Non-invasive stimulation reveals ventromedial prefrontal cortex function in reward prediction and reward processing.

Introduction: Studies suggest an involvement of the ventromedial prefrontal cortex (vmPFC) in reward prediction and processing, with reward-based learning relying on neural activity in response to unpredicted rewards or non-rewards (reward prediction error, RPE). Here, we investigated the causal role of the vmPFC in reward prediction, processing, and RPE signaling by transiently modulating vmPFC excitability using transcranial Direct Current Stimulation (tDCS). Methods: Participants received excitatory or inhibitory tDCS of the vmPFC before completing a gambling task, in which cues signaled varying reward probabilities and symbols provided feedback on monetary gain or loss. We collected self-reported and evaluative data on reward prediction and processing. In addition, cue-locked and feedback-locked neural activity via magnetoencephalography (MEG) and pupil diameter using eye-tracking were recorded. Results: Regarding reward prediction (cue-locked analysis), vmPFC excitation (versus inhibition) resulted in increased prefrontal activation preceding loss predictions, increased pupil dilations, and tentatively more optimistic reward predictions. Regarding reward processing (feedback-locked analysis), vmPFC excitation (versus inhibition) resulted in increased pleasantness, increased vmPFC activation, especially for unpredicted gains (i.e., gain RPEs), decreased perseveration in choice behavior after negative feedback, and increased pupil dilations. Discussion: Our results support the pivotal role of the vmPFC in reward prediction and processing. Furthermore, they suggest that transient vmPFC excitation via tDCS induces a positive bias into the reward system that leads to enhanced anticipation and appraisal of positive outcomes and improves reward-based learning, as indicated by greater behavioral flexibility after losses and unpredicted outcomes, which can be seen as an improved reaction to the received feedback.

A 5-min paradigm to evoke robust emotional reactivity in neuroimaging studies.

The advent of the Research Domain Criteria (RDoC) approach to funding translational neuroscience has highlighted a need for research that includes measures across multiple task types. However, the duration of any given experiment is quite limited, particularly in neuroimaging contexts, and therefore robust estimates of multiple behavioral domains are often difficult to achieve. Here we offer a "turn-key" emotion-evoking paradigm suitable for neuroimaging experiments that demonstrates strong effect sizes across widespread cortical and subcortical structures. This short series could be easily added to existing fMRI protocols, and yield a reliable estimate of emotional reactivity to complement research in other behavioral domains. This experimental adjunct could be used to enable an initial comparison of emotional modulation with the primary behavioral focus of an investigator's work, and potentially identify new relationships between domains of behavior that have not previously been recognized.

Transcranial Direct Current Stimulation of the Ventromedial Prefrontal Cortex Modulates Perceptual and Neural Patterns of Fear Generalization.

BACKGROUND: Overgeneralization of fear is a pathogenic marker of anxiety and stress-related disorders and has been linked with perceptual discrimination deficits, reduced fear inhibition, and prefrontal hyporeactivity to safety-signaling stimuli. We aimed to examine whether behavioral and neural patterns of fear generalization are influenced by the fear-inhibiting ventromedial prefrontal cortex (vmPFC). METHODS: Three groups of healthy participants received excitatory (n = 27), inhibitory (n = 26), or sham (n = 26) transcranial direct current stimulation of the vmPFC after a fear conditioning phase and before a fear generalization phase. We obtained, as dependent variables, fear ratings and unconditioned stimulus-expectancy ratings, perceptual aspects of fear generalization (perceptual discrimination), pupil dilations, and source estimations of event-related fields elicited by conditioned and generalization stimuli. RESULTS: After inhibitory (compared with excitatory and sham) vmPFC stimulation, we observed reduced performance in perceptual discrimination and less negative inhibitory gradients in frontal structures at midlatency and late time intervals. Fear and unconditioned stimulus-expectancy ratings as well as pupil dilation remained unaffected by stimulation. CONCLUSIONS: These findings reveal a causal contribution of vmPFC reactivity to generalization patterns and suggest that vmPFC hyporeactivity consequent on inhibitory vmPFC stimulation may serve as a model for pathological processes of fear generalization (reduced discrimination, impaired fear inhibition via frontal brain structures). This encourages further basic and clinical research on the potential of targeted brain stimulation to modulate fear generalization and overgeneralization.

Repeated noninvasive stimulation of the ventromedial prefrontal cortex reveals cumulative amplification of pleasant compared to unpleasant scene processing: A single subject pilot study.

The ventromedial prefrontal cortex (vmPFC) is a major hub of the reward system and has been shown to activate specifically in response to pleasant / rewarding stimuli. Previous studies demonstrate enhanced pleasant cue reactivity after single applications of transcranial direct current stimulation (tDCS) to the vmPFC. Here we present a pilot case study in which we assess the cumulative impact of multiple consecutive vmPFC-tDCS sessions on the processing of visual emotional stimuli in an event-related MEG recording design. The results point to stable modulation of increased positivity biases (pleasant > unpleasant stimulus signal strength) after excitatory vmPFC stimulation and a reversed pattern (pleasant < unpleasant) after inhibitory stimulation across five consecutive tDCS sessions. Moreover, cumulative effects of these emotional bias modulations were observable for several source-localized spatio-temporal clusters, suggesting an increase in modulatory efficiency by repeated tDCS sessions. This pilot study provides evidence for improvements in the effectiveness and utility of a novel tDCS paradigm in the context of emotional processing.

Fear generalization of implicit conditioned facial features - Behavioral and magnetoencephalographic correlates.

Acquired fear responses often generalize from conditioned stimuli (CS) towards perceptually similar, but harmless generalization stimuli (GS). Knowledge on similarities between CS and GS may be explicit or implicit. Employing behavioral measures and whole-head magnetoencephalography, we here investigated the neurocognitive mechanisms underpinning implicit fear generalization. Twenty-nine participants underwent a classical conditioning procedure in which 32 different faces were either paired with an aversive scream (16 CS+) or remained unpaired (16 CS-). CS+ and CS- faces systematically differed from each other regarding their ratio of eye distance and mouth width. High versus low values on this "threat-related feature (TF)" implicitly predicted the presence or absence of the aversive scream. In pre- and post-conditioning phases, all CS and 32 novel GS faces were presented. 16 GS+ â€‹faces shared the TF of the 16 CS+ â€‹faces, while 16 â€‹GS- faces shared the TF of the 16 CS- faces. Behavioral tests confirmed that participants were fully unaware of TF-US contingencies. CS+ â€‹compared to CS- faces revealed higher unpleasantness, arousal and US-expectancy ratings. A generalization of these behavioral fear responses to GS+ â€‹compared to GS- faces was observed by trend only. Source-estimations of event-related fields showed stronger neural responses to both CS+ and GS+ â€‹compared to CS- and GS- in anterior temporal (<100 â€‹ms) and temporo-occipital (<150 â€‹ms; 553-587 â€‹ms) ventral brain regions. Reverse effects were found in dorsal frontal areas (<100 â€‹ms; 173-203 â€‹ms; 257-290 â€‹ms). Neural data also revealed selectively enhanced responses to CS+ â€‹but not GS+ â€‹stimuli in occipital regions (110-167 â€‹ms; 330-413 â€‹ms), indicating perceptual discrimination. Our data suggest that the prioritized perceptual analysis of threat-associated conditioned faces in ventral networks rapidly generalizes to novel faces sharing threat-related features. This generalization process occurs in absence of contingency awareness and may thus contribute to implicit attentional biases. The coexisting perceptual discrimination suggests that fear generalization is not a mere consequence of insufficient stimulus discrimination but rather an active, integrative process.

Noninvasive Stimulation of the Ventromedial Prefrontal Cortex Indicates Valence Ambiguity in Sad Compared to Happy and Fearful Face Processing.

The ventromedial prefrontal cortex (vmPFC) is known to be specifically involved in the processing of stimuli with pleasant, rewarding meaning to the observer. By the use of non-invasive transcranial direct current stimulation (tDCS), it was previously possible to show evidence for this valence specificity and to modulate the impact of the vmPFC on emotional network processing. Prior results showed increased neural activation during pleasant relative to unpleasant stimulus processing after excitatory compared to inhibitory vmPFC-tDCS. As dysfunctional vmPFC activation patterns are associated with major depressive disorder (MDD), tDCS of this region could render an attractive application in future therapy. Here, we investigated vmPFC-tDCS effects on sad compared to happy face processing, as sad faces are often used in the study of mood disorders. After counterbalanced inhibitory or excitatory tDCS, respectively, healthy participants viewed happy and sad faces during magnetoencephalography (MEG) recording. In addition, tDCS effects on an interpretational bias of ambiguous happy-sad face morphs and an attentional bias of a dot-probe task with happy and sad faces as emotional primes were investigated. Finally, in conjoint analyses with data from a previous sibling study (happy and fearful faces) we examined whether excitatory vmPFC-tDCS would reveal a general increase in processing of pleasant stimuli independent of the type of unpleasant stimuli applied (sad vs. fearful faces). MEG and behavioral results showed that happy faces promoted a relative positivity bias after excitatory compared to inhibitory tDCS, visible in left orbitofrontal cortex and in the emotion-primed dot-probe task. A converse pattern in the MEG data during sad face processing suggests the possible involvement of an empathy network and thus significantly differed from neuronal processing of fearful face processing. Implications for the bearing of vmPFC modulation on emotional face processing and the impact of specific unpleasant face expressions are discussed.

Noninvasive stimulation of the ventromedial prefrontal cortex modulates emotional face processing.

The ventromedial prefrontal cortex (vmPFC) is associated with emotional states that can be characterized as positive affect. Moreover, a variety of psychiatric disorders that are associated with disturbed reactions toward reward- or safety-signaling stimuli reveal functional or structural anomalies within this area. Thus, neuromodulation of this region via transcranial direct current stimulation (tDCS) offers an attractive opportunity to noninvasively influence pleasant emotional and reward processing. Recent experiments revealed hemodynamic and electrophysiological evidence for valence specific modulations of emotional scene processing after excitatory and inhibitory tDCS of the vmPFC. Here, we identified that tDCS modulation of vmPFC during emotional face processing results in effects convergent with scene processing, in that excitatory tDCS increased neural reactivity during happy compared to fearful face perception, whereas inhibitory stimulation led to a converse effect. In addition, behavioral data (affect identification of ambiguous expressive faces) revealed a bias toward preferential processing of happy compared to fearful faces after excitatory compared to after inhibitory stimulation. These results further support the vmPFC as an appropriate target for noninvasive neuromodulation of an appetitive processing network in patients suffering from disturbed cognition of reward- and safety-signaling stimuli. It should however be noted that electrophysiological pre-tDCS differences at earlier time intervals of emotional face and scene processing appeared amplified by tDCS, which remains to be investigated.

Noninvasive Stimulation of the Ventromedial Prefrontal Cortex Enhances Pleasant Scene Processing.

Depressive patients typically show biased attention towards unpleasant and away from pleasant emotional material. Imaging studies suggest that dysfunctions in a distributed neural network, including the ventromedial prefrontal cortex (vmPFC), are associated with this processing bias. Accordingly, changes in vmPFC activation should mediate changes in processing of emotional stimuli. Here, we investigated the effect of inhibitory and excitatory transcranial direct current stimulation (tDCS) of the vmPFC on emotional scene processing in two within-subject experiments using functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). Both studies showed that excitatory relative to inhibitory tDCS amplifies processing of pleasant compared to unpleasant scenes in healthy participants. This modulatory effect occurred in a distributed network including sensory and prefrontal cortex regions and was visible during very early to late processing stages. Findings are discussed with regard to neurophysiological models of emotional processing. The convergence of stimulation effects across independent groups of healthy participants and complementary neuroimaging methods (fMRI, MEG) provides a basis for further investigation of a potentially therapeutic use of this novel stimulation approach in patients with depression or other affective disorders.