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. 2022 Sep 20;12(1):394.
doi: 10.1038/s41398-022-02174-8.

Stimulation of the ventromedial prefrontal cortex blocks the return of subcortically mediated fear responses

Christoph Szeska  1 , Hannah Pünjer  2 , Steffen Riemann  3 , Marcus Meinzer  3 , Alfons O Hamm  2
Affiliations

Stimulation of the ventromedial prefrontal cortex blocks the return of subcortically mediated fear responses

Christoph Szeska et al. Transl Psychiatry. .

Abstract

The ventromedial prefrontal cortex (vmPFC) mediates the inhibition of defensive responses upon encounters of cues, that had lost their attribute as a threat signal via previous extinction learning. Here, we investigated whether such fear extinction recall can be facilitated by anodal transcranial direct current stimulation (tDCS). Extinction recall was tested twenty-four hours after previously acquired fear was extinguished. Either anodal tDCS or sham stimulation targeting the vmPFC was applied during this test. After stimulation ceased, we examined return of fear after subjects had been re-exposed to aversive events. Fear was assessed by reports of threat expectancy and modulations of autonomic (skin conductance, heart rate) and protective reflex (startle potentiation) measures, the latter of which are mediated by subcortical defense circuits. While tDCS did not affect initial extinction recall, it abolished the return of startle potentiation and autonomic components of the fear response. Results suggest hierarchical multi-level vmPFC functions in human fear inhibition and indicate, that its stimulation might immunize against relapses into pathological subcortically mediated defensive activation.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Schematic structure of the experimental design and an experimental trial.
a Experimental structure. The first day started with a preacquisition phase, where CS+ and CS− were presented twice without any US. Next, the US-intensity was adjusted to be perceived as unpleasant, but not painful by the participant (shock workup). During the following acquisition, first (extinction 1) and second half of extinction training (extinction 2), CS+ and CS− were presented 10 times, each. During acquisition, 6 CS+ trials were paired with the US, while no US was presented during the CS− or during extinction. The second experimental session followed 24 h later and began with an extinction recall phase, where CS+ and CS− were each presented 10 times without any US. A following return of fear test started with a reinstatement procedure, during which the background color of the monitor changed to white and three non-signaled USs were administered. Then, CS+ and CS− were each presented 10 times without the US. TDCS electrodes were always attached aside from preacquisition and shock workup, but electrical currents were only applied during extinction 1 (sham stimulation) and extinction recall (tDCS vs. sham) to minimize contextual effects. b Trial structure. A prompting slide required participants to rate the expectancy (in percent range 0–100) to receive a shock during an upcoming CS presentation (English translation: “Next, this picture will follow. How likely do you think is it, to receive an electrical shock during the upcoming presentation of this picture?”). After a three-second post-rating interval, the CS was presented full-size, followed by an inter-trial interval (ITI). Startle probes were administered during CSs and ITIs.
Fig. 2
Fig. 2. Biophysical modeling of the current’s distribution and magnitude induced by anodal tDCS applying a 3 × 3 cm² anode over AF3 and a 10 × 10 cm² cathode over PO8.
The left panel depicts changes in electrical field intensity (V/m) when tDCS is applied in the described montage, while the right panel depicts the according location of the anode (red) and cathode (blue) according to the 10–20 EEG system (see “Methods” for details on biophysical modeling).
Fig. 3
Fig. 3. Day 1: Establishment and extinction of the fear response.
Overall mean US-expectancy ratings (a), range-corrected first interval skin conductance responses (b), standardized (T-transformed) startle potentiation (c; response levels above 0 show a relative potentiation of the startle responses relative to the ITI control condition; note the relative increase in startle magnitudes probed during CS− from instructed acquisition to non-instructed extinction) and heart rate change (d) during the CS+ (blue lines) vs. the CS− (purple lines) during preacquisition, instructed fear acquisition as well as the first (extinction 1) and second half of extinction training (extinction 2). US-expectancy, skin conductance and startle potentiation are averaged across blocks of two trials, while heart rate change is averaged across all trials of a respective phase. Error bars represent the standard error of the mean.
Fig. 4
Fig. 4. Day 2: Transcranial direct current stimulation targeting the vmPFC does not impact on initial extinction recall.
Overall mean US-expectancy ratings (a), range-corrected first interval skin conductance responses (b), standardized (T-transformed) startle potentiation relative to inter-trial interval (c) and heart rate change (d) during the CS+ (blue lines) vs. the CS− (purple lines) during the extinction recall for the sham (left panels) and tDCS condition (right panels). US-expectancy, skin conductance and startle potentiation are averaged across blocks of two trials, while heart rate change is averaged across all trials of the extinction recall. Error bars represent the standard error of the mean.
Fig. 5
Fig. 5. Day 2: Transcranial direct current stimulation targeting the vmPFC during extinction recall blocks the return subcortically mediated fear responses.
Overall mean US-expectancy ratings (a), range-corrected first interval skin conductance responses (b), standardized (T-transformed) startle potentiation relative to inter-trial interval (c) and heart rate change (d) during the CS+ (blue lines) vs. the CS− (purple lines) during the last block of extinction recall and return of fear test for the sham (left panels) and tDCS condition (right panels). US-expectancy, skin conductance and startle potentiation are averaged across blocks of two trials, while heart rate change is averaged across all trials of the return of fear test. Error bars represent the standard error of the mean. The bolt-icon represents repeated (three times) administration of the US at the beginning of the return of fear test.
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