bioRxiv (Cold Spring Harbor Laboratory), Nov 8, 2021
BackgroundThe hypothalamic neuropeptide oxytocin (OXT) may exert anxiolytic and stress-reducing a... more BackgroundThe 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 fMRI study aimed at determining whether effects of OXT on stress-associated amygdala intrinsic networks are mediated by 5-HT.MethodsWe employed a randomized placebo-controlled double-blind parallel-group pharmacological fMRI resting state experiment during which n = 112 healthy male participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD) or the corresponding placebo-control protocols (ATDc) before the administration of intranasal OXT or placebo intranasal spray, respectively.ResultsOXT 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, while this effect of OXT was significantly attenuated during transiently decreased central serotonergic signaling induced via ATD. 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.ConclusionsTogether, the findings provide first evidence that effects of OXT on stress-associated amygdala-hippocampal-midbrain pathways are critically mediated by the 5-HT system in men.
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Nov 1, 2021
Background Overarching conceptualizations propose that the complex social-emotional effects of ox... more Background Overarching conceptualizations propose that the complex social-emotional effects of oxytocin (OXT) in humans are partly mediated by interactions with other neurotransmitter systems. Recent animal models suggest that the anxiolytic effects of OXT are critically mediated by the serotonin (5-HT) system, yet direct evidence in humans is lacking. To determine the role of 5-HT in OXT-induced attenuation of amygdala threat reactivity and sensitization/ desensitization, we conducted a parallel-group randomized placebo-controlled double-blind experiment during which n = 121 healthy subjects underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD, TRYP -) or the corresponding placebo-control protocols before the administration of intranasal OXT or placebo intranasal spray, respectively. Mean and repetition-dependent changes in threatspecific amygdala reactivity towards threatening stimuli (angry faces) as assessed by fMRI served as the primary outcome. No treatment main or interaction effects on amygdala threat reactivity were observed, yet OXT switched bilateral amygdala threat sensitization to desensitization and this effect was significantly attenuated during decreased central 5-HT signaling via pretreatment with TRYP -. The present findings provide the first evidence for a role of OXT in threatspecific amygdala desensitization in humans and suggest that these effects are critically mediated by the 5-HT system. OXT may have a therapeutic potential to facilitate amygdala desensitization and adjunct up-regulation of 5-HT neurotransmission may facilitate OXT's anxiolytic potential. The trial was preregistered on clinicaltrials.gov (, ID NCT03426176) .
Chronic intranasal oxytocin administration daily is increasingly proposed as a therapy for social... more Chronic intranasal oxytocin administration daily is increasingly proposed as a therapy for social dysfunction but some clinical trials have reported small or no beneficial outcomes. No empirical evidence proves that this is optimal therapeutically or whether oxytocin receptor genotype influences treatment sensitivity. In a randomized, placebo-controlled pre-registered trial on 138 adult male subjects we investigated effects of single and repeated oxytocin treatment (24IU daily or alternatively days for 5 days). Primary neural outcomes assessed core therapeutic mechanisms of action, i.e. amygdala fear reactivity and amygdala-prefrontal intrinsic functional connectivity and modulation by oxytocin receptor polymorphisms (rs53576, rs2254298). The expected oxytocin-induced reduction in amygdala fear reactivity and associated anxious-arousal following single-dose administration was abolished after daily treatment but maintained when administered every other day. Oxytocin selectively reduced amygdala and arousal fear reactivity in AA homozygotes of rs53576 and A+ carriers of rs2254298. By contrast, oxytocin-enhanced intrinsic amygdala-prefrontal coupling was maintained independent of dose frequency and genotype. Together the findings provide the first evidence that infrequent rather than daily oxytocin administration protocols may be therapeutically most efficient and that its neural and behavioral anxiolytic actions are highly genotype-dependent. .
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2020
Intranasal oxytocin (OXT) has been associated with effects on diverse social-emotional domains in... more Intranasal oxytocin (OXT) has been associated with effects on diverse social-emotional domains in humans, however progress towards a therapeutic application of OXT in disorders with social-emotion impairments is currently hampered by poor replicability. Limited statistical power and individual differences in biological factors, such as oxytocin receptor (OXTR) genetics, may have contributed to these variable findings. To this end, employing a validated oxytocin-sensitive trait judgment paradigm, we present a pharmaco-genetic study aiming at (1) replicating previous findings suggesting that intranasal oxytocin (24 IU) reduces the self-referential bias in a large sample of n = 170 male subjects, (2) determining whether variations in common receptor polymorphisms (rs237887, rs2268491, rs2254298, rs53576, rs2268498) influence sensitivity to oxytocin's behavioral effects. We confirmed that in the whole sample oxytocin influenced self-other distinction in terms of reduced decision time. However, oxytocin only influenced decision time in rs53576 G carriers, whereas effects on subsequent memory performance were only found in rs2268498 TT homozygotes. In summary, the current study partially replicates our previous findings showing that oxytocin reduces the self-referential bias and suggests that sensitivity to its effects in this domain are receptor genotype dependent.
Background: Major Depressive (MDD) and Generalized Anxiety Disorder (GAD) are highly debilitating... more Background: Major Depressive (MDD) and Generalized Anxiety Disorder (GAD) are highly debilitating and often co-morbid disorders. The disorders exhibit partly overlapping dysregulations on the behavioral and neurofunctional level, and the determination of disorder-specific alterations may promote neuro-mechanistic and diagnostic specificity. Methods: In order to determine disorder-specific alterations in the domain of emotion-cognition interactions the present study examined emotional context-specific inhibitory control in treatment-naïve, first-episode MDD (n = 37) and GAD (n = 35) patients and healthy controls (n = 35) by employing a validated affective go/no-go fMRI paradigm. Findings: On the behavioral level MDD but not GAD patients exhibited impaired inhibitory control irrespective of emotional context. On the neural level, no alterations were observed during the positive context, yet specifically MDD patients demonstrated attenuated recruitment of a broad bilateral network encompassing inferior/medial parietal, posterior frontal, and mid-cingulate regions during inhibitory control in the negative context. GAD patients exhibited a stronger engagement of the left dorsolateral prefrontal cortex relative to MDD patients and within the GAD group better inhibitory control in negative contexts was associated with higher recruitment of this region. Interpretation: Findings from the present study suggest disorder-and emotional context-specific behavioral and neurofunctional deficits in inhibitory control in MDD in negative emotional contexts and may point to a depression-specific neuropathological and diagnostic marker. In contrast, GAD patients may maintain intact inhibitory performance via compensatory recruitment of prefrontal regulatory regions.
Touch plays a crucial role in affiliative behavior and social communication. The neuropeptide oxy... more Touch plays a crucial role in affiliative behavior and social communication. The neuropeptide oxytocin is released in response to touch and may act to facilitate the rewarding effects of social touch. However, no studies to date have determined whether oxytocin facilitates behavioral or neural responses to non-socially administered affective touch and possible differential effects of touch valence. In a functional MRI experiment using a randomized placebo-controlled, within-subject design in 40 male subjects we investigated the effects of intranasal oxytocin (24IU) on behavioral and neural responses to positive, neutral and negative valence touch administered to the arm via different types of materials at a frequency aimed to optimally stimulate C-fibers. Results showed that oxytocin significantly increased both the perceived pleasantness of touch and activation of the orbitofrontal cortex independent of touch valence. The effects of OT on touch-evoked orbitofrontal activation were also positively associated with basal oxytocin concentrations in blood. Additionally, anterior insula activity and the functional connectivity between the amygdala and right anterior insula were enhanced only in response to negative valence touch. Overall, the present study provides the first evidence that oxytocin may facilitate the rewarding effects of all types of touch, irrespective of valence.
medRxiv (Cold Spring Harbor Laboratory), Sep 26, 2021
The neuropeptide oxytocin (OXT) can modulate social cognition by facilitating attention towards s... more The neuropeptide oxytocin (OXT) can modulate social cognition by facilitating attention towards social cues and may be a potential therapeutic intervention for social attention impairment in disorders such as autism. Intranasal administration of OXT is widely used to examine its functional effects in both adults and children. However, we have recently shown that administration orally as a lingual spray also modulates neural responses to emotional faces and is potentially better tolerated for therapeutic use. Here, we therefore examined if 24IU OXT administered orally is also effective in facilitating social attention. In a randomized, placebo-controlled, pharmacological study we used a validated emotional antisaccade eye-tracking paradigm to explore effects of oral OXT on bottom-up and top-down attention processing in 80 healthy male subjects. Our findings showed in terms of top-down attention, oral OXT increased both errors and response latencies for all social stimuli (angry, fearful, happy, sad and neutral emotion faces) but not non-social stimuli (oval shape) in the anti-saccade condition. Comparison with our previous intranasal OXT study using the same task paradigm revealed both routes have a similar effect on increasing anti-saccade errors. However, compared with intranasal OXT, oral OXT significantly decreased error rates for social stimuli in the pro-saccade condition, indicative of increased bottom-up attention processing. Additionally, OXT administration both either route produced an anxiolytic effect evidenced by reduced state anxiety scores. Together, these findings suggest that orally administered OXT has a similar effect on top-down social attention control and anxiety as intranasal administration but more potently influences bottom-up control.
Acute and chronic administration of intranasal oxytocin and vasopressin have been extensively uti... more Acute and chronic administration of intranasal oxytocin and vasopressin have been extensively utilized in both animal models and human preclinical and clinical studies over the last few decades to modulate various aspects of social cognition and their underlying neural mechanisms, although effects are not always consistent. The use of an intranasal route of administration is largely driven by evidence that it permits neuropeptides to penetrate directly into the brain by circumventing the blood-brain barrier, which has been considered relatively impermeable to them. However, this interpretation has been the subject of considerable debate. In this review, we will focus on research in both animal models and humans, which investigates the different potential routes via which these intranasally administered neuropeptides may be producing their various effects on social cognition. We will also consider the contribution of different methods of intranasal application and additionally the importance of dose magnitude and frequency for influencing G protein-coupled receptor signaling and subsequent functional outcomes. Overall, we conclude that while some functional effects of intranasal oxytocin and vasopressin in the domain of social cognition may result from direct penetration into the brain following intranasal administration, others may be contributed by the neuropeptides either entering the peripheral circulation and crossing the blood-brain barrier and/or producing vagal stimulation via peripheral receptors. Furthermore, to complicate matters, functional effects via these routes may differ, and both dose magnitude and frequency can produce very different functional outcomes and therefore need to be optimized to produce desired effects.
The International Journal of Neuropsychopharmacology, Jun 1, 2019
Background: While the neuropeptide oxytocin can facilitate empathy and altruistic behavior, it ma... more Background: While the neuropeptide oxytocin can facilitate empathy and altruistic behavior, it may also promote self-serving tendencies in some contexts, and it remains unclear if it would increase altruistic or self-interest behaviors when they compete within a social situation. Methods: The current between-subject, double-blind, placebo-controlled fMRI study investigated the effect of intranasal oxytocin on empathy for social exclusion using a modified online ball-tossing game that incorporated monetary rewards and the potential to display both altruistic and self-interest behaviors. Results: Results showed that when subjects in both oxytocin and placebo groups were observing a player being excluded (victim) by other players in the game, there was activation in the mentalizing network. When subjects then played both with the victim and the players who had excluded them, they threw more balls to the victim player, indicative of an altruistic response. However, subjects in the oxytocin group threw more balls to the excluder players indicative of greater self-interest, since the latter would be perceived as more likely to reciprocate to maximize financial gain. This behavioral effect of oxytocin was associated with greater medial orbitofrontal cortex activation when playing with the excluders and negatively correlated with trait-altruism scores. Conclusions: Overall, our findings suggest that in the context of competing motivations for exhibiting altruistic or selfinterest behavior, oxytocin enhanced self-interest and this was associated with greater activation in frontal reward areas.
The respective roles of the neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) in modula... more The respective roles of the neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) in modulating social cognition and for therapeutic intervention in autism spectrum disorder have not been fully established. In particular, while numerous studies have demonstrated effects of oxytocin in promoting social attention the role of AVP has not been examined. The present study employed a randomized, double-blind, placebo (PLC)-controlled between-subject design to explore the social- and emotion-specific effects of AVP on both bottom-up and top-down attention processing with a validated emotional anti-saccade eye-tracking paradigm in 80 healthy male subjects (PLC = 40, AVP = 40). Our findings showed that AVP increased the error rate for social (angry, fearful, happy, neutral and sad faces) but not non-social (oval shapes) stimuli during the anti-saccade condition and reduced error rates in the pro-saccade condition. Comparison of these findings with a previous study (sample size: PLC = 33, OXT = 33) using intranasal oxytocin revealed similar effects of the two peptides on anti-saccade errors, although with some difference in effects of specific face emotions, but a significantly greater effect of AVP on pro-saccades. Both peptides also produced a post-task anxiolytic effect by reducing state anxiety. Together these findings suggested that both AVP and OXT decrease goal-directed top-down attention control to social salient stimuli but that AVP more potently increased bottom-up social attentional processing.
There is considerable interest in the potential therapeutic role of the neuropeptide oxytocin in ... more There is considerable interest in the potential therapeutic role of the neuropeptide oxytocin in altering attentional bias towards emotional social stimuli in psychiatric disorders. However, it is still unclear whether oxytocin primarily influences attention towards positive or negative valence social stimuli. Here in a double-blind, placebo controlled, between subject design experiment in 60 healthy male subjects we have used the highly sensitive dual-target rapid serial visual presentation (RSVP) paradigm to investigate whether intranasal oxytocin (40IU) treatment alters attentional bias for emotional faces. Results show that oxytocin improved recognition accuracy of neutral and happy expression faces presented in the second target position (T2) during the period of reduced attentional capacity following prior presentation of a first neutral face target (T1), but had no effect on recognition of negative expression faces (angry, fearful, sad). Oxytocin also had no effect on recognition of non-social stimuli (digits) in this task. Recognition accuracy for neutral faces at T2 was negatively associated with autism spectrum quotient (ASQ) scores in the placebo group, and oxytocin's facilitatory effects were restricted to a sub-group of subjects with higher ASQ scores. Our results therefore indicate that oxytocin primarily enhances the allocation of attentional resources towards faces expressing neutral or positive emotion and does not influence that towards negative emotion ones or non-social stimuli. This effect of oxytocin is strongest in healthy individuals with higher autistic trait scores, thereby providing further support for its potential therapeutic use in autism spectrum disorder.
Evidence from animal studies suggests that the social attraction and bonding effects of the neuro... more Evidence from animal studies suggests that the social attraction and bonding effects of the neuropeptide oxytocin (OXT) are mediated by its modulation of dopamine (DA) release in brain reward centers, but this has not yet been demonstrated in humans. DA release can be measured by positron emission tomography (PET) using the radioligand [11C]raclopride. Its binding to DA D2 receptors (D2R) is sensitive and reciprocally related to endogenous DA, especially in the striatum. In a randomized double-blind placebo-controlled within-subjects trial on 18 adult male volunteers we combined [11C]raclopride PET and a facial attractiveness rating task to establish whether intranasal OXT (24 IU) increased both the perceived attractiveness of unfamiliar female faces and striatal DA release compared with placebo administration. While our behavioral data confirmed that subjects rated unfamiliar female faces as more attractive following OXT treatment, and this correlated with an increased perfusion rate in the striatum, there was no evidence for altered [11C]raclopride binding in the striatum or pallidum. Instead under OXT we rather observed an increased [11C]raclopride binding and reduced perfusion rate in subregions of the right dorsomedial prefrontal gyrus and superior parietal Abbreviations: MNI, Montreal Neurological Institute; MRI, magnetic resonance imaging; PET, positron emission tomography.
Shyness and social anxiety are correlated to some extent and both are associated with hyper-respo... more Shyness and social anxiety are correlated to some extent and both are associated with hyper-responsivity to social stimuli in the frontal cortex and limbic system. However to date no studies have investigated whether common structural and functional connectivity differences in the brain may contribute to these traits. We addressed this issue in a cohort of 61 healthy adult subjects. Subjects were first assessed for their levels of shyness (Cheek and Buss Shyness scale) and social anxiety (Liebowitz Social Anxiety scale) and trait anxiety. They were then given MRI scans and voxel-based morphometry and seed-based, resting-state functional connectivity analysis investigated correlations with shyness and anxiety scores. Shyness scores were positively correlated with gray matter density in the cerebellum, bilateral superior temporal gyri and parahippocampal gyri and right insula. Functional connectivity correlations with shyness were found between the superior temporal gyrus, parahippocampal gyrus and the frontal gyri, between the insula and precentral gyrus and inferior parietal lobule, and between the cerebellum and precuneus. Additional correlations were found for amygdala connectivity with the medial frontal gyrus, superior frontal gyrus and inferior parietal lobule, despite the absence of any structural correlation. By contrast no structural or functional connectivity measures correlated with social or trait anxiety. Our findings show that shyness is specifically associated with structural and functional connectivity changes in cortical and limbic regions involved with processing social stimuli. These associations are not found with social or trait anxiety in healthy subjects despite some behavioral correlations with shyness.
medRxiv (Cold Spring Harbor Laboratory), May 22, 2022
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
bioRxiv (Cold Spring Harbor Laboratory), Nov 8, 2021
BackgroundThe hypothalamic neuropeptide oxytocin (OXT) may exert anxiolytic and stress-reducing a... more BackgroundThe 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 fMRI study aimed at determining whether effects of OXT on stress-associated amygdala intrinsic networks are mediated by 5-HT.MethodsWe employed a randomized placebo-controlled double-blind parallel-group pharmacological fMRI resting state experiment during which n = 112 healthy male participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD) or the corresponding placebo-control protocols (ATDc) before the administration of intranasal OXT or placebo intranasal spray, respectively.ResultsOXT 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, while this effect of OXT was significantly attenuated during transiently decreased central serotonergic signaling induced via ATD. 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.ConclusionsTogether, the findings provide first evidence that effects of OXT on stress-associated amygdala-hippocampal-midbrain pathways are critically mediated by the 5-HT system in men.
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Nov 1, 2021
Background Overarching conceptualizations propose that the complex social-emotional effects of ox... more Background Overarching conceptualizations propose that the complex social-emotional effects of oxytocin (OXT) in humans are partly mediated by interactions with other neurotransmitter systems. Recent animal models suggest that the anxiolytic effects of OXT are critically mediated by the serotonin (5-HT) system, yet direct evidence in humans is lacking. To determine the role of 5-HT in OXT-induced attenuation of amygdala threat reactivity and sensitization/ desensitization, we conducted a parallel-group randomized placebo-controlled double-blind experiment during which n = 121 healthy subjects underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD, TRYP -) or the corresponding placebo-control protocols before the administration of intranasal OXT or placebo intranasal spray, respectively. Mean and repetition-dependent changes in threatspecific amygdala reactivity towards threatening stimuli (angry faces) as assessed by fMRI served as the primary outcome. No treatment main or interaction effects on amygdala threat reactivity were observed, yet OXT switched bilateral amygdala threat sensitization to desensitization and this effect was significantly attenuated during decreased central 5-HT signaling via pretreatment with TRYP -. The present findings provide the first evidence for a role of OXT in threatspecific amygdala desensitization in humans and suggest that these effects are critically mediated by the 5-HT system. OXT may have a therapeutic potential to facilitate amygdala desensitization and adjunct up-regulation of 5-HT neurotransmission may facilitate OXT's anxiolytic potential. The trial was preregistered on clinicaltrials.gov (, ID NCT03426176) .
Chronic intranasal oxytocin administration daily is increasingly proposed as a therapy for social... more Chronic intranasal oxytocin administration daily is increasingly proposed as a therapy for social dysfunction but some clinical trials have reported small or no beneficial outcomes. No empirical evidence proves that this is optimal therapeutically or whether oxytocin receptor genotype influences treatment sensitivity. In a randomized, placebo-controlled pre-registered trial on 138 adult male subjects we investigated effects of single and repeated oxytocin treatment (24IU daily or alternatively days for 5 days). Primary neural outcomes assessed core therapeutic mechanisms of action, i.e. amygdala fear reactivity and amygdala-prefrontal intrinsic functional connectivity and modulation by oxytocin receptor polymorphisms (rs53576, rs2254298). The expected oxytocin-induced reduction in amygdala fear reactivity and associated anxious-arousal following single-dose administration was abolished after daily treatment but maintained when administered every other day. Oxytocin selectively reduced amygdala and arousal fear reactivity in AA homozygotes of rs53576 and A+ carriers of rs2254298. By contrast, oxytocin-enhanced intrinsic amygdala-prefrontal coupling was maintained independent of dose frequency and genotype. Together the findings provide the first evidence that infrequent rather than daily oxytocin administration protocols may be therapeutically most efficient and that its neural and behavioral anxiolytic actions are highly genotype-dependent. .
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2020
Intranasal oxytocin (OXT) has been associated with effects on diverse social-emotional domains in... more Intranasal oxytocin (OXT) has been associated with effects on diverse social-emotional domains in humans, however progress towards a therapeutic application of OXT in disorders with social-emotion impairments is currently hampered by poor replicability. Limited statistical power and individual differences in biological factors, such as oxytocin receptor (OXTR) genetics, may have contributed to these variable findings. To this end, employing a validated oxytocin-sensitive trait judgment paradigm, we present a pharmaco-genetic study aiming at (1) replicating previous findings suggesting that intranasal oxytocin (24 IU) reduces the self-referential bias in a large sample of n = 170 male subjects, (2) determining whether variations in common receptor polymorphisms (rs237887, rs2268491, rs2254298, rs53576, rs2268498) influence sensitivity to oxytocin's behavioral effects. We confirmed that in the whole sample oxytocin influenced self-other distinction in terms of reduced decision time. However, oxytocin only influenced decision time in rs53576 G carriers, whereas effects on subsequent memory performance were only found in rs2268498 TT homozygotes. In summary, the current study partially replicates our previous findings showing that oxytocin reduces the self-referential bias and suggests that sensitivity to its effects in this domain are receptor genotype dependent.
Background: Major Depressive (MDD) and Generalized Anxiety Disorder (GAD) are highly debilitating... more Background: Major Depressive (MDD) and Generalized Anxiety Disorder (GAD) are highly debilitating and often co-morbid disorders. The disorders exhibit partly overlapping dysregulations on the behavioral and neurofunctional level, and the determination of disorder-specific alterations may promote neuro-mechanistic and diagnostic specificity. Methods: In order to determine disorder-specific alterations in the domain of emotion-cognition interactions the present study examined emotional context-specific inhibitory control in treatment-naïve, first-episode MDD (n = 37) and GAD (n = 35) patients and healthy controls (n = 35) by employing a validated affective go/no-go fMRI paradigm. Findings: On the behavioral level MDD but not GAD patients exhibited impaired inhibitory control irrespective of emotional context. On the neural level, no alterations were observed during the positive context, yet specifically MDD patients demonstrated attenuated recruitment of a broad bilateral network encompassing inferior/medial parietal, posterior frontal, and mid-cingulate regions during inhibitory control in the negative context. GAD patients exhibited a stronger engagement of the left dorsolateral prefrontal cortex relative to MDD patients and within the GAD group better inhibitory control in negative contexts was associated with higher recruitment of this region. Interpretation: Findings from the present study suggest disorder-and emotional context-specific behavioral and neurofunctional deficits in inhibitory control in MDD in negative emotional contexts and may point to a depression-specific neuropathological and diagnostic marker. In contrast, GAD patients may maintain intact inhibitory performance via compensatory recruitment of prefrontal regulatory regions.
Touch plays a crucial role in affiliative behavior and social communication. The neuropeptide oxy... more Touch plays a crucial role in affiliative behavior and social communication. The neuropeptide oxytocin is released in response to touch and may act to facilitate the rewarding effects of social touch. However, no studies to date have determined whether oxytocin facilitates behavioral or neural responses to non-socially administered affective touch and possible differential effects of touch valence. In a functional MRI experiment using a randomized placebo-controlled, within-subject design in 40 male subjects we investigated the effects of intranasal oxytocin (24IU) on behavioral and neural responses to positive, neutral and negative valence touch administered to the arm via different types of materials at a frequency aimed to optimally stimulate C-fibers. Results showed that oxytocin significantly increased both the perceived pleasantness of touch and activation of the orbitofrontal cortex independent of touch valence. The effects of OT on touch-evoked orbitofrontal activation were also positively associated with basal oxytocin concentrations in blood. Additionally, anterior insula activity and the functional connectivity between the amygdala and right anterior insula were enhanced only in response to negative valence touch. Overall, the present study provides the first evidence that oxytocin may facilitate the rewarding effects of all types of touch, irrespective of valence.
medRxiv (Cold Spring Harbor Laboratory), Sep 26, 2021
The neuropeptide oxytocin (OXT) can modulate social cognition by facilitating attention towards s... more The neuropeptide oxytocin (OXT) can modulate social cognition by facilitating attention towards social cues and may be a potential therapeutic intervention for social attention impairment in disorders such as autism. Intranasal administration of OXT is widely used to examine its functional effects in both adults and children. However, we have recently shown that administration orally as a lingual spray also modulates neural responses to emotional faces and is potentially better tolerated for therapeutic use. Here, we therefore examined if 24IU OXT administered orally is also effective in facilitating social attention. In a randomized, placebo-controlled, pharmacological study we used a validated emotional antisaccade eye-tracking paradigm to explore effects of oral OXT on bottom-up and top-down attention processing in 80 healthy male subjects. Our findings showed in terms of top-down attention, oral OXT increased both errors and response latencies for all social stimuli (angry, fearful, happy, sad and neutral emotion faces) but not non-social stimuli (oval shape) in the anti-saccade condition. Comparison with our previous intranasal OXT study using the same task paradigm revealed both routes have a similar effect on increasing anti-saccade errors. However, compared with intranasal OXT, oral OXT significantly decreased error rates for social stimuli in the pro-saccade condition, indicative of increased bottom-up attention processing. Additionally, OXT administration both either route produced an anxiolytic effect evidenced by reduced state anxiety scores. Together, these findings suggest that orally administered OXT has a similar effect on top-down social attention control and anxiety as intranasal administration but more potently influences bottom-up control.
Acute and chronic administration of intranasal oxytocin and vasopressin have been extensively uti... more Acute and chronic administration of intranasal oxytocin and vasopressin have been extensively utilized in both animal models and human preclinical and clinical studies over the last few decades to modulate various aspects of social cognition and their underlying neural mechanisms, although effects are not always consistent. The use of an intranasal route of administration is largely driven by evidence that it permits neuropeptides to penetrate directly into the brain by circumventing the blood-brain barrier, which has been considered relatively impermeable to them. However, this interpretation has been the subject of considerable debate. In this review, we will focus on research in both animal models and humans, which investigates the different potential routes via which these intranasally administered neuropeptides may be producing their various effects on social cognition. We will also consider the contribution of different methods of intranasal application and additionally the importance of dose magnitude and frequency for influencing G protein-coupled receptor signaling and subsequent functional outcomes. Overall, we conclude that while some functional effects of intranasal oxytocin and vasopressin in the domain of social cognition may result from direct penetration into the brain following intranasal administration, others may be contributed by the neuropeptides either entering the peripheral circulation and crossing the blood-brain barrier and/or producing vagal stimulation via peripheral receptors. Furthermore, to complicate matters, functional effects via these routes may differ, and both dose magnitude and frequency can produce very different functional outcomes and therefore need to be optimized to produce desired effects.
The International Journal of Neuropsychopharmacology, Jun 1, 2019
Background: While the neuropeptide oxytocin can facilitate empathy and altruistic behavior, it ma... more Background: While the neuropeptide oxytocin can facilitate empathy and altruistic behavior, it may also promote self-serving tendencies in some contexts, and it remains unclear if it would increase altruistic or self-interest behaviors when they compete within a social situation. Methods: The current between-subject, double-blind, placebo-controlled fMRI study investigated the effect of intranasal oxytocin on empathy for social exclusion using a modified online ball-tossing game that incorporated monetary rewards and the potential to display both altruistic and self-interest behaviors. Results: Results showed that when subjects in both oxytocin and placebo groups were observing a player being excluded (victim) by other players in the game, there was activation in the mentalizing network. When subjects then played both with the victim and the players who had excluded them, they threw more balls to the victim player, indicative of an altruistic response. However, subjects in the oxytocin group threw more balls to the excluder players indicative of greater self-interest, since the latter would be perceived as more likely to reciprocate to maximize financial gain. This behavioral effect of oxytocin was associated with greater medial orbitofrontal cortex activation when playing with the excluders and negatively correlated with trait-altruism scores. Conclusions: Overall, our findings suggest that in the context of competing motivations for exhibiting altruistic or selfinterest behavior, oxytocin enhanced self-interest and this was associated with greater activation in frontal reward areas.
The respective roles of the neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) in modula... more The respective roles of the neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) in modulating social cognition and for therapeutic intervention in autism spectrum disorder have not been fully established. In particular, while numerous studies have demonstrated effects of oxytocin in promoting social attention the role of AVP has not been examined. The present study employed a randomized, double-blind, placebo (PLC)-controlled between-subject design to explore the social- and emotion-specific effects of AVP on both bottom-up and top-down attention processing with a validated emotional anti-saccade eye-tracking paradigm in 80 healthy male subjects (PLC = 40, AVP = 40). Our findings showed that AVP increased the error rate for social (angry, fearful, happy, neutral and sad faces) but not non-social (oval shapes) stimuli during the anti-saccade condition and reduced error rates in the pro-saccade condition. Comparison of these findings with a previous study (sample size: PLC = 33, OXT = 33) using intranasal oxytocin revealed similar effects of the two peptides on anti-saccade errors, although with some difference in effects of specific face emotions, but a significantly greater effect of AVP on pro-saccades. Both peptides also produced a post-task anxiolytic effect by reducing state anxiety. Together these findings suggested that both AVP and OXT decrease goal-directed top-down attention control to social salient stimuli but that AVP more potently increased bottom-up social attentional processing.
There is considerable interest in the potential therapeutic role of the neuropeptide oxytocin in ... more There is considerable interest in the potential therapeutic role of the neuropeptide oxytocin in altering attentional bias towards emotional social stimuli in psychiatric disorders. However, it is still unclear whether oxytocin primarily influences attention towards positive or negative valence social stimuli. Here in a double-blind, placebo controlled, between subject design experiment in 60 healthy male subjects we have used the highly sensitive dual-target rapid serial visual presentation (RSVP) paradigm to investigate whether intranasal oxytocin (40IU) treatment alters attentional bias for emotional faces. Results show that oxytocin improved recognition accuracy of neutral and happy expression faces presented in the second target position (T2) during the period of reduced attentional capacity following prior presentation of a first neutral face target (T1), but had no effect on recognition of negative expression faces (angry, fearful, sad). Oxytocin also had no effect on recognition of non-social stimuli (digits) in this task. Recognition accuracy for neutral faces at T2 was negatively associated with autism spectrum quotient (ASQ) scores in the placebo group, and oxytocin's facilitatory effects were restricted to a sub-group of subjects with higher ASQ scores. Our results therefore indicate that oxytocin primarily enhances the allocation of attentional resources towards faces expressing neutral or positive emotion and does not influence that towards negative emotion ones or non-social stimuli. This effect of oxytocin is strongest in healthy individuals with higher autistic trait scores, thereby providing further support for its potential therapeutic use in autism spectrum disorder.
Evidence from animal studies suggests that the social attraction and bonding effects of the neuro... more Evidence from animal studies suggests that the social attraction and bonding effects of the neuropeptide oxytocin (OXT) are mediated by its modulation of dopamine (DA) release in brain reward centers, but this has not yet been demonstrated in humans. DA release can be measured by positron emission tomography (PET) using the radioligand [11C]raclopride. Its binding to DA D2 receptors (D2R) is sensitive and reciprocally related to endogenous DA, especially in the striatum. In a randomized double-blind placebo-controlled within-subjects trial on 18 adult male volunteers we combined [11C]raclopride PET and a facial attractiveness rating task to establish whether intranasal OXT (24 IU) increased both the perceived attractiveness of unfamiliar female faces and striatal DA release compared with placebo administration. While our behavioral data confirmed that subjects rated unfamiliar female faces as more attractive following OXT treatment, and this correlated with an increased perfusion rate in the striatum, there was no evidence for altered [11C]raclopride binding in the striatum or pallidum. Instead under OXT we rather observed an increased [11C]raclopride binding and reduced perfusion rate in subregions of the right dorsomedial prefrontal gyrus and superior parietal Abbreviations: MNI, Montreal Neurological Institute; MRI, magnetic resonance imaging; PET, positron emission tomography.
Shyness and social anxiety are correlated to some extent and both are associated with hyper-respo... more Shyness and social anxiety are correlated to some extent and both are associated with hyper-responsivity to social stimuli in the frontal cortex and limbic system. However to date no studies have investigated whether common structural and functional connectivity differences in the brain may contribute to these traits. We addressed this issue in a cohort of 61 healthy adult subjects. Subjects were first assessed for their levels of shyness (Cheek and Buss Shyness scale) and social anxiety (Liebowitz Social Anxiety scale) and trait anxiety. They were then given MRI scans and voxel-based morphometry and seed-based, resting-state functional connectivity analysis investigated correlations with shyness and anxiety scores. Shyness scores were positively correlated with gray matter density in the cerebellum, bilateral superior temporal gyri and parahippocampal gyri and right insula. Functional connectivity correlations with shyness were found between the superior temporal gyrus, parahippocampal gyrus and the frontal gyri, between the insula and precentral gyrus and inferior parietal lobule, and between the cerebellum and precuneus. Additional correlations were found for amygdala connectivity with the medial frontal gyrus, superior frontal gyrus and inferior parietal lobule, despite the absence of any structural correlation. By contrast no structural or functional connectivity measures correlated with social or trait anxiety. Our findings show that shyness is specifically associated with structural and functional connectivity changes in cortical and limbic regions involved with processing social stimuli. These associations are not found with social or trait anxiety in healthy subjects despite some behavioral correlations with shyness.
medRxiv (Cold Spring Harbor Laboratory), May 22, 2022
doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by pee... more doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
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