Oromucosal Administration of Oxytocin: The Development of 'Oxipops'.

The role of the hypothalamic neuropeptide oxytocin in influencing the brain and behavior has been the subject of widespread research over the last few decades due, most notably, to its reported involvement in promoting social cognition and motivation, reducing anxiety, and relieving pain. It is also increasingly being considered as an important therapeutic intervention in a variety of disorders with social dysfunction as a symptom. While, in recent years, studies in humans have administered oxytocin primarily via an intranasal route, since it may partly enter the brain directly this way via the olfactory and trigeminal nerves, there is increasing evidence that many of its functional effects can be peripherally mediated via increasing its concentration in the blood. This has opened up an oromucosal administration route as an alternative, which is beneficial since the oral consumption of peptides is problematic due to their rapid breakdown in the acidic environment of the gastrointestinal system. In this review we will discuss both the methodologies we have developed for administering oxytocin via lingual application and medicated lollipops, 'oxipops', in terms of increasing blood concentrations and the bioavailability of the peptide, and also their validation in terms of functional effects on the brain and behavior. While areas under the curve are significantly greater in terms of plasma oxytocin concentrations following intranasally relative to oromucosally administered oxytocin, with the estimated absolute bioavailability of the latter being around 4.4% compared with 11.1% for intranasal administration, the time to peak concentrations (around 30 min) and functional effects on the brain and behavior are broadly similar. We will also discuss potential therapeutic advantages of the oromucosal administration of oxytocin in different clinical contexts and its wider application for other peptides which are increasingly being developed for therapeutic use.

A brief real-time fNIRS-informed neurofeedback training of the prefrontal cortex changes brain activity and connectivity during subsequent working memory challenge.

Working memory (WM) represents a building-block of higher cognitive functions and a wide range of mental disorders are associated with WM impairments. Initial studies have shown that several sessions of functional near-infrared spectroscopy (fNIRS) informed real-time neurofeedback (NF) allow healthy individuals to volitionally increase activity in the dorsolateral prefrontal cortex (DLPFC), a region critically involved in WM. For the translation to therapeutic or neuroenhancement applications, however, it is critical to assess whether fNIRS-NF success transfers into neural and behavioral WM enhancement in the absence of feedback. We therefore combined single-session fNIRS-NF of the left DLPFC with a randomized sham-controlled design (N = 62 participants) and a subsequent WM challenge with concomitant functional MRI. Over four runs of fNIRS-NF, the left DLPFC NF training group demonstrated enhanced neural activity in this region, reflecting successful acquisition of neural self-regulation. During the subsequent WM challenge, we observed no evidence for performance differences between the training and the sham group. Importantly, however, examination of the fMRI data revealed that - compared to the sham group - the training group exhibited significantly increased regional activity in the bilateral DLPFC and decreased left DLPFC - left anterior insula functional connectivity during the WM challenge. Exploratory analyses revealed a negative association between DLPFC activity and WM reaction times in the NF group. Together, these findings indicate that healthy individuals can learn to volitionally increase left DLPFC activity in a single training session and that the training success translates into WM-related neural activation and connectivity changes in the absence of feedback. This renders fNIRS-NF as a promising and scalable WM intervention approach that could be applied to various mental disorders.

Neural and behavioral evidence for oxytocin's facilitatory effects on learning in volatile and stable environments.

Outcomes of past decisions profoundly shape our behavior. However, choice-outcome associations can become volatile and adaption to such changes is of importance. The present study combines pharmaco-electroencephalography with computational modeling to examine whether intranasal oxytocin can modulate reinforcement learning under a volatile vs. a stable association. Results show that oxytocin increases choice accuracy independent of learning context, which is paralleled by a larger N2pc and a smaller P300. Model-based analyses reveal that while oxytocin promotes learning by accelerating value update of outcomes in the volatile context, in the stable context it does so by improving choice consistency. These findings suggest that oxytocin's facilitatory effects on learning may be exerted via improving early attentional selection and late neural processing efficiency, although at the computational level oxytocin's actions are highly adaptive between learning contexts. Our findings provide proof of concept for oxytocin's therapeutic potential in mental disorders with adaptive learning dysfunction.

"Listen to your heart": A novel interoceptive strategy for real-time fMRI neurofeedback training of anterior insula activity.

Real-time fMRI (rt-fMRI) neurofeedback (NF) training is a novel non-invasive technique for volitional brain modulation. Given the important role of the anterior insula (AI) in human cognitive and affective processes, it has become one of the most investigated regions in rt-fMRI studies. Most rt-fMRI insula studies employed emotional recall/imagery as the regulation strategy, which may be less effective for psychiatric disorders characterized by altered emotional processing. The present study thus aimed to examine the feasibility of a novel interoceptive strategy based on heartbeat detection in rt-fMRI guided AI regulation and its associated behavioral changes using a randomized double-blind, sham feedback-controlled between-subject design. 66 participants were recruited and randomly assigned to receive either NF from the left AI (LAI) or sham feedback from a control region while using the interoceptive strategy. N = 57 participants were included in the final data analyses. Empathic and interoceptive pre-post training changes were collected as behavioral measures of NF training effects. Results showed that participants in the NF group exhibited stronger LAI activity than the control group with LAI activity being positively correlated with interoceptive accuracy following NF training, although there were no significant increases of LAI activity over training sessions. Importantly, ability of LAI regulation could be maintained in a transfer session without feedback. Successful LAI regulation was associated with strengthened functional connectivity of the LAI with cognitive control, memory and learning, and salience/interoceptive networks. The present study demonstrated for the first time the efficacy of a novel regulation strategy based on interoceptive processing in up-regulating LAI activity. Our findings also provide proof of concept for the translational potential of this strategy in rt-fMRI AI regulation of psychiatric disorders characterized by altered emotional processing.

A central serotonin regulating gene polymorphism (TPH2) determines vulnerability to acute tryptophan depletion-induced anxiety and ventromedial prefrontal threat reactivity in healthy young men.

Serotonin (5-HT) has long been implicated in adaptive emotion regulation as well as the development and treatment of emotional dysregulations in mental disorders. Accumulating evidence suggests a genetic vulnerability may render some individuals at a greater risk for the detrimental effects of transient variations in 5-HT signaling. The present study aimed to investigate whether individual variations in the Tryptophan hydroxylase 2 (TPH2) genetics influence susceptibility for behavioral and neural threat reactivity dysregulations during transiently decreased 5-HT signaling. To this end, interactive effects between TPH2 (rs4570625) genotype and acute tryptophan depletion (ATD) on threat reactivity were examined in a within-subject placebo-controlled pharmacological fMRI trial (n = 51). A priori genotype stratification of extreme groups (GG vs. TT) allowed balanced sampling. While no main effects of ATD on neural reactivity to threat-related stimuli and mood state were observed in the entire sample, accounting for TPH2 genotype revealed an ATD-induced increase in subjective anxious arousal in the GG but not the TT carriers. The effects were mirrored on the neural level, such that ATD specifically reduced ventromedial prefrontal cortex reactivity towards threat-related stimuli in the GG carriers. Furthermore, the ATD-induced increase in subjective anxiety positively associated with the extent of ATD-induced changes in ventromedial prefrontal cortex activity in response to threat-related stimuli in GG carriers. Together the present findings suggest for the first time that individual variations in TPH2 genetics render individuals susceptible to the anxiogenic and neural effects of a transient decrease in 5-HT signaling.

Oxytocin administration enhances pleasantness and neural responses to gentle stroking but not moderate pressure social touch by increasing peripheral concentrations.

Background: Social touch constitutes a key component of human social relationships, although in some conditions with social dysfunction, such as autism, it can be perceived as unpleasant. We have previously shown that intranasal administration of oxytocin facilitates the pleasantness of social touch and activation of brain reward and social processing regions, although it is unclear if it influences responses to gentle stroking touch mediated by cutaneous C-touch fibers or pressure touch mediated by other types of fibers. Additionally, it is unclear whether endogenous oxytocin acts via direct entry into the brain or by increased peripheral blood concentrations. Methods: In a randomized controlled design, we compared effects of intranasal (direct entry into the brain and increased peripheral concentrations) and oral (only peripheral increases) oxytocin on behavioral and neural responses to social touch targeting C-touch (gentle-stroking) or other (medium pressure without stroking) cutaneous receptors. Results: Although both types of touch were perceived as pleasant, intranasal and oral oxytocin equivalently enhanced pleasantness ratings and responses of reward, orbitofrontal cortex, and social processing, superior temporal sulcus, regions only to gentle-stroking not medium pressure touch. Furthermore, increased blood oxytocin concentrations predicted the pleasantness of gentle stroking touch. The specificity of neural effects of oxytocin on C-touch targeted gentle stroking touch were confirmed by time-course extraction and classification analysis. Conclusions: Increased peripheral concentrations of oxytocin primarily modulate its behavioral and neural responses to gentle social touch mediated by C-touch fibers. Findings have potential implications for using oxytocin therapeutically in conditions where social touch is unpleasant. Funding: Key Technological Projects of Guangdong Province grant 2018B030335001. Clinical trial number: NCT05265806.

Sniffing oxytocin: Nose to brain or nose to blood?

In recent years ample studies have reported that intranasal administration of the neuropeptide oxytocin can facilitate social motivation and cognition in healthy and clinical populations. However, it is still unclear how effects are mediated since intranasally administered oxytocin can both directly enter the brain (nose to brain) and increase peripheral vascular concentrations (nose to blood). The relative functional contributions of these routes are not established and have received insufficient attention in the field. The current study used vasoconstrictor pretreatment to prevent intranasal oxytocin (24 IU) from increasing peripheral concentrations and measured effects on both resting-state neural (electroencephalography) and physiological responses (electrocardiogram, electrogastrogram and skin conductance). Results demonstrated that intranasal oxytocin alone produced robust and widespread increases of delta-beta cross-frequency coupling (CFC) from 30 min post-treatment but did not influence peripheral physiological measures. As predicted, vasoconstrictor pretreatment greatly reduced the normal increase in peripheral oxytocin concentrations and, importantly, abolished the majority of intranasal oxytocin effects on delta-beta CFC. Furthermore, time-dependent positive correlations were found between increases in plasma oxytocin concentrations and corresponding increases in delta-beta CFC following oxytocin treatment alone. Our findings suggest a critical role of peripheral vasculature-mediated routes on neural effects of exogenous oxytocin administration with important translational implications for its use as an intervention in psychiatric disorders.

Angiotensin blockade enhances motivational reward learning via enhancing striatal prediction error signaling and frontostriatal communication.

Adaptive human learning utilizes reward prediction errors (RPEs) that scale the differences between expected and actual outcomes to optimize future choices. Depression has been linked with biased RPE signaling and an exaggerated impact of negative outcomes on learning which may promote amotivation and anhedonia. The present proof-of-concept study combined computational modeling and multivariate decoding with neuroimaging to determine the influence of the selective competitive angiotensin II type 1 receptor antagonist losartan on learning from positive or negative outcomes and the underlying neural mechanisms in healthy humans. In a double-blind, between-subjects, placebo-controlled pharmaco-fMRI experiment, 61 healthy male participants (losartan, n = 30; placebo, n = 31) underwent a probabilistic selection reinforcement learning task incorporating a learning and transfer phase. Losartan improved choice accuracy for the hardest stimulus pair via increasing expected value sensitivity towards the rewarding stimulus relative to the placebo group during learning. Computational modeling revealed that losartan reduced the learning rate for negative outcomes and increased exploitatory choice behaviors while preserving learning for positive outcomes. These behavioral patterns were paralleled on the neural level by increased RPE signaling in orbitofrontal-striatal regions and enhanced positive outcome representations in the ventral striatum (VS) following losartan. In the transfer phase, losartan accelerated response times and enhanced VS functional connectivity with left dorsolateral prefrontal cortex when approaching maximum rewards. These findings elucidate the potential of losartan to reduce the impact of negative outcomes during learning and subsequently facilitate motivational approach towards maximum rewards in the transfer of learning. This may indicate a promising therapeutic mechanism to normalize distorted reward learning and fronto-striatal functioning in depression.

The right inferior frontal gyrus as pivotal node and effective regulator of the basal ganglia-thalamocortical response inhibition circuit.

Background: The involvement of specific basal ganglia-thalamocortical circuits in response inhibition has been extensively mapped in animal models. However, the pivotal nodes and directed causal regulation within this inhibitory circuit in humans remains controversial. Objective: The main aim of the present study was to determine the causal information flow and critical nodes in the basal ganglia-thalamocortical inhibitory circuits and also to examine whether these are modulated by biological factors (i.e. sex) and behavioral performance. Methods: Here, we capitalize on the recent progress in robust and biologically plausible directed causal modeling (DCM-PEB) and a large response inhibition dataset (n = 250) acquired with concomitant functional magnetic resonance imaging to determine key nodes, their causal regulation and modulation via biological variables (sex) and inhibitory performance in the inhibitory circuit encompassing the right inferior frontal gyrus (rIFG), caudate nucleus (rCau), globus pallidum (rGP), and thalamus (rThal). Results: The entire neural circuit exhibited high intrinsic connectivity and response inhibition critically increased causal projections from the rIFG to both rCau and rThal. Direct comparison further demonstrated that response inhibition induced an increasing rIFG inflow and increased the causal regulation of this region over the rCau and rThal. In addition, sex and performance influenced the functional architecture of the regulatory circuits such that women displayed increased rThal self-inhibition and decreased rThal to GP modulation, while better inhibitory performance was associated with stronger rThal to rIFG communication. Furthermore, control analyses did not reveal a similar key communication in a left lateralized model. Conclusions: Together, these findings indicate a pivotal role of the rIFG as input and causal regulator of subcortical response inhibition nodes.

Opposing associations of Internet Use Disorder symptom domains with structural and functional organization of the striatum: A dimensional neuroimaging approach.

Background: Accumulating evidence suggests brain structural and functional alterations in Internet Use Disorder (IUD). However, conclusions are strongly limited due to the retrospective case-control design of the studies, small samples, and the focus on general rather than symptom-specific approaches. Methods: We here employed a dimensional multi-methodical MRI-neuroimaging design in a final sample of n = 203 subjects to examine associations between levels of IUD and its symptom-dimensions (loss of control/time management, craving/social problems) with brain structure, resting state and task-based (pain empathy, affective go/no-go) brain function. Results: Although the present sample covered the entire range of IUD, including normal, problematic as well as pathological levels, general IUD symptom load was not associated with brain structural or functional alterations. However, the symptom-dimensions exhibited opposing associations with the intrinsic and structural organization of the brain, such that loss of control/time management exhibited negative associations with intrinsic striatal networks and hippocampal volume, while craving/social problems exhibited a positive association with intrinsic striatal networks and caudate volume. Conclusions: Our findings provided the first evidence for IUD symptom-domain specific associations with progressive alterations in the intrinsic structural and functional organization of the brain, particularly of striatal systems involved in reward, habitual and cognitive control processes.

Oro-mucosal administration of oxytocin using medicated lollipops alters social attention, similar to intranasal and lingual routes: Implications for therapeutic use.

A key functional effect of intranasal administration of the neuropeptide oxytocin is on top-down control of social attention. However, an oro-mucosal administration route may be better tolerated for chronic therapeutic use and evidence suggests that some functional effects of oxytocin can be mediated via peripheral routes. The current study investigated if oxytocin administered orally using medicated lollipops can both increase blood oxytocin concentrations and influence social attention and state anxiety. In a randomized, double-blind, clinical trial adult male participants received oral oxytocin (24IU) or placebo 30-min before completing a well-established anti-saccade paradigm which can assess treatment effects on both top-down and bottom-up attention. Oxytocin administration modulated top-down social attentional processing by increasing anti-saccade error rates on both social and non-social stimuli although it only increased response latencies for social cues. Anti-saccade errors were also positively associated with the proportionate increase in plasma oxytocin concentrations. A comparison analysis showed that oral oxytocin administration increased blood concentrations to a similar degree as given by lingual spray, although less than when given intranasally. Importantly, attentional and anxiolytic effects of oxytocin in the anti-saccade task were similar across intranasal, lingual, and oral administration routes. These findings demonstrate that oral administration of oxytocin, similar to via intranasal and lingual routes, can modulate top-down social attention and state anxiety and support its potential for therapeutic use. They also provide further evidence that functional effects of exogenously administered oxytocin can be mediated indirectly either by crossing the blood brain barrier or producing receptor mediated vagal stimulation, as opposed to via direct entry into the brain.

The central autonomic system revisited - Convergent evidence for a regulatory role of the insular and midcingulate cortex from neuroimaging meta-analyses.

The autonomic nervous system regulates dynamic body adaptations to internal and external environment changes. Capitalizing on two different algorithms (that differ in empirical assumptions), we scrutinized the meta-analytic convergence of human neuroimaging studies investigating the neural basis of peripheral autonomic signal processing. Among the selected studies, we identified 42 records reporting 44 different experiments and testing 758 healthy individuals. The results of the two different algorithms converge in identifying the bilateral dorsal anterior insula and midcingulate cortex as the critical areas of the central autonomic system (CAN). Applying an unbiased approach, we were able to identify a single condition-independent functional circuit that supports CAN activity. Partially overlapping with the salience network this functional circuit includes the bilateral insular cortex and midcingulate cortex as well as the bilateral inferior parietal lobules. Remarkably, the critical regions of the CAN observed in this meta-analysis overlapped with the salience network as well as regions commonly reported across different cognitive and affective neuroimaging paradigms and regions being dysregulated across different mental and neurological disorders.

Choice of Voxel-based Morphometry processing pipeline drives variability in the location of neuroanatomical brain markers.

Fundamental and clinical neuroscience has benefited tremendously from the development of automated computational analyses. In excess of 600 human neuroimaging papers using Voxel-based Morphometry (VBM) are now published every year and a number of different automated processing pipelines are used, although it remains to be systematically assessed whether they come up with the same answers. Here we examined variability between four commonly used VBM pipelines in two large brain structural datasets. Spatial similarity and between-pipeline reproducibility of the processed gray matter brain maps were generally low between pipelines. Examination of sex-differences and age-related changes revealed considerable differences between the pipelines in terms of the specific regions identified. Machine learning-based multivariate analyses allowed accurate predictions of sex and age, however accuracy differed between pipelines. Our findings suggest that the choice of pipeline alone leads to considerable variability in brain structural markers which poses a serious challenge for reproducibility and interpretation.

Oral Administration of Oxytocin, Like Intranasal Administration, Decreases Top-Down Social Attention.

BACKGROUND: The neuropeptide oxytocin (OXT) modulates social cognition by increasing attention to social cues and may have therapeutic potential for impaired social attention in conditions such as autism spectrum disorder. Intranasal administration of OXT is widely used to examine the drug's functional effects in both adults and children and is assumed to enter the brain directly via this route. However, OXT can also influence brain function through increased blood concentrations, and we have recently shown that orally (lingual) administered OXT also modulates neural responses to emotional faces and may be better tolerated for therapeutic use. Here, we examine whether 24 IU OXT administered orally can facilitate social attention. METHODS: In a randomized, placebo-controlled pharmacologic study, we used a validated emotional antisaccade eye-tracking paradigm to explore the effects of oral OXT on bottom-up and top-down attention processing in 80 healthy male participants. RESULTS: Our findings showed that in terms of top-down attention, oral OXT increased errors for both social (angry, fearful, happy, sad, and neutral emotion faces) and nonsocial stimuli (oval shapes) in the antisaccade condition but increased response latencies only in the social condition. It also significantly reduced post-task state anxiety, but this reduction was not correlated with task performance. A comparison with our previous intranasal OXT study using the same task revealed that both routes have a similar effect on increasing antisaccade errors and response latencies and on reducing state anxiety. CONCLUSIONS: Overall, our findings suggest that oral administration of OXT produces similar effects on top-down social attention control and anxiety to intranasal administration and may therefore have therapeutic utility.

Molecular genetic associations between a prominent serotonin transporter gene polymorphism (5-HTTLPR/rs25531) and individual differences in tendencies toward autistic traits and generalized internet use disorder in China and Germany.

BACKGROUND: The serotonin transporter polymorphism 5-HTTLPR is an extensively investigated genetic marker of autistic traits or autism spectrum disorder, and recently has also been studied in the realm of internet use disorder (IUD), yet the findings remain controversial. Therefore, the present study aimed to explore associations between 5-HTTLPR (also including SNP rs25531) and autistic traits/IUD tendencies and to assess whether the relationship between autistic traits and IUD tendencies varies by this genetic marker in participants from China and Germany. METHODS: A total of 540 Chinese and 563 German subjects were genotyped for 5-HTTLPR/rs25531 and completed the Adult Autism Spectrum Quotient questionnaire and the short version of the Internet Addiction Test. RESULTS: Carriers of the low expressing S'S' genotype (S, LG ) showed significantly higher levels of autistic traits than the high expressing allele (e.g. LA ) carriers in both samples. There was no significant effect of 5-HTTLPR/rs25531 on IUD either in the Chinese or Germany samples, whereas positive correlations between autistic traits and IUD varied by 5-HTTLPR/rs25531 genotypes and also differed between Chinese and German samples. In the Chinese sample, positive correlations were mainly driven by S'S' and S'L' carriers, while they were mainly determined by S'L' and L'L' carriers in the German sample. Further analyses revealed that the associations between autistic traits and IUD tended in parts to be more strongly pronounced in the complete German sample compared to the complete Chinese sample, and also varied depending on 5-HTTLPR/rs25531 genotypes (in S'S' carriers: China > Germany; in S'L' and L'L' carriers: China < Germany; both in terms of more positive associations). CONCLUSIONS: Our findings suggest carriers of low expressing alleles (S, LG ) are more likely to show higher autistic traits in both Chinese and German samples. Furthermore, the present work shows that both 5-HTTLPR/rs25531 and cultural differences might be of relevance to understand associations between autistic traits and IUD tendencies, but this needs to be further backed up.

Oxytocinergic Modulation of Stress-Associated Amygdala-Hippocampus Pathways in Humans Is Mediated by Serotonergic Mechanisms.

BACKGROUND: The hypothalamic neuropeptide oxytocin (OXT) may exert anxiolytic and stress-reducing actions via modulatory effects on amygdala circuits. Animal models and initial findings in humans suggest that some of these effects are mediated by interactions with other neurotransmitter systems, in particular the serotonin (5-HT) system. Against this background, the present pharmacological resting-state functional magnetic resonance imaging study aimed to determine whether effects of OXT on stress-associated amygdala intrinsic networks are mediated by 5-HT. METHODS: We employed a randomized, placebo-controlled, double-blind parallel-group, pharmacological functional magnetic resonance imaging resting-state experiment with 4 treatment groups in n = 112 healthy male participants. Participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD) or a corresponding placebo-control protocol before the administration of intranasal OXT (24 IU) or placebo intranasal spray. RESULTS: OXT and 5-HT modulation exerted interactive effects on the coupling of the left amygdala with the ipsilateral hippocampus and adjacent midbrain. OXT increased intrinsic coupling in this pathway, whereas this effect of OXT was significantly attenuated during transiently decreased central serotonergic signaling induced via acute tryptophan depletion. In the absence of OXT or 5-HT modulation, this pathway showed a trend for an association with self-reported stress perception in everyday life. No interactive effects were observed for the right amygdala. CONCLUSIONS: Together, the findings provide the first evidence, to our knowledge, that the effects of OXT on stress-associated amygdala-hippocampal-midbrain pathways are critically mediated by the 5-HT system in humans.

Angiotensin Antagonist Inhibits Preferential Negative Memory Encoding via Decreasing Hippocampus Activation and Its Coupling With the Amygdala.

BACKGROUND: Exaggerated arousal and dysregulated emotion-memory interactions are key pathological dysregulations that accompany the development of posttraumatic stress disorder (PTSD). Current treatments for PTSD are of moderate efficacy, and preventing the dysregulations during exposure to threatening events may attenuate the development of PTSD symptomatology. METHODS: In a preregistered double-blind, between-subject, placebo-controlled pharmaco-functional magnetic resonance imaging design, this proof-of-concept study examined the potential of a single dose of the angiotensin II type 1 receptor antagonist losartan (LT) to attenuate the mnemonic advantage of threatening stimuli and the underlying neural mechanism via combining an emotional subsequent memory paradigm with LT (n = 29) or placebo (n = 30) and a surprise memory test after a 24-hour washout. RESULTS: LT generally improved memory performance and abolished emotional memory enhancement for negative but not positive material, while emotional experience during encoding remained intact. LT further suppressed hippocampus activity during encoding of subsequently remembered negative stimuli. At the network level, LT reduced coupling between the hippocampus and the basolateral amygdala during successful memory formation of negative stimuli. CONCLUSIONS: Our findings suggest that LT may have the potential to attenuate memory formation for negative but not positive information by decreasing hippocampus activity and its functional coupling strength with the amygdala. These findings suggest a promising potential of LT to prevent preferential encoding and remembering of negative events, a mechanism that could prevent the emotion-memory dysregulations underlying the development of PTSD symptomatology.

Transcutaneous auricular vagus nerve stimulation increases eye-gaze on salient facial features and oxytocin release.

Non-invasive, transcutaneous electrical stimulation of the auricular branch of the vagus nerve (taVNS) via the ear is used therapeutically in epilepsy, pain, and depression, and may also have beneficial effects on social cognition. However, the underlying mechanisms of taVNS are unclear and evidence regarding its role in social cognition improvement is limited. To investigate the impact of taVNS on social cognition we have studied its effects on gaze toward emotional faces in combination with eye-tracking and on the release of the neuropeptide oxytocin which plays a key role in influencing social cognition and motivation. A total of 54 subjects were enrolled (49 were included in the final analysis) in a sham-controlled, participant-blind, crossover experiment, consisting of two treatment sessions 1 week apart. In one session participants received 30-min taVNS (tragus), and in the other, they received 30-min sham (earlobe) stimulation with the treatment order counterbalanced. The proportion of time spent viewing the faces and facial features (eyes, nose, and mouth) was measured together with resting pupil size. Additionally, saliva samples were taken for the measurement of oxytocin concentrations by enzyme-linked immunoassay. Saliva oxytocin concentrations increased significantly after taVNS compared to sham stimulation, while resting pupil size did not. In addition, taVNS increased time spent viewing the nose region irrespective of face emotion, and this was positively correlated with increased saliva oxytocin concentrations. Our findings suggest that taVNS biases visual attention toward socially salient facial features across different emotions and this is associated with its effects on increasing endogenous oxytocin release.

Disorder- and cognitive demand-specific neurofunctional alterations during social emotional working memory in generalized anxiety disorder and major depressive disorder.

BACKGROUND: Generalized Anxiety Disorder (GAD) and Major Depressive Disorder (MDD) are both characterized by cognitive and social impairments. Determining disorder-specific neurobiological alterations in GAD and MDD by means of functional magnetic resonance imaging (fMRI) may promote determination of precise diagnostic markers. METHODS: This study aimed to examine disorder-specific behavioral and neural alterations at the intersection of social and cognitive processing in treatment-naïve first-episode GAD (n = 35) and MDD (n = 37) patients compared to healthy controls (n = 35) by employing a social-emotional n-back fMRI paradigm. RESULTS: No behavioral differences between patients and healthy controls were observed. However, GAD patients exhibited decreased bilateral dorsomedial prefrontal cortex (dmPFC) engagement during the 0-back condition yet increased dmPFC engagement during the 1-back condition compared to MDD and healthy participants. In contrast, MDD patients exhibited increased dmPFC-insula coupling during 0-back, yet decreased coupling during 1-back, compared to GAD and healthy participants. Dimensional symptom-load analysis confirmed that increased dmPFC-insula connectivity during 0-back was positively associated with depressive symptom load. LIMITATIONS: The moderate sample size in the present study did not allow us to further explore gender differences. In addition, some patients exhibited GAD and MDD comorbidity according to the M.I.N.I. interview. Finally, the paradigm we used did not allow to further disentangle emotion-specific effects on working memory. CONCLUSIONS: These findings suggest that the dmPFC engaged in integrating affective and cognitive components and self-other processing exhibits GAD-specific neurofunctional dysregulations whereas functional dmPFC communication with the insula, a region involved in salience processing, may represent an MDD-specific neurofunctional deficit.