Effects of oxytocin administration and conditioned oxytocin on brain activity: An fMRI study

It has been demonstrated that secretion of several hormones can be classically conditioned, however, the underlying brain responses of such conditioning have never been investigated before. In this study we aimed to investigate how oxytocin administration and classically conditioned oxytocin influence brain responses. In total, 88 females were allocated to one of three groups: oxytocin administration, conditioned oxytocin, or placebo, and underwent an experiment consisting of three acquisition and three evocation days. Participants in the conditioned group received 24 IU of oxytocin together with a conditioned stimulus (CS) during t

Oxytocin and cancer: An emerging link

The neuropeptide hormone oxytocin, which is released from the posterior pituitary gland, is involved in a number of physiological processes. Understanding of its effects is gradually increasing due to new research in this area. While mostly recognized as a reproductive system hormone, oxytocin also regulates other organ systems such as the brain and cardiovascular system. Recently, research has focused on unraveling its involvement in cancer, and emerging evidence suggests a potential role for oxytocin as a cancer biomarker. This review summarizes observations linking oxytocin and cancer, with a special emphasis on prostate cancer, where it may promote cell proliferation. Research suggests that oxytocin effects may depend on cell type, concentration of the hormone, its interactions with other hormones in the microenvironment, and the precise localization of its receptor on the cell membrane. Future research is needed to further elucidate the involvement of oxytocin in cancer, and whether it could be a clinical cancer biomarker or therapeutic target

ERP-tutkimus oksitosiinihormonin vaikutuksista tunteiden havaitsemiseen pienten lasten äideillä

Vanhemman sensitiivisyydellä tarkoitetaan vanhemman taitoa lukea tarkasti lapsensa tuottamia vihjeitä sekä kykyä vastata näihin vihjeisiin nopeasti ja tarkasti. Oksitosiinihormonin puolestaan tiedetään liittyvän hoivakäyttäytymiseen, kuten hellään kosketukseen ja positiiviseen tunneilmaisuun. Sekä vanhemman sensitiivisyydellä että oksitosiinihormonilla on olennainen rooli kiintymyssuhteen muodostumisessa. Näin ollen onkin tärkeää saada tietoa siitä, kuinka oksitosiini vaikuttaa vanhemman herkkyyteen havaita lapsen kasvot ja kasvojen tunneilmaisut. Tutkimuksessa selvitettiin, miten intranasaalisen oksitosiinin antaminen vaikuttaa kasvojen havaitsemiseen pienten lasten äideillä. Tutkimuksen tarkoitus oli selvittää, ovatko intranasaalisen oksitosiinin vaikutukset kasvojen havaitsemiseen erilaiset riippuen kasvojen iästä ja tunneilmaisusta. Satunnaistettuun kaksoissokkotutkimukseen osallistui yhteensä 52 äitiä, joiden lapset olivat 12-17 kuukauden ikäisiä. Äidit kävivät tutkittavana kaksi kertaa, joista toisella kerralla he saivat nenäsuihkeena lumevalmistetta, toisella kerralla oksitosiinihormonia. Äitien tehtävänä oli tunnistaa näytöllä esitettyjä kasvokuvia, jotka kuuluivat neljään eri kategoriaan: vauvan iloiset kasvot, vauvan surulliset kasvot, aikuisen iloiset kasvot ja aikuisen surulliset kasvot. Samalla mitattiin äitien aivoaktivaatiota kasvokuviin elektroenkefalografiaa (EEG) hyödyntäen. ERP-menetelmällä mitattiin N170-, EPN- ja LPP-jännitevasteita, joiden tiedetään liittyvän keskeisesti kasvojen prosessointiin. Ensimmäinen hypoteesi oli, että äitien vasteet ovat voimakkaampia vauvojen kuin aikuisten kasvokuviin, ja surullisiin kuin iloisiin kasvokuviin. Toinen hypoteesi oli, että vasteet vauvojen kasvoihin ovat voimakkaampia oksitosiini- kuin lumetilanteessa. Kolmas hypoteesi oli, että oksitosiinitilanteessa vahvistuisivat vasteet erityisesti vauvojen surullisiin tunneilmaisuihin. Lisäksi oletettiin, että äidin kiintymyssuhdemielikuvat omasta äitisuhteestaan voivat moderoida sitä, kuinka intranasaalinen oksitosiini häneen vaikuttaa. Näin ollen neljäs hypoteesi oli, että oksitosiini voimistaisi vasteita enemmän äideillä, joilla oli alhaiset välttelevän ja ahdistuneen kiintymyksen pistemäärät. Tutkimuksessa saatiin osittain hypoteeseja tukevia tuloksia. Surulliset kasvot synnyttivät iloisia kasvoja voimakkaammat N170- ja EPN-vasteet. EPN-vaste oli voimakkaampi vauvojen kuin aikuisten kasvokuviin, kun taas N170-vasteeseen kasvojen iällä ei ollut vaikutusta. EPN- ja N170-vasteet olivat voimakkaimmat vauvan surullisiin tunneilmaisuihin. Oksitosiinin havaittiin yleisesti voimistavan EPN-vastetta, kun taas N170-vasteeseen sillä oli marginaalinen, vastetta heikentävä vaikutus. Oksitosiini heikensi N170- ja EPN-vastetta vauvan surullisiin tunneilmaisuihin. Lisäksi oikean aivopuoliskon EPN-vaste oli aikuisten kasvot nähtäessä heikompi oksitosiini- kuin lumetilanteessa. LPP-vasteeseen kasvojen iällä, tunneilmaisulla tai oksitosiinilla ei ollut vaikutusta. Tutkittavien oman äitisuhteen kiintymyssuhdemielikuvien havaittiin muuntavan oksitosiinin vaikutusta; tutkittavilla, joilla oman äitisuhteen välttelevät ja ahdistuneet kiintymyssuhdemielikuvat olivat vähäisiä, oksitosiini heikensi EPN-vastetta. Äideillä, joilla välttelevät kiintymyssuhdemielikuvat olivat vähäisiä, oksitosiini heikensi EPN-vastetta erityisesti vauvan surullisiin tunneilmaisuihin. Tutkimuksen tulokset viittaavat siihen, että oksitosiinihormoni vaikuttaa äitien aivoaktivaatioon heidän havainnoidessaan kasvoja ja niillä esiintyviä tunteita

Oxytocin reduces neural activity in the pain circuitry when seeing pain in others

Our empathetic abilities allow us to feel the pain of others. This phenomenon of vicarious feeling arises because the neural circuitry of feeling pain and seeing pain in others is shared. The neuropeptide oxytocin (OXT) is considered a robust facilitator of empathy, as intranasal OXT studies have repeatedly been shown to improve cognitive empathy (e.g. mind reading and emotion recognition). However, OXT has not yet been shown to increase neural empathic responses to pain in others, a core aspect of affective empathy. Effects of OXT on empathy for pain are difficult to predict, because OXT evidently has pain-reducing properties. Accordingly, OXT might paradoxically decrease empathy for pain. Here, using functional neuroimaging we show robust activation in the neural circuitry of pain (insula and sensorimotor regions) when subjects observe pain in others. Crucially, this empathy-related activation in the neural circuitry of pain is strongly reduced after intranasal OXT, specifically in the left insula. OXT on the basis of our neuroimaging data thus remarkably decreases empathy for pain, but further research including behavioral measures is necessary to draw definite conclusions

Oxytocin reduces neural activity in the pain circuitry when seeing pain in others

Our empathetic abilities allow us to feel the pain of others. This phenomenon of vicarious feeling arises because the neural circuitry of feeling pain and seeing pain in others is shared. The neuropeptide oxytocin (OXT) is considered a robust facilitator of empathy, as intranasal OXT studies have repeatedly been shown to improve cognitive empathy (e.g. mind reading and emotion recognition). However, OXT has not yet been shown to increase neural empathic responses to pain in others, a core aspect of affective empathy. Effects of OXT on empathy for pain are difficult to predict, because OXT evidently has pain-reducing properties. Accordingly, OXT might paradoxically decrease empathy for pain. Here, using functional neuroimaging we show robust activation in the neural circuitry of pain (insula and sensorimotor regions) when subjects observe pain in others. Crucially, this empathy-related activation in the neural circuitry of pain is strongly reduced after intranasal OXT, specifically in the left insula. OXT on the basis of our neuroimaging data thus remarkably decreases empathy for pain, but further research including behavioral measures is necessary to draw definite conclusions

Frontotemporal dementia, music perception and social cognition share neurobiological circuits:A meta-analysis

Frontotemporal dementia (FTD) is a neurodegenerative disease that presents with profound changes in social cognition. Music might be a sensitive probe for social cognition abilities, but underlying neurobiological substrates are unclear. We performed a meta-analysis of voxel-based morphometry studies in FTD patients and functional MRI studies for music perception and social cognition tasks in cognitively normal controls to identify robust patterns of atrophy (FTD) or activation (music perception or social cognition). Conjunction analyses were performed to identify overlapping brain regions. In total 303 articles were included: 53 for FTD (n = 1153 patients, 42.5% female; 1337 controls, 53.8% female), 28 for music perception (n = 540, 51.8% female) and 222 for social cognition in controls (n = 5664, 50.2% female). We observed considerable overlap in atrophy patterns associated with FTD, and functional activation associated with music perception and social cognition, mostly encompassing the ventral language network. We further observed overlap across all three modalities in mesolimbic, basal forebrain and striatal regions. The results of our meta-analysis suggest that music perception and social cognition share neurobiological circuits that are affected in FTD. This supports the idea that music might be a sensitive probe for social cognition abilities with implications for diagnosis and monitoring

Effects of hormones, genetics, and sex on typical and atypical brain organization

The first part of this thesis discusses developmental influences on the human connectome in relation to autism and attention deficit hyperactivity disorder (ADHD), conditions associated with alterations in brain connectivity and marked by social impairments. It reports an experiment investigating whether the connectomes of individuals with autism or ADHD differ from the connectome of neurotypical individuals, and what the underlying genetic basis could be for any differences in neural architecture. Chapter 2 reports an analysis of networks in children with autism or ADHD, using structural covariance magnetic resonance imaging (scMRI). We found overlapping as well as distinct network features across both conditions. Chapter 3 reports an analysis of how gene expression might be associated with the basic building blocs of these structural covariance networks. We found that synaptic and transcriptionally downregulated genes were replicably associated with cortical thickness differences in children with autism, but not in children with ADHD. In addition, the first part also aims to elucidate the potential modulation effects of sex on autism neurobiology. Chapter 4 reports an analysis of structural covariance networks in male and female adults with and without autism. We found that biological sex is a modulator of neurobiological heterogeneity in autism. Chapter 5 reports pilot data aiming to identify an electrophysiological signature of these network properties using electroencephalography (EEG). We find little evidence for theories about network asymmetry, but indications of altered frontal network integration. The second part of the thesis examines the acute effects of hormones on brain connectomics. Hormones are an integral part of the mechanism of social behaviour. In a series of hormone administration studies, we report experiments to test the acute effects of steroid and peptide hormones on brain functional connectivity (Chapters 6 and 7). Chapter 6 reports an oxytocin administration study that used a novel data-driven approach to assess resting-state fMRI connectivity in women. Although the number of fMRI studies on oxytocin have increased over past years, little is known about its effect on women. We found that oxytocin robustly enhances cortico-subcortical connectivity, and that this effect positively correlates with autistic traits. This is interesting given that oxytocin has been proposed as a potential therapeutic in autism. Chapter 7 reports an experiment testing if testosterone modulates connectivity in a specific social environment (a fear response). This was confirmed during the social task, but not during baseline resting-state, highlighting the role of testosterone in functional connectivity in this specific context. Chapter 8 is the concluding chapter that integrates all the empirical findings in the thesis. We discuss their implications for our understanding of autism and ADHD, and of the role of steroid and peptide hormones in the typically and atypically developing connectome. Chapter 8 also reflects on the limitations of the experiments reported, and sets out future directions for research in this area.Medical Research Council, Autism Research Trust, Pinsent Darwin Trust, Cambridge Trus

L'interrelation entre l'empathie et la régulation émotionnelle : corrélats neuronaux et autonomiques

L’empathie et la régulation émotionnelle sont des processus vitaux au fonctionnement socioémotionnel sain. Le terme « empathie » réfère à la capacité de partager et comprendre les émotions d’autrui. La régulation émotionnelle se définit quant à elle par la capacité de moduler ses propres états émotionnels. En neurosciences, bien qu’il ait été proposé d’un point de vue théorique que l’empathie et la régulation émotionnelle soient intimement liées, ces deux entités sont actuellement étudiés en vase clos. Par ailleurs, la littérature scientifique regorge d’études en neuro-imagerie fonctionnelle examinant les corrélats cérébraux de l’empathie pour la douleur. Or, l’empathie est une fonction sociale polyvalente se déployant dans une vaste étendue d’interactions socioémotionnelles. Tout comme la régulation émotionnelle, la valence émotionnelle demeure rarement examinée dans le contexte de l’empathie et l’interrelation entre la régulation et la valence émotionnelle est inexplorée. La thèse a pour objectif d’examiner la relation entre l’empathie, la régulation émotionnelle et la valence émotionnelle, de même que les corrélats neurophysiologiques sous-jacents. Un premier article de revue narrative décrit les régions cérébrales clés impliquées dans l’empathie pour la douleur, qui incluent notamment le cortex cingulaire antérieur médian et l’insula antérieure. Cet article a aussi permis de dégager de la littérature des facteurs régulant la réponse cérébrale associés à l’empathie pour la douleur. Ceux-ci incluent différents stimuli visuels, dont des membres du corps en douleur ou des expressions faciales de douleur. Ces derniers influencent les processus perceptuels de régulation. Les instructions offertes aux participants constituent un autre facteur pouvant influencer la réponse cérébrale, notamment leur orientation (vers soi ou vers autrui). Celles-ci influencent les processus cognitifs de régulation. Dans le deuxième article, une méta-analyse quantitative des études en neuroimagerie fonctionnelle sur l’observation de la douleur est présentée. Celle-ci révèle un réseau central d’activation associé à l’empathie pour la douleur (cortex cingulaire antérieur médian, insula antérieure). Ce réseau s’activerait indépendamment des processus perceptuels et cognitifs de régulation. On démontre également que différents processus perceptuels sont associés spécifiquement à des activations dans les régions sensorimotrices (observation de membres du corps en douleur) et à des activations dans une région impliquée dans l’imitation d’action et la communication non-verbale (observation d’expressions faciales de douleur). Différents processus cognitifs de régulation sont associés spécifiquement à l’activation d’une région impliquée dans l’intéroception et la conscience de soi (perspective orientée vers soi) ou à l’activation de régions impliquées dans le réseau attentionnel (perspective orientée vers le stimulus). Dans le but d’examiner expérimentalement l’effet de la régulation émotionnelle sur l’empathie, une étude psychophysiologique a été ensuite menée. Un nouveau paradigme expérimental a été développé. Lors du visionnement de vidéos illustrant des scènes d’interactions socioémotionnelles, des participants étaient invités à réguler leurs émotions par la réévaluation cognitive. L’empathie situationnelle, l’activité électrodermale et cardiaque ont été mesurées. Les résultats démontrent que la régulation émotionnelle module l’empathie situationnelle et qu’elle est associée à une augmentation de la variabilité du rythme cardiaque. Ces résultats suggèrent que la régulation émotionnelle est sous-tendue par l’implication du système parasympathique dans l’empathie. Aussi, l’observation d’émotions positives en comparaison à des émotions négatives est associée à moins d’empathie situationnelle en parallèle à une légère augmentation de la variabilité du rythme cardiaque. Ces résultats suggèrent une plus grande implication des processus de régulation lors de iii l’empathie pour les émotions positives. En somme, cette étude démontre que les processus de régulation dans l’empathie seraient sous-tendus préférentiellement par le système parasympathique. Elle soulève par ailleurs que la valence émotionnelle est un paramètre important à considérer dans l’étude de l’empathie, puisqu’elle influence différemment les réponses subjectives et autonomiques associées. En plus d’offrir une vision plus intégrative de la relation entre l’empathie et la régulation émotionnelle elle soutient empiriquement leur lien. Les données de celle-ci démontrent que l’empathie est un phénomène dynamique pouvant être influencé par les processus perceptuels et cognitifs de régulation, lesquels influenceront différemment la réponse cérébrale et autonomique. En définitive, cette thèse contribuera à développer des modèles plus nuancés reliant l’empathie et la régulation émotionnelle ainsi que les bases neurophysiologiques qui y sont associées.Empathy and emotion regulation are vital processes for healthy socioemotional functioning. Empathy refers to the ability to share and understand others’ emotions while emotion regulation is defined as by the ability to modulate one owns’ emotional state. It is commonly described, from a theoretical perspective, that empathy and emotion regulation are intimately related. However, empathy and emotion regulation have been largely studied separately. In addition, the vast majority of the neuroscience literature on empathy is based on functional neuroimaging studies of vicarious pain. Empathy is although a versatile social function deployed in a large range of socio-emotional interactions. Like emotion regulation, emotional valence is rarely examined in the context of empathy and the relation between emotion regulation and emotional valence during empathy is currently unexplored. The objective of this thesis was to examine the relation between empathy, emotion regulation, and emotional valence, as well as their underlying neurophysiological correlates. In a narrative review article, the key brain regions involved in pain empathy are described, which includes the median anterior cingulate cortex and the anterior insula. In addition, factors that regulate the brain response during pain empathy were pointed out. These included different visual stimuli that regulate differently perceptual processes, such as body parts being submitted to noxious pain or facial expressions of pain. Instructions offered to the participants is also a factor that cognitively regulate the brain response during pain empathy, such as instructions oriented towards oneself or the other. In a second article, a quantitative meta-analysis on functional neuroimaging studies of pain empathy is presented. This study revealed a core network of activation related to pain empathy (median anterior cingulate cortex, anterior insula), which activates independently from perceptual and cognitive processes of regulation. This study also demonstrated that different perceptual processes distinctively activate sensorimotor regions (observation of limbs in painful situations) and a region involved in action imitation and non-verbal communication (facial expressions of pain). Furthermore, different cognitive regulatory processes distinctively activate a region involved in interoception and selfawareness (self-oriented perspective) and regions involved in the attentional network (perspective oriented towards the stimulus). In order to examine experimentally the effect of emotion regulation on empathy, a psycho-physiological study was then conducted. A new paradigm was developed. During the viewing of short videos depicting socioemotional interactions, participants were invited to regulate their emotions using cognitive reappraisal. Situational empathy was measured. Electrodermal and cardiac activity was gathered. Results showed that emotion regulation can increase or decrease situational empathy and is associated to an increase of the heart rate variability. These results suggest that emotion regulation is underpinned by the parasympathetic system during empathy. Moreover, viewing positive emotions, compared to negative emotions, was associated with less situational empathy and a slight increase of the heart rate variability. These results suggest a greater need in emotion regulation processes during empathy for positive emotions. In sum, this study demonstrates that emotion regulation process during empathy is preferentially underlied by the parasympathetic system. This work also highlights that emotional valence is an important parameter to consider when studying empathy, as it influences the underying subjective and autonomic responses. In addition to offer a more integrative vision of the relation between empathy and emotion regulation and supports their link empirically. The findings demonstrate that empathy is a dynamic phenomenon that can be regulated by v perceptual and cognitive processes. Ultimately, this thesis will contribute more nuanced models of empathy that will consider emotion regulation processes and the underlying neurophysiological basis

Quantification of appetite-regulating hormones in children with hypothalamic and common obesity

Background. Current understanding of the appetite-regulating neuroendocrine circuitry remains incomplete, and efficacious treatments for both common and hypothalamic obesity (HyOb) are lacking. Concurrently, the expanded role of oxytocin (OXT) in energy homeostasis and human behaviour is beginning to be understood. Objectives. To optimise and translate an OXT enzyme immunoassay (EIA) to elucidate whether there were any unique differences in the plasma endocrine milieu in patients with HyOb. Methods. Optimisation work was carried out using EIAs with polyclonal and monoclonal secondary antibodies. Obese (BMI>+2 SDS) and lean (BMI≤+2 SDS) children with (HyOb and HyLean) and without (Ob and Lean) hypothalamic disorders (septo-optic dysplasia or suprasellar tumours) were phenotyped using the Dykens’ Hyperphagia Questionnaire Score (DHQS). Plasma concentrations of leptin, insulin, OXT, BDNF, αMSH, acylated ghrelin, AgRP and copeptin were measured. Results. Solid phase extraction demonstrated markedly variable OXT recovery, and potentially increased rather than decreased interference. A polyclonal secondary antibody-containing EIA showed significant cross-reactivity with several peptides in human plasma compared to a monoclonal secondary antibody-containing EIA. Of the 122 children recruited (50 HyOb, 29 HyLean, 24 Ob, 19 Lean, mean age 11.3±3.9 years) there were no differences in DHQS or hormone concentrations between HyOb and Ob groups. Obesity was associated with compensatorily increased leptin and insulin, and decreased ghrelin and AgRP concentrations. More rapidly increasing BMI was independently associated with a younger age and lower plasma αMSH concentrations. OXT concentrations did not show any correlation with BMI or DHQS. Conclusion. The use of plasma extraction processes and EIAs in the literature needs re-examination. The plasma endocrine milieu in HyOb vs. common obesity does not differ, with a compensatory increase in anorexigens and decrease in orexigens. Lower plasma αMSH was associated with more rapid weight gain, suggesting that MC4R agonists may be a therapeutic option in all forms of obesity