memories (e.g., CS+ = US) and can inhibit fearful responding (Grasser & Jovanovic, 2021; Lacagnina et al., 2019; Myers & Davis, 2007; Quirk et al., 2006). This safety learning is typically more tenuous than the original threat learning. As such, the return of fear is common (Myers & Davis, 2007; Vervliet et al., 2013), particularly among individuals with anxiety and related disorder(s) (Hermans et al., 2005; Vervliet et al., 2013). This is often evaluated by testing for the return of fear after the passage of time (spontaneous recovery), with the presentation of context cues related to fear conditioning (context renewal), or with additional presentations of the US (reinstatement).

The canonical fear circuit is composed of the amygdala, hippocampus, and medial prefrontal cortex (mPFC) (Milad & Quirk, 2012; Phelps et al., 2004; Sehlmeyer et al., 2009). Like the amygdala (Phelps et al., 2004), activation in the dorsal mPFC, including the dorsal anterior cingulate cortex (dACC), is positively associated with fearful responding (Herry et al., 2008; Senn et al., 2014) during fear conditioning, extinction learning, and extinction recall (Fullana et al., 2018). Conversely, activation in the ventral mPFC (vmPFC), including the rostral anterior cingulate cortex (rACC) and orbital frontal cortex (OFC), is negatively associated with fearful responding (Hiser & Koenigs, 2018; Milad & Rauch, 2007) during extinction learning, particularly during later extinction training trials (i.e., after some safety learning has occurred) (Milad et al., 2007; Bremner et al., 2005) or during tests of extinction recall (Hartley et al., 2011; Milad et al., 2005, 2009). Moreover, abnormal functioning of the vmPFC is associated with deficits in the acquisition and recall of extinction learning in multiple anxiety and related disorders (Cooper & Dunsmoor, 2021; Marin et al., 2014; Milad et al., 2009), with severity of anxious symptomatology, (Apergis-Schoute et al., 2017; Cavedini et al., 2002; Fullana et al., 2017, 2018; Gold et al., 2020; Hermann et al., 2007; Koenigs & Grafman, 2009; Lange et al., 2020), and with clinical response to exposure-based CBTs (Helpman et al., 2016; Lange et al., 2020; Marin et al., 2016).

More than 30 controlled studies have examined the effects of non-invasive brain stimulation – namely, transcranial magnetic stimulation (TMS) and transcranial direct current stimulation – on fear extinction learning, consolidation, and recall (Marković et al., 2021). The extant literature suggests that both TMS and tDCS can effectively modulate fear and safety learning and memories (Marković et al., 2021). The largest effect sizes appear to be observed when brain stimulation is used to increase excitability of the vmPFC (Adams et al., 2020; Marković et al., 2021).

tDCS is a non-invasive technique that can modulate resting neuronal membrane potential by passing a weak electrical current between two or more electrodes (an anode and cathode), at least one of which is placed on the scalp, typically over a target region (Nitsche et al., 2008). Neurons beneath the anode can be depolarized, thus increasing the likelihood of action potentials, whereas neurons beneath the cathode can be hyperpolarized, thus decreasing the likelihood of action potentials (Nitsche et al., 2008). As such, tDCS can be used to influence long-term potentiation (LTP) beneath the anode and long-term depression (LTD)-like plasticity beneath the cathode (Fritsch et al., 2010; Nitsche & Paulus, 2001). tDCS can also modulate activity and functional connectivity within and between targeted areas (Kunze et al., 2016; Peña-Gómez et al., 2012) and related networks (Wörsching et al., 2018). Importantly, with larger doses of tDCS (i.e., greater amperage and duration) these effects can persist for more than an hour after stimulation (Nitsche & Paulus, 2001; Stagg et al., 2009; Stagg & Nitsche, 2011).

Traditional tDCS is bipolar; electrical current is passed between two electrodes, one or both of which are placed on the scalp. The effects of bipolar tDCS are most pronounced beneath the anode and cathode, but tissue between the electrodes can also be significantly affected (Liu et al., 2018; Ruffini et al., 2014, 2017). Multifocal tDCS can significantly improve spatial precision compared to bipolar tDCS by passing current from one or more stimulation electrode and two or more smaller return electrodes (Ruffini et al., 2014, 2017). Multifocal tDCS can be used to target single regions, as the effects of tDCS on areas surrounding the target electrode are reduced and the effects of return current can be substantially mitigated if a sufficient number of return electrodes are used (Liu et al., 2018; Ruffini et al., 2014, 2017). For example, multifocal tDCS may allow for more precise targeting of the vmPFC than bipolar tDCS (Adams et al., 2020; Liu et al., 2018; Ruffini et al., 2014, 2017). This is important because the vmPFC and the adjacent dorsal mPFC have opposite effects on fearful responding (Herry et al., 2008; Milad et al., 2009; Senn et al., 2014; Sierra-Mercado et al., 2006).

Consistent with research showing that bipolar tDCS targeting the mPFC accelerated therapeutic safety learning during therapeutic exposure (Bulteau et al., 2022; Cobb et al., 2021; van ‘t Wout-Frank et al., 2019), recent research suggests that multifocal tDCS targeting ventral portions of the mPFC (see Figures 1 and 2) significantly accelerates within-session therapeutic safety learning – as measured by subjective distress ratings - during repeated in vivo exposure in patients with OCD when administered before exposure (Adams et al., 2022). Analyses of fMRI data suggested that the same multifocal frontopolar tDCS montage significantly reduced anticorrelated functional connectivity between the default mode network (DMN) and salience network (SN), including reduced functional connectivity between the frontal pole and right anterior insula (Adams et al., 2022). These findings are important given research showing that DMN activity is positively associated in safety signal processing and fear inhibition, SN activity is positively associated with fear conditioning and fearful responding, and SN activation likely inhibits DMN activity (Cocchi et al., 2013; Fullana et al., 2018; Goulden et al., 2014; Marstaller et al., 2017; Sidlauskaite et al., 2014; Sridharan et al., 2008; Wen et al., 2021).

Figure 1.

Figure 1.

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Standardized procedures were adapted to assess fear conditioning, extinction, and recall (spontaneous recovery and context renewal) across three days. Multifocal frontopolar tDCS was administered offline on day 2 before extinction training; electrode montage shown in top panel. Note: CX+ = conditioning (threat) context, CX− = extinction (safe) context, CS− = neutral stimulus, CS+E = extinguished conditioned stimulus, and CS+NE = non-extinguished conditioned stimulus.

Figure 2.

Figure 2.

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1.5 mA multifocal tDCS was administered using a Starstim transcranial electric stimulator, with a 1 cm2 anode over Fpz (10–20 EEG) surrounded by five cathodes in a circumferential array (AF3, AF4, F3, FZ, and F4). Simulation of the electrical fields produced by this montage was performed using Stimweaver and showed enhance electrical field potentials throughout the mPFC, particularly the anterior mPFC and medial frontopolar cortex, with limited effects on surrounding grey matter, including tissue beneath the cathodes. Portions of this figure are also shown in Adams et al., 2022.

Multiple studies have used bipolar tDCS to modulate fear extinction and safety learning. Many have aimed to stimulate the vmPFC, though electrode arrangements and timing of tDCS relative to extinction training have varied widely (Adams et al., 2020; Faucher et al., 2021; Marković et al., 2021). For example, tDCS targeting the vmPFC before and during extinction training (anode and cathode over the left and right ventrolateral PFC [F7/F8, 10–20 EEG], respectively), accelerated the rate of extinction learning compared to sham stimulation (Dittert et al., 2018; van ‘t Wout et al., 2016; Vicario et al., 2020). However, tDCS targeting the vmPFC administered after extinction training (during consolidation) impaired extinction recall in healthy volunteers (Ney et al., 2021) but improved extinction recall in PTSD patients (van’t Wout et al., 2017).

Most tDCS and extinction studies have utilized two-day extinction paradigms, where fear extinction training directly followed fear conditioning (Adams et al., 2020; Bation et al., 2016; Dittert et al., 2018; Faucher et al., 2021; Lipp et al., 2020; Marković et al., 2021; van ‘t Wout et al., 2016; Vicario et al., 2020). Fear extinction directly following original conditioning likely relies on different neural mechanisms than extinction learning that occurs after the original fear is consolidated (Myers et al., 2006). For example, prefrontal LTP-like plasticity plays a limited role when extinction is trained shortly after fear conditioning but is likely of greater importance when extinction is trained after fear conditioning is consolidated into long-term memory (Myers et al., 2006). Moreover, it is impossible to know if the administration of tDCS before, during, or after extinction training that occurs shortly after conditioning influences the consolidation of conditioning or the acquisition or consolidation of extinction learning. Furthermore, exposure-based therapies are more likely to target extinction of long-term fear memories than of recently acquired fears (Cooper & Dunsmoor, 2021; Kida, 2019). As such, paradigms that adequately separate conditioning and extinction learning provide a clearer analogue to exposure-based interventions than two-day paradigms and are better suited for studying extinction augmentation strategies such as tDCS.

Two tDCS studies have utilized conditioning and extinction paradigms; fear conditioning, extinction learning, and (when included) extinction recall were measured on separate days. The most recent study to utilize a three-day extinction paradigm found that, compared to sham tDCS, bipolar “cathodal” tDCS targeting the right dorsolateral PFC (dlPFC) (cathode over F4 [10–20 EEG] and anode over the contralateral deltoid) prior to extinction training did not significantly affect the acquisition or recall of extinction learning but did significantly reduce behavioral avoidance of the CS− during a delayed test of extinction recall (Ganho-Ávila et al., 2019). In a follow-up MRI study, this same group reported that these tDCS procedures modulated left anterior insula functional connectivity (Lee et al., 2023). The only 3-day study to target the mPFC randomized psychiatrically healthy control participants to receive bipolar tDCS (1.5mA for 20-minutes), transcranial alternative current stimulation (tACS), or sham stimulation during extinction training (Abend et al., 2016) . tDCS and tACS did not affect the acquisition of extinction learning, relative to sham stimulation (Abend et al., 2016). However, tACS and tDCS potentiated self-reported fear of the CS+ during a test of spontaneous recovery and analyses of SCR data suggested that tDCS led to the overgeneralization of fear to the CS− (Abend et al., 2016).

No published research has investigated the effects of multifocal tDCS on extinction learning or recall – all prior studies have used less spatially precise bipolar tDCS. The current study aimed to investigate the effects of multifocal tDCS targeting ventral portions of the mPFC before extinction training on the acquisition and recall of fear extinction learning using published multifocal frontopolar tDCS procedures (Adams et al., 2022) and a validated three-day fear conditioning, extinction, and recall paradigm (Milad et al., 2009, 2013). We hypothesized that, compared to sham tDCS, multifocal frontopolar tDCS would accelerate the acquisition of fear extinction learning and reduce spontaneous recovery during extinction recall testing.

2.1. Method

2.1.1. Procedures

Thirty-five adult volunteers who denied current psychiatric diagnoses were recruited from the greater New Haven area to complete study procedures. Volunteers completed a brief phone screen to probe for common psychiatric diagnoses. During the first study visit, participants completed a Yale Human Investigations Committee (HIC/IRB)-approved (#0803003626) informed consent form, a standard tDCS safety screening (Bikson et al., 2009; Brunoni et al., 2011), a demographic form, and self-report ratings of depression and anxiety (Kroenke & Spitzer, 2002; Spitzer et al., 2006). Participants then completed the habituation and fear conditioning procedures (see below). Participants returned 18–36 hours later for visit two, at which time they were randomized (single-blind) to receive 20 minutes of Sham- or Active-tDCS, immediately followed by fear extinction procedures. Visit two concluded with a tDCS side-effects questionnaire (Brunoni et al., 2011) and placebo check. Participants returned 18–36 hours later for visit three, during which they completed tests of extinction recall, were debriefed, and were then compensated $75 for their time.

2.1.2. Materials

2.1.3.1. A standard Fear Conditioning and Extinction Task

A standard Fear Conditioning and Extinction Task (Milad et al., 2009, 2013) was adapted for the present study (see Figure 1) to include five test phases administered across three consecutive days. Three stimuli (CSs) were presented against the backdrop of two virtual contexts (CXs). CSs were red, blue, and yellow shapes that “illuminated” in the position of a green lamp situated near the center of each CX, which were pictures of an office and a conference room. Each trial began with the presentation of a CX for three seconds without a CS. The CS then appeared with the CX and remained on screen for six seconds. The unconditioned stimulus (US), which was an individualized “highly annoying but not painful” shock (0–100 volts; STIMISO; BIOPAC Systems; Goleta, CA) delivered to the right hand for 500ms, co-terminated with the CS during conditioning trials. Each trial was followed by a 12–18 second inter-trial interval.

Day 1 of the task began with brief verbal and textual instructions and was followed by determination of US voltage. 500ms shocks were repeatedly administered, starting at zero volts, and slowly ramping until the participant identified a shock intensity that was “highly annoying but not painful”. Participants then completed a brief habituation phase, during which were told that they would not be shocked and each CX/CS combination was presented twice in random order. Next, during conditioning, the three CS were repeatedly presented in the conditioning context (CX+; office). The yellow CS (CS−) was presented 16 times and was never paired with the US. The red and blue lights (CS+) were presented eight times each and were paired with the US on 62.5% of trials in a pseudo-random order. CS were presented in a pseudo-random order (Milad et al., 2013) but CS and CX were not counterbalanced in the present study.

Extinction training for the CS+E was completed on day 2. This began by attaching shock electrodes to the participant’s fingers and instructing them that they “may or may not be shocked during this next phase of the experiment”. During extinction, the CS− and red CS+ (extinguished CS+ [CS+E]) were each presented 16 times against the extinction CX (CX−; conference room) in a pseudo-random order for a total of 32 trials. No shock was delivered during the extinction phase.

Extinction recall was tested on day 3 and included two phases: spontaneous recovery and context renewal. Shock electrodes were attached but inactive and participants were instructed that they “may or may not be shocked during this next phase of the experiment”. During spontaneous recovery, the three CSs were presented in a pseudo-random order against the backdrop of the CX− for a total of 32 trials: eight CS+E and non-extinguished CS+ [CS+NE] trials, and 16 CS− trials. Context renewal was identical but the three CSs were presented against the backdrop of the CX+. Importantly, the CS+NE was not extinguished on day 2 so the 8 CS+NE trials during the extinction recall phase were extinction training trials.

2.1.2.2. Electrodermal Activity (EDA)

Electrodermal Activity (EDA) was continuously measured at 1kHz during all phases of the conditioning and extinction procedures, using a constant 0.5V through disposable electrodes filled with isotonic paste and placed on the distal phalanx of the 2nd and 3rd fingers on the participant’s left hand. Signal was acquired with a BIOPAC MP150 system and Acknowledge software. Skin conductance response (SCR) to the CSs was calculated by subtracting the mean EDA during the last 2 sec of the CX presentation from the maximum EDA during the CS per past research (Milad et al., 2013).

2.1.2.3. Transcranial Direct Current Stimulation (tDCS)

Transcranial Direct Current Stimulation (tDCS) was delivered using a battery driven Starstim transcranial electric stimulator (Neuroelectrics®, Cambridge, MA) through 1cm2 ceramic electrodes. A single anode was placed over the frontal pole (Fpz, 10–10 EEG), which was surrounded by five return electrodes (AF7, AF8, F3, F4, and Fz at 0.3mA, Figure 2). Accordingly, adjacent electrodes were ~10% of the total distance from inion to nasion or tragus to tragus. For example, a participant with an inion to nasion measurement of 35cm would have the anode (Fpz) placed 3.5cm above the nasion and Fz would be 7cm from Fpz. Current was set to 1.5 mA and was ramped in and out for 30 seconds to minimize sensory side effects. Modeling of electrical field distribution suggests that this montage concentrates positive current density in ventral portions of the mPFC, particularly the anterior frontal pole, while negative current is of limited strength beneath the five cathodes. Participants in the Active-tDCS condition received 20-min of tDCS (+30 s ramp in/out) prior to extinction training. Participants in the Sham-tDCS condition received 30 s ramp in/out followed by 20-min of no stimulation. These sham procedures produce sensations that are similar to active tDCS and are thought to have a trivial effect on the brain (Brunoni et al., 2011, 2014). Past research suggests that blinded participants were unable to distinguish between these active and sham tDCS procedures (Adams et al., 2022).

2.1.4. Measures

2.1.4.1. Generalized Anxiety Disorder – 7 (GAD-7)

Generalized Anxiety Disorder – 7 (GAD-7) is a 7-item self-report measure used to assess levels of trait anxiety over the last 2 weeks (Spitzer et al., 2006).The GAD-7 has strong test-retest reliability and internal consistency (Spitzer et al., 2006).

2.1.4.2. Patient Health Questionnaire (PHQ-9)

Patient Health Questionnaire (PHQ-9) is a 9-item self-report measure that assesses the severity of depression over the last 2 weeks (Kroenke & Spitzer, 2002). The PHQ-9 has excellent test-retest reliability and internal consistency (Kroenke et al., 2001).

2.1.4.1.3. tDCS Adverse Effects Questionnaire (tDCS-AEQ)

tDCS Adverse Effects Questionnaire (tDCS-AEQ) assesses the presence of ten common tDCS side effects rated on a scale from zero (absent) to three (severe) (Brunoni et al., 2011). If a participant endorsed the presence of a side effect, they were then asked to rate the degree to which they believed the side effect was related to tDCS using a scale from zero (“none”) to four (“definitely”). A final question was added to the end of the tDCS-AEQ to assess the degree to which each participant believed they received active (real) or sham (placebo) stimulation using a bi-polar scale anchored at zero (“not sure”) and ranging from −2 (“definitely sham”) to +2 (“definitely active”). Psychometric properties of the tDCS-AEQ have yet to be evaluated.

2.1.5. Participants

A plurality of participants reported white/Caucasian race (48.6%). A majority reported non-Hispanic ethnicity (86%) and female sex (57%). The average participant age was 34.17 years (SE=2.14) and participants reported minimal symptoms of anxiety ([GAD-7] M=1.23, SE=0.51) and depression ([PHQ-9] M=1.60, SE=0.86). See Table 1.

Table 1.

Background data for study volunteers (n = 35)

Sham-tDCS
(n = 17)		 Active-tDCS
(n = 18)
Age M=35.76, SE=12.26 M=32.67, SE=12.78
Gender 83% female 66% female
Race 41.2% Caucasian 55.6% Caucasian
Ethnicity 94.1% non-Hispanic 77.8% non-Hispanic
GAD-7 M=1, SE=2.12 M=1.44, SE=2.88
PHQ-9 M=0.94, SE=1.20 M=2.22, SE=3.66
Real vs. Placebo tDCS? M=0.56, SE =0.24 M= 0.27, SE=1.28
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3.1. Results

3.1.1. Preliminary Analyses

Chi-square analyses and one-way ANOVAs showed that there were no significant group (Sham- vs. Active-tDCS) differences in race (p=.39), ethnicity (p=.17), sex (p=.63), or age (p=.47). Participants reported minimal anxiety and depression on the GAD-7 and PHQ-9; differences between groups were not significant (anxiety [p=.61]; depression [p=.18]). The modal response for the real vs. placebo tDCS question on the tDCS-AEQ was “unsure” (M=0.42, SE=0.20), and differences between groups were not significant (p=.47), suggesting that sham tDCS was an effective placebo and participant blinding was successful. See Table 1.

3.1.2. Fear Conditioning

Average shock intensity selected by participants in the Active-tDCS group was quite similar (M = 42.58 volts, SE = 5.17) to average shock intensity selected by participants in the Sham-tDCS group (M = 43.06, SE = 6.22)]. Group differences were not significantly different F(1,32) = 0.004, p = 0.953.

Mixed ANOVAs were used to examine differential conditioning to the CS+E and CS+NE relative to the CS−. Average SCR to the CS’s was the DV, the between-subject effect was group (Sham- vs. Active-tDCS), and the within-subject effect was CS type (i.e., CS− vs. CS+E and CS− vs. CS+NE). CS− values from the first half of conditioning (CS− trials 1–8) and CS− values from the second half of conditioning (CS− trials 9–16) were used for the first (CS+E) and second (CS+NE) mixed ANOVAs, respectively.

For the CS− vs. CS+E contrast, there was not a significant group*CS interaction (F [1, 31] = 0.10, p = 0.756, ηp2 = 0.00) or main effect of group (F [1, 31] = 1.95, p = 0.172, ηp2 = 0.06), but there was a significant effect of CS type (F [1, 31] = 17.45, p < .001, ηp2 = 0.36), such that average SCR was significantly greater for the CS+E (M = 0.37, SE = 0.06) than the CS− (M = 0.23, SE = 0.04), which indicates successful differential conditioning to the CS+E relative to the CS− (Figure 3). See Supplemental Figure 1 for trial-by-trial data. For the CS− vs. CS+NE contrast, there was not a significant group*CS interaction (F [1, 31] = 0.00, p = 0.983, ηp2 = 0.00), main effect of group (F [1, 31] = 0.24, p = 0.631, ηp2 = 0.01), or main effect of CS (F [1, 31] = 2.58, p = 0.118, ηp2 = 0.08), though the effect was medium sized and trending in the expected direction (Figure 3); average SCR to the CS+NE (M = 0.19, SE = 0.04) was nominally greater than average SCR to the CS− (M = 0.14, SE = 0.03). See Supplemental Figure 1 for trial-by-trial data.

Figure 3.

Figure 3.

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A significant main effect of CS-type (early CS− vs. CS+E) suggest differential conditioning of the CS+E. The main effect of CS-type (late CS− vs. CS+NE) was not statistically significant, suggesting that conditioning of the CS+NE was not successful, though effects were medium sized and trending in the expected direction. There were no group (Sham- vs. Active-tDCS) by CS-type interactions, suggesting that the magnitude of conditioning did not differ between the two groups. Plotted values are mean and standard error. *** = p < .001.

3.1.3. Fear Extinction Training

Mixed ANOVAs were used to analyze the main and interactive effects of group (Sham vs. Active-tDCS) and trials (1–16) on CS− and CS+E SCR values during extinction training on day 2. Huynh-Feldt procedures were used to correct for violations of sphericity. For SCR to the CS− during extinction training on day 2, the effects of group (F [1, 33] = 0.25 , p = 0.620, ηp2 = 0.01), trials (F [6.47, 213.61] = 1.19, p = 0.276, ηp2 = 0.04), and group*trials (F [6.47, 213.61] = 1.05, p = 0.398, ηp2 = 0.03) were not significant, suggesting that SCR to the CS− did not significantly change across the 16 extinction trials and that there were not significant group differences in SCR to the CS−. For SCR to the CS+E during extinction training on day 2, the effect of group was not significant (F [1, 33] = 0.08, p = 0.777, ηp2 = 0.00), but the effect of trials (F [5.35, 176.55] = 2.82, p = 0.016, ηp2 = 0.08) and the group*trials interaction (F [5.35, 176.55] = 2.48, p = 0.03, ηp2 = 0.07) were significant, such that SCR to the CS+E reduced across extinction trials and the extinction slope differed across experimental groups. See Figure 4.

Figure 4.

Figure 4.

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Mixed ANOVA showed that the group (Sham- vs. Active-tDCS) by trials (1–16) interaction effect was significant across the 16 CS+E extinction trials. Post-hoc contrasts showed that SCR was lower during the first two trials for participants who received Active-tDCS than who received Sham-tDCS. Plotted values are mean and standard error. *** = p < .001.

Consistent with past research showing that vmPFC activation differs between early and late extinction training (Milad et al., 2007; Bremner et al., 2005; Milad et al., 2013), follow-up mixed ANOVAs were used to examine the differential effects of tDCS on SCR to the CS+E during early (trials 1–4) and late (trials 13–16) extinction learning. The main effect of group was not significant during early extinction learning (F [1, 33] = 2.46, p = 0.126, ηp2 = 0.07) but was trending in the expected direction and the effect was medium sized. During early extinction learning, the main effect of trials (F [2.17, 71.52] = 10.58, p < .001, ηp2 = 0.24) and the group*trials interaction (F [2.17, 71.52] = 5.12, p = 0.007, ηp2 = 0.13) were significant. For participants in the Sham-tDCS condition, SCR to the CS+E started relatively high – higher than average CS+E SCR during conditioning – and dropped rapidly after the second extinction trial. Conversely, for participants in the Active-tDCS condition, SCR to the CS+E started low and remained low. Consistent with these observations, post-hoc independent sample t-tests showed that SCR to the CS+E was significantly (ps<.001) lower during the first two extinction trials for participants in the Active-tDCS condition relative to those in the Sham-tDCS condition; group differences were non-significant (ps>.05) for extinction trials three and four. During late extinction learning, the main effects of group (F [1, 33] = 1.05, p = 0.313, ηp2 = 0.03) and trials (F [2.36, 77.89] = 0.07, p = 0.955, ηp2 = 0.00) and the group*trials interaction (F [2.36, 77.89] = 1.10, p = 0.347, ηp2 = 0.03) were not significant, which indicates that SCR to the CS+E did not significantly change across the last four extinction trials and that slopes did not differ across the two experimental groups.

Mixed ANOVAs were used to analyze the main and interactive effects of group (Sham vs. Active-tDCS) and trials (1–16) on SCR values to the CS+NE during extinction training on day 3, which was approximately 24 hours after sham or active tDCS was administered. The main effect of group (F [1, 33] = 0.52, p = 0.475, ηp2 = 0.02) was not significant. The main effect of trials was significant (F [4.91, 162.07] = 5.84, p < .001, ηp2 = 0.15) and the group*trials interaction was marginally significant (F [4.91, 162.07] = 2.16, p = 0.062, ηp2 = 0.06), suggesting that SCR to the CS+NE decreased across extinction trials and that there were nominal group differences in the rate of change (Figure 5). Inspection of data suggest that there was a modest difference in SCR slopes such that participants in the Sham-tDCS condition evinced steeper reductions in SCR to the CS+NE during the second half of conditioning. However, group differences in SCR to the CS+NE were not significant for any of the day 3 extinction trials; this included the first four trials, which did not significantly differ between experimental groups (ps = 0.132 – 0.560).

Figure 5.

Figure 5.

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During extinction training to the CS+NE on Day 3 (~24 hrs. after tDCS), the main effect of trials was significant (p < .001), suggesting that SCR to the CS+NE decreased across the 8 extinction trials. The group (Sham- vs. Active-tDCS) by trials (1–8) interaction effect was trending toward significance (p = .062). There were no significant group differences in SCR to the CS+NE on any extinction trials, but the SCR slope during the second half of extinction training appeared to be marginally steeper for participants in the sham group. Plotted values are mean and standard error.

3.1.4. Return of Fear

Mixed ANOVAs were used to examine the return of fear by modeling change from the last two CS+E extinction trials (15 and 16) to the first two spontaneous recovery (1 and 2) or context renewal (1 and 2) trials. During spontaneous recovery, the main effects of group (F[ 1, 33] = 1.56, p = 0.220, ηp2 = 0.05) and trials (F [2.50, 82.60] = 0.71, p = 0.527, ηp2 = 0.02) and the group*trials interaction effect (F [2.50, 82.60] = 0.66, p = 0.553, ηp2 = 0.02) were not significant, indicating that there was not significant spontaneous recovery and that recovery slopes did not significantly differ across the two experimental groups. See Supplemental Figure 2a.

During context renewal, the main effect of trials was significant (F [2.57, 84.89] = 6.73, p < .001, ηp2 = 0.17), suggesting successful renewal of fear when the CS+E was presented in the conditioning context (CX+). The main effect of group (F [1, 33] = 0.26, p = 0.611, ηp2 = 0.01) and the group*trials interaction effect (F [2.57, 84.89] = 0.16, p = 0.896, ηp2 = 0.01) were not significant, indicating that the degree of context fear renewal did not significantly differ across the two experimental groups. Inspection of context renewal data suggested that SCR to the CS+E rose sharply between the last trial of day 2 and the first trial of context renewal; SCR to the CS+E during context renewal was almost identical across the two experimental groups. See Supplemental Figure 2b.

4.1. Discussion

To our knowledge, this is the first study to examine the effects of multifocal frontopolar tDCS on fear extinction learning and one of the first to test the effects of tDCS on fear extinction learning and recall using procedures that sufficiently space conditioning and extinction training to probe inhibitory safety learning and its recall. The present study tested the hypothesis that multifocal frontopolar tDCS would accelerate the acquisition of fear extinction learning and diminish spontaneous recovery. Results suggest that multifocal frontopolar tDCS reduced fear reactivity during extinction training but did not impact extinction recall. However, the ways in which frontopolar tDCS influenced fear reactivity during extinction differed from what was hypothesized.

Participants who received Sham-tDCS exhibited an extinction slope commonly seen in healthy samples (Crombie et al.; McLaughlin et al., 2014); SCR to the CS+E started at a level comparable to conditioning, reduced rapidly after the second trial, and then plateaued by the fourth trial. Unexpectedly, the extinction slope was nearly flat for individuals who received Active-tDCS before extinction training; SCR to the CS+E was low on the first trial (before any extinction training had occurred), diminished slightly through the first four trials, and then plateaued. This suggests that extinction training reduced fearful responding to the CS+E for participants who received Sham-tDCS, but participants who received Active-tDCS exhibited minimal fear activation to the CS+E throughout extinction training. In other words, rather than accelerating extinction training, multifocal frontopolar tDCS appeared to reduce fear reactivity before extinction training had occurred. This is somewhat consistent with a recent study that found that bipolar tDCS targeting the vmPFC (anode over AF3 and cathode over PO8) blocked SCR (and fear potentiated startle) to the CS+ following reinstatement (Szeska et al., 2022), though they did not detect effects of tDCS on threat expectancy ratings. Like the present study, these effects were observed shortly after tDCS administration, though Szeska and colleagues (2022) administered tDCS online with extinction recall testing.

To some degree, the present results mirror the effects reported by Milad and colleagues (Milad et al., 2004; 2002) in their seminal work on vmPFC (infralimbic cortex [IL]) signaling and fear extinction in rats. Namely, they demonstrated that direct electrical stimulation of vmPFC 100–400ms after CS+ presentation (Milad & Quirk, 2002) – which parallels the latency between CS+ presentation and vmPFC firing following extinction training in rats - reduced fearful responding (freezing) to a CS+ conditioned 24 hours earlier. Like the present study, they observed effects of stimulation from the outset of extinction training (day 2) “rats that received tones paired with IL stimulation showed markedly less freezing than controls on day 2. This effect was evident from the very first trial (Milad & Quirk, 2002, p. 7).” In a replication study, Vidal-Gonzalez and colleagues (2006) reported that fearful responding to the CS+ after only two trials of vmPFC stimulation 100–400ms after presentation of the CS+ was comparable to fearful responding of rats that had undergone twelve trials of extinction training with no intervention. In fact, their results looked similar to those reported in the current study (compare Figure 3 from (Vidal-Gonzalez et al., 2006) to Figure 4 of the current study). Interestingly, Vilad-Gonzalez and colleagues (2006) reported an effect of vmPFC stimulation during extinction on a spontaneous recovery test when a strong US was used (0.5mA) but did not find an effect when a weaker US (0.3mA) was used, suggesting that the strength of conditioning may dictate the durability of vmPFC stimulation effects. It is possible that effects of frontopolar tDCS on extinction recall would have been observed in the current study if a more aversive US were used. There are, of course, many important differences between these animal studies and the current study, particularly the species, precision of stimulation (intracellular vs. transcranial), and timing of CS+ presentation relative to stimulation (offline before extinction vs. 100–400ms after each CS+).

SCR to all CS diminished across the 32 conditioning trials (Supplemental Figure 1). This suggests that participants habituated to the CS throughout conditioning and may have also habituated to the US. This habituation likely affected differential conditioning calculations for the CS+NE, which was conditioned in the latter half of day 2. Despite comparisons of average SCR to the CS− and CS+NE showing minimal differences, there was significant fear reactivity to the CS+NE on day 3. In fact, average SCR to the CS+NE during the first extinction trials on day 3 were greater than SCR to the CS+NE at any point during conditioning. This suggests that more conditioning to the CS+NE may have occurred than was evident on day 1.

Extinction to the CS+NE on day 3, which was 48 hours after conditioning and 24 hours after tDCS, was similar across the two experimental groups; though there was a marginal difference in the rate of extinction such that late extinction learning for participants in the Sham-tDCS group was somewhat greater compared to participants in the Active-tDCS group. In contrast to extinction training to the CS+E that occurred immediately after tDCS, there were no group differences in SCR to the CS+NE during the first several extinction trials. This provides additional evidence that group differences in SCR during CS+E extinction were due to the brief effects of tDCS on the brain. If the effects observed on day 2 were due to unknown group differences, then similar effects would have likely been observed on day 3.

The current study findings are unique from prior studies demonstrating that tDCS targeting the vmPFC can modulate emotional reactivity during fear extinction training (Adams et al., 2020; Faucher et al., 2021; Marković et al., 2021; Dittert et al., 2018; van ‘t Wout et al., 2016; Vicario et al., 2020). First, past tDCS literature suggested that that bipolar tDCS targeting the vmPFC may accelerate fear extinction learning or marginally reduce fearful responding across multiple extinction trials (Adams et al., 2020; Faucher et al., 2021; Marković et al., 2021; Dittert et al., 2018; van ‘t Wout et al., 2016; Vicario et al., 2020), while the current results suggest that multifocal frontopolar tDCS may altogether reduce fearful responding to the CS+ before extinction learning has occurred. Second, the current study is one of the first to utilize experimental procedures that included sufficient time between fear conditioning, extinction, and recall procedures and tDCS procedures to support strong inferences about what specific learning processes were being affected by tDCS (e.g., conditioning consolidation vs. extinction learning). Direct comparison of the current study with the two past studies (Abend et al., 2016; Ganho-Ávila et al., 2019) is difficult as procedures were quite different for each study. Despite major differences, the study by Abend and colleagues (2016) is the closest methodologically to the present study as both studies targeted the frontal pole and both studies separated conditioning, extinction, and tDCS by similar time intervals. Despite these similarities, they found no effects of tDCS of tACS during extinction training but did find that, compared to sham stimulation, tACS potentiated autonomic and self-report measures of fear during a test of spontaneous recover while tDCS only potentiated self-reported fear during a test of spontaneous recovery.

There are several potential explanations for the differences between the current study and Abend and colleagues (2016). Abend and colleagues delivered tDCS and tACS during extinction training (Abend et al., 2016) as opposed to offline tDCS before extinction in the current study. Research has yet to directly compare the effects of offline and online tDCS on fear extinction processes, though it is reasonable to suspect that they would have different effects (Dedoncker et al., 2016; Hill et al., 2016; Mancuso et al., 2016). Abend and colleagues (2016) targeted the frontal pole by placing a large (5×7cm) anode above the nasion (approximately Fpz) and a large cathode under the occipital bone. It is likely that these tES procedures stimulated larger portions of the brain than the multifocal procedures used in the current study. Electrical field modeling from a study with similar bipolar tDCS procedures as Abend and colleagues suggested that positive current density peaked in ventral portions of the mPFC but extended throughout the PFC, including the dorsal mPFC (Hämmerer et al., 2016). Moreover, negative current density likely peaked over the cerebellum (van Dun et al., 2016), which has been consistently associated with fear extinction processes in human neuroimaging research (Batsikadze et al., 2022; Doubliez et al., 2023; Fullana et al., 2018). Lastly, conditioning and extinction procedures differed from the current study in several important ways, which likely influenced study results. For example, Abend and colleagues (2016) presented the CS (affective faces) without context (against a blank screen) during conditioning procedures and included 9 trials per study phase. As noted above, the present study may have yielded different results if simpler conditioning and extinction procedures were used (e.g., CS without context).

The current findings are only somewhat consistent with past research showing that tDCS targeting the mPFC can augment response to therapeutic exposure (Adams et al., 2022; Bulteau et al., 2022; van ‘t Wout-Frank et al., 2019). Most salient is the study by Adams and colleagues that showed that the same frontopolar tDCS procedures accelerated the rate by which subjective distress was reduced across 50-minutes of in vivo exposure in people with OCD. This study did not find group (Sham- vs. Active-tDCS) differences in subjective distress at baseline or during the first several minutes of exposure, though large differences in the rate of distress reductions were detected during the first 10-minute exposure trial. There are several plausible explanations for the differences seen between this in vivo study and the present extinction study.

First, the present study included psychiatrically healthy community volunteers whereas the in vivo exposure included people with OCD. Neural abnormalities associated with OCD may have influenced the way that tDCS impacted the brain. For example, functional connectivity between the SN and DMN is aberrant in OCD (diminished and perhaps reversed) relative to healthy controls. If the effects of frontopolar tDCS on affective responding are mediated by changes in functional connectivity, then baseline dynamics likely play a large role in how tDCS will influence behavior. Future research should explore the effects of frontopolar tDCS on fear extinction in people with OCD or other anxious psychopathology (e.g., PTSD).

Second, the present study only included objective measures of fearful responding (i.e., SCR) whereas the in vivo exposure study only included measures of subjective distress. Autonomic arousal and self-reported fear are likely mediated by distinct brain circuits (LeDoux & Pine, 2016; Savage et al., 2021; Zhou et al., 2021), so it follows that the effects of frontopolar tDCS on subjective and autonomic correlates of fear are going to differ. Future research on the effects of frontopolar tDCS on response to therapeutic exposure should include objective measures of autonomic arousal and future research on tDCS and extinction learning should include subjective measures such as threat expectancy ratings.

Third, it is possible that fear extinction is not a satisfactory model for ERP. Published research has yet to test associations between fear extinction mechanisms and response to ERP, which is likely dependent on more than extinction learning (Jacoby & Abramowitz, 2016). Moreover, most (Forcadell et al., 2017; Raeder et al., 2020; Waters & Pine, 2016), but not all (Adolph et al., 2023; Waters & Pine, 2016) empirical studies have failed to demonstrate that change in SCR to the CS+ during extinction training is significantly associated with response to therapeutic exposure. Research has, however, reliably shown that vmPFC activation and change in US expectancy during extinction predict response to therapeutic exposure (Ball et al., 2017; Forcadell et al., 2017; Lange et al., 2020; Raeder et al., 2020; Rousseau et al., 2019).

Previous research suggests that administration of the same multifocal tDCS procedures used in the present study may reduce anticorrelations between the DMN and SN, particularly between the medial frontal pole and the right anterior insula (Adams et al., 2022). This may be of relevance to the current findings for several reasons. Activation of the SN, which is linked to the fear reactivity and is negatively associated with fear extinction learning (Fullana et al., 2018), can inhibit the DMN (Cocchi et al., 2013; Goulden et al., 2014; Sidlauskaite et al., 2014; Sridharan et al., 2008), which is linked to the processing of safety cues, safety learning, and relaxation (Marstaller et al., 2017; Wen et al., 2021). If frontopolar tDCS reduces anticorrelations between the DMN and SN, then it may also diminish SN-mediated inhibition of the DMN when processing salient danger cues such as the CS+. In other words, fear signal processing may not be inhibited directly but, rather, the detection of fearful cues, which activates the SN, is less likely to result in the inhibition of the DMN, which is responsible for safety signal processing. Alternatively, reduced DMN inhibition by the SN may increase the ability of DMN regions to support a relaxed state, irrespective of the cues being presented (Menon, 2011). Neuroimaging data were not collected in the current study, so this interpretation is speculative. Research that interleaves tDCS with fMRI while employing the same extinction procedures used herein would be required to test such hypotheses (see NCT03572543 for an ongoing trial).

Group differences were not significant during the return of fear tests on day 3. In fact, there was limited evidence of spontaneous recovery in either group. This could be interpreted as evidence of poor conditioning or strong extinction. However, participants showed robust context renewal, which suggests adequate conditioning. Taken together, minimal recovery and robust renewal may suggest that learning of threat and safety were context dependent. The CX− was never paired with the US and therefore signaled safety during extinction training and spontaneous recovery. Conversely, the US was only presented against the CX+ backdrop. It is 29ossible that presentation of the CS+E against the CX− backdrop reduced fear reactivity or accelerated fear reductions to the CS during extinction and recovery. Spontaneous recovery effects may have been more likely if CS were presented without context cues. This may have also led to slower or less robust extinction.

The lack of group differences in return of fear tests suggest that the effects of tDCS on safety learning may not be persistent. It is also possible that persistent effects were masked by weak conditioning, robust extinction learning, or context-dependent learning of threat and safety. Although the present results do not suggest that frontopolar tDCS influenced the return of fear, this may still be possible with modified procedures. For example, no context or consistent context across conditioning, extinction, and recall testing, fewer extinction trials, a different schedule of reinforcement during conditioning, or an extinction resistant sample (e.g., PTSD) might have yielded different results during tests of extinction recall. Moreover, the current study did not include a test of reinstatement or measures of threat expectancies (Abend et al., 2016; Szeska et al., 2022), which could be influenced by frontopolar tDCS and should be included in future research.

5.1. Conclusions

The present findings suggest that increasing the excitability of safety learning regions via offline excitatory multifocal frontopolar tDCS may reduce fearful responding to a conditioned stimulus. Although years of theory suggests that initial fear activation is required for successful therapeutic exposure (Foa & Kozak, 1986), most research suggests that initial fear activation is either a weak predictor or null predictor of exposure efficacy (Craske et al., 2008, 2014; Jacoby & Abramowitz, 2016). If initial fear activation is not a requisite condition for successful exposure, then the present results may provide a means to improve exposure-based treatments by reducing fearful responding to phobic stimuli (and associated discomfort) or decreasing the amount (e.g., number of trials) of exposure needed to extinguish phobic fears. This could increase tolerability of exposures, reduce treatment duration and patient burden, and improve patient outcomes.

Supplementary Material

1

Highlights.

  • Active multifocal frontopolar tDCS reduced fearful responding during extinction.

  • The effects of tDCS were only apparent during early extinction training.

  • tDCS may modulate fear or safety signal processing or learning.

Acknowledgements

We would like to thank Dr. Mohammed Milad, PhD., for designing and generously sharing materials to help with our preparation of the fear conditioning and extinction procedures used in this study. We would also like to thank Jeff Eilbott for his assistance programming the extinction task.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Disclosures

Dr. Adams and the reported studies were supported by the National Institute of Mental Health (NIMH; K23MH111977, T32MH062994, and L30MH111037). Brain stimulation equipment was loaned by Starstim® to support study pilots and was purchased using funds from the Detre Foundation (R13306) and an American Psychiatric Association (APA) Psychiatric Fellowship Award (R12965). These studies were also supported by the State of Connecticut through its support of the Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Pittenger is supported by the Taylor Family Foundation and the NIMH (R01MH116038 and K24MH121571). The views in this article are those of the authors, not of the State of Connecticut or of other funders.

Dr. Adams serves or has served as a consultant for Transcend Therapeutics and Actic Inc. Dr. Kelmendi serves as the Chief Scientific Advisor for Transcend Therapeutics and has served as a consultant in the past year for Ceruvia Lifesciences and Transcend Therapeutics. Dr. Pittenger serves or has served as a consultant for Biohaven, Teva, Lundbeck, Brainsway, Transcend, Ceruvia, and Freedom, and receives royalties and/or honoraria from Oxford University Press and Elsevier, and has filed a patent on the use of NIRS neurofeedback in the treatment of anxiety, which is not relevant to the current work. Ms. George, Ms. Forte, Mr. Hubert, and Mr. Rippey have no financial disclosures/conflicts to report.

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