Revaluing the Role of vmPFC in the Acquisition of Pavlovian Threat Conditioning in Humans

Abstract

The role of the ventromedial prefrontal cortex (vmPFC) in human pavlovian threat conditioning has been relegated largely to the extinction or reversal of previously acquired stimulus-outcome associations. However, recent neuroimaging evidence questions this view by also showing activity in the vmPFC during threat acquisition. Here we investigate the casual role of vmPFC in the acquisition of pavlovian threat conditioning by assessing skin conductance response (SCR) and declarative memory of stimulus-outcome contingencies during a differential pavlovian threat-conditioning paradigm in eight patients with a bilateral vmPFC lesion, 10 with a lesion outside PFC and 10 healthy participants (each group included both females and males). Results showed that patients with vmPFC lesion failed to produce a conditioned SCR during threat acquisition, despite no evidence of compromised SCR to unconditioned stimulus or compromised declarative memory for stimulus-outcome contingencies. These results suggest that the vmPFC plays a causal role in the acquisition of new learning and not just in the extinction or reversal of previously acquired learning, as previously thought. Given the role of the vmPFC in schema-related processing and latent structure learning, the vmPFC may be required to construct a detailed representation of the task, which is needed to produce a sustained conditioned physiological response in anticipation of the unconditioned stimulus during threat acquisition.SIGNIFICANCE STATEMENT Pavlovian threat conditioning is an adaptive mechanism through which organisms learn to avoid potential threats, thus increasing their chances of survival. Understanding what brain regions contribute to such a process is crucial to understand the mechanisms underlying adaptive as well as maladaptive learning, and has the potential to inform the treatment of anxiety disorders. Importantly, the role of the ventromedial prefrontal cortex (vmPFC) in the acquisition of pavlovian threat conditioning has been relegated largely to the inhibition of previously acquired learning. Here, we show that the vmPFC actually plays a causal role in the acquisition of pavlovian threat conditioning.

Keywords: aversive learning; fear conditioning; latent structure learning; schema processing; threat acquisition; ventromedial prefrontal cortex.

Figure 1.

Location and overlap of brain lesions of vmPFC patients. Representative axial slices showing individual patients' lesions, and representative axial slices and midsagittal view showing cumulative lesions overlap. The white horizontal lines on the sagittal view indicate the positions of the axial slices. The white numbers below the axial slices indicate the z-coordinates of each slice. The color bar indicates the number of overlapping lesions. The left hemisphere is on the left side. Maximal overlap occurs in BAs 10 and 11.

Figure 2.

Trial by trial mean SCR to CS⁺ and CS^– during acquisition and extinction for the three groups. Error bars represent the 95% confidence interval.

Figure 3.

Acquisition of threat conditioning. A, Cumming estimation plots showing raw data and paired mean difference of SCR amplitude to CS⁺ and CS^– for the vmPFC group, the brain-damaged control group, and the healthy control group. On the top axes, each paired set of observations is connected by a line. Also, 95% confidence intervals are indicated by vertical error bars, and group means are depicted as white gaps between the bars. On the lower axes, 95% confidence intervals are indicated by vertical error bars, and mean differences, plotted as a bootstrap sampling distribution (5000 samples), are depicted as dots. B, Grand average event-related SCR illustrates mean SCR over time to CS⁺ (no shock trials), CS^– and CS⁺/US (shock trials). SCR is expressed as a proportion of the baseline (1 s before CS onset). Continuous vertical lines indicate the time of onset and offset of the CSs. Dashed line indicates shock onset in CS⁺/US trials.

Figure 4.

US intensity, SCR amplitude, and latency to US. A–C, Cumming estimation plots showing raw data and mean difference of US intensity (A), SCR amplitude to the US (B), and SCR latency to the US (C) for the brain damaged control group and the healthy control group against the vmPFC group. On the top axes, 95% confidence intervals are indicated by vertical error bars and group means are depicted as white gaps between the bars. On the lower axes, 95% confidence intervals are indicated by vertical error bars and mean differences, plotted as a bootstrap sampling distribution (5000 samples), are depicted as dots.

Figure 5.

Results for the voxel-based lesion–symptom mapping analysis. The image shows the location of the cluster of lesioned voxels associated with reduced differential SCR during threat acquisition (MNI coordinates: −5, 47, −14).