The microbiota-gut-brain axis in hippocampus-dependent learning and memory: current state and future challenges.

A fundamental shift in neuroscience suggests bidirectional interaction of gut microbiota with the healthy and dysfunctional brain. This microbiota-gut-brain axis has mainly been investigated in stress-related psychopathology (e.g. depression, anxiety). The hippocampus, a key structure in both the healthy brain and psychopathologies, is implicated by work in rodents that suggests gut microbiota substantially impact hippocampal-dependent learning and memory. However, understanding microbiota-hippocampus mechanisms in health and disease, and translation to humans, is hampered by the absence of a coherent evaluative approach. We review the current knowledge regarding four main gut microbiota-hippocampus routes in rodents: through the vagus nerve; via the hypothalamus-pituitary-adrenal-axis; by metabolism of neuroactive substances; and through modulation of host inflammation. Next, we suggest an approach including testing (biomarkers of) the four routes as a function of the influence of gut microbiota (composition) on hippocampal-dependent (dys)functioning. We argue that such an approach is necessary to proceed from the current state of preclinical research to beneficial application in humans to optimise microbiota-based strategies to treat and enhance hippocampal-dependent memory (dys)functions.

Do common antibiotic treatments influence emotional processing?

Antibiotics are among the most commonly prescribed medications worldwide, yet research in recent years has revealed the detrimental effect they can have on the human microbiome, with implications for health. The community of microorganisms inhabiting the gut has been shown to regulate physiological and neural processes. Since studies in both humans and animal models have revealed that the gut microbiome can affect the brain, influencing emotion and cognition, here we investigate whether antibiotic treatment is associated with changes in emotional processing and mood with a between-subject design in 105 young healthy adult volunteers, using both psychological tests and questionnaires. As both the immune system and vagal signalling can mediate the microbiome-gut-brain axis, we also assess whether there is any evidence of such changes in participant physiology. We find that individuals who have taken antibiotics in the past three months show a stronger emotional bias towards sadness and at a physiological level they have a higher heart rate (though this does not mediate the relationship with negative bias). While we cannot rule out a possible role of prior infection, our findings are in any case highly relevant in light of research revealing that antibiotics are linked to increased susceptibility to depression and anxiety. Our results also have implications for listing antibiotic use as an exclusion criterion in studies on emotional processing and psychophysiology.

Gut Feelings: Vagal Stimulation Reduces Emotional Biases.

The vagus nerve is a key physical constituent of the gut-brain axis. Increasing attention has recently been paid to the role that the gut, and the microorganisms inhabiting it, play in emotion and cognition. Animal studies have revealed the importance of the vagus nerve in mediating communication between the gut microbiome and the central nervous system, resulting in changes in emotional behaviour. This has renewed interest in understanding the role of vagal signalling in human emotion, particularly since human studies have also shown that alterations in gut microbiome composition can affect emotion. While stimulating the vagus nerve can help treat some cases of severe depression, here we investigate whether vagal afferent signalling can influence emotional processing in healthy subjects. We use the dot-probe task to determine the effect of transcutaneous vagus nerve stimulation on attentional biases towards emotional stimuli in 42 volunteers. Participants received both active and sham treatments using a within-subject design. We show that transcutaneous vagus nerve stimulation reduces the emotional bias towards faces expressing sadness and happiness, indicating a decrease in emotional reactivity. While our novel findings reveal the effect that vagal signalling can have on emotional biases in healthy subjects, future studies should seek to develop our understanding of the ways in which the microbiome interacts with, and stimulates, the vagus nerve. Since we find a reduction in emotional bias, most notably towards sadness, this may partly account for the effective use of vagus nerve stimulation in treatment-resistant depression. While its clinical application currently involves surgical stimulation, our results support the potential benefit of transcutaneous vagus nerve stimulation as a non-invasive, intermittent adjunctive therapy for patients with depression, given its frequent association with emotional biases.

Recognizing emotions in bodies: Vagus nerve stimulation enhances recognition of anger while impairing sadness.

According to the Polyvagal theory, the vagus nerve is the key phylogenetic substrate that supports efficient emotion recognition for promoting safety and survival. Previous studies showed that the vagus nerve affects people's ability to recognize emotions based on eye regions and whole facial images, but not static bodies. The purpose of this study was to verify whether the previously suggested causal link between vagal activity and emotion recognition can be generalized to situations in which emotions must be inferred from images of whole moving bodies. We employed transcutaneous vagus nerve stimulation (tVNS), a noninvasive brain stimulation technique that stimulates the vagus nerve by a mild electrical stimulation to the auricular branch of the vagus, located in the anterior protuberance of the outer ear. In two sessions, participants received active or sham tVNS before and while performing three emotion recognition tasks, aimed at indexing their ability to recognize emotions from static or moving bodily expressions by actors. Active tVNS, compared to sham stimulation, enhanced the recognition of anger but reduced the ability to recognize sadness, regardless of the type of stimulus (static vs. moving). Convergent with the idea of hierarchical involvement of the vagus in establishing safety, as put forward by the Polyvagal theory, we argue that our findings may be explained by vagus-evoked differential adjustment strategies to emotional expressions. Taken together, our findings fit with an evolutionary perspective on the vagus nerve and its involvement in emotion recognition for the benefit of survival.

Transcutaneous vagus nerve stimulation modulates attentional resource deployment towards social cues.

Transcutaneous vagus nerve stimulation (tVNS) has been shown to promote inferences of emotional states based on eye-related information provided by facial expressions of emotions. Eye gaze direction can influence the allocation of attentional sources when processing facial emotional stimuli. Here we sought for further evidence indicating whether tVNS effects would be specific to emotional expressions or to gaze - both socially relevant stimuli - and whether they reflect the enhancement of attention. In two separate sessions receiving either active or sham tVNS, forty-three healthy young volunteers completed a Rapid Serial Visual Presentation task in which participants identified the gender of a target face (T1) with direct (salient social cue) or averted gaze (subtler social cue) with different emotional expressions or a neutral expression, and then judged the orientation of a landscape (T2) that appeared at different temporal lags after T1. Active tVNS, compared to sham stimulation, enhanced conditional T2 accuracy for both neutral and emotional faces and independently of the temporal lag, but only when gaze was directed at the participant. This suggests that tVNS modulates attention to a direct gaze (salient social cue) irrespective of the expressed emotion. We interpret that the effects of tVNS seem to reflect enhanced perception of gaze direction, which in turn attracts attention, making the observer more sensitive and increasing the impact of the socially relevant facial cue. We conclude that tVNS is a promising technique for enhancing social information processing in healthy humans.

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.

Rumination impairs the control of stimulus-induced retrieval of irrelevant information, but not attention, control, or response selection in general.

The aim of the study was to throw more light on the relationship between rumination and cognitive-control processes. Seventy-eight adults were assessed with respect to rumination tendencies by means of the LEIDS-r before performing a Stroop task, an event-file task assessing the automatic retrieval of irrelevant information, an attentional set-shifting task, and the Attentional Network Task, which provided scores for alerting, orienting, and executive control functioning. The size of the Stroop effect and irrelevant retrieval in the event-five task were positively correlated with the tendency to ruminate, while all other scores did not correlate with any rumination scale. Controlling for depressive tendencies eliminated the Stroop-related finding (an observation that may account for previous failures to replicate), but not the event-file finding. Taken altogether, our results suggest that rumination does not affect attention, executive control, or response selection in general, but rather selectively impairs the control of stimulus-induced retrieval of irrelevant information.

Vagal signaling and the somatic marker hypothesis: The effect of transcutaneous vagal nerve stimulation on delay discounting is modulated by positive mood.

Controlling impulsivity and delaying gratifications are key features of effective self-control. Delay Discounting (DD) indexes the ability to delay rewards and previous research has shown that discounting is influenced by affective states such as mood. According to the Somatic Marker Hypothesis (SMH), afferent somatic signals, such as mood, are carried by the vagus and can influence decision making. In the current study, we employed transcutaneous vagus nerve stimulation (tVNS), a novel non-invasive brain stimulation technique that stimulates the auricular branch of the afferent vagus nerve (located in the outer ear), to assess its effects on decision impulsivity, while taking into account individuals' mood and resting-state HRV as a possible confounding factor. Employing a within-subjects cross-over design, 94 participants received active or sham tVNS while performing delay discounting in two separate sessions. As compared to sham, active tVNS increased discounting, but only for individuals reporting lower positive mood, regardless of the level of negative mood reported. We evidence that the effect of tVNS on reward discounting depends on the level of positive mood. This result suggests that positive mood state might be a proxy of task-relevant arousal, likely influencing the effectiveness of afferent vagal stimulation on self-control processes, as temporal discounting.

Cocaine enhances figural, but impairs verbal 'flexible' divergent thinking.

Anecdotal evidence suggests that cocaine use will help overcome creative 'blocks' by enhancing flexible thinking. Given that cocaine is likely to enhance dopamine (DA) levels, which in turn are positively associated with divergent thinking (DT); is a possibility that is tested in the present study. Furthermore, the impact of cocaine is tested on convergent thinking (CT), another aspect of creative thinking, which has been reported to be impaired with high DA levels. It was hypothesized that cocaine would enhance DT and impair CT. A placebo-controlled within-subjects study including 24 healthy poly-drug users was set up to test the influence of oral cocaine (300 mg) on creativity. Verbal CT was assessed with the Remote Associates Task (RAT); figural CT was assessed with the Picture Concepts Task (PCT) and the Tower of London (TOL). Verbal DT was assessed with the Alternative Uses Task (AUT); figural DT was assessed with the Pattern/Line Meanings Task (PLMT). Findings showed that, compared to placebo, cocaine impaired figural CT (TOL) and flexible DT of verbal stimuli (AUT), while it enhanced figural DT (PLMT). No significant effects of cocaine were observed regarding the PCT and RAT. It was demonstrated that cocaine-induced effects on creativity in poly-drug users are stimulus-dependent. Cocaine enhanced performance on figural DT but impaired performance on verbal (flexible) DT. Cocaine impaired CT on only one figural task and but not on the other tasks. As creativity is an important aspect in cognitive therapies, it is important to further understand these discrepancies in creativity task performance.

An integrative perspective on the interplay between early maladaptive schemas and mental health: The role of self-compassion and emotion regulation.

OBJECTIVES: We aimed to test whether negative emotion regulation difficulties and self-compassion mediate the relationship between early maladaptive schemas (EMSs) and symptoms of psychopathology and life satisfaction. METHODS: Data were collected from 296 adults (179 females, 117 males), whose age ranged from 17 to 52 years. The mediating roles of self-compassion and negative emotion regulation were examined via Hayes' procedure (PROCESS) for multiple mediation. RESULTS: Negative emotion regulation was the only mediator to psychopathological symptoms, with no additional role for self-compassion, whereas self-compassion mediated only to life satisfaction, with no additional role for negative emotion regulation. CONCLUSIONS: The results provide evidence for unique mediating roles of negative emotion regulation and self-compassion, depending on the outcome variable. That helps to understand how problems that may be identified in terms of positive and negative domains are related to EMSs, and allows to put forward potential strategies within the frame of schema therapy.

Variable heart rate and a flexible mind: Higher resting-state heart rate variability predicts better task-switching.

The neurovisceral integration model proposes that heart rate variability (HRV) is linked to prefrontal cortex activity via the vagus nerve, which connects the heart and the brain. HRV, an index of cardiac vagal tone, has been found to predict performance on several cognitive control tasks that rely on the prefrontal cortex. However, the link between HRV and the core cognitive control function "shifting" between tasks and mental sets is under-investigated. Therefore, the present study tested the neurovisceral integration model by examining, in 90 participants, the relationship between vagally mediated resting-state HRV and performance in a task-switching paradigm that provides a relatively process-pure measure of cognitive flexibility. As predicted, participants with higher resting-state HRV (indexed both by time domain and frequency domain measures) showed smaller switch costs (i.e., greater flexibility) than individuals with lower resting-state HRV. Our findings support the neurovisceral integration model and indicate that higher levels of vagally mediated resting-state HRV promote cognitive flexibility.

Transcutaneous vagus nerve stimulation (tVNS) enhances divergent thinking.

Creativity is one of the most important cognitive skills in our complex and fast-changing world. Previous correlative evidence showed that gamma-aminobutyric acid (GABA) is involved in divergent but not convergent thinking. In the current study, a placebo/sham-controlled, randomized between-group design was used to test a causal relation between vagus nerve and creativity. We employed transcutaneous vagus nerve stimulation (tVNS), a novel non-invasive brain stimulation technique to stimulate afferent fibers of the vagus nerve and speculated to increase GABA levels, in 80 healthy young volunteers. Creative performance was assessed in terms of divergent thinking (Alternate Uses Task) and convergent thinking tasks (Remote Associates Test, Creative Problem Solving Task, Idea Selection Task). Results demonstrate active tVNS, compared to sham stimulation, enhanced divergent thinking. Bayesian analysis reported the data to be inconclusive regarding a possible effect of tVNS on convergent thinking. Therefore, our findings corroborate the idea that the vagus nerve is causally involved in creative performance. Even thought we did not directly measure GABA levels, our results suggest that GABA (likely to be increased in active tVNS condition) supports the ability to select among competing options in high selection demand (divergent thinking) but not in low selection demand (convergent thinking).

Supplementation of gamma-aminobutyric acid (GABA) affects temporal, but not spatial visual attention.

In a randomized, double-blind, and placebo-controlled experiment, the acute effects of gamma-aminobutyric acid (GABA) supplementation on temporal and spatial attention in young healthy adults were investigated. A hybrid two-target rapid serial visual presentation task was used to measure temporal attention and integration. Additionally, a visual search task was used to measure the speed and accuracy of spatial attention. While temporal attention depends primarily on the distribution of limited attentional resources across time, spatial attention represents the engagement and disengagement by relevant and irrelevant stimuli across the visual field. Although spatial attention was unaffected by GABA supplementation altogether, we found evidence supporting improved performance in the temporal attention task. The attentional blink was numerically, albeit not significantly, attenuated at Lag 3, and significantly fewer order errors were committed at Lag 1, compared to the placebo condition. No effect was found on temporal integration rates. Although there is controversy about whether oral GABA can cross the blood-brain barrier, our results offer preliminary evidence that GABA intake might help to distribute limited attentional resources more efficiently, and can specifically improve the identification and ordering of visual events that occur in close temporal succession.

Overweight and Cognitive Performance: High Body Mass Index Is Associated with Impairment in Reactive Control during Task Switching.

The prevalence of weight problems is increasing worldwide. There is growing evidence that high body mass index (BMI) is associated with frontal lobe dysfunction and deficits in cognitive control. The present study aims to clarify the association between weight status and the degree of impairment in cognitive flexibility, i.e., the ability to efficiently switch from one task to another, by disentangling the preparatory and residual domains of task switching. Twenty-six normal weight (BMI < 25, five males) and twenty-six overweight (BMI ≥ 25, seven males) university students performed a task-switching paradigm that provides a relatively well-established diagnostic measure of proactive vs. reactive control with regard to cognitive flexibility. Compared to individuals with a BMI lower than 25, overweight (i.e., ≥25) was associated with increased switching costs in the reactive switching condition (i.e., when preparation time is short), representing reduced cognitive flexibility in the preparatory domain. In addition, the overweight group reported significantly more depression and binge eating symptoms, although still indicating minimal depression. No between-group differences were found with regard to self-reported autism spectrum symptoms, impulsiveness, state- and trait anxiety, and cognitive reactivity to depression. The present findings are consistent with and extend previous literature showing that elevated BMI in young, otherwise healthy individuals is associated with significantly more switching costs due to inefficiency in the retrieval, implementation, and maintenance of task sets, indicating less efficient cognitive control functioning.

High vagally mediated resting-state heart rate variability is associated with superior action cascading.

The neurovisceral integration model suggests that individual differences in heart rate variability (HRV), an index of vagal tone, may relate to prefrontal cortical activity and predict performance on cognitive control tasks. The aim of this study was to further verify this model by investigating the relationship between vagally-mediated resting-state HRV and action cascading, a crucial cognitive control function which refers to the ability to cope with multiple response options when confronted with various task goals. Resting-state HRV and performance on the stop-change paradigm, which provides a relatively well-established diagnostic measure of action cascading and response inhibition, was assessed in 88 healthy volunteers (age range 18-33). Compared to individuals with low resting-state HRV, participants with high resting-state HRV showed enhanced action cascading performance, both when a disruption (stopping) and change towards an alternative response were required simultaneously, and when requirements were cascaded (i.e. when the stopping process had already finished at the time the change was required). Our findings represent an important step towards extending our understanding of the neurovisceral integration model in cognitive control.

Color vision predicts processing modes of goal activation during action cascading.

One of the most important functions of cognitive control is action cascading: the ability to cope with multiple response options when confronted with various task goals. A recent study implicates a key role for dopamine (DA) in this process, suggesting higher D1 efficiency shifts the action cascading strategy toward a more serial processing mode, whereas higher D2 efficiency promotes a shift in the opposite direction by inducing a more parallel processing mode (Stock, Arning, Epplen, & Beste, 2014). Given that DA is found in high concentration in the retina and modulation of retinal DA release displays characteristics of D2-receptors (Peters, Schweibold, Przuntek, & Müller, 2000), color vision discrimination might serve as an index of D2 efficiency. We used color discrimination, assessed with the Lanthony Desaturated Panel D-15 test, to predict individual differences (N = 85) in a stop-change paradigm that provides a well-established measure of action cascading. In this task it is possible to calculate an individual slope value for each participant that estimates the degree of overlap in task goal activation. When the stopping process of a previous task goal has not finished at the time the change process toward a new task goal is initiated (parallel processing), the slope value becomes steeper. In case of less overlap (more serial processing), the slope value becomes flatter. As expected, participants showing better color vision were more prone to activate goals in a parallel manner as indicated by a steeper slope. Our findings suggest that color vision might represent a predictor of D2 efficiency and the predisposed processing mode of goal activation during action cascading.