Neural substrates underlying the effects of oxytocin: a quantitative meta-analysis of pharmaco-imaging studies

Abstract The hypothalamic peptide oxytocin (OT) is crucial in social adaptation and used to treat emotional and social deficits. Here, we conducted a systematic, quantitative meta-analysis of functional-MRI studies intranasally administering OT (IN-OT) to uncover neural substrates underlying the IN-OT effects and to elucidate differential IN-OT effects between healthy and clinical populations. Meta-analyses were conducted on 66 IN-OT fMRI studies, stratified by psychopathology, valence and sex. IN-OT increased bilateral amygdala, caudate head, and superior temporal activity in healthy individuals and increased dorsal anterior cingulate activity in patients. Moreover, IN-OT decreased amygdala activity in both patients and healthy individuals but did so to a greater degree in patients than healthy individuals. The OT-increased amygdala activity was only found on the negative social and affective processes, whereas the OT-decreased amygdala activity was mainly contributed by contrasts on negative-valenced processes. IN-OT increased parahippocampal activity and decreased amygdala activity during negative socio-affective processing. During positive socio-affective processes, IN-OT increased caudate head activity. This study indicates convergent neural substrates and the underlying neuropsychological mechanisms for IN-OT effects on social and affective processes. The common and different effects of IN-OT on patients and healthy individuals and the modulation of OT effects by valence have critical implications. oxytocin, social adaptation, fMRI, amygdala, meta-analysis Introduction The neuropeptide oxytocin (OT), an evolutionarily ancient neuropeptide and neuromodulator, is an important molecular substrate for social adaptation due to its effects on social and emotional functioning. Moreover, OT is emerging as a pharmacological target for the treatment of mental disorders characterized by social or emotional deficits (Heinrichs et al., 2009; Meyer-Lindenberg et al., 2011; Bakermans-Kranenburg and van Ijzendoorn, 2013; Stavropoulos and Carver, 2013; Ma et al., 2016a). Previous studies have shown consistent effects of OT on various social and emotional processes (such as emotion recognition and in-group cooperation), as well as controversial OT effects on some other processes (e.g. minding-reading and trust). Discrepant effects of intranasal administration of OT (IN-OT) have been reported in some social cognitive and affective processes. For example, whereas several studies have shown that IN-OT increases trust (Kosfeld et al., 2005; Baumgartner et al., 2008; Mikolajczak et al., 2010; Klackl et al., 2013), other studies have shown that IN-OT does not influence or even decreases trust (Barraza, 2010; Ebert et al., 2013; Yao et al., 2014). The discrepant or even opposing effects of IN-OT have been proposed to result from contextual factors and personal characteristics (Bartz et al., 2011; Ma et al., 2016a), such as the cooperative-competitive context and personality traits. However, convergent IN-OT effects on some social and affective processes have been observed in previous empirical studies and confirmed by several meta-analyses. IN-OT has been reliably shown to improve facial emotional recognition (e.g. Guastella et al., 2008; Marsh et al., 2010; Domes et al., 2014) and to promote in-group cooperation (e.g. De Dreu et al., 2010, 2011; De Dreu, 2012; Ma et al., 2015a). Moreover, several recent meta-analyses on the behavioral effects of IN-OT have confirmed convergent effects of IN-OT on facial emotional recognition, in-group cooperation, and stress responses (van IJzendoorn and Bakermans-Kranenburg, 2012; Shahrestani et al., 2013; Cardoso et al., 2014). The effects of OT are due to its role as a neuromodulator in the brain (Neumann, 2007; Bartz and Hollander, 2008); hence, numerous functional MRI studies have examined the effects of IN-OT on social cognitive and affective processes. However, the issues regarding the discrepant effects of IN-OT, the modulations of OT effects by personal milieu and context, and the potential differences in OT effects between healthy and patient groups have challenged the enthusiasm toward the translational potentials of OT (Bartz et al., 2011; Meyer-Lindenberg et al., 2011). The current meta-analysis first applied the activation likelihood estimation (ALE) technique for quantitative coordinate-based meta-analyses of pharmacological neuroimaging studies that have compared IN-OT vs placebo (PL) to reveal convergent neural substrates underlying the effects of IN-OT. IN-OT has been shown to either increase or decrease brain responses during social and affective processing (Zink and Meyer-Lindenberg, 2012; Bethlehem et al., 2013). Therefore, a meta-analytic perspective on IN-OT fMRI findings is critically needed in the field to determine whether there are convergent neural substrates underlying the IN-OT effects. There have been two meta-analyses of OT fMRI studies (Rocchetti et al., 2014; Wigton et al., 2015), both including only 11 OT fMRI studies (published before February 2013). The limited number of OT fMRI studies at that time constrained the analyses and findings. Due to the multifaceted positive effects of IN-OT and its potential in clinical trials, a rapidly increasing number of pharmaco-fMRI studies have examined the effects of IN-OT since 2013. The current meta-analysis of 66 pharmaco-fMRI studies (published before March 2017) sought to reveal convergent activity mediating IN-OT effects on social and affective processes. Second, we sought to elucidate unspecified neuropsychological mechanisms underlying IN-OT effect. Different mechanisms have been proposed (Bartz et al., 2011; Weisman and Feldman, 2013) to explain the OT effects. Recently, in the social adaptation model, OT has been proposed to promote social functioning through different neuropsychological mechanisms, including reduction of negative affect, promotion of rewarding experiences from positive social interaction, and heightened social salience (Ma et al., 2016a). Thus, we applied separate ALE meta-analyses to examine the IN-OT effects on positive and negative social and affective processing, serving as a quantitative examination of these mechanisms. Third, we sought to examine the IN-OT effects on clinical and healthy populations separately. Most previous OT fMRI studies have examined neural substrates mediating OT effects in the healthy population. The effects of IN-OT have been shown to be modulated by cognitive style (Ma et al., 2015a), attachment style (Bartz et al., 2010), personality traits (Scheele et al., 2014; Perry et al., 2015; Ma et al., 2016b), social support (Winslow and Insel, 2004), and early life experiences (Meinlschmidt and Heim, 2007; Riem et al., 2014). These factors may differ between clinical and healthy populations (MacDonald and Feifel, 2013). Therefore, a key issue for OT translation is to reveal the common and differential IN-OT effects (...truncated)