Oxytocin enhances cognitive control of food craving in women.

In developed countries, obesity has become an epidemic resulting in enormous health care costs for society and serious medical complications for individuals. The homeostatic regulation of food intake is critically dependent on top-down control of reward-driven food craving. There is accumulating evidence from animal studies that the neuropeptide oxytocin (OXT) is involved in regulating hunger states and eating behavior, but whether OXT also contributes to cognitive control of food craving in humans is still unclear. We conducted a counter-balanced, double-blind, within-subject, pharmacological magnetic resonance imaging experiment involving 31 healthy women who received 24 IU of intranasal OXT or placebo and were scanned twice while they were exposed to pictures of palatable food. The participants were instructed either to imagine the immediate consumption or to cognitively control the urge to eat the food. Our results show a trend that OXT specifically reduced food craving in the cognitive control condition. On the neural level, these findings were paralleled by an increase of activity in the middle and superior frontal gyrus, precuneus, and cingulate cortex under OXT. Interestingly, the behavioral OXT effect correlated with the OXT-induced changes in the prefrontal cortex and precuneus. Collectively, the present study provides first evidence that OXT plays a key role in the cognitive regulation of food craving in women by strengthening activity in a broad neurocircuitry implicated in top-down control and self-referential processing. Hum Brain Mapp 37:4276-4285, 2016. © 2016 Wiley Periodicals, Inc.

Opposing effects of oxytocin on moral judgment in males and females.

Current perspectives on the evolutionary roots of human morality suggest it arose to incentivize social cooperation by promoting feelings of disgust toward selfish behavior, although the underlying neural mechanisms remain unclear. To investigate whether the ancient mammalian neuropeptide oxytocin (OXT) influences self-referential processing in the domains of emotion evaluation and moral decision making, we conducted a pharmaco-functional magnetic resonance imaging (fMRI) and a behavioral experiment involving 157 healthy women and men who were treated with either OXT (24 IU) or placebo (PLC) intranasally. Our results show that OXT facilitated cortical midline responses during self-processing of disgust and selectively promoted self-interest moral judgments in men. In contrast, in women OXT increased the reaction time difference between accepted and rejected moral dilemmas and led them to suppress their self-interest and respond more altruistically for the benefit of others. Taken together, these findings suggest an OXT-related sexual dimorphism in human moral behavior which evolved adaptively to optimize both protection and nurturing of offspring by promoting selfish behavior in men and altruistic behavior in women.

Oxytocin enhances attractiveness of unfamiliar female faces independent of the dopamine reward system.

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 gyrus. The absence of OXT effects on dopamine release and D2 receptors in brain reward centers, despite increased striatal activity, implies that the peptide may facilitate perceived attraction via non-dopaminergic actions.

Elevated cerebrospinal fluid and blood concentrations of oxytocin following its intranasal administration in humans.

There has been an unprecedented interest in the modulatory effects of intranasal oxytocin on human social cognition and behaviour, however as yet no study has actually demonstrated that this modality of administration increases concentrations of the peptide in the brain as well as blood in humans. Here using combined blood and cerebrospinal fluid (CSF) sampling in subjects receiving either 24 IU of oxytocin (n = 11) or placebo (n = 4) we have shown that oxytocin levels significantly increased in both plasma and CSF. However, whereas oxytocin plasma concentrations peaked at 15 min after intranasal administration and decreased after 75 min, CSF concentrations took up to 75 min to reach a significant level. Moreover, there was no correlation (r = <0.10) between oxytocin plasma and CSF concentrations. Together, these data provide crucial insights into the plasma and CSF kinetics of intranasally administered oxytocin.

Nicotinic acetylcholine receptors contribute to learning-induced metaplasticity in the hippocampus.

Hippocampal learning is thought to induce metaplasticity, which can facilitate subsequent learning. Administered at single low doses, the N-methyl-d-aspartate-type glutamate receptor antagonist memantine predominantly blocks α7 nicotinic acetylcholine receptors (α7 nAChRs). Placebo-controlled administration of a single low dose of memantine in a pharmaco-fMRI experiment may thus help characterize the role of α7 nAChRs in hippocampal metaplasticity. We hypothesized that if α7 nAChRs contribute to learning-induced metaplasticity in the hippocampus, blockade of these receptors with low-dose memantine would selectively interfere with a facilitation of subsequent learning without impairing hippocampal learning per se. To specifically test this hypothesis, we devised a randomized controlled trial in which healthy volunteers were administered a 20-mg single oral dose of memantine or placebo and scanned on three subsequent runs of a hippocampal learning task. Our results indicate no discrepancies in behavioral learning between low-dose memantine- and placebo-treated participants in the first and second run of this task. In the third run, however, only the placebo-treated group showed facilitated behavioral learning, an effect paralleled by decreased neural responses in the hippocampal cornu ammonis region. Our findings suggest that blockade of α7 nAChRs selectively interfered with a learning-induced facilitation of subsequent learning while leaving unimpaired hippocampal learning per se. Taken together, our results provide support for a relevant contribution of α7 nAChRs to learning-associated metaplasticity in the hippocampus.

Inferior frontal gyrus preserves working memory and emotional learning under conditions of impaired noradrenergic signaling.

Compensation has been widely applied to explain neuroimaging findings in neuropsychiatric patients. Functional compensation is often invoked when patients display equal performance and increased neural activity in comparison to healthy controls. According to the compensatory hypothesis increased activity allows the brain to maintain cognitive performance despite underlying neuropathological changes. Due to methodological and pathology-related issues, however, the functional relevance of the increased activity and the specific brain regions involved in the compensatory response remain unclear. An experimental approach that allows a transient induction of compensatory responses in the healthy brain could help to overcome these issues. To this end we used the non-selective beta-blocker propranolol to pharmacologically induce sub-optimal noradrenergic signaling in healthy participants. In two independent functional MRI (fMRI) experiments participants received either placebo or propranolol before they underwent a cognitive challenge (Experiment 1: working memory; Experiment 2: emotional learning: Pavlovian fear conditioning). In Experiment 1 propranolol had no effects on working memory performance, but evoked stronger activity in the left inferior frontal gyrus (IFG). In Experiment 2 propranolol produced no effects on emotional memory formation, but evoked stronger activity in the right IFG. The present finding that sub-optimal beta-adrenergic signaling did not disrupt performance and concomitantly increased IFG activity is consistent with, and extends, current perspectives on functional compensation. Together, our findings suggest that under conditions of impaired noradrenergic signaling, heightened activity in brain regions located within the cognitive control network, particularly the IFG, may reflect compensatory operations subserving the maintenance of behavioral performance.

Oxytocin modulates social distance between males and females.

In humans, interpersonal romantic attraction and the subsequent development of monogamous pair-bonds is substantially predicted by influential impressions formed during first encounters. The prosocial neuropeptide oxytocin (OXT) has been identified as a key facilitator of both interpersonal attraction and the formation of parental attachment. However, whether OXT contributes to the maintenance of monogamous bonds after they have been formed is unclear. In this randomized placebo-controlled trial, we provide the first behavioral evidence that the intranasal administration of OXT stimulates men in a monogamous relationship, but not single ones, to keep a much greater distance (~10-15 cm) between themselves and an attractive woman during a first encounter. This avoidance of close personal proximity occurred in the physical presence of female but not male experimenters and was independent of gaze direction and whether the female experimenter or the subject was moving. We further confirmed this unexpected finding using a photograph-based approach/avoidance task that showed again that OXT only stimulated men in a monogamous relationship to approach pictures of attractive women more slowly. Importantly, these changes cannot be attributed to OXT altering the attitude of monogamous men toward attractive women or their judgments of and arousal by pictures of them. Together, our results suggest that where OXT release is stimulated during a monogamous relationship, it may additionally promote its maintenance by making men avoid signaling romantic interest to other women through close-approach behavior during social encounters. In this way, OXT may help to promote fidelity within monogamous human relationships.

Oxytocin facilitates protective responses to aversive social stimuli in males.

The neuropeptide oxytocin (OXT) can enhance the impact of positive social cues but may reduce that of negative ones by inhibiting amygdala activation, although it is unclear whether the latter causes blunted emotional and mnemonic responses. In two independent double-blind placebo-controlled experiments, each involving over 70 healthy male subjects, we investigated whether OXT affects modulation of startle reactivity by aversive social stimuli as well as subsequent memory for them. Intranasal OXT potentiated acoustic startle responses to negative stimuli, without affecting behavioral valence or arousal judgments, and biased subsequent memory toward negative rather than neutral items. A functional MRI analysis of this mnemonic effect revealed that, whereas OXT inhibited amygdala responses to negative stimuli, it facilitated left insula responses for subsequently remembered items and increased functional coupling between the left amygdala, left anterior insula, and left inferior frontal gyrus. Our results therefore show that OXT can potentiate the protective and mnemonic impact of aversive social information despite reducing amygdala activity, and suggest that the insula may play a role in emotional modulation of memory.

Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment.

OBJECTIVE: To identify biological evidence for Alzheimer disease (AD) in individuals with subjective memory impairment (SMI) and unimpaired cognitive performance and to investigate the longitudinal cognitive course in these subjects. METHOD: [¹8F]fluoro-2-deoxyglucose PET (FDG-PET) and structural MRI were acquired in 31 subjects with SMI and 56 controls. Cognitive follow-up testing was performed (average follow-up time: 35 months). Differences in baseline brain imaging data and in memory decline were assessed between both groups. Associations of memory decline with brain imaging data were tested. RESULTS: The SMI group showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe. Gray matter volume was reduced in the right hippocampus in the SMI group. At follow-up, subjects with SMI showed a poorer performance than controls on measures of episodic memory. Longitudinal memory decline in the SMI group was associated with reduced glucose metabolism in the right precuneus at baseline. CONCLUSION: The cross-sectional difference in 2 independent neuroimaging modalities indicates early AD pathology in SMI. The poorer memory performance at follow-up and the association of reduced longitudinal memory performance with hypometabolism in the precuneus at baseline support the concept of SMI as the earliest manifestation of AD.

Prosocial effects of oxytocin and clinical evidence for its therapeutic potential.

There has been unprecedented interest in the prosocial effects of the neuropeptide oxytocin in humans over the last decade. A range of studies has demonstrated correlations between basal oxytocin levels and the strength of social and bonding behaviors both in healthy individuals and in those suffering from psychiatric disorders. Mounting evidence suggests associations between polymorphisms in the oxytocin receptor gene and prosocial behaviors and there may also be important epigenetic effects. Many studies have now reported a plethora of prosocial effects of intranasal application of oxytocin, including the domains of trust, generosity, socially reinforced learning, and emotional empathy. The main focus of this review will be to summarize human preclinical work and particularly the rapidly growing number of clinical studies which have identified important links between oxytocin and a wide range of psychiatric disorders, and have now started to directly assess its therapeutic potential.

Volume loss of the medial temporal lobe structures in subjective memory impairment.

BACKGROUND/AIMS: Subjective memory impairment (SMI) has been suggested as a manifestation of Alzheimer's Disease (AD) preceding mild cognitive impairment (MCI). In this study, we determined the volumes of the hippocampus, the entorhinal cortex (EC) and the amygdala to provide biological evidence for AD in SMI. METHODS: Regional volumetric measures were manually traced on 3-Tesla MRI scans. RESULTS: Total brain volume did not differ between the groups. Individuals with SMI had reduced volumes of the hippocampus bilaterally (right p = 0.001; left p < 0.001), the bilateral EC (right p = 0.031, left p = 0.006) and the right amygdala (p = 0.01) compared to the control group. CONCLUSION: Volume reduction of bilateral hippocampus, bilateral EC and right amygdala supports the concept of SMI as a very early manifestation of AD prior to MCI. SMI may indicate awareness of a degenerative process that can still be functionally compensated.

Minimally invasive intramedullary nailing of midshaft clavicular fractures using titanium elastic nails.

BACKGROUND: In up to 31% of cases, nonsurgical treatment of midshaft clavicular fractures leads to unsatisfactory results such as nonunion, brachial plexus irritation, shortening and limited function of the shoulder. To date, various implants have been developed for open reduction including intramedullary wires, screws, and plates. This study discusses elastic stable intramedullary nailing of midshaft clavicular fractures. METHODS: Between 2000 and 2005, 31 midshaft clavicular fractures were treated by intramedullary nailing with a titanium elastic nail (TEN). Subjective and clinical outcome were evaluated after an average follow-up of 26 (6-46) months. Patients were divided into three groups: patients with isolated clavicular fractures (group 1, n = 9); patients with additional injuries (group 2, n = 15), and patients with multiple injuries (group 3, n = 7). RESULTS: Nonunion was not observed. No patient sustained a refracture after TEN removal. Medial migration of the TEN in seven patients and iatrogenic perforation of the lateral cortex in one patient required secondary shortening on five occasions. Nail breakage after fracture healing was observed twice. Subjective outcome did not differ significantly between the three groups. Constant and Murley Score and the Disability of the Arm, Shoulder, and Hand Questionnaire Score showed no significant difference in the clinical outcome of the three groups. CONCLUSION: Intramedullary fixation of midshaft clavicular fractures with a TEN is a safe minimally invasive surgical technique achieving primary stability for practice. It can be seen as an alternative to plate or screw fixation or nonsurgical treatment, as it produces excellent cosmetic and functional results regardless whether patients suffered from isolated clavicular fractures, additional injuries, or multiple traumas.

Elastic stable intramedullary nailing of midclavicular fractures in adults: 32 patients followed for 1-5 years.

BACKGROUND: Osteosynthesis of clavicular fractures is sometimes indicated. Since plate fixation may lead to complications, we have used elastic stable intramedullary nailing and report our experience of midclavicular fractures in 32 adults. PATIENTS AND METHODS: From 2000 to 2005, we treated 32 adults (26 men), median age 40 (19-66) years, by intramedullary nailing with a titanium elastic nail (TEN). All patients were re-examined after median 27 (12-59) months. RESULTS: Nonunion was not observed. 20 clavicles healed without shortening. 12 clavicles healed with shortening of more than 5 mm. Migration of the TEN in 8 patients required secondary shortening of the nail in 5 of them. Nail breakage after fracture healing was observed twice. The nails were removed in 29 patients after a median of 6 (1.3-15) months postoperatively. No patient sustained a re-fracture after TEN removal. The mean Constant score was 95 (SD 1.9) points and the mean DASH score was 5 (SD 2.3) points. INTERPRETATION: Intramedullary stabilization of midclavicular fractures with a titanium elastic nail is a minimally invasive technique with good cosmetic and functional results. Intramedullary fixation can be seen as an alternative to plate fixation and nonoperative treatment.