PDF(1574 KB)
The Effects of Oxytocin on the Cognitive and Neurophysiological Mechanisms of Anxiety Disorders
Zhang Yuetong, Zhao Hengyue, Jiang Yumeng, Feng Pan
Journal of Psychological Science ›› 2026, Vol. 49 ›› Issue (2) : 485-495.
PDF(1574 KB)
PDF(1574 KB)
The Effects of Oxytocin on the Cognitive and Neurophysiological Mechanisms of Anxiety Disorders
Anxiety disorders, also known as anxiety neuroses, are characterized by recurrent episodes of anxiety. They are one of the most common mental disorders, with causes including neurobiological, environmental, and psychosocial factors, among others. Their prevalence has risen sharply in recent years as social pressures have increased. Anxiety disorders have an early onset, usually begin in childhood or adolescence and continue into adulthood. Chronic anxiety and the excessive experience of negative emotions can greatly impair a patient’s social functioning and quality of life, in addition to damaging the body's immunity and adaptability to life.
Oxytocin (oxytocin) is a neuropeptide that acts as a neurotransmitter in the brain. Initially known for its peripheral physiological role in labor and breastfeeding, it has recently been emphasized because it is also released in the central nervous system and exerts neuromodulatory functions in various brain regions associated with facial emotion recognition, empathy, trust, parent-child interaction, attachment, stress, and cognition. The anxiolytic effects of oxytocin have been extensively studied, in which exogenous nasal spray administration reduces anxiety and depressive symptoms. Compared with anxiolytic drugs, oxytocin is expected to be an adjunctive drug in the treatment of anxiety disorders because of its low side effects and low likelihood of drug dependence when applied to the clinical management of patients with anxiety disorders. Oxytocin affects people's social behaviors and incrases the level of individual sedation by acting on the HPA (hypothalamic-pituitary-adrenergic) axis, acting on the hypothalamus through the ventricular system and the circulation in the body. Oxytocin combines with the receptor to release adrenocorticotropic hormone, reduce social anxiety and avoidance behaviors by acting on the serotonin system and stimulating the release of serotonin, modulate fear responses, and alleviate anxiety symptoms in individuals with anxiety disorders by acting on the GABA system to inhibit central neurotransmission and reduce amygdala activation. In addition, oxytocin, as a potential adjunctive therapeutic agent, exhibits unique synergistic effects in the psychotherapy of anxiety disorders. Oxytocin is able to act as a synergist for psychotherapy by influencing parts of the therapeutic alliance, belief renewal, and empathy. When oxytocin is synergized with other medications, it has also been found that co-medication strategies show great potential in treating anxiety disorders.
Although the role of oxytocin has been confirmed by several studies, the current findings are not entirely consistent and the reasons behind the different results have not been deeply explored. In addition, the specific use of oxytocin in clinical applications is yet to be examined, and future research should focus on the following aspects. First, it is crucial to determine the optimal dosage of oxytocin and the window of time for onset of action in the clinical treatment of anxiety disorders. The dose and frequency of administration of oxytocin, a potential anxiolytic therapeutic agent, are important factors influencing efficacy. The efficacy of oxytocin treatment at different doses and frequencies in patients with anxiety disorders can be assessed by randomized controlled trials (RCTs). Second, the synergistic effects of oxytocin with other medications or psychotherapies should be thoroughly investigated to enrich the understanding of oxytocin's mechanism of action and to achieve more precise and effective clinical interventions. Third, the neurological basis and cognitive neural mechanism of oxytocin's effect on the core symptoms of anxiety disorders should be further explored, and neuroimaging and electrophysiological methods should be utilized to further reveal the exact pathways of oxytocin's action in the brain. Finally, studies on oxytocin's effects on different subtypes of anxiety disorders can be carried out to consider individual differences and develop personalized treatment strategies.
anxiety disorder / oxytocin / cognitive mechanisms / neurophysiological mechanisms
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恐惧是一种基本的情绪, 在人类的生存和适应中发挥着重要作用。先前的研究表明, 杏仁核、背侧前扣带回、脑岛等脑区是条件化恐惧习得的认知神经基础, 杏仁核、海马和腹内侧前额叶等脑区在恐惧消退过程中发挥重要作用。研究发现, 催产素与恐惧习得和恐惧消退过程密切相关。恐惧习得过程中, 催产素影响杏仁核、背侧前扣带回的活动, 影响杏仁核与背侧前扣带回和脑干间的功能连接, 促进或抑制恐惧习得过程; 恐惧消退过程中, 催产素影响了杏仁核和腹内侧前额叶的活动, 并且影响杏仁核与内侧前额叶和海马间的功能连接, 促进或抑制恐惧消退过程。未来研究应从性别差异、神经网络模型、身心发育和病理研究等角度展开, 力图深入理解催产素影响恐惧情绪加工的认知神经机制。
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恐惧是一种与进化密切相关的情绪, 对人类的生存与适应具有重要价值。过度的恐惧可能会导致恐惧症、焦虑症和创伤后应激障碍等病理性恐惧的产生。而催产素对各种病理性恐惧的干预和治疗具有重要的价值。因此, 研究拟采用行为和fMRI技术, 系统探究催产素影响条件化恐惧情绪加工的认知神经机制。重点关注: (1)催产素影响恐惧习得的认知神经机制; (2)催产素影响恐惧记忆巩固的认知神经机制; (3)催产素影响恐惧记忆再巩固的认知神经机制; (4)催产素影响恐惧消退的认知神经机制。这项研究的开展对于探究催产素影响条件化恐惧情绪加工的认知神经机制具有很高的科学价值, 对于各种病理性恐惧的干预与治疗也具有重要的应用价值。
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催产素被誉为“爱的荷尔蒙”, 与依恋有着密切关系。以往研究已证明不同来源的催产素对不安全依恋者的人际适应性会产生不同的影响, 主要表现为内源性催产素水平越低, 不安全依恋者的人际适应性越差; 外源性催产素增强了依恋回避个体的人际适应性, 但降低了高依恋焦虑个体的人际适应性; A、G等位基因与不安全依恋者的人际适应性有关。此外还借助依恋理论和社会显著假说解释了上述影响, 不安全依恋者的防御性排斥、环境因素和个体差异调节了催产素的效应。未来应比较催产素受体基因与不安全依恋者人际适应性关系的差异, 催产素影响不安全依恋者人际适应性的性别差异问题, 并在人际互动过程中研究催产素对不安全依恋者人际适应性的影响, 以增强催产素研究的生态效度。
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催产素是一种亲社会激素, 对人类的共情反应有重要的影响作用, 主要表现为可以促进情绪识别率, 增强对他人不幸的共情关注, 并弱化自身的个体忧伤水平等。从作用机制上来看, 催产素可能是通过促进具身模仿能力, 弱化自我中心主义倾向及调节情感表征过程来影响人类的共情反应的。未来研究可以进一步关注催产素对不同类型共情反应的影响及其催产素影响共情反应的性别差异问题, 并积极将催产素应用于共情缺陷的临床干预中。
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The mammalian neuropeptide oxytocin has well-characterized effects in facilitating prosocial and affiliative behavior. Additionally, oxytocin decreases physiological and behavioral responses to social stress. In the present study we investigated the effects of oxytocin on cognitive appraisals after a naturalistic social stress task in healthy male students. In a randomized, double-blind, placebo-controlled trial, 48 participants self-administered either an oxytocin or placebo nasal spray and, following a wait period, completed an impromptu speech task. Eye gaze to a pre-recorded video of an audience displayed during the task was simultaneously collected. After the speech, participants completed questionnaires assessing negative cognitive beliefs about speech performance. Whilst there was no overall effect of oxytocin compared to placebo on either eye gaze or questionnaire measures, there were significant positive correlations between trait levels of anxiety and negative self-appraisals following the speech. Exploratory analyses revealed that whilst higher trait anxiety was associated with increasingly poorer perceptions of speech performance in the placebo group, this relationship was not found in participants administered oxytocin. These results provide preliminary evidence to suggest that oxytocin may reduce negative cognitive self-appraisals in high trait anxious males. It adds to a growing body of evidence that oxytocin seems to attenuate negative cognitive responses to stress in anxious individuals.Copyright © 2012 Elsevier Ltd. All rights reserved.
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Anxiety disorders, including panic disorder with or without agoraphobia, generalized anxiety disorder, social anxiety disorder, specific phobias, and separation anxiety disorder, are the most prevalent mental disorders and are associated with immense health care costs and a high burden of disease. According to large population-based surveys, up to 33.7% of the population are affected by an anxiety disorder during their lifetime. Substantial underrecognition and undertreatment of these disorders have been demonstrated. There is no evidence that the prevalence rates of anxiety disorders have changed in the past years. In cross-cultural comparisons, prevalence rates are highly variable. It is more likely that this heterogeneity is due to differences in methodology than to cultural influences. Anxiety disorders follow a chronic course; however, there is a natural decrease in prevalence rates with older age. Anxiety disorders are highly comorbid with other anxiety disorders and other mental disorders.
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The neuropeptide oxytocin (OT) regulates rodent, primate and human social behaviors and stress responses. OT binding studies employing (125)I-d(CH2)5-[Tyr(Me)2,Thr4,Tyr-NH2(9)] ornithine vasotocin ((125)I-OTA), has been used to locate and quantify OT receptors (OTRs) in numerous areas of the rat brain. This ligand has also been applied to locating OTRs in the human brain. The results of the latter studies, however, have been brought into question because of subsequent evidence that (125)I-OTA is much less selective for OTR vs. vasopressin receptors in the primate brain. Previously we used a monoclonal antibody directed toward a region of the human OTR to demonstrate selective immunostaining of cell bodies and fibers in the preoptic-anterior hypothalamic area and ventral septum of a cynomolgus monkey (Boccia et al., 2001). The present study employed the same monoclonal antibody to study the location of OTRs in tissue blocks containing cortical, limbic and brainstem areas dissected from fixed adult, human female brains. OTRs were visualized in discrete cell bodies and/or fibers in the central and basolateral regions of the amygdala, medial preoptic area (MPOA), anterior and ventromedial hypothalamus, olfactory nucleus, vertical limb of the diagonal band, ventrolateral septum, anterior cingulate and hypoglossal and solitary nuclei. OTR staining was not observed in the hippocampus (including CA2 and CA3), parietal cortex, raphe nucleus, nucleus ambiguus or pons. These results suggest that there are some similarities, but also important differences, in the locations of OTRs in human and rodent brains. Immunohistochemistry (IHC) utilizing a monoclonal antibody provides specific localization of OTRs in the human brain and thereby provides opportunity to further study OTR in human development and psychiatric conditions.Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.
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Adherence to lifestyle recommendations for prevention of cardiovascular disease remains a critical issue. We examined the association of anxiety and depression with healthy behaviors in a large population of subjects at risk of cardiovascular disease. We studied 1612 consecutive subjects referred for evaluation of cardiovascular risk factors. Separated scores reflecting unhealthy behaviors (physical inactivity, smoking and poor diet) were combined to produce a global unhealthy lifestyle score. The Hospital Anxiety and Depression scale (HAD) was used to assess both anxiety and depression. Both anxiety and depression were significantly associated with physical inactivity in both sexes and with an unhealthy diet in men but not in women. Anxiety and depression were both significantly correlated to smoking habits in men whereas only depression was related to smoking in women. In both sexes, the global score reflecting unhealthy lifestyles was positively associated with the degree of anxiety and depression. In multivariate analysis, both anxiety and depression appeared as independent determinant of unhealthy lifestyle in both sexes, with a stronger influence for depression. Depression and to a lesser extent anxiety are associated with a cluster of unhealthy behaviors in subjects at risk of cardiovascular disease, suggesting the difficulty of modifying lifestyle in patients with anxious-depressive disorders.
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Fear acquisition and extinction have been demonstrated as core mechanisms for the development and maintenance of mental disorders, with different contributions of processing cues vs contexts. The hypothalamic peptide oxytocin (OXT) may have a prominent role in this context, as it has been shown to affect fear learning. However, investigations have focused on cue conditioning, and fear extinction. Its differential role for cue and context fear acquisition is still not known. In a randomized, double-blind, placebo (PLC)-controlled design, we administered an intranasal dose of OXT or PLC before the acquisition of cue and context fear conditioning in healthy individuals (n = 52), and assessed brain responses, skin conductance responses and self-reports (valence/arousal/contingency). OXT compared with PLC significantly induced decreased responses in the nucleus accumbens during early cue and context acquisition, and decreased responses of the anterior cingulate cortex and insula during early as well as increased hippocampal response during late context, but not cue acquisition. The OXT group additionally showed significantly higher arousal in late cue and context acquisition. OXT modulates various aspects of cue and context conditioning, which is relevant from a mechanism-based perspective and might have implications for the treatment of fear and anxiety.© The Author (2017). Published by Oxford University Press.
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Anxiety disorders are a diverse group of clinical states. Post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), eg, share elevated anxiety symptoms, but differ with respect to fear-related memory dysregulation. As the hippocampus is implicated in both general anxiety and fear memory, it may be an important brain locus for mapping the similarities and differences among anxiety disorders. Anxiety and fear also functionally associate with different subdivisions of the hippocampus along its longitudinal axis: the human posterior (rodent dorsal) hippocampus is involved in memory, through connectivity with the medial prefrontal-medial parietal default-mode network, whereas the anterior (rodent ventral) hippocampus is involved in anxiety, through connectivity with limbic-prefrontal circuits. We examined whether differential hippocampal network functioning may help account for similarities and differences in symptoms in PTSD and GAD. Network-sensitive functional magnetic resonance imaging-based resting-state intrinsic connectivity methods, along with task-based assessment of posterior hippocampal/default-mode network function, were used. As predicted, in healthy subjects resting-state connectivity dissociated between posterior hippocampal connectivity with the default-mode network, and anterior hippocampal connectivity to limbic-prefrontal circuitry. The posterior hippocampus and the associated default-mode network, across both resting-state connectivity and task-based measures, were perturbed in PTSD relative to each of the other groups. By contrast, we found only modest support for similarly blunted anterior hippocampal connectivity across both patient groups. These findings provide new insights into the neural circuit-level dysfunctions that account for similar vs different features of two major anxiety disorders, through a translational framework built on animal work and carefully selected clinical disorders.
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Oxytocin is a neuropeptide that is active in the central nervous system and is generally considered to be involved in prosocial behaviors and feelings. In light of its documented positive effect on maternal behavior, we designed a study to ascertain whether oxytocin exerts any therapeutic effects on depressive symptoms in women affected by maternal postnatal depression. A group of 16 mothers were recruited in a randomized double-blind study: the women agreed to take part in a brief course of psychoanalytic psychotherapy (12 sessions, once a week) while also being administered, during the 12-weeks period, a daily dose of intranasal oxytocin (or a placebo). The pre-treatment evaluation also included a personality assessment of the major primary-process emotional command systems described by Panksepp (1998) and a semi quantitative assessment by the therapist of the mother's depressive symptoms and of her personality. No significant effect on depressive symptomatology was found following the administration of oxytocin (as compared to a placebo) during the period of psychotherapy. Nevertheless, a personality trait evaluation of the mothers, conducted in our overall sample group, showed a decrease in the narcissistic trait only within the group who took oxytocin. The depressive (dysphoric) trait was in fact significantly affected by psychotherapy (this effect was only present in the placebo group so it may reflect a positive placebo effect enhancing the favorable influence of psychotherapy on depressive symptoms) but not in the presence of oxytocin. Therefore, the neuropeptide would appear to play some role in the modulation of cerebral functions involved in the self-centered (narcissistic) dimension of the suffering that can occur with postnatal depression. Based on these results, there was support for our hypothesis that what is generally defined as postnatal depression may include disturbances of narcissistic affective balance, and oxytocin supplementation can counteract that type of affective disturbance. The resulting improvements in well-being, reflected in better self-centering in post-partuent mothers, may in turn facilitate better interpersonal acceptance of (and interactions with) the child and thereby, improved recognition of the child's needs.
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A growing body of research suggests that the construct of emotion regulation is important for understanding the onset, maintenance, and treatment of anxiety disorders. In this review, we provide a selective overview of this emerging field and highlight the major sources of evidence. First, evidence suggests that the construct of emotion regulation can be differentiated from the construct of emotion. Second, there is a large and consistent body of research demonstrating that emotion regulation strategies can modulate emotional responding, and this finding is observed in both behavioral and neuroimaging studies. Third, measures of emotion regulation explain incremental variance in measures of anxiety disorder symptoms not accounted for by measures of negative affect. Although the research implicating emotion regulation in the anxiety disorders is promising, future research will be necessary to further clarify causal mechanisms explaining how emotion regulation confers vulnerability for anxiety disorders and to improve the clarity and consistency of definitions of emotion regulation.
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Animal studies have shown the role of oxytocin in affiliation and attachment, and recent evidence suggests that oxytocin is also involved in human models of approach behaviour, possibly by modulating the processing of emotionally valenced stimuli. Although oxytocin administration has been reported to decrease neural responses to facial emotional information, the effects on a wider range of behavioural measures of emotional processing shown to be sensitive to antidepressant manipulation have not been examined. The aim of this study was to investigate whether intranasally administered oxytocin affects the processing of positive and negative affective information in healthy male volunteers across tasks measuring attention, perception and memory. Twenty-nine male healthy volunteers were randomly allocated to receive a single dose of oxytocin nasal spray (24 UI) or placebo. 50 min later, participants completed a battery of psychological tests measuring emotional processing. A single dose of intranasally administered oxytocin slowed reaction time to correctly identify fearful facial expressions and reduced the misclassification of positive emotions as negative ones. These effects occurred in the absence of significant differences in subjective ratings of mood and anxiety. These results suggest that oxytocin modulates emotion processing in healthy male volunteers. This action may contribute to the emerging role of the neuropeptide in promoting affiliative and approach behaviours by reducing the salience of potentially ambiguous and threatening social stimuli.
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FK506 is a macrolide immunosuppressant agent used in solid organ and bone marrow transplantation and for autoimmune disorders. FK506 is reported to have a number of neuropsychiatric side effects, including anxiety and tremor. Because FK506 was implicated in causing akathisia in a case report, we did a prospective, cross-sectional study of 25 renal transplant recipients to determine whether akathisia occurred and/or had a relationship to FK506 plasma levels. The Symptom Checklist-90-R, Hamilton Anxiety (HAM-A), and Akathisia Rating (ARS) scales were administered. Higher FK506 plasma levels correlated with higher HAM-A scores. ARS scores did not correlate with FK506 plasma levels; however, when FK506 plasma levels were divided into "high" (> or = 0.9 ng/mL) and "low" (< 0.9 ng/mL) groups, total ARS and HAM-A scores were significantly higher in the "high" group. We discuss implications of these findings as well as management.
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Power ultrasound as an emerging processing technology has been investigated for stimulating seeds to enhance germination and accumulation of health-promoting metabolites, such as γ-aminobutyric acid (GABA) and phenolic compounds. This work was undertaken to evaluate the effects of power ultrasound (25 kHz) on the nutritional properties of germinated oats, and the microstructure of oat groats after treatment. The changes in the external and internal microstructures of the ultrasound-treated oats kernel were investigated using Environmental Scanning Electron Microscopy (ESEM) and 3D X-ray Micro Computed Tomography (Micro-CT). Physicochemical properties of oats including GABA, free sugars, avenanthramides, total phenolic content, and antioxidant capacities were enhanced after germination. Furthermore, the power ultrasound treatment for 5 min after soaking significantly enhanced the GABA (48-96 h), alanine (24-96 h), succinic acid (48-72 h), total phenolic content (24 h), and total avenanthramides (24 h) in the germinated oats.Copyright © 2019 Elsevier Ltd. All rights reserved.
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The expression of emotion in faces serves numerous meaningful functions, such as conveying messages of danger or approach, facilitating communication, and promoting the formation of social bonds and relationships. The study of facial expressions of emotion has become integral to research in social psychology and social neuroscience, particularly with respect to the neuropeptide oxytocin. This chapter examines how oxytocin influences the processing of emotion in faces by reviewing intranasal administration studies of automatic processing, selective attention, and emotion recognition. Two important trends in the literature have been identified: exogenous oxytocin attenuates early attentional biases towards negative stimuli and increases selective attention and recognition of emotional cues in faces, particularly around the eyes. Both of these effects can be traced to well-delineated neural circuits involving amygdala, early visual processing areas, and reward circuits, and both purportedly facilitate approach-related behavior when affiliative opportunities are available. These data are integrated into a conceptual model incorporating contextual factors and moderating influences, as oxytocinergic effects on cognition and social behavior appear to vary in persons along indices of social competence, interpersonal sensitivity, and early adversity. Limitations of this literature and future directions for research are briefly discussed.
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Oxytocin regulates parturition, lactation, parental nurturing, and many other social behaviors in both sexes. The circuit mechanisms by which oxytocin modulates social behavior are receiving increasing attention. Here, we review recent studies on oxytocin modulation of neural circuit function and social behavior, largely enabled by new methods of monitoring and manipulating oxytocin or oxytocin receptor neurons in vivo. These studies indicate that oxytocin can enhance the salience of social stimuli and increase signal-to-noise ratios by modulating spiking and synaptic plasticity in the context of circuits and networks. We highlight oxytocin effects on social behavior in nontraditional organisms such as prairie voles and discuss opportunities to enhance the utility of these organisms for studying circuit-level modulation of social behaviors. We then discuss recent insights into oxytocin neuron activity during social interactions. We conclude by discussing some of the major questions and opportunities in the field ahead. Expected final online publication date for the, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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This essay describes the evolution of stress as a medical scientific idea. Claude Bernard, Walter B. Cannon and Hans Selye provided key founding concepts for the current view. Bernard introduced the idea of the internal environment bathing cells - the milieu intérieur - maintained by continual compensatory changes of bodily functions. Cannon coined the word, "homeostasis," referring to a set of acceptable ranges of values for internal variables. Cannon taught that threats to homeostasis evoke activation of the sympathoadrenal system as a functional unit. Selye defined stress as a state characterized by a uniform response pattern, regardless of the particular stressor, that could lead to long-term pathologic changes. "Allostasis" was introduced as a concept in recognition that there is no single ideal set of steady-state conditions in life; instead, setpoints and other response criteria change continuously. Stress is now viewed neither as a perturbation nor a stereotyped response pattern but as a condition characterized by a perceived discrepancy between information about a monitored variable and criteria for eliciting patterned effector responses. Different stressors elicit different patterns of activation of the sympathetic nervous, adrenomedullary hormonal, hypothalamic-pituitary-adrenocortical and other effectors, closing negative feedback loops. This systems concept of stress yields predictions that observation or experimentation can test and that are applicable to normal physiology and to a variety of acute and chronic disorders.
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The neuropeptide oxytocin (OXT) is thought to attenuate anxiety by dampening amygdala reactivity to threat in individuals with generalized social anxiety disorder (GSAD). Because the brain is organized into networks of interconnected areas, it is likely that OXT impacts functional coupling between the amygdala and other socio-emotional areas of the brain. Therefore, the aim of the current study was to examine the effects of OXT on amygdala functional connectivity during the processing of fearful faces in GSAD subjects and healthy controls (HCs). In a randomized, double-blind, placebo (PBO)-controlled, within-subjects design, 18 HCs and 17 GSAD subjects performed a functional magnetic resonance imaging task designed to probe amygdala response to fearful faces following acute intranasal administration of PBO or OXT. Functional connectivity between the amygdala and the rest of the brain was compared between OXT and PBO sessions using generalized psychophysiological interaction analyses. Results indicated that within individuals with GSAD, but not HCs, OXT enhanced functional connectivity between the amygdala and the bilateral insula and middle cingulate/dorsal anterior cingulate gyrus during the processing of fearful faces. These findings suggest that OXT may have broad pro-social implications such as enhancing the integration and modulation of social responses.
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| [30] |
Oxytocin has a crucial role in social behaviour, although its effects on social cognition are not fully understood. Past research shows that oxytocin enhances encoding and conceptual recognition of positive social stimuli over social-threat stimuli. In this study, we evaluated whether oxytocin modified responses to positive and threatening social stimuli at an earlier perceptual stage of processing using the visual search task. In a double-blind, randomized, placebo-controlled, between-subject design, oxytocin (24 IU) or a placebo was administered to 104 healthy volunteers. Participants returned to complete the visual search paradigm 45min later. Results showed that angry faces were detected more efficiently than happy faces. Participants also gazed longer and more frequently toward angry faces. Oxytocin did not, however, influence response time, accuracy, or gaze toward angry or happy faces, even when participants were separated into high- and low-social anxiety. The results of this study suggest that oxytocin may not influence the detection of positive and threatening social stimuli at early perceptual levels of processing. Oxytocin may have greater influence in altering the cognitive processing of social valence at more conceptual and elaborate levels of processing.
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Amygdala and ventrolateral prefrontal cortex (vlPFC) dysfunction manifests in adolescents with anxiety disorders when they view negatively valenced stimuli in threatening contexts. Such fear-circuitry dysfunction may also manifest when anticipated social evaluation leads socially anxious adolescents to misperceive peers as threatening.To determine whether photographs of negatively evaluated smiling peers viewed during anticipated social evaluation engage the amygdala and vlPFC differentially in adolescents with and without social anxiety.Case-control study.Government clinical research institute.Fourteen adolescents with anxiety disorders associated with marked concerns of social evaluation and 14 adolescents without a psychiatric diagnosis matched on sex, age, intelligence quotient, and socioeconomic status.Blood oxygenation level-dependent signal measured with event-related functional magnetic resonance imaging. Before and during neuroimaging scans, participants anticipating social evaluation completed peer- and self-appraisals. Event-related analyses were tailored to participants' ratings of specific peers.Participants classified 40 pictures of same-age peers as ones with whom they did or did not want to engage in a social interaction. Anxious adolescents showed greater amygdala activation than healthy adolescents when anticipating evaluation from peers previously rated as undesired for an interaction. Psychophysiological interaction connectivity analyses also revealed a significant positive association between amygdala and vlPFC activation in anxious vs healthy adolescents in response to these stimuli.Anticipating social evaluation from negatively perceived peers modulates amygdala and vlPFC engagement differentially in anxious and healthy adolescents. Amygdala and vlPFC dysfunction manifests in adolescent anxiety disorders in specific contexts of anticipated peer evaluation.
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| [33] |
The presence of social support has been associated with decreased stress responsiveness. Recent animal studies suggest that the neuropeptide oxytocin is implicated both in prosocial behavior and in the central nervous control of neuroendocrine responses to stress. This study was designed to determine the effects of social support and oxytocin on cortisol, mood, and anxiety responses to psychosocial stress in humans.In a placebo-controlled, double-blind study, 37 healthy men were exposed to the Trier Social Stress Test. All participants were randomly assigned to receive intranasal oxytocin (24 IU) or placebo 50 min before stress, and either social support from their best friend during the preparation period or no social support.Salivary free cortisol levels were suppressed by social support in response to stress. Comparisons of pre- and poststress anxiety levels revealed an anxiolytic effect of oxytocin. More importantly, the combination of oxytocin and social support exhibited the lowest cortisol concentrations as well as increased calmness and decreased anxiety during stress.Oxytocin seems to enhance the buffering effect of social support on stress responsiveness. These results concur with data from animal research suggesting an important role of oxytocin as an underlying biological mechanism for stress-protective effects of positive social interactions.
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| [34] |
Anxiety is associated with poor health outcomes among chronic kidney disease (CKD) patients. This review summarizes the prevalence and risk factors associated with elevated anxiety symptoms and disorders among CKD patients.Articles evaluating the prevalence and risk factors associated with elevated anxiety symptoms and disorders among CKD patients, as diagnosed via DSM 4th or 5th edition criteria, clinical interviews or validated questionnaires, were searched in Medline®, Embase®, PsychINFO® and CINAHL®. Using random-effects meta-analyses, the prevalence of elevated anxiety symptoms and disorders were estimated. A narrative review on the risk factors associated with elevated anxiety symptoms and disorders was presented.From 4941 articles, 61 studies were included. The pooled prevalence of anxiety disorders (9 studies, n = 1071) among CKD patients across studies was 19% while that of elevated anxiety symptoms (52 studies, n = 10,739) was 43%. Across continents, prevalence of elevated anxiety symptoms was highest in Europe and Asia. Between pre-dialysis and dialysis patients, the prevalence of elevated anxiety symptoms was not statistically different at 31% and 42% respectively. Common risk factors associated with elevated anxiety symptoms included concomitant depression, lower parathyroid hormone levels, increased comorbidities, increased duration of hospitalization, reduced perceived quality of life, and decreased vitality levels.Given the high prevalence of anxiety disorders and elevated anxiety symptoms, more studies are required to assess the role and outcomes of anxiety screening among CKD patients. This could facilitate early identification of at-risk patients and potentially improve their clinical outcomes.Copyright © 2020 Elsevier Inc. All rights reserved.
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| [35] |
Vasopressin and oxytocin strongly modulate autonomic fear responses, through mechanisms that are still unclear. We describe how these neuropeptides excite distinct neuronal populations in the central amygdala, which provides the major output of the amygdaloid complex to the autonomic nervous system. We identified these two neuronal populations as part of an inhibitory network, through which vasopressin and oxytocin modulate the integration of excitatory information from the basolateral amygdala and cerebral cortex in opposite manners. Through this network, the expression and endogenous activation of vasopressin and oxytocin receptors may regulate the autonomic expression of fear.
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| [36] |
Current concepts of human sociality highlight a fundamental role of the hypothalamic peptide oxytocin (OXT) in the formation and maintenance of social relationships. However, emerging evidence indicates that OXT does not invariably facilitate social bonding but also produces nonprosocial effects that may have evolved to promote offspring survival. From a mechanistic perspective, we hypothesize that OXT modulates interoceptive signals and self-referential processing, which may result in various social outcomes depending on context- and person-dependent variables such as early-life adversity. Based on this theoretical framework, we discuss translational implications for clinical trials and identify open questions for future research. Specifically, we propose that disrupted OXT signaling due to the loss of affectionate bonds may contribute to emotional disequilibrium and confer elevated risk for the onset of stress-related disorders. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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| [37] |
Despite its relatively well-understood role as a reproductive and pro-social peptide, oxytocin (OT) tells a more convoluted story in terms of its modulation of fear and anxiety. This nuanced story has been obscured by a great deal of research into the therapeutic applications of exogenous OT, driving more than 400 ongoing clinical trials. Drawing from animal models and human studies, we review the complex evidence concerning OT's role in fear learning and anxiety, clarifying the existing confusion about modulation of fear versus anxiety. We discuss animal models and human studies demonstrating the prevailing role of OT in strengthening fear memory to a discrete signal or cue, which allows accurate and rapid threat detection that facilitates survival. We also review ostensibly contrasting behavioral studies that nonetheless provide compelling evidence of OT attenuating sustained contextual fear and anxiety-like behavior, arguing that these OT effects on the modulation of fear vs. anxiety are not mutually exclusive. To disambiguate how endogenous OT modulates fear and anxiety, an understudied area compared to exogenous OT, we survey behavioral studies utilizing OT receptor (OTR) antagonists. Based on emerging evidence about the role of OTR in rat dorsolateral bed nucleus of stria terminalis (BNST) and elsewhere, we postulate that OT plays a critical role in facilitating accurate discrimination between stimuli representing threat and safety. Supported by human studies, we demonstrate that OT uniquely facilitates adaptive fear but reduces maladaptive anxiety. Last, we explore the limited literature on endogenous OT and its interaction with corticotropin-releasing factor (CRF) with a special emphasis on the dorsolateral BNST, which may hold the key to the neurobiology of phasic fear and sustained anxiety.
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| [38] |
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| [39] |
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| [40] |
Little is known about lifetime prevalence or age of onset of DSM-IV disorders.To estimate lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the recently completed National Comorbidity Survey Replication.Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview.Nine thousand two hundred eighty-two English-speaking respondents aged 18 years and older.Lifetime DSM-IV anxiety, mood, impulse-control, and substance use disorders.Lifetime prevalence estimates are as follows: anxiety disorders, 28.8%; mood disorders, 20.8%; impulse-control disorders, 24.8%; substance use disorders, 14.6%; any disorder, 46.4%. Median age of onset is much earlier for anxiety (11 years) and impulse-control (11 years) disorders than for substance use (20 years) and mood (30 years) disorders. Half of all lifetime cases start by age 14 years and three fourths by age 24 years. Later onsets are mostly of comorbid conditions, with estimated lifetime risk of any disorder at age 75 years (50.8%) only slightly higher than observed lifetime prevalence (46.4%). Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups.About half of Americans will meet the criteria for a DSM-IV disorder sometime in their life, with first onset usually in childhood or adolescence. Interventions aimed at prevention or early treatment need to focus on youth.
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| [41] |
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| [42] |
The hypothalamic neuropeptide oxytocin (OT), which controls childbirth and lactation, receives increasing attention for its effects on social behaviors, but how it reaches central brain regions is still unclear. Here we gained by recombinant viruses selective genetic access to hypothalamic OT neurons to study their connectivity and control their activity by optogenetic means. We found axons of hypothalamic OT neurons in the majority of forebrain regions, including the central amygdala (CeA), a structure critically involved in OT-mediated fear suppression. In vitro, exposure to blue light of channelrhodopsin-2-expressing OT axons activated a local GABAergic circuit that inhibited neurons in the output region of the CeA. Remarkably, in vivo, local blue-light-induced endogenous OT release robustly decreased freezing responses in fear-conditioned rats. Our results thus show widespread central projections of hypothalamic OT neurons and demonstrate that OT release from local axonal endings can specifically control region-associated behaviors.Copyright © 2012 Elsevier Inc. All rights reserved.
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| [43] |
The neuropeptide oxytocin is proposed as a promising therapy for social dysfunction by modulating amygdala-mediated social-emotional behavior. Although clinical trials report some benefits of chronic treatment, it is unclear whether efficacy may be influenced by dose frequency or genotype.
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| [44] |
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| [45] |
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| [46] |
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| [47] |
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| [48] |
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| [49] |
The hypothalamo-pituitary-adrenal (HPA) axis plays important roles in the adaptive changes in physiology that occur during pregnancy and lactation. Although the axis still exhibits a pulsatile pattern of secretion, the normal diurnal rhythm of pulse amplitude is lost during lactation, such that mean basal levels remain constant throughout the day. In addition, the peripartum period is associated with a remarkable plasticity in stress-induced HPA activity, in that the increase of HPA activity normally seen in response to either physical or psychological stresses in the non-reproductive state become severely attenuated or absent in the lactating animal. This stabilization of both basal and stress-induced HPA activity may be important for maintaining a constant endocrine environment, thereby preventing any programming effects on the developing offspring. Attenuation of the stress response is initiated in late pregnancy and is temporally associated with luteolysis, indicating possible steroid hormone involvement. Indeed, mimicking the luteolytic changes in oestrogen and progesterone levels in non-pregnant animals induces a similar attenuation of the stress response. Furthermore down-regulation of the stress response is, at least in part, centrally mediated since in the period following luteolysis rats will show a decreased level of stress-induced neuronal activation of the PVN, as measured by the expression of either c-fos or CRH mRNAs. Persistence of this adapted state is dependent upon the continued suckling stimulus, as removal of the offspring litter rapidly leads to resumption of HPA responses to and the appearance of an exaggerated diurnal rhythm. The underlying mechanisms responsible for this stress hyporesponsiveness may include plasticity of noradrenergic and oxytocin pathways. In view of its role in other reproductive behaviors, a stress-inhibiting effect of oxytocin may reflect a more widespread co-ordinating role in the peripartum animal.
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| [50] |
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| [51] |
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| [52] |
Peripartum hormones and sensory cues from young modify the maternal brain in ways that can render females either at risk for, or resilient to, elevated anxiety and depression. The neurochemical systems underlying these aspects of maternal emotional and mood states include the inhibitory neurotransmitter GABA and the neuropeptide oxytocin (OXT). Data from laboratory rodents indicate that increased activity at the GABA(A) receptor contributes to the postpartum suppression of anxiety-related behaviour that is mediated by physical contact with offspring, whereas dysregulation in GABAergic signalling results in deficits in maternal care, as well as anxiety- and depression-like behaviours during the postpartum period. Similarly, activation of the brain OXT system accompanied by increased OXT release within numerous brain sites in response to reproductive stimuli also reduces postpartum anxiety- and depression-like behaviours. Studies of peripartum women are consistent with these findings in rodents. Given the similar consequences of elevated central GABA and OXT activity on maternal anxiety and depression, balanced and partly reciprocal interactions between these two systems may be essential for their effects on maternal emotional and mood states, in addition to other aspects of postpartum behaviour and physiology.© 2014 British Society for Neuroendocrinology.
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| [53] |
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| [54] |
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| [55] |
Oxytocin is a neuropeptide involved in a wide variety of social behaviors in diverse species. Recent research on its effects in humans has generated an arresting picture of its role in the dynamic function of the social brain. This review presents a broad overview of this uniquely social peptide, with a particular focus on extant studies of its effects in humans. After a short discussion of the evolutionary history of the oxytocin system, critical aspects of its peripheral and central physiology, and several salient technical issues surrounding human oxytocin research, a systematic review of studies of the effects of intranasal oxytocin in humans is presented. These effects include alterations in social decision making, processing of social stimuli, certain uniquely social behaviors (e.g., eye contact), and social memory. Oxytocin's prosocial influence is then framed by an evolutionary perspective on its role in mammalian social bonding and attachment. Finally, limitations in current human oxytocin research and oxytocin's potential therapeutic applications are discussed. Key conclusions are (1) human research with intranasal oxytocin has uniquely enhanced our understanding of the microstructure and function of the human social brain, and (2) the oxytocin system is a promising target for therapeutic interventions in a variety of conditions, especially those characterized by anxiety and aberrations in social function.
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| [56] |
Clinically significant separation anxiety [SA] has been identified as being common among patients who do not respond to psychiatric interventions, regardless of intervention type (pharmacological or psychotherapeutic), across anxiety and mood disorders. An attachment formation and maintenance domain has been proposed as contributing to anxiety disorders. We therefore directly determined prevalence of SA in a population of adult treatment non-responders suffering from primary anxiety. In these separation anxious nonresponders, we pilot-tested an SA-focused, attachment-based psychotherapy for anxiety, Panic-Focused Psychodynamic Psychotherapy-eXtended Range [PFPP-XR], and assessed whether hypothesized biomarkers of attachment were engaged. We studied separation anxiety [SA] in 46 adults (ages 23-70 [mean 43.9 (14.9)]) with clinically significant anxiety symptoms (Hamilton Anxiety Rating Scale [HARS]≥15), and reporting a history of past non-response to psychotherapy and/or medication treatments. Thirty-seven (80%) had clinically significant symptoms of separation anxiety (Structured Clinical Interview for Separation Anxiety Symptoms [SCI-SAS] score≥8). Five of these subjects completed an open clinical trial of Panic Focused Psychodynamic Psychotherapy eXtended Range [PFPP-XR], a 21-24 session, 12-week manualized attachment-focused anxiolytic psychodynamic psychotherapy for anxiety. Patients improved on "adult threshold" SCI-SAS (current separation anxiety) (p=.016), HARS (p=0.002), and global severity, assessed by the Clinical Global Impression Scale (p=.0006), at treatment termination. Salivary oxytocin levels decreased 67% after treatment (p=.12). There was no significant change in high or low frequency HRV after treatment, but change in high frequency HRV inversely correlated with treatment change in oxytocin (p<.02), and change in low frequency HRV was positively associated with change in oxytocin (p<.02). SA is surprisingly prevalent among non-responders to standard anti-anxiety treatments, and it may represent a novel transdiagnostic target for treatment intervention in this population. Anxiety and global function improved in a small trial of a brief, manualized, attachment-focused psychodynamic psychotherapy, potentially supporting the clinical relevance of attachment dysfunction in this sample. The large decrease in oxytocin levels with treatment, although not statistically significant in this very small sample, suggests the need for further study of oxytocin as a putative biomarker or mediator of SA response. These pilot data generate testable hypotheses supporting an attachment domain underlying treatment-resistant anxiety, and new treatment strategies. Copyright © 2016 Elsevier Inc. All rights reserved.
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| [57] |
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| [58] |
Generalized anxiety disorder (GAD) is a prevalent anxiety disorder, but its neurobiological basis has been poorly studied. A few cognitive models have been proposed for understanding GAD development and maintenance. The aim of this study is to review functional Magnetic Resonance Image (fMRI) studies conducted with GAD patients and evaluate if they support and underpin the theoretical cognitive models proposed for this anxiety disorder.A literature systematic review was undertaken in PubMed and ISI databases with no time limits.From the studies included in this review, 10 explored the "emotional dysregulation model", showing, prefrontal cortex (PFC) and anterior cingulate cortex (ACC) hypofunction and deficient top-down control system during emotion regulation tasks, despite conflicting techniques and results. Only one study explored the "conditioned fear overgeneralization theory", other the "intolerance of uncertainty model" and two studies were unspecific (worry induction tasks). Between those, there were 4 studies evaluating pre- and post-treatment with antidepressants or "mindfulness".The studies׳ methodologies differ between one another making it difficult to identify a common finding.Emotion dysregulation seems to be an important cognitive dysfunction in GAD patients and fMRI studies suggest that it is related to PFC and ACC hypofunction as well as a deficient cortex-amygdala functional connectivity.Copyright © 2014 Elsevier B.V. All rights reserved.
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| [59] |
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| [60] |
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| [61] |
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| [62] |
Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression.In this study, we examined genotypes in 653 individuals and tested whether SNP variation in OXTR correlates with severity of features of self-reported experience on the Depression Anxiety and Stress Scale (DASS), and whether this correlation is enhanced when early life trauma is taken into account. We also assessed the effects of OXTR SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples.A significant effect of OXTR genotype on DASS anxiety, stress and depression scores was found and ELS events, in combination with several different OXTR SNPs, were significantly associated with differences in DASS scores with one SNP (rs139832701) showing significant association or a trend towards association for all three measures. Several OXTR SNPs were correlated with alterations in OXTR RNA expression and rs3831817 replicated across both sets of tissues.These results support the hypothesis that the oxytocin system plays a role in the pathophysiology of mood and anxiety disorders.Copyright © 2014 Elsevier Ltd. All rights reserved.
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| [63] |
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| [64] |
Oxytocin and vasopressin are regulators of anxiety, stress-coping, and sociality. They are released within hypothalamic and limbic areas from dendrites, axons, and perikarya independently of, or coordinated with, secretion from neurohypophysial terminals. Central oxytocin exerts anxiolytic and antidepressive effects, whereas vasopressin tends to show anxiogenic and depressive actions. Evidence from pharmacological and genetic association studies confirms their involvement in individual variation of emotional traits extending to psychopathology. Based on their opposing effects on emotional behaviors, we propose that a balanced activity of both brain neuropeptide systems is important for appropriate emotional behaviors. Shifting the balance between the neuropeptide systems towards oxytocin, by positive social stimuli and/or psychopharmacotherapy, may help to improve emotional behaviors and reinstate mental health.Copyright © 2012 Elsevier Ltd. All rights reserved.
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| [65] |
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| [66] |
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| [67] |
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| [68] |
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| [69] |
In schizophrenia, social cognition is strongly linked to functional outcome and is increasingly seen as a viable treatment target. The goal of the Social Cognition Psychometric Evaluation (SCOPE) study is to identify and improve the best existing measures of social cognition so they can be suitably applied in large-scale treatment studies. Initial phases of this project sought to (1) develop consensus on critical domains of social cognition and (2) identify the best existing measures of social cognition for use in treatment studies.Experts in social cognition were invited to nominate key domains of social cognition and the best measures of those domains. Nominations for measures were reduced according to set criteria, and all available psychometric information about these measures was summarized and provided to RAND panelists. Panelists rated the quality of each measure on multiple criteria, and diverging ratings were discussed at the in-person meeting to obtain consensus.Expert surveys identified 4 core domains of social cognition-emotion processing, social perception, theory of mind/mental state attribution, and attributional style/bias. Using RAND panel consensus ratings, the following measures were selected for further evaluation: Ambiguous Intentions Hostility Questionnaire, Bell Lysaker Emotion Recognition Task, Penn Emotion Recognition Test, Relationships Across Domains, Reading the Mind in the Eyes Test, The Awareness of Social Inferences Test, Hinting Task, and Trustworthiness Task.While it was possible to establish consensus, only a limited amount of psychometric information is currently available for the candidate measures, which underscores the need for well-validated and standardized measures in this area.© The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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| [70] |
Extracellular recordings were obtained from 555 paraventricular (PVN) nucleus neurons in pentobarbital-anesthetized male rats. Cells were examined for their spontaneous activity patterns and response to single 1-Hz electrical stimulation of the neurohypophysis, median eminence, amygdala, lateral septum (LS) and midbrain periaqueductal gray (PAG). Neurohypophyseal stimulation evoked antidromic activation from 109 neurons. Among spontaneously active neurohypophyseal neurons, evidence of a recurrent inhibitory pathway usually required pituitary stimulus intensities twice threshold for antidromic activation. Orthodromic excitatory or inhibitory responses followed amygdala and LS stimulation, but not PAG stimulation. The amygdala influence was predominantly inhibitory to 'phasic' (putative vasopressin-secreting) PVN neurohypophyseal neurons. Neurohypophyseal stimulation evoked orthodromic responses from 124 PVN cells; some of these neurons were also responsive to stimulation in other sites. Median eminence stimulation evoked antidromic responses from 37 PVN neurons; some of these cells also displayed phasic activity but no evidence for recurrent inhibition. Twelve cells in this group were also activated antidromically from both the median eminence and the neurohypophysis; collision tests suggest that the median eminence innervation may be an axon collateral of a neurohypophyseal pathway. Amygdala stimulation was inhibitory to some cells in this category. Amygdala, LS and PAG stimulation evoked antidromic activation from a small number of PVN cells, but none of these cells appeared to innervate more than one area, including the neurohypophysis, and none displayed phasic activity. Orthodromic responses were recorded among other PVN neurons after stimulation in these sites; however, PAG stimulation was the least effective stimulation area. These observations provide additional electrophysiological data that confirm efferent PVN connections to all areas tested, afferent connections from amygdala and LS but not PAG, and the possibility for coordinated activity among PVN neurons through local recurrent or common afferent connections.
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| [71] |
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| [72] |
In challenging environments including both numerous threats and scarce resources, the survival of an organism depends on its ability to quickly escape from dangers and to seize opportunities to gain rewards. The phylogenetically ancient neurohormonal oxytocin (OXT) system has been shown to influence both approach and avoidance (AA) behavior in men, but evidence for comparable effects in women is still lacking. We thus conducted a series of pharmacological behavioral experiments in a randomized double-blind study involving 76 healthy heterosexual women treated with either OXT (24 IU) or placebo intranasally. In Experiment 1, we tested how OXT influenced the social distance subjects maintained between themselves and either a female or male experimenter. In Experiment 2, we applied a reaction time based AA task. In Experiment 3 we investigated effects on pen-personal space by measuring the lateral attentional bias in a line bisection task. We found that OXT specifically decreased the distance maintained between subjects and the male but not the female experimenter and also accelerated approach toward pleasant social stimuli in the AA task. However, OXT did not influence the size of pen-personal space, suggesting that it does not alter perception of personal space per se, but rather that a social element is necessary for OXT's effects on AA behavior to become evident. Taken together, our results point to an evolutionarily adaptive mechanism by which OXT in women selectively promotes approach behavior in positive social contexts.
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| [73] |
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| [74] |
The neuropeptides oxytocin (OT) and vasopressin (AVP) are recognized for their modulation of social processes in humans when delivered peripherally. However, there is surprisingly little evidence for acute social effects of peripherally administered OT or AVP in animal models. On the other hand, the party drug 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') has powerful prosocial effects in rats that appear to occur through stimulation of central OT release. Here, we directly compared the social effects of peripherally administered OT and AVP with those of MDMA, and examined a possible role for the vasopressin 1A receptor (V1AR) in the observed prosocial effects. Adult male Long-Evans rats were tested in a social interaction paradigm after OT (0.1, 0.25, 0.5, and 1 mg/kg, intraperitoneal (IP)), AVP (0.001, 0.0025, 0.005, 0.01, and 0.1 mg/kg, IP), and MDMA (2.5, 5 mg/kg, IP), or combined low doses of OT and MDMA, or AVP and MDMA. The effects of pretreatment with the non-peptide OT receptor antagonist compound 25 (C25; 5 mg/kg, IP) and the V1AR antagonist SR49059 (1 mg/kg, IP) were also examined. OT (0.5 mg/kg), AVP (0.01 mg/kg), and MDMA (5 mg/kg) potently increased 'adjacent lying', where rats meeting for the first time lie passively next to each other. C25 did not inhibit adjacent lying induced by OT, whereas SR49059 inhibited adjacent lying induced by MDMA (5 mg/kg), OT (0.5 mg/kg), and AVP (0.01 mg/kg). Interestingly, when ineffective doses of OT and MDMA, or AVP and MDMA, were combined, a robust increase in adjacent lying was observed. These results show for the first time acute prosocial effects of peripherally injected OT and AVP in laboratory rats, and suggest a commonality of action of OT, AVP, and MDMA in stimulating social behavior that involves V1ARs.
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| [75] |
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| [76] |
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| [77] |
Numerous studies in animals and humans have established that oxytocin (OT) reduces anxiety. In rats, the prelimbic (PL) subregion of the medial prefrontal cortex (mPFC) is among the brain areas implicated in the anxiolytic actions of OT. However, questions remain about the anatomical and receptor specificity of OT and its mechanism of action. Here we assessed whether the regulation of anxiety by mPFC OT is restricted to the PL subregion and evaluated whether oxytocin receptor (OTR) activation is required for OT to have an anxiolytic effect. We also examined whether OT interacts with GABA in the mPFC to reduce anxiety and investigated the extent to which OT in the mPFC affects activation of mPFC GABA neurons as well as neuronal activation in the amygdala, a primary target of the mPFC which is part of the neural network regulating anxiety. We found that OT reduced anxiety-like behavior when delivered to the PL, but not infralimbic or anterior cingulate subregions of the mPFC. The anxiolytic effect of OT in the PL mPFC was blocked by pretreatment with an OTR, but not a vasopressin receptor, antagonist as well as with a GABA receptor antagonist. Lastly, administration of OT to the PL mPFC was accompanied by increased activation of GABA neurons in the PL mPFC and altered neuronal activation of the amygdala following anxiety testing. These results demonstrate that OT in the PL mPFC attenuates anxiety-related behavior and may do so by engaging GABAergic neurons which ultimately modulate downstream brain regions implicated in anxiety.Copyright © 2017 Elsevier Ltd. All rights reserved.
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| [78] |
The postpartum period is commonly accompanied by emotional changes, which for many new mothers includes a reduction in anxiety. Previous research in rodents has shown that the postpartum attenuation in anxiety is dependent on offspring contact and has further implicated enhanced GABAergic neurotransmission as an underlying mechanism. However, the specific brain regions where GABA acts to regulate the offspring-induced reduction in postpartum anxiety requires further investigation. Here, we test the hypothesis that offspring interactions suppress anxiety-like behavior in postpartum female rats via GABA signaling in the medial prefrontal cortex (mPFC). Our results show a postpartum reduction in anxiety-like behavior, an effect which was abolished by localized infusion of the GABA receptor antagonist bicuculline in the mPFC. We also show that activation of GABA receptors in the mPFC by the agonist muscimol was effective in restoring anxiolyisis in mothers separated from their pups. Lastly, we show that heightened anxiety-like behavior in pup-separated mothers was accompanied by a lower number and percentage of activated GABAergic neurons within the mPFC. Together, these results suggest that mother-offspring interactions reduce anxiety-like behavior in postpartum females via GABA neurotransmission in the mPFC and in doing so provide insight into mechanisms that may become dysfunctional in mothers who experience high postpartum anxiety.Copyright © 2020 Elsevier B.V. All rights reserved.
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| [78] |
Social relationships throughout lifespan are critical for health and wellbeing. Oxytocin, often called the 'hormone of attachment' has been suggested as playing an important role in early-life nurturing and resulting social bonding. The objective of this paper is to synthesize the associations between oxytocin levels and interactions between infants and parents that may trigger oxytocin release, and in turn facilitate attachments.A comprehensive cross-disciplinary systematic search was completed using electronic databases. The inclusion criteria included studies that focused on mother-infant and father-infant interaction and measured both baseline and post-interaction oxytocin levels.Seventeen studies were included in the final systematic review. The reviewed studies used mother-infant and/or father-infant play and skin-to-skin contact between maternal-infant and paternal-infant dyads to examine the oxytocin role in early life bonding and parenting processes. Studies showed a positive correlation between parent-infant contact and oxytocin levels in infancy period. Increased maternal oxytocin levels were significantly related to more affectionate contact behaviors in mothers following mother-infant contact, synchrony, and engagement. Meanwhile, increased paternal oxytocin levels were found to be related to more stimulatory contact behaviors in fathers following father-infant contact. Oxytocin levels significantly increased in infants, mothers and fathers during skin-to-skin contact and parents with higher oxytocin levels exhibited more synchrony and responsiveness in their infant interactions.The review suggests that oxytocin plays an important role in the development of attachment between infants and parents through early contact and interaction. The complexities of oxytocinergic mechanisms are rooted in neurobiological, genetic, and social factors.© 2019 Chinese Nursing Association. Production and hosting by Elsevier B.V.
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| [79] |
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| [80] |
The anterior cingulate cortex (ACC) is critically involved not only in affective and anxiety processing, but also in error and conflict monitoring. To investigate how anxiety interacts with processing affective ambiguity, 15 anxious and 15 nonanxious individuals were scanned while performing a validated affective appraisal task, in which the fraction of faces of a particular affect or gender was parametrically controlled to provide various levels of ambiguity. The anxious group showed less ventral and greater dorsal ACC activation during ambiguous affective relative to ambiguous gender stimuli. For anxious individuals, dorsal ACC activation was related to a more biased response. Collectively, these data indicate that anxious individuals activate the dorsal and ventral components of the ACC differently during affective appraisal.
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| [81] |
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| [82] |
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| [83] |
Methamphetamine (METH) use is a public health crisis that disproportionately affects men who have sex with men (MSM). There are currently no FDA-approved pharmacological interventions to treat methamphetamine use disorder (MUD). MUD is associated with social impairments and extremely high treatment attrition rates. Administration of oxytocin, a neuropeptide involved in social attachment, may be a novel approach to addressing these issues. Moreover, oxytocin administration has shown promise for reducing METH-related addictive behavior in animal models, but has not yet been investigated in clinical trials for MUD. Last, oxytocin is known to modulate stress responsivity via regulation of the autonomic nervous system, which is dysregulated in METH users. We hypothesize that oxytocin, in combination with group psychotherapy, will increase treatment engagement, reduce addiction behavior, and mitigate stress hyperreactivity.This is a randomized, double blind trial of oxytocin 40-IU (n = 24) or placebo (n = 24) administered intranasally prior to each of six weekly motivational interviewing group therapy (MIGT) sessions for MUD in MSM.(a) session attendance.(b) group cohesion, (c) anxiety, (d) METH craving, (e) METH use, and (f) in-session cardiac physiology.Participants receiving oxytocin had significantly higher group therapy attendance than those receiving placebo, OR 3.26, 95% CI [1.27-8.41], p = .014. There was a small effect of oxytocin on group cohension, but not anxiety or craving. METH use did not change over the six-week MIGT course in either treatment arm. Participants receiving oxytocin had lower average heart rates during MIGT sessions and higher heart rate variability. There were positive main effects of MIGT over Time regardless of study drug.This evidence, and the lack of any serious adverse events, suggests that oxytocin may safely increase treatment attendance. One possible mechanism by which it may do so is its modulation of the autonomic nervous system. Further investigation is warranted.Published by Elsevier Inc.
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| [84] |
Generalized social phobia (GSP) is characterized by fear of social interactions and sensitivity to disapproval by others. Given the established role of the amygdala as part of a distributed neural system for the processing of emotional cues, we hypothesized that subjects with GSP would exhibit greater amygdala activation in response to harsh (angry, fearful, and contemptous) vs accepting (happy) facial emotional expressions compared with healthy control subjects (HCs).Fifteen subjects with DSM-IV GSP and 15 age-, sex-, handedness-, and education-matched HCs, free of psychotropic medication for at least 12 weeks, viewed 60 color photographs from a standardized set of human facial stimuli, during which the task was to identify the sex of the person in the photograph. Data were collected across 3 functional (echo-planar) runs using a Siemens 1.5-T magnet, and analyzed using Analysis of Functional Neuroimaging software (Medical College of Wisconsin, Milwaukee).In the left allocortex (including the amygdala, uncus, and parahippocampal gyrus), subjects with GSP produced a significantly greater percent blood oxygen level-dependent signal change than did HCs for contemptous compared with happy faces (GSP: 0.72% vs HC: -0.01%; F(1,29) = 9.56, P =.004, Cohen d = 1.15) and for angry compared with happy faces (GSP: 0.45% vs HC: -0.09%; F(1,29) = 6.78, P =.02, Cohen d = 1.00). Subjects with GSP and HCs did not produce a statistically different percent signal change for fearful or nonexpressive faces compared with the happy faces in this region.These findings are consistent with a role for differential amygdala (and associated limbic) functioning in GSP. The pronounced response to contemptuous and angry facial expressions suggests that the amygdala in GSP may be particularly active in the processing of disorder-salient stimuli.
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| [85] |
The Netherlands Study of Depression and Anxiety (NESDA; N=2981) is an ongoing longitudinal, multi-site, naturalistic, cohort study examining the etiology, course, and consequences of depression and anxiety. In this article we synthesize and evaluate fifteen years of NESDA research on prominent psychological risk factors for the onset, persistence, recurrence, and comorbidity of affective disorders.A narrative review of 62 NESDA articles examining the specificity and predictive value of neuroticism, behavioral inhibition, repetitive negative thinking, experiential avoidance, cognitive reactivity, locus of control, (implicit) self-esteem, (implicit) disorder-specific self-associations, and attentional bias for the course of affective disorders.All self-reported risk factors showed cross-sectional relationships with singular and comorbid affective disorders, and prospective relationships with the development and chronicity of depression and anxiety disorders. High neuroticism, low self-esteem, and negative repetitive thinking showed most prominent transdiagnostic relationships, whereas cognitive reactivity showed most pronounced depression-specific associations. Implicit self-esteem showed predictive validity for the persistence and recurrence of anxiety and depression over and above self-reported risk factors. Automatic approach-avoidance behavior and attentional bias for negative, positive, or threat words showed no relationship with affective disorders.NESDA identified both (a) transdiagnostic factors (e.g., neuroticism, low implicit self-esteem, repetitive negative thinking) that may help explain the comorbidity between affective disorders and overlap in symptoms, and (b) indications for disorder-specific risk factors (e.g., cognitive responsivity) which support the relevance of distinct disorder categories and disorder-specific mechanisms. Thus, the results point to the relevance of both transdiagnostic and disorder-specific targets for therapeutic interventions.Copyright © 2021. Published by Elsevier B.V.
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Oxytocin (OT), often called the 'hormone of love' or 'hormone of attachment,' plays a fundamental role in the establishment and quality of parent-infant bonding. However, emerging evidence indicates that OT can also produce antisocial behavior. To clarify these effects, we review studies examining the role of endogenous and exogenous OT on several determinants of attachment: parental sensitivity, and bonding or synchrony in parent-child dyads. Contextual and individual factors moderating the effect of intranasal OT and its peripheral levels are also reviewed. Finally, potential therapeutic applications for OT and current limitations in human OT research are examined. This systematic literature review was based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, with two electronic databases and other bibliographic sources. We identified a total of 47 relevant studies for inclusion in our review. Most of the findings are in accordance with recent ideas that OT administration may increase parent-child prosocial interaction, showing that OT exerts beneficial effects on processes thought to promote bonding, sensitivity, and synchrony. However, we found that OT can induce antisocial behavior (e.g., anxiety) or adverse effects (modulation of maternal care recollections) that are moderated by different contextual (e.g., maltreatment level, presence of unfamiliar people) and individual (attachment style) factors. This review reinforces the importance of context- and individual-dependent factors, which must be taken into account when analyzing the psychophysiological effects of OT.© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.
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Oxytocin, a neuropeptide synthesized by the hypothalamus, plays a central role in human social behavior, social cognition, anxiety, mood, stress modulation, and fear learning and extinction. The relationships between oxytocin and psychiatric disorders including depression, anxiety, schizophrenia, and autism spectrum disorder have been extensively studied. In this chapter, we focus on the current knowledge about oxytocin and anxiety disorder. We discuss the anxiolytic effects of oxytocin in preclinical and clinical findings, possible related neurobehavioral mechanisms (social cognition, fear learning, and extinction), related neurotransmitter and neuroendocrine systems (hypothalamus-pituitary-adrenal axis, serotoninergic, and GABAergic systems), and studies regarding plasma levels of oxytocin, genetic and epigenetic findings, and effects of intranasal oxytocin in DSM-5 anxiety disorder (primarily social anxiety disorder and separation anxiety disorder) patients.
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