Intranasal oxytocin suppresses seizure-like behaviors in a mouse model of NGLY1 deficiency.

NGLY1 deficiency is a genetic disease caused by biallelic mutations of the Ngly1 gene. Although epileptic seizure is one of the most severe symptoms in patients with NGLY1 deficiency, preclinical studies have not been conducted due to the lack of animal models for epileptic seizures in NGLY1 deficiency. Here, we observed the behaviors of male and female Ngly1-/- mice by video monitoring and found that these mice exhibit spontaneous seizure-like behaviors. Gene expression analyses and enzyme immunoassay revealed significant decreases in oxytocin, a well-known neuropeptide, in the hypothalamus of Ngly1-/- mice. Seizure-like behaviors in Ngly1-/- mice were transiently suppressed by a single intranasal administration of oxytocin. These findings suggest the therapeutic potential of oxytocin for epileptic seizure in patients with NGLY1 deficiency and contribute to the clarification of the disease mechanism.

Quantifying abnormal emotion processing: A novel computational assessment method and application in schizophrenia.

Abnormal emotion processing is a core feature of schizophrenia spectrum disorders (SSDs) that encompasses multiple operations. While deficits in some areas have been well-characterized, we understand less about abnormalities in the emotion processing that happens through language, which is highly relevant for social life. Here, we introduce a novel method using deep learning to estimate emotion processing rapidly from spoken language, testing this approach in male-identified patients with SSDs (n = 37) and healthy controls (n = 51). Using free responses to evocative stimuli, we derived a measure of appropriateness, or "emotional alignment" (EA). We examined psychometric characteristics of EA and its sensitivity to a single-dose challenge of oxytocin, a neuropeptide shown to enhance the salience of socioemotional information in SSDs. Patients showed impaired EA relative to controls, and impairment correlated with poorer social cognitive skill and more severe motivation and pleasure deficits. Adding EA to a logistic regression model with language-based measures of formal thought disorder (FTD) improved classification of patients versus controls. Lastly, oxytocin administration improved EA but not FTD among patients. While additional validation work is needed, these initial results suggest that an automated assay using spoken language may be a promising approach to assess emotion processing in SSDs.

Intranasal oxytocin as a treatment for anxiety and autism: From subclinical to clinical applications.

Animal and human studies have demonstrated that intranasal oxytocin (OT) can penetrate the brain and induce cognitive, emotional, and behavioral changes, particularly in social functioning. Consequently, numerous investigations have explored the potential of OT as a treatment for anxiety and autism, conditions characterized by social deficits. Although both subclinical and clinical studies provide converging evidence of the therapeutic effects of OT in reducing anxiety levels and improving social symptoms in autism, results are not always consistent. Additionally, the pharmacological mechanism of OT requires further elucidation for its effective clinical application. Therefore, this review aims to examine the contentious findings concerning the effects of OT on anxiety and autism, offer interpretations of the inconsistent results from the perspectives of individual differences and varying approaches to OT administration, and shed light on the underlying mechanisms of OT. Ultimately, standardization of dosage, frequency of administration, formulation characteristics, and nasal spray devices is proposed as essential for future human studies and clinical applications of OT treatment.

Maintenance oxytocin in the immediate postpartum period: Frequency, determinants and practices in a tertiary maternity unit.

OBJECTIVE: To prevent post-partum haemorrhage (PPH), national and international guidelines recommend the administration of a prophylactic injection of oxytocin after all vaginal births. Although additional maintenance oxytocin is not recommended in the immediate postpartum, its administration is quite common (30 % of French births in 2021). To assess in a single center, the frequency and determinants associated with the administration of maintenance oxytocin in immediate postpartum. STUDY DESIGN: A retrospective observational single-centre study was conducted in a tertiary-care university centre in Paris (France), with data from April-May 2022. All women who gave birth vaginally at or after 37 weeks, except for those with immediate PPH. Univariate and multivariate analysis were performed to compare determinants between the group receiving maintenance oxytocin and the control group without this intervention. A sensitivity analysis in a population of women at low risk of PPH was performed. Maternal, obstetrical, perinatal and organisational determinants were collected. RESULTS: This study included 584 patients, 278 (47.6 %) of whom received maintenance oxytocin. We observed a significantly higher rate of maintenance oxytocin administration to parous women (OR 1.57, 90 %CI 1.09-2.27) and women with a history of PPH (OR 2.88, 90 %CI 1.08-9.08). Additional maintenance oxytocin was also administered more often when the midwife handling the birth had more than 5 years of practice since completion of training (OR 1.77, 1.24-2.53) or during night-time births (OR 1.47, 90 %CI 1.03-2.10). CONCLUSION: Maintenance oxytocin administration is a frequent practice, performed for almost half the patients in our center. This practice is associated with maternal and obstetric factors, but also with health professionals' individual decisions and practices.

Routine vaginal examination to assess labor progress at 8 compared to 4 hours after early amniotomy following Foley balloon ripening in the labor induction of multiparas: a randomized trial.

BACKGROUND: Vaginal examination to monitor labor progress is recommended at least every 4 hours, but it can cause pain and embarrassment to women. Trial data are limited on the best intensity for vaginal examination. Vaginal examination is not needed for oxytocin dose titration after an amniotomy has been performed and oxytocin infusion started. The Foley balloon commonly ripens the cervix without strong contractions. Amniotomy and oxytocin infusion are usually required to drive labor. OBJECTIVE: This study aimed to evaluate the first vaginal examination at 8 vs 4 hours after amniotomy-oxytocin after Foley ripening in multiparous labor induction. STUDY DESIGN: A randomized controlled trial was conducted from October 2021 to September 2022 at the University Malaya Medical Center, Kuala Lumpur, Malaysia. Multiparas at term were recruited at admission for labor induction. Participants were randomized to a first routine vaginal examination at 8 or 4 hours after Foley balloon ripening and amniotomy. Titrated oxytocin infusion was routinely commenced after amniotomy to initiate contractions. The 2 primary outcomes were the time from amniotomy to delivery (noninferiority hypothesis) and maternal satisfaction (superiority hypothesis). Data were analyzed using the Student t test, Mann-Whitney U test, and chi-square test (or Fisher exact test), as suitable for the data. RESULTS: A total of 204 women were randomized, 102 to each arm. Amniotomy to birth intervals were 4.97±2.47 hours in the 8-hour arm and 5.79±3.17 hours in the 4-hour arm (mean difference, -0.82; 97.5% confidence interval, -1.72 to 0.08; P=.041; Bonferroni correction), which were noninferior within the prespecified 2-hour upper margin, and the maternal satisfaction scores (11-point 0-10 numerical rating scale) with allocated labor care were 9 (interquartile range, 8-9) in the 8-hour arm and 8 (interquartile range, 7-9) in the 4-hour arm (P=.814). In addition, oxytocin infusion to birth interval difference was noninferior within the 97.5% confidence interval (-1.59 to 0.23) margin of 1.3 hours. Of the maternal outcomes, the amniotomy to first vaginal examination intervals were 3.9±1.8 hours in the 8-hour arm and 3.4±1.3 hours in the 4-hour arm (P=.026), and the numbers of vaginal examinations were 2.00 (interquartile range, 2.00-3.00) in the 8-hour arm and 3.00 (interquratile range, 2.00-3.25) in the 4-hour arm (P<.001). For the 8-hour arm, the first vaginal examination was less likely to be as scheduled and more likely to be indicated by sensation to bear down (P<.001), and the epidural analgesia rates were lower (13/102 participants [12.7%] in the 8-hour arm vs 28/102 participants [27.5%] in the 4-hour arm; relative risk, 0.46; 95% confidence interval, 0.26-0.84; P=.009). Other outcomes of the mode of delivery, indications for cesarean delivery, and delivery blood loss were not different. Neonatal outcomes were not different. CONCLUSION: Routine first vaginal examination at 8 hours compared with that at 4 hours was noninferior for the time to birth but did not improve maternal satisfaction.

Optimal starting dosing regimen of intravenous oxytocin for labor induction based on the population kinetic-pharmacodynamic model of uterine contraction frequency.

BACKGROUND: Intravenous oxytocin is commonly used for labor induction. However, a consensus on the initial dosing regimen is lac with conflicting research findings and varying guidelines. This study aimed to develop a population kinetic-pharmacodynamic (K-PD) model for oxytocin-induced uterine contractions considering real-world data and relevant influencing factors to establish an optimal starting dosing regimen for intravenous oxytocin. METHODS: This retrospective study included pregnant women who underwent labor induction with intravenous oxytocin at Peking University Third Hospital in 2020. A  population K-PD model was developed to depict the time course of uterine contraction frequency (UCF), and covariate screening identified significant factors affecting the pharmacokinetics and pharmacodynamics of oxytocin. Model-based simulations were used to optimize the current starting regimen based on specific guidelines. RESULTS: Data from 77 pregnant women with 1095 UCF observations were described well by the K-PD model. Parity, cervical dilation, and membrane integrity are significant factors influencing the effectiveness of oxytocin. Based on the model-based simulations, the current regimens showed prolonged onset times and high infusion rates. This study proposed a revised approach, beginning with a rapid infusion followed by a reduced infusion rate, enabling most women to achieve the target UCF within approximately 30 min with the lowest possible infusion rate. CONCLUSION: The K-PD model of oxytocin effectively described the changes in UCF during labor induction. Furthermore, it revealed that parity, cervical dilation, and membrane integrity are key factors that influence the effectiveness of oxytocin. The optimal starting dosing regimens obtained through model simulations provide valuable clinical references for oxytocin treatment.

Age-dependent effects of oxytocin in brain regions enriched with oxytocin receptors.

Although intranasal oxytocin administration to tap into central functions is the most commonly used non-invasive means for exploring oxytocin's role in human cognition and behavior, the way by which intranasal oxytocin acts on the brain is not yet fully understood. Recent research suggests that brain regions densely populated with oxytocin receptors may play a central role in intranasal oxytocin's action mechanisms in the brain. In particular, intranasal oxytocin may act directly on (subcortical) regions rich in oxytocin receptors via binding to these receptors while only indirectly affecting other (cortical) regions via their neural connections to oxytocin receptor-enriched regions. Aligned with this notion, the current study adopted a novel approach to test 1) whether the connections between oxytocin receptor-enriched regions (i.e., the thalamus, pallidum, caudate nucleus, putamen, and olfactory bulbs) and other regions in the brain were responsive to intranasal oxytocin administration, and 2) whether oxytocin-induced effects varied as a function of age. Forty-six young (24.96 ± 3.06 years) and 44 older (69.89 ± 2.99 years) participants were randomized, in a double-blind procedure, to self-administer either intranasal oxytocin or placebo before resting-state fMRI. Results supported age-dependency in the effects of intranasal oxytocin administration on connectivity between oxytocin receptor-enriched regions and other regions in the brain. Specifically, compared to placebo, oxytocin decreased both connectivity density and connectivity strength of the thalamus for young participants while it increased connectivity density and connectivity strength of the caudate for older participants. These findings inform the mechanisms underlying the effects of exogenous oxytocin on brain function and highlight the importance of age in these processes.

The relationship between oxytocin and empathy for others' pain: Testing the mediating effect of first-hand pain sensitivity.

Although previous studies have shown that oxytocin attenuates first-hand pain sensitivity, studies of its effects on empathetic reactions to the observation of others' pain have yielded inconsistent and controversial results. Given the link between first-hand pain and empathy for others' pain, we hypothesized that oxytocin affects empathy for others' pain by modulating first-hand pain sensitivity. Using a double-blind, placebo-controlled, between-participant experimental design, healthy participants (n = 112) were randomly assigned to either an intranasal oxytocin or placebo group. Pain sensitivity was evaluated by pressure pain threshold, and empathetic responses were assessed by ratings in response to viewing video clips depicting others in physically painful scenarios. Results showed that pressure pain thresholds decreased over time in both groups, indicating increased sensitivity to first-hand pain after repeated measurements. However, this decrease was smaller for participants who received intranasal oxytocin, indicative of oxytocin-induced attenuation of first-hand pain sensitivity. In addition, although empathetic ratings were comparable between oxytocin and placebo groups, first-hand pain sensitivity fully mediated the impact of oxytocin on pain empathetic ratings. Thus, intranasal oxytocin can indirectly affect pain empathetic ratings by reducing first-hand pain sensitivity. These findings expand our understanding of the relationship among oxytocin, pain, and empathy.

Comparative study between oxytocin and combination of tranexamic acid and ethamsylate in reducing intra-operative bleeding during emergency and elective cesarean section after 38 weeks of normal pregnancy.

OBJECTIVE: Cesarean Section (CS) is associated with an increased risk of hemorrhage. Many drugs are used to decrease this risk. We aim to compare the combination of ethamsylate and tranexamic acid, oxytocin, and placebo in women undergoing CS. METHODS: We conducted a double-blinded, randomized, placebo-controlled trial between October and December 2020 in four university hospitals in Egypt. The study included all pregnant women in labor without any complications who accepted to participate in the study between October and December 2020. The participants were divided into three groups. The subjects were randomly allocated to receive either oxytocin (30 IU in 500 ml normal saline during cesarean section), combined one gram of tranexamic acid with 250 mg of ethamsylate once before skin incision, or distilled water. Our main outcome was the amount of blood loss during the operation. The secondary outcomes were the need for blood transfusion, hemoglobin and hematocrit changes, hospital stay, operative complications, and the need for a hysterectomy. The one-way ANCOVA test was used to compare the quantitative variables between the three groups while the Chi-square test was used to compare the qualitative variables. Post hoc analysis then was performed to compare the difference between every two groups regarding the quantitative variables. RESULTS: Our study included 300 patients who were divided equally into three groups. Tranexamic acid with ethamsylate showed the least intra-operative blood loss (605.34 ± 158.8 ml) compared to oxytocin (625.26 ± 144.06) and placebo (669.73 ± 170.69), P = 0.015. In post hoc analysis, only tranexamic acid with ethamsylate was effective in decreasing the blood loss compared to placebo (P = 0.013); however, oxytocin did not reduce blood loss compared to saline (P = 0.211) nor to tranexamic acid with ethamsylate (P = 1). Other outcomes and CS complications showed no significant difference between the three groups except for post-operative thrombosis which was significantly higher in the tranexamic and ethamsylate group, P < 0.00001 and the need for a hysterectomy which was significantly increased in the placebo group, P = 0.017. CONCLUSION: The combination of tranexamic acid and ethamsylate was significantly associated with the least amount of blood loss. However, in pairwise comparisons, only tranexamic acid with ethamsylate was significantly better than saline but not with oxytocin. Both oxytocin and tranexamic acid with ethamsylate were equally effective in reducing intra-operative blood loss and the risk of hysterectomy; however, tranexamic acid with ethamsylate increased the risk of thrombotic events. Further research with a larger number of participants is needed. TRIAL REGISTRATION: The study was registered on Pan African Clinical Trials Registry with the following number: PACTR202009736186159 and was approved on 04/09/2020.

Null results of oxytocin and vasopressin administration on mentalizing in a large fMRI sample: evidence from a randomized controlled trial.

BACKGROUND: Although potential links between oxytocin (OT), vasopressin (AVP), and social cognition are well-grounded theoretically, most studies have included all male samples, and few have demonstrated consistent effects of either neuropeptide on mentalizing (i.e. understanding the mental states of others). To understand the potential of either neuropeptide as a pharmacological treatment for individuals with impairments in social cognition, it is important to demonstrate the beneficial effects of OT and AVP on mentalizing in healthy individuals. METHODS: In the present randomized, double-blind, placebo-controlled study (n = 186) of healthy individuals, we examined the effects of OT and AVP administration on behavioral responses and neural activity in response to a mentalizing task. RESULTS: Relative to placebo, neither drug showed an effect on task reaction time or accuracy, nor on whole-brain neural activation or functional connectivity observed within brain networks associated with mentalizing. Exploratory analyses included several variables previously shown to moderate OT's effects on social processes (e.g., self-reported empathy, alexithymia) but resulted in no significant interaction effects. CONCLUSIONS: Results add to a growing literature demonstrating that intranasal administration of OT and AVP may have a more limited effect on social cognition, at both the behavioral and neural level, than initially assumed. Randomized controlled trial registrations: ClinicalTrials.gov; NCT02393443; NCT02393456; NCT02394054.

The Relationship Between Uterine Activity, Oxytocin Dosing, Labor Progress, and Mode of Birth in Nulliparas with Obesity: Minimal Usefulness of Montevideo Unit Measurement.

BACKGROUND: Maternal obesity and cesarean birth disproportionately affect Black parturients; thus, prevention of cesarean birth is a key modifiable factor to improve pregnancy outcomes and reduce disparities. The primary driver of unplanned cesarean birth among people with higher body mass index is prolonged labor duration. However, strategies to optimize outcomes in these situations have not been established. We aimed to evaluate the influence of oxytocin augmentation on uterine activity and labor progression in nulliparas with obesity. METHODS: This secondary analysis involved nulliparas with obesity (BMI ≥30 kg/m2) who had spontaneous labor onset followed by oxytocin augmentation and an intrauterine pressure catheter. Using Linear Mixed Models, we evaluated relationships between uterine activity measured in Montevideo units (MVU), oxytocin dose, and rate of cervical dilation normalized by labor duration. RESULTS: In this diverse sample (35.6% Caucasian, 16.11% African American, 40.2% Hispanic) of nulliparas with obesity (n = 87; BMI 35.54 ± 4.38 kg/m2), 31% ended labor with cesarean birth. Among those with vaginal birth, only 13% had MVU ≥200 prior to the final 2 hours of labor. MVUs were only minimally responsive to oxytocin dose and were not associated with labor progression nor birth route. CONCLUSION: MVU measurements may not be useful to diagnose labor arrest in nulliparas with obesity. Optimizing care for birthing people with obesity is essential for improving perinatal outcomes and for reducing racial health disparities.

Prophylactic Methylergonovine and Oxytocin Compared With Oxytocin Alone in Patients Undergoing Intrapartum Cesarean Birth: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether the administration of prophylactic methylergonovine in addition to oxytocin in patients undergoing intrapartum cesarean birth reduces the need for additional uterotonic agents. METHODS: This was a single-center, placebo-controlled, randomized trial of patients undergoing intrapartum cesarean birth. Patients were randomly allocated to receive intravenous oxytocin 300 mL/minute plus intramuscular methylergonovine 0.2 mg (1 mL) or intravenous oxytocin 300 mL/minute plus intramuscular normal saline (1 mL). The primary outcome was the receipt of additional uterotonic agents. Secondary outcomes included surgeon assessment of uterine tone, incidence of postpartum hemorrhage, quantitative blood loss, and blood transfusion. To detect a twofold decrease in the need for additional uterotonic agents (assuming a 42% baseline) with a two-sided type 1 error of 5% and power of 80%, a sample size of 76 patients per group was required. RESULTS: From June 2019 through February 2021, 80 patients were randomized to receive methylergonovine plus oxytocin and 80 were randomized to receive to oxytocin alone. Significantly fewer patients who were allocated to the methylergonovine group received additional uterotonic agents (20% vs 55%, relative risk [RR] 0.4, 95% CI 0.2-0.6). Participants receiving methylergonovine were more likely to have satisfactory uterine tone (80% vs 41%, RR 1.9, 95% CI 1.5-2.6), lower incidence of postpartum hemorrhage (35% vs 59%, RR 0.6, 95% CI 0.4-0.9), lower mean quantitative blood loss (967 mL vs 1,315 mL; mean difference 348, 95% CI 124-572), and a lower frequency of blood transfusion (5% vs 23%, RR 0.2, 95% CI 0.1-0.6). CONCLUSION: The administration of prophylactic methylergonovine in addition to oxytocin in patients undergoing intrapartum cesarean birth reduces the need for additional uterotonic agents. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03904446.

Intranasal oxytocin attenuates the effects of monetary feedback on procedural learning.

Procedural learning is a vital brain function that allows us to acquire motor skills during development or re-learn them after lesions affecting the motor system. Procedural learning can be improved by feedback of different valence, e.g., monetary or social, mediated by dopaminergic circuits. While processing motivationally relevant stimuli, dopamine interacts closely with oxytocin, whose effects on procedural learning, particularly feedback-based approaches, remain poorly understood. In a randomized, double-blind, placebo-controlled trial, we investigated whether oxytocin modulates the differential effects of monetary and social feedback on procedural learning. Sixty-one healthy male participants were randomized to receive a placebo or oxytocin intranasally. The participants then performed a modified serial reaction time task. Oxytocin plasma concentrations were measured before and after applying the placebo or verum. Groups did not differ regarding general reaction times or measures of procedural learning. For the placebo group, monetary feedback improved procedural learning compared to a neutral control condition. In contrast, the oxytocin group did not show a differential effect of monetary or social feedback despite a significant increase in oxytocin plasma levels after intranasal application. The data suggest that oxytocin does not influence procedural learning per se. Instead, oxytocin seems to attenuate the effects of monetary feedback on procedural learning specifically.

Protective Effects of Intranasally Administrated Oxytocin-Loaded Nanoparticles on Pentylenetetrazole-Kindling Epilepsy in Terms of Seizure Severity, Memory, Neurogenesis, and Neuronal Damage.

Pentylenetetrazole (PTZ)-induced kindling is an animal model for studying human temporal lobe epilepsy (TLE), which is characterized by alterations of hippocampal neurons and memory. Although the intranasal (IN) administration of oxytocin (OT) has limited efficiency, nanoparticles (NPs) are a promising candidate to deliver OT to the brain. However, there are very limited data on epilepsy research about oxytocin-loaded nanoparticles (NP-OTs). The aim of this study is to investigate the effects of IN administration of chronic NP-OTs on the hippocampus of PTZ-induced male epileptic rats in terms of seizure severity, memory, neurogenesis, and neuronal damage. Saline/OT/NP-OTs were administrated to both control (Ctrl) and PTZ groups intranasally. Consequently, saline and PTZ were injected, respectively, 25 times every 48 h. Then, seizure severity (score and latency) was calculated for the PTZ groups. A spatial working memory evaluation test (SWMET) was performed after the last injection. Hippocampus histopathology, neurogenesis, and apoptosis were demonstrated. Serum total antioxidant status (TAS) and total oxidant status (TOS) levels and the oxidative stress index (OSI) were measured. We showed that OTs and NP-OTs prevented the kindling development and had positive effects on seizure severity. SWMET-related behaviors were also recovered in the PTZ + NP-OT group. A significant increase of neurogenesis and decrease of apoptosis in the hippocampus of the PTZ + NP-OT group were observed, while OTs and NP-OTs had protective effects against PTZ-induced damage to hippocampal neurons. Our results indicate that the chronic administration of NP-OTs may have positive effects on hippocampal damage via increasing neurogenesis and decreasing apoptosis and seizure severity.

Intranasal oxytocin alters attention to emotional facial expressions, particularly for males and those with depressive symptoms.

Intranasal oxytocin (OT) can enhance emotion recognition, perhaps by promoting increased attention to social cues. Some studies indicate that individuals with difficulties processing social information, including those with psychopathology, show more pronounced effects in response to OT. As such, there is interest in the potential therapeutic use of OT in populations with deficits in social cognition. The present study examined the effects of intranasal OT on the processing of facial features and selective attention to emotional facial expressions, as well as whether individual differences in depressive symptom severity predict sensitivity to intranasal OT. In a double-blind placebo-controlled within-subject design, eye tracking was used to measure attention to facial features in an emotional expression appraisal task, and attention to emotional expressions in a free-viewing task with a quadrant of multiple faces. OT facilitated the processing of positive cues, enhancing the maintenance of attention to the mouth region of happy faces and to happy faces within a quadrant, with similar effect sizes, despite the latter effect not being statistically significant. Further, persons with depressive symptoms, and particularly males, were sensitive to OT's effects. For males only, OT, relative to placebo, increased attentional focus to the mouth region of all faces. Individuals with depressive symptoms showed less attentional focus on angry (males only) and sad facial expressions, and more attention to happy faces (particularly for males). Results indicate increased sensitivity to OT in males and persons at risk for depression, with OT administration promoting a positive bias in selective attention to social stimuli.

Early life oxytocin treatment improves thermo-sensory reactivity and maternal behavior in neonates lacking the autism-associated gene Magel2.

Atypical responses to sensory stimuli are considered as a core aspect and early life marker of autism spectrum disorders (ASD). Although recent findings performed in mouse ASD genetic models report sensory deficits, these were explored exclusively during juvenile or adult period. Whether sensory dysfunctions might be present at the early life stage and rescued by therapeutic strategy are fairly uninvestigated. Here we found that under cool environment neonatal mice lacking the autism-associated gene Magel2 present pup calls hypo-reactivity and are retrieved with delay by their wild-type dam. This neonatal atypical sensory reactivity to cool stimuli was not associated with autonomic thermoregulatory alteration but with a deficit of the oxytocinergic system. Indeed, we show in control neonates that pharmacogenetic inactivation of hypothalamic oxytocin neurons mimicked atypical thermosensory reactivity found in Magel2 mutants. Furthermore, pharmacological intranasal administration of oxytocin to Magel2 neonates was able to rescue both the atypical thermosensory response and the maternal pup retrieval. This preclinical study establishes for the first-time early life impairments in thermosensory integration and suggest a therapeutic potential benefit of intranasal oxytocin treatment on neonatal atypical sensory reactivity for autism.

Oxytocin infusion rates for maintaining uterine tone during non-elective cesarean section in laboring patients: a randomized, controlled trial.

PURPOSE: Oxytocin infusions for uterine tone maintenance are recommended following initial low oxytocin doses during cesarean section. Very limited literature is available on the optimal infusion rates in laboring patients who have been earlier exposed to oxytocin. METHODS: 105 patients, having received oxytocin for induction/augmentation of labor, received oxytocin infusions at rates of 2.5 IU/h (Group 2.5), 5 IU/h (Group 5) or 10 IU/h (Group 10) following 3 IU slow bolus. The primary outcome measure was estimated intraoperative blood loss; secondary outcome measures included uterine tone adequacy, requirements for additional uterotonics, and any side effects. Minor postpartum hemorrhage (PPH) was defined as blood loss > 500 ml and major/severe hemorrhage as blood loss > 1000 ml. RESULTS: Group 10 had minimum blood loss (311.1 ± 44.9 ml) and uterotonic requirements compared to other groups (p < 0.001). Group 2.5 had maximum blood loss (549.4 ± 74.3 ml) and uterotonic requirements; Group 5 had intermediate values (402.0 ± 49.5 ml). Twenty-six patients in group 2.5 had minor PPH against only one in group 5 and none in group 10 (p < 0.001). No patient in either group had major PPH. The incidence of hypotension was higher in group 10 than in group 2.5 (p = 0.004). Nausea and vomiting were also more frequent in group 10 than in the other two groups. CONCLUSION: Oxytocin infusions at 5 IU/h and 10 IU/h are more effective in reducing blood loss and preventing PPH than 2.5 IU/h. The dose of 10 IU/h, although the most efficacious, is associated with a high incidence of side effects. Hence, further studies are needed to find out the optimal maintenance infusion rate of oxytocin during cesarean section in laboring patients who have received oxytocin earlier.

Sublingual Misoprostol versus Oxytocin to Induce Labor in Term Premature Rupture of Membranes in Pregnant Women: A Randomized Single-Blind Controlled Trial.

OBJECTIVE: The aim of this study was to compare maternal and neonatal outcomes between sublingual misoprostol and oxytocin on stimulating labor in term premature rupture of membranes (PROM) in pregnant women. Materials and method. This randomized single-blind control trial was conducted at Bhumibol Adulyadej Hospital (BAH), Royal Thai Air Force, Bangkok, Thailand, between September 2020 and February 2021. Subjects were term pregnant women who had PROM and came to BAH for delivery. Participants were allocated into study (misoprostol) and control (oxytocin) groups. The study and control groups were, respectively, administered sublingual misoprostol and intravenous oxytocin to induce labor. Induction time and second stage of labor were recorded. Neonatal outcomes and maternal and fetal complications were also recorded and analyzed. RESULT: A total of 170 women were enrolled and equally divided into study and control groups. Mean maternal age, body mass index, parity, gestational age, and bishop score of both groups were comparable. Induction time of the study group was statistically shorter than the control group (338 and 399 min, respectively). Duration of active phase (450/427 min) and the second stage (19/21 min) of labor between study and control groups were not significantly different. Cesarean section delivery rate of study was lower than the control group (13.3 and 28.8%, p = 0.002). Intrapartum complications, neonatal outcomes, and intra- and postpartum complications among both groups were not significantly differentiated. There was no instance of postpartum hemorrhage or uterine rupture in the present study. CONCLUSION: Induction time and cesarean section rates of sublingual misoprostol group were significantly lower than the intravenous oxytocin group in full-term PROM pregnancy.

Temporal Dynamics of Intranasal Oxytocin in Human Brain Electrophysiology.

Oxytocin (OT) is a key modulator of human social cognition, popular in behavioral neuroscience. To adequately design and interpret intranasal OT (IN-OT) research, it is crucial to know for how long it affects human brain function once administered. However, this has been mostly deduced from peripheral body fluids studies, or uncommonly used dosages. We aimed to characterize IN-OT's effects on human brain function using resting-state EEG microstates across a typical experimental session duration. Nineteen healthy males participated in a double-blind, placebo-controlled, within-subject, cross-over design of 24 IU of IN-OT in 12-min windows 15 min-to-1 h 42min after administration. We observed IN-OT effects on all microstates, across the observation span. During eyes-closed, IN-OT increased duration and contribution of A and contribution and occurrence of D, decreased duration and contribution of B and C; and increased transition probability C-to-B and C-to-D. In eyes-open, it increased A-to-C and A-to-D. As microstates A and D have been related to phonological auditory and attentional networks, respectively, we posit IN-OT may tune the brain for reception of external stimuli, particularly of social nature-tentatively supporting current neurocognitive hypotheses of OT. Moreover, we contrast our overall results against a comprehensive literature review of IN-OT time-course effects in the brain, highlighting comparability issues.

Environmental enrichment and intranasal oxytocin administration reverse maternal separation-induced impairments of prosocial choice behavior.

Adverse early life experiences influence behavioral and physiological functions and increase vulnerability to neuropsychiatric disorders. Maternal separation (MS) is an established animal model that reproduces the features of chronic stress or adverse experiences during early life. Previous studies have been shown that MS may lead to impairments of social behaviors. Here, we investigated the effects of MS on mutual reward preferences in a double T-maze prosocial choice task. Since enriched environment (EE) and intranasal oxytocin (OT) administration have beneficial effects on cognition and social behaviors, in the present study we tested whether these treatments, alone or in combination, would affect prosocial behavior of rats which underwent MS during infancy. Rat pups underwent MS paradigm for 180 min/day from postnatal day (PND) 1-21. From PND 22-34, rats were exposed to an EE and/or received intranasal OT (2 µg/µl, 7 days). Hence, the 8 groups consisted of control (CTRL), MS, CTRL+EE, CTRL+OT and the saline groups. Assessment of prosocial choice behavior was started in adolescence. MS impaired prosocial choice behavior and reduced mutual reward preferences. Getting exposed to EE and intranasal OT administration could overcome MS-induced deficits and promoted mutual reward preferences of MS rats. Combination of short-term EE and OT strengthened prosocial behavior. Obtained results showed that EE and OT may be considered as profitable therapeutic approaches for promoting some aspects of social behavior.