Probiotics are microorganisms that provide health benefits when consumed. In animals, probiotics reverse gut microbiome-related alterations in depression-like symptoms, in cognition, and in hormonal stress response. However, in humans, a causal understanding of the gut-brain link in emotion and cognition is lacking. Additionally, whether the effects of probiotics on neurocognition are visible only in presence of stress, remains unclear. We investigated the effects of a multispecies probiotic (Ecologic®Barrier) on specific neurocognitive measures of emotion reactivity, emotion regulation, and cognitive control using fMRI. Critically, we also tested whether probiotics can buffer against the detrimental effects of acute stress on working memory. In a double blind, randomized, placebo-controlled, between-subjects intervention study, 58 healthy participants were tested once before and once after a 28-day intervention.Without stress induction, probiotics did not affect brain, behavioral, or related self-report measures. However, relative to placebo, the probiotics group did show a significant stress-related increase in working memory performance after supplementation. This change was associated with intervention-related neural changes in frontal cortex during cognitive control exclusively in the probiotics group. Overall, our results show neurocognitive effects of a multispecies probiotic in healthy women only under challenging situations, buffering against the detrimental effects of stress on cognition.

Fear generalization is a prominent feature of anxiety disorders and post-traumatic stress disorder (PTSD). It is defined as enhanced fear responding to a stimulus that bears similarities, but is not identical to a threatening stimulus. Pattern separation, a hippocampal-dependent process, is critical for stimulus discrimination; it transforms similar experiences or events into non-overlapping representations. This study is the first in humans to investigate the extent to which fear generalization relies on behavioral pattern separation abilities. Participants (N = 46) completed a behavioral task taxing pattern separation, and a neuroimaging fear conditioning and generalization paradigm. Results show an association between lower behavioral pattern separation performance and increased generalization in shock expectancy scores, but not in fear ratings. Furthermore, lower behavioral pattern separation was associated with diminished recruitment of the subcallosal cortex during presentation of generalization stimuli. This region showed functional connectivity with the orbitofrontal cortex and ventromedial prefrontal cortex. Together, the data provide novel experimental evidence that pattern separation is related to generalization of threat expectancies, and reduced fear inhibition processes in frontal regions. Deficient pattern separation may be critical in overgeneralization and therefore may contribute to the pathophysiology of anxiety disorders and PTSD.

Stress negatively affects cognitive performance. Probiotics remediate somatic and behavioral stress responses, hypothetically by acting on the gut microbiota. Here, in exploratory analyses, we assessed gut microbial alterations after 28-days supplementation of multi-strain probiotics (EcologicBarrier consisting of Lactobacilli, Lactococci, and Bifidobacteria in healthy, female subjects (probiotics group n = 27, placebo group n = 29). In an identical pre-session and post-session, subjects performed a working memory task before and after an acute stress intervention. Global gut microbial beta diversity changed over time, but we were not able to detect differences between intervention groups. At the taxonomic level, Time by Intervention interactions were not significant after multiple comparison correction; the relative abundance of eight genera in the probiotics group was higher (uncorrected) relative to the placebo group: Butyricimonas, Parabacteroides, Alistipes, Christensenellaceae_R-7_group, Family_XIII_AD3011_group, Ruminococcaceae_UCG-003, Ruminococcaceae_UCG-005, and Ruminococcaceae_UCG-010. In a second analysis step, association analyses were done only within this selection of microbial genera, revealing the probiotics-induced change in genus Ruminococcaceae_UCG-003 was significantly associated with probiotics’ effect on stress-induced working memory changes (rspearman(27) = 0.565; pFDR = 0.014) in the probiotics group only and independent of potential confounders (i.e., age, BMI, and baseline dietary fiber intake). That is subjects with a higher increase in Ruminococcaceae_UCG-003 abundance after probiotics were also more protected from negative effects of stress on working memory after probiotic supplementation. The bacterial taxa showing an increase in relative abundance in the probiotics group are plant fiber degrading bacteria and produce short-chain fatty acids that are known for their beneficial effect on gut and brain health, e.g., maintaining intestinal-barrier and blood–brain-barrier integrity. This study shows that gut microbial alterations, modulated through probiotics use, are related to improved cognitive performance in acute stress circumstances.

Dopamine, one of the main neurotransmitters in the mammalian brain, has been implicated in the coding of prediction errors that govern reward learning as well as fear extinction learning. Psychotherapy too can be viewed as a form of error-based learning, because it challenges erroneous beliefs and behavioral patterns in order to induce long-term changes in emotions, cognitions, and behaviors. Exposure therapy, for example, relies in part on fear extinction principles to violate erroneous expectancies of danger and induce novel safety learning that inhibits and therefore reduces fear in the long term. As most forms of psychotherapy, however, exposure therapy suffers from non-response, dropout, and relapse. This narrative review focuses on the role of midbrain and prefrontal dopamine in novel safety learning and investigates possible pathways through which dopamine-based interventions could be used as an adjunct to improve both the response and the long-term effects of the therapy. Convincing evidence exists for an involvement of the midbrain dopamine system in the acquisition of new, safe memories. Additionally, prefrontal dopamine is emerging as a key ingredient for the consolidation of fear extinction. We propose that applying a dopamine prediction error perspective to psychotherapy can inspire both pharmacological and non-pharmacological studies aimed at discovering innovative ways to enhance the acquisition of safety memories. Additionally, we call for further empirical investigations on dopamine-oriented drugs that might be able to maximize consolidation of successful fear extinction and its long-term retention after therapy, and we propose to also include investigations on non-pharmacological interventions with putative prefrontal dopaminergic effects, like working memory training.

Prolonged fasting influences threat and reward processing, two fundamental systems underpinning adaptive behaviors. In animals, overnight fasting sensitizes the mesolimbic-dopaminergic activity governing avoidance, reward, and fear-extinction learning. Despite evidence that overnight fasting may also affect reward and fear learning in humans, effects on human avoidance learning have not been studied yet. Here, we examined the effects of 16h-overnight fasting on instrumental avoidance and relief from threat omission. To this end, 50 healthy women were randomly assigned to a fasting (N=25) or a re-feeding group (N=25) and performed an Avoidance-Relief Task. We found that fasting decreases unnecessary avoidance during signaled safety; this effect was mediated via a reduction in relief pleasantness during signaled absence of threat. A fasting-induced reduction in relief was also found during fear extinction learning. We conclude that fasting optimizes avoidance and safety learning. Future studies should test whether these effects also hold for anxious individuals.

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Stress negatively affects cognitive performance. Probiotics remediate somatic and behavioral stress responses, hypothetically by acting on the gut microbiota. Here, we assessed gut microbial alterations after 28-days supplementation of multi-strain probiotics (EcologicBarrier consisting of Lactobacilli, Lactococci and Bifidobacteria in healthy, female subjects (probiotics group n=27, placebo group n=29). In an identical pre- and post-session, subjects performed a working memory task before and after an acute stress intervention. One-month supplementation of probiotics changed the gut microbial community (within probiotics group Pweighted unifrac=0.008). This change was driven by a nominal increase in eight genera in the probiotics group relative to the placebo group: Butyricimonas, Parabacteroides, Alistipes, Christensenellaceae_R-7_group, Family_XIII_AD3011_group, Ruminococcaceae_UCG-003, Ruminococcaceae_UCG-005 and Ruminococcaceae_UCG-010. Of these, the probiotics-induced change in genus Ruminococcaceae_UCG-003 was significantly associated with probiotics’ effect on stress-induced working memory changes (rspearman(27) = 0.565; pFDR = 0.014) in the probiotics group only and independent of potential confounders (i.e., age, BMI, and baseline dietary fibre intake). That is, subjects with a higher increase in Ruminococcaceae_UCG-003 abundance after probiotics were also more protected from negative effects of stress on working memory after probiotic supplementation. The bacterial taxa showing an increase in relative abundance in the probiotics group are plant fibre degrading bacteria and produce short-chain fatty acids that are known for their beneficial effect on gut and brain health, e.g. maintaining intestinal- and blood-brain-barrier integrity. This study shows that gut microbial alterations, modulated through probiotics use, are related to improved cognitive performance in acute stress circumstances.