Facilitated extinction but impaired extinction recall by eye movement manipulation in humans - Indications for action mechanisms and the applicability of eye movement desensitization.

Eye movement desensitization and reprocessing (EMDR) therapy utilizes the manipulation of eye movements to reduce affective distress during fear-exposure. Animal research recently suggested a potential neural mechanism underlying these effects, by which increased activity of the superior colliculus (SC), mediating visual attention, increases the inhibition of the basolateral amygdala (BLA), mediating defensive plasticity. We tested such mechanism in forty healthy humans using a multiple-day single-cue fear conditioning and extinction paradigm. The activity of the SC during extinction was experimentally manipulated by eye movements, as half of the participants executed saccadic eye movements (n = 20; major SC involvement), while the other half executed smooth eye pursuits (n = 20; minor SC involvement). Amygdala-mediated fear-potentiated startle responses and fear bradycardia, as well as threat expectancy was analyzed. Saccadic eye movements facilitated the extinction of fear bradycardia and fear-potentiated startle responses. Higher saccadic accuracy and range correlated with reduced fear-potentiated startle. However, during extinction recall, fear-potentiated startle and fear bradycardia resurged and partly reached levels obtained after fear acquisition. Threat expectancy was not affected by different eye movements and was not elevated during extinction recall. Within limitations, results support an inhibitory SC-BLA pathway in humans by which eye movements may reduce low-level defensive responding, but not threat expectancy. Yet, manipulating eye movements during extinction learning seems to impair extinction recall for behavioral and physiological defensive response indices. Thus, increasing SC activity might enhance initial efficacy of exposure treatment, but additional strategies seem necessary for sustained fear attenuation.

Effect of non-invasive transcutaneous auricular vagus nerve stimulation on cerebral motor excitability-Study protocol for a randomized, sham controlled trial.

Transcutaneous auricular vagus nerve stimulation (taVNS) is becoming increasingly established in the treatment of various neurological and psychiatric diseases. However, only a few studies have focused on the overall influence of taVNS on cortical excitability in general. The planned study will investigate the effect of taVNS on the excitability of the motor cortex in young healthy subjects. The aim of the study is to gain better understand of the physiological mechanism of taVNS to contribute to new fields of application of taVNS in new areas such as the treatment of stroke or multiple sclerosis. This protocol describes a single-center, prospective, double blind, sham-controlled trial that evaluates the effect of taVNS on motor cortex excitability with a planned sample size of 30 participants. The effect of taVNS is investigated by neuronavigation and electromyography (EMG) coupled transcranial magnetic stimulation (TMS) applied before and after taVNS stimulation. The following parameters are assessed: resting motor threshold (RMT), active motor threshold (AMT), recruitment curve (RC), short intracortical inhibition (SICI), intracortical facilitation (ICF). All parameters will be assessed for taVNS on the basis of perception threshold and tolerance threshold. All investigations performed in the study were reviewed and approved by the local ethics committee of the University Medical Center Greifswald (study reference number: BB048/22). Clinical trial registration: www.drks.de, number: DRKS00029937.

Sometimes I feel the fear of uncertainty: How intolerance of uncertainty and trait anxiety impact fear acquisition, extinction and the return of fear.

It is hypothesized that the ability to discriminate between threat and safety is impaired in individuals with high dispositional negativity, resulting in maladaptive behavior. A large body of research investigated differential learning during fear conditioning and extinction protocols depending on individual differences in intolerance of uncertainty (IU) and trait anxiety (TA), two closely-related dimensions of dispositional negativity, with heterogenous results. These might be due to varying degrees of induced threat/safety uncertainty. Here, we compared two groups with high vs. low IU/TA during periods of low (instructed fear acquisition) and high levels of uncertainty (delayed non-instructed extinction training and reinstatement). Dependent variables comprised subjective (US expectancy, valence, arousal), psychophysiological (skin conductance response, SCR, and startle blink), and neural (fMRI BOLD) measures of threat responding. During fear acquisition, we found strong threat/safety discrimination for both groups. During early extinction (high uncertainty), the low IU/TA group showed an increased physiological response to the safety signal, resulting in a lack of CS discrimination. In contrast, the high IU/TA group showed strong initial threat/safety discrimination in physiology, lacking discriminative learning on startle, and reduced neural activation in regions linked to threat/safety processing throughout extinction training indicating sustained but non-adaptive and rigid responding. Similar neural patterns were found after the reinstatement test. Taken together, we provide evidence that high dispositional negativity, as indicated here by IU and TA, is associated with greater responding to threat cues during the beginning of delayed extinction, and, thus, demonstrates altered learning patterns under changing environments.

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

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.

Attentive immobility in the face of inevitable distal threat-Startle potentiation and fear bradycardia as an index of emotion and attention.

During fear conditioning, a cue (CS) signals an inevitable distal threat (US) and evokes a conditioned response that can be described as attentive immobility (freezing). The organism remains motionless and monitors the source of danger while startle responses are potentiated, indicating a state of defensive hypervigilance. Although in animals vagally mediated fear bradycardia is also reliably observed under such circumstances, results are mixed in human fear conditioning. Using a single-cue fear conditioning and extinction protocol, we tested cardiac reactivity and startle potentiation indexing low-level defensive strategies in a fear-conditioned (n = 40; paired presentations of CS and US) compared with a non-conditioned control group (n = 40; unpaired presentations of CS and US). Additionally, we assessed shock expectancy ratings on a trial-by-trial basis indexing declarative knowledge of the previous contingencies. Half of each group underwent extinction under sham or active transcutaneous vagus nerve stimulation (tVNS), serving as additional proof of concept. We found stronger cardiac deceleration during CS presentation in the fear learning relative to the control group. This learned fear bradycardia was positively correlated with conditioned startle potentiation but not with declarative knowledge of CS-US contingencies. TVNS abolished differences in heart rate changes between both groups and removed the significant correlation between late cardiac deceleration and startle potentiation in the fear learning group. Results suggest, fear-conditioned cues evoke attentive immobility in humans, characterized by cardiac deceleration and startle potentiation. Such defensive response pattern is elicited by cues predicting inevitable distal threat and resembles conditioned fear responses observed in rodents.

Promoting long-term inhibition of human fear responses by non-invasive transcutaneous vagus nerve stimulation during extinction training.

Inhibiting fear-related thoughts and defensive behaviors when they are no longer appropriate to the situation is a prerequisite for flexible and adaptive responding to changing environments. Such inhibition of defensive systems is mediated by ventromedial prefrontal cortex (vmPFC), limbic basolateral amygdala (BLA), and brain stem locus-coeruleus noradrenergic system (LC-NAs). Non-invasive, transcutaneous vagus nerve stimulation (tVNS) has shown to activate this circuit. Using a multiple-day single-cue fear conditioning and extinction paradigm, we investigated long-term effects of tVNS on inhibition of low-level amygdala modulated fear potentiated startle and cognitive risk assessments. We found that administration of tVNS during extinction training facilitated inhibition of fear potentiated startle responses and cognitive risk assessments, resulting in facilitated formation, consolidation and long-term recall of extinction memory, and prevention of the return of fear. These findings might indicate new ways to increase the efficacy of exposure-based treatments of anxiety disorders.