Medial prefrontal cortex stimulation modulates the processing of conditioned fear

Abstract

The extinction of conditioned fear depends on an efficient interplay between the amygdala and the medial prefrontal cortex (mPFC). In rats, high-frequency electrical mPFC stimulation has been shown to improve extinction by means of a reduction of amygdala activity. However, so far it is unclear whether stimulation of homologues regions in humans might have similar beneficial effects. Healthy volunteers received one session of either active or sham repetitive transcranial magnetic stimulation (rTMS) covering the mPFC while undergoing a 2-day fear conditioning and extinction paradigm. Repetitive TMS was applied offline after fear acquisition in which one of two faces (CS+ but not CS-) was associated with an aversive scream (UCS). Immediate extinction learning (day 1) and extinction recall (day 2) were conducted without UCS delivery. Conditioned responses (CR) were assessed in a multimodal approach using fear-potentiated startle (FPS), skin conductance responses (SCR), functional near-infrared spectroscopy (fNIRS), and self-report scales. Consistent with the hypothesis of a modulated processing of conditioned fear after high-frequency rTMS, the active group showed a reduced CS+/CS- discrimination during extinction learning as evident in FPS as well as in SCR and arousal ratings. FPS responses to CS+ further showed a linear decrement throughout both extinction sessions. This study describes the first experimental approach of influencing conditioned fear by using rTMS and can thus be a basis for future studies investigating a complementation of mPFC stimulation to cognitive behavioral therapy (CBT).

Keywords: fear conditioning; learning; medial prefrontal cortex (mPFC); memory consolidation and extinction; transcranial magnetic stimulation (TMS).

Figure 1

Experimental design. Flashes indicate startle stimuli during CS presentations as primary measure of the conditioned response.

Figure 2

Fear-potentiated startle magnitudes for CS+ and CS− trials for active (A) and placebo (B) group and the difference score (C) accordingly. In all experimental phases mean responses and standard errors of the mean (SEM) are depicted. Asterisks indicate significant differences (^*p < 0.05, ^***p < 0.001). (C) illustrates CS+ and CS− trials as difference scores to indicate that groups did not differ in their conditioned response during the acquisition phase [independent t-contrast: t₍₄₃₎ = 1.47, p > 0.05].

Figure 3

Conditioned responses (CS+ minus CS−) indexed by fear potentiated startle magnitudes for acquisition (a), extinction (e), and extinction recall (er). For reasons of clarity two trials were averaged for each phase, respectively. Note that in the middle of each phase online valence and arousal ratings were conducted. Error bars indicate the standard error of the mean (SEM).

Figure 4

Conditioned responses (CS+ minus CS−) for both groups indexed by Fear-potentiated startle magnitudes (mean + SEM). The active group exhibit a significant linear trend through both extinction phases indicated by a proportionately CR decrement from fear acquisition (first data point) throughout both extinction phases. For the active group, all dependent t-tests (p_one-tailed < 0.05) for acquisition with each extinction phase showed significant results, except for acquisition vs. late extinction day 1 which revealed only a trend-wise significant p-value (p < 0.1). For the sham group, only the early extinction day 1 compared to the acquisition phase revealed a significant difference thereby indicating extinction learning; all other scores resemble the acquisition phase (p > 0.05).

Figure 5

Skin conductance responses (SCR) for CS+ and CS− trials during acquisition, extinction learning on day 1, and extinction recall on day 2, per group, respectively. Depicted are means and standard errors of the mean. Asterisks indicate significant differences (^*p < 0.05, ^***p < 0.001).

Figure 6

For reasons of visualization arousal difference scores (CS+ minus CS−) were depicted (M + SEM) during familiarization, acquisition, extinction learning, and extinction recall for the active (n = 32) and the sham group (n = 30). Groups significantly differed during extinction learning (^*p < 0.05), i.e., sham showed higher arousal for CS+ than CS− trials.

Figure 7

Functional NIRS results (O₂Hb) during both extinction phases (n = 25). Left: T-map superimposed on a standard brain. During the early extinction learning the active group showed a higher signal for CS+ than the sham group in a cluster of 10 probeset channels covering the medial prefrontal cortex. The bar charts in the middle and on the right depict the corresponding beta estimates for CS+ and CS− trials (^**p_one-tailed < 0.01). The sham group showed a trend-wise significant (^#p_one-tailed < 0.1) signal increase from early to late extinction learning in response to CS+ trials while the active group persisted to show a high concentration level.