Offline tDCS modulates prefrontal-cortical-subcortical-cerebellar fear pathways in delayed fear extinction

Abstract

Transcranial direct current stimulation (tDCS) has been studied as an add-on enhancer of extinction-based treatments for anxiety disorders. However, previous studies have failed to address one issue of translational significance: the to-be extinguished fear memory must be consolidated. Additionally, extant literature shows conflicting results about the anxiolytic effect of tDCS delivered to the right dorsolateral prefrontal cortex. To address these issues, we recruited thirty-four female participants to participate in a two-day fear conditioning procedure. On Day 1, laboratory fear acquisition was confirmed by self-reported contingency ratings. On Day 2, participants were randomly assigned to either the control group (n=18; completed the extinction session) or the tDCS group (n=16; whom received 20min tDCS session of 1mA [cathode -F4; anode -contralateral deltoid immediately before extinction).Functional magnetic resonance imagining data showed that tDCS modulates the late phase of the delayed extinction process. In particular, neural activity of the frontal middle cortex, the left frontal superior cortex, and the left and right paracentral and postcentral cortices is increased during the processing of the CS-, supporting the processing of uncertainty. Furthermore, during the processing of threat, tDCS leads to an increased information flow from the contralateral prefrontal cortex along the cortical-amygdalo-hippocampalcerebellar pathways. Thus, the boosted processing of uncertainty and the stronger coupling during threat processing might well be the mechanisms by which tDCS boosts stimuli discrimination, leading to decreased symptoms and enhanced clinical gains.Running head: Using tDCS to interfere with fear extinction Running head: Using tDCS to interfere with fear extinction of anxiety symptoms. According to this model, the fear response is elicited by environmental threats through an associative learning whereby the neutral stimulus (conditioned stimulus, CS+) is paired with an aversive stimulus (unconditioned stimulus, US) and a danger predicting value is assigned to it, eliciting the conditioned fear response (CR; 14). A deregulated fear response may lead to incorrect detection of danger and sustained anxiety-related symptoms (e.g. hyper-vigilance and excessive worrying). Thus, to eliminate the consolidated CR, extinction (the translational equivalent to exposure-based therapies) is implemented, consisting of consecutive presentations of the CS+ alone, leading to a new learning that inhibits the CS+/US association (18).By delivering tDCS to the right or left DLPFC to enhance fear extinction, researchers aimed to artificially modulate brain activity and decrease the fear response (19)(20)(21)(22). Counterintuitively, whereas previous studies have shown that tDCS using the anode electrode over the DLPFC leads to decreased fear, this gain was also associated with the adverse effect of decreasing stimuli discrimination (21,23). Differently, using the cathodal electrode over the DLPFC led to no effect in decreas...

The cerebellum and fear extinction: evidence from rodent and human studies

“…Additionally, non-invasive brain stimulation could provide a method for altering cerebellar activity during fear extinction (Klaus and Schutter, 2022), and test fMRI observations. For instance, transcranial direct current stimulation (tDCS) applied over the right dorsolateral prefrontal cortex before and during extinction was found to change connectivity in the anterior lobe of the cerebellum and lobule VI (Ganho-Ávila et al, 2022). However, likely due to the highly convoluted cerebellar cortex the effects of cerebellar tDCS have been difficult to reproduce in cerebellar-dependent learning paradigms, such as eyeblink conditioning and reach adaptation (Kimpel et al, 2020).…”