Oxytocin Attenuates Affective Evaluations of Conditioned Faces and Amygdala Activity

“Thus, an oxytocin effect in humans should be evident in altered behavior (Kosfeld et al., 2005) and also in how we affectively experience others.”

“One expression of this is augmentation of activity in fusiform face area (FFA) to fearful facial expressions (Vuilleumier and Pourtois, 2007), in addition to influences on subcortical and brainstem structures involved in behavioral fear responses (Davis and Whalen, 2001).”

“Oxytocin effects on affective evaluations In line with previous studies in which oxytocin was administrated externally (Pitman et al., 1993; Heinrichs et al., 2003, 2004; Kirsch et al., 2005; Kosfeld et al., 2005; Domes et al., 2007a), we did not observe any significant effect on mood ratings…”

“We used a sequence with axial slices tilted by 30° and a flip angle of 90° that reduces signal dropout attributable to susceptibility-induced field inhomogeneities in amygdala and orbitofrontal cortex (Obfc) (Deichmann et al., 2002).”

“In the placebo group, we observed increased activity in the extended/dorsal amygdala and in other regions previously shown to be involved in fear conditioning and extinction such as insula, Obfc, and ACC (Gottfried and Dolan, 2004; Phelps et al., 2004; Kalisch et al., 2006; Milad et al., 2007).”

“Importantly, the amygdala, a brain area that has been implicated in the processing of social cues that denote threat [51], is also rich in OT receptors and its activity here tends to be reduced by OT administration upon exposure to threatening stimuli [18], [16], [17].”

“Finally, OT can attenuate the effect of aversive conditioned responses to neutral faces, associated with activity in the anterior cingulate gyrus and right medial temporal lobe (Petrovic et al., 2008).”

“, 2005) and which could be replicated in several studies using different stimulation paradigms (e.g., Domes et al., 2007; Baumgartner et al., 2008; Petrovic et al., 2008).”

“Converging evidence indicates an anxiolytic potential of intranasal OXT reflected by reduced amygdala responses but increased amygdala–prefrontal cortex (PFC) functional connectivity in response to threatening stimuli in healthy adults (Domes et al., 2007; Eckstein et al., 2015; Petrovic et al., 2008; Striepens et al.…”

“Intranasal administration of OT affects nodes within the extinction neurocircuit, including increasing medial prefrontal cortex (mPFC) activation and decreasing amygdala activity.[10, 11] Further, OT increases resting-state connectivity between these nodes.”

“For example, intranasal oxytocin was found to attenuate amygdala responses related to threatening scenes (12) and to conditioned fear of faces (13).”

“We chose a 30 UI dose of oxytocin because several recent studies used higher doses than the common 24 IU (Petrovic et al., 2008; Singer et al., 2008; Ditzen et al., 2009; Feifel et al., 2010; Mikolajczak et al., 2010) and because the original experiment that provided evidence that intranasally…”

“OT binding in animals is associated with the modulation of midbrain dopamine and serotonin (Pfister and Muir, 1989; Liu and Wang, 2003).”

“Using fMRI to image brain activity, several studies have found reductions of amygdala activation among male participants in response to different facial expressions after oxytocin compared to placebo administration (Domes et al., 2007a; Kirsch et al., 2005; Meyer-Lindenberg, 2008; Petrovic et al., 2008), although some…”

“2008), OXT also abolishes the negative evaluation of aversely conditioned faces by attenuating ACC and amygdala response (Petrovic et al., 2008).”

“…is the evolutionarily highly conserved hypothalamic peptide oxytocin (OXT), which modulates neural activity in both the fusiform face area (Petrovic et al., 2008) and amygdala (Domes et al., 2010; Eckstein et al., 2014a; Striepens et al., 2012) and is currently being assessed for its…”

“In addition to the promising avenues for OT in ASD, there are increasing evidence for the role of OT in reducing anxiety, fear, and stress, in part by dampening amygdala activity (Bethlehem et al. 2013; Domes et al. 2007a; Labuschagne et al. 2010; Meyer-Lindenberg et al. 2011; Petrovic et al. 2008).”

“The reduction in the SCRs observed in the NT group might be due to attenuated amygdala activity after oxytocin treatment, which has been reported for face processing in previous studies [43-46].”

“…emotional behavior: in particular, oxytocin increases trust (Kosfeld et al., 2005; Baumgartner et al., 2008), reduces amygdala activation upon exposure to aversive stimuli (Kirsch et al., 2005; Singer et al., 2008), and attenuates affective evaluations of conditioned faces (Petrovic et al., 2008).”

“In several clinical studies [188-190], presentation of fear stimuli to normal controls, including aversive pictures such as emotional facial expressions, increased activity in the amygdala.”

“…studies suggest that intranasal OT decreases amygdala activity in males (Domes et al., 2007; Kirsch et al., 2005; Labuschagne et al., 2010; Petrovic et al., 2008; Quintana et al., 2016b), it appears to increase amygdala activity in females, even when controlling for menstrual cycle phase…”

“, 2009), and intranasal administration of oxytocin appears to facilitate empathic responding and cooperation (Kirsch et al., 2005; Kosfeld et al., 2005; Baumgartner et al., 2008; Guastella et al., 2008; Petrovic et al., 2008; De Dreu et al., 2010; De Dreu, 2012a; Israel et al., 2013).”

“In general, these studies suggest that OXT “dampens” the activity of amygdala and thus may have a prosocial effect by either reducing negative reactions to social cues and/or reducing (aversive) associative learning in response to socially relevant cues (Petrovic et al., 2008).”

“Previous studies have extensively examined effects of OT in terms of the initial instinct to trust or fear in the absence of (known) prior information (Kirsch et al., 2005; Kosfeld et al., 2005; Baumgartner et al., 2008; Petrovic et al., 2008).”

“Likewise, intranasal administration of oxytocin has been shown to attenuate the amygdala’s response to faces (Domes et al., 2007; Gamer et al., 2010; Koch et al., 2015), fear inducing stimuli (Kirsch et al., 2005; Petrovic et al., 2008), and betrayals of trust (Baumgartner et al., 2008).”

“Three (Bertsch et al., 2013; Gamer et al., 2010; Petrovic et al., 2008) showed modulation of the amygdala, while two (Petrovic et al.”

“By the same token, successful fear conditioning of neutral faces has been shown previously (e.g., Davis, Johnstone, Mazzulla, Oler, & Whalen, 2010; Pejic, Hermann, Vaitl, & Stark 2013; Petrovic et al., 2008), suggesting that fear conditioning of face cues itself represents a strong affective manipulation irrespective…”

“In typically developing male participants, amygdala activation is attenuated in response to faces (Petrovic et al. 2008); however, typically developing female participants exhibit the opposite pattern (Herpertz et al. 2010).”

“Oxytocin is heavily involved in the processing of negative social stimuli in humans (Kirsch et al., 2005; Petrovic et al., 2008; Labuschagne et al., 2010) and increasing evidence demonstrates Address for correspondence: R. Clark-Elford or Pradeep J. Nathan, Department of Psychiatry, University of…”

“…that have reported response times indicate that OT slows response times when subjects are making reward-sharing decisions (Chang et al., 2012), classifying emotional stimuli (Petrovic et al., 2008; Di Simplicio et al., 2009), or making decisions to seek social information (Ebitz et al., 2013).”

“Previous studies with adult faces have proposed various mechanisms explaining the effects of oxytocin on enhanced emotion recognition, such as modulation of eye gaze [24,41,42], decreased effortful processing of affective information [43], wider pupil dilatation [44], or decreased amygdala activation [45,46].”

“…possible interpretations pertain to the role of OT in increasing approach-related behaviors (Kemp & Guastella, 2011), abolishing negative affect (Petrovic et al. 2008) and increasing attention to socially relevant information (Leknes et al. 2013), which together constitute mechanisms that could…”

“Administration of oxytocin may dampen neural systems subserving social fear (Kirsch et al., 2005; Petrovic et al., 2008), which might reduce aversion to betrayal (Baumgartner et al.”

“Additionally, some groups have reported attenuation of aversive conditioning of fearconditioned face stimuli following intranasal oxytocin (32 IU) administration [55].”

“The amygdala plays a major role in social decision making [98,99].”

“In men, OT reduces amygdala activation in response to emotional face processing and perception of threatening situations (Kirsch et al., 2005; Domes et al., 2007; Petrovic et al., 2008; Singer et al., 2008), whereas the converse is seen in women (Domes et al.”

“…aremore rationalwhen they couple reward (in the formof amonetary pay-off) with faces (Evans et al., 2010), and they are more able to accurately rate the likability of faces, regardless of whether or not the participants had previously been conditioned to fear them (Petrovic et al., 2008).”

“Several brain imaging studies point to an inhibition of amygdala activity following OT infusion in humans (Kirsch et al., 2005; Petrovic et al., 2008).”

“Oxytocin has also been demonstrated to be anxiolytic, modulating activation in the amygdala, the hypothalamic–pituitary–adrenal axis, and the ACC (Carter, 1998; Kirsch et al., 2005; Tops et al., 2007; Baumgartner et al., 2008; Petrovic et al., 2008).”

“, 2003) For example, INOT have shown varying effects on social outcome measures such as face processing (Fischer- Shofty et al., 2010; Petrovic et al., 2008; Rimmele et al., 2009), empathy (Domes et al.”

“2005), reduces fear and anxiety (Heinrichs et al. 2003; Kirsch et al. 2005; Petrovic et al. 2008), enhances social memory (Guastella et al.”

“…et al. , 2013) or approach-withdrawal (Ditzen et al. , 2009; Kemp and Guastella, 2011) mechanism, is supported by several lines of neuroimaging and behavioural evidence (Petrovic et al. , 2008; Shamay-Tsoory et al. , 2009; Gamer et al. , 2010; De Dreu et al. , 2010, 2011; Bartz et al. , 2011).”

“In humans, oxytocin is known as a strong modulator of social behavior and increases gaze to eye regions, social cognition, social memory, empathy, perceptions of trustworthiness, and cooperation within one’s own group (Bartz et al., 2010; Baumgartner et al., 2008; De Dreu et al., 2010; Domes et al., 2010; Di Simplicio…”

“Others also demonstrated an oxytocindriven modulation of distributed neuronal networks for social cognition, in which the amygdala played a central role [6,18,43].”

“For example, in women exposed to infant crying, intranasal oxytocin modulates activity in the inferior frontal gyrus (Riem et al., 2011), fathers given oxytocin rather than placebo stimulate their toddler's exploration more and show less hostility (Naber et al., 2010), and in males exposed to…”

“A related line of research has examined the ability of oxytocin to enhance fear extinction and ameliorate exacerbated responses to conditioned stimuli among individuals with anxiety disorders and PTSD (Acheson et al., 2013; Eckstein et al., 2014; Petrovic et al., 2008).”

“Depending on the paradigrn studied, there may also be reduced coupling of amygdala to brainstem regions involved in the fear response (Figure 1)(24) or decreased activation in regions involved in facial recognition (Figure 2).(27) However, such findings may differ in males and females.”

“The potential benefits of oxytocin administration are further supported by findings that in healthy adults, oxytocin administration also increased trust for strangers [15] and improved perception of how sympathetic someone was deemed to be after a threatening experience with him or her [20].”

“First, several studies have found that oxytocin administration reduces the normal increase in amygdala activation associated with the perception of threatening situations (e.g., Petrovic et al., 2008; Singer et al., 2008).”

“, 2015) and human studies (Kanat et al., 2015; Petrovic et al., 2008) suggest that oxytocin impacts salience processing via modulation of amygdala activity.”

“Unauthorized reproduction of this article is prohibited. related to decreased reactivity to threat-related faces or stimuli in men (Baumgartner et al., 2008, Petrovic et al., 2008).”

“1 3 in electrodermal research skin conductance responses were typically measured only from the non-dominant hand, and these values were considered as valid measurements of arousal for the whole body (Hempel et al. 2005; Lane et al. 1997; Petrovic et al. 2008; Kekecs et al. 2016).”

“Further, OT decreases cortisol stress responses induced by negative social interactions (Ditzen et al., 2009; Linnen et al., 2012), and attenuates amygdala responses to negative stimuli (Kirsch et al., 2005; Petrovic et al., 2008).”

“…of oxytocin when patients played several variations of a neuroeconomic game, as well as subsequent neuroimaging experiments of fear (Kirsch et al., 2005), conditioned fear (Petrovic et al., 2008), and fearful faces (Domes et al., 2007; Gamer et al., 2010), seemed initially to support this model.”

“These ROIs were chosen due to their crucial role in face processing and their sensitivity to OT during social-related tasks [49, 56, 59, 50, 57, 58, 61].”

“…trained using the pairing of a mild shock with images of people directing their gaze towards or away from the observer show suppression of amygdala activity when given intranasal oxytocin; the suppression is even greater for images with direct rather than indirect gaze (Petrovic et al., 2008).”

“2012a, b), reduces conditioned negative responses (Petrovic et al. 2008), and facilitates extinction recall (Acheson et al.”

“In (team) sports, the ability to recognize emotions accurately is important, because it is essential for the communication of social goals and intentions between team members.”

“Altered activation of other brain areas, including the hippocampus, the insula, the anterior cingulate cortex (ACC), and the orbitofrontal cortex, has also been reported in response to the presentation of social stimuli with either positive or negative values, after acute intranasal OT administration (Labuschagne et a…”

“…stimuli like negative facial expressions (Kirsch et al., 2005; Domes et al., 2007; Gamer et al., 2010) and attenuated the deterioration of ratings of likeability for male faces induced by aversive conditioning, likewise in parallel to a reduction in amygdala activation (Petrovic et al., 2008).”

“…2015; Hou et al., 2015; Eckstein et al., 2016), and enhanced extinction recall, indicated by reduced startle responses to the CS (Acheson et al., 2013), or in attenuated negative evaluation of previously fear conditioned faces, when being administered after conditioning (Petrovic et al., 2008).”