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Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine
... As an aim of this study was to explore citation linkages between implementation science and translational science, all publications from the translational science literature search and implementation science literature search were combined to create a directed citation network map. In Figure 3 Morris et al. [32], Meyer-Lindenberg et al. [33], and Workman et al. [34]. al. [46] was the only publication with a 100%+ increase in citation links between the implementation science directed citation network map and the combined directed citation network map (from n=4 citation links to n=10 citation links). ...
... Aparılan çoxsaylı tədqiqatlarla OXTR genində 30-dan çox polimorfizm aşkarlanmış, ailə və populyasiya əsaslı təhlillərlə bu polimorfizmlərdən bəzilərinin ASP ilə əlaqəli olduğu təyin edilmişdir [23]. Hazırda 3-cü introndakı rs2254298 tək nukleotid polimorfizmi oksitosinergik [31], xüsusilə də sosial fəaliyyətdəki [8], [6], [34], [38] fərqləri izah etmək üçün prespektivli namizəd gen kimi müəyyən edilmişdir. Müqayisəli genomika insanın təkamülü ərzində OXTR genində bir nöqtədə quaninin (G) nukleotidinin adeninlə (A) əvəz olunduğu bir mutasiyanın olduğunu göstərmişdir. ...
... The brain OXT system promotes various cognitive and social functions, and exerts robust anxiolytic and anti-stress effects (reviewed in refs. [1,2]), and is, thus, discussed as a potential therapeutic target for stress-related psychopathologies [3][4][5][6][7]. In this context, a detailed understanding of the multiple modes of action of OXT at cellular level -both in neurons and astrocytes -is of high relevance. ...
Astrocytes are an indispensable part of signal processing within the mammalian brain. Thus, the mode of action of a neuropeptide such as oxytocin (OXT) can only be fully understood considering this integral part of the CNS. Here, we show that OXT regulates astrocytic gene expression, intracellular signaling and specific proteins both in vitro and in vivo. This translates into rapid regulation of astroglial structural and functional properties including cytoskeletal plasticity, coverage of synapses and gap-junction coupling. At the molecular level, we identify the previously undescribed Sp1-Gem signaling cascade as the key driver for these cell type-specific OXT effects. Finally at the behavioral level, we found in vivo that OXT requires astrocytes to exert its well described anxiolytic properties within the hypothalamic paraventricular nucleus. Thus, our study points to OXT receptor-expressing astrocytes as a critical component of the brain OXT system.
... Furthermore, DCVs are mobile, typically not docked, and can fuse with the plasma membrane in the soma and dendrites, although most (80%) fuse in the axon (Persoon et al., 2018). Despite the importance of neuromodulator secretion for neuronal development, synaptic plasticity, and many emotions and behaviors (Cheng et al., 2011;Malva et al., 2012;Meyer-Lindenberg et al., 2011;Pang et al., 2004), little is known about the basic fusion principles of DCVs. For example, it is unclear what sources of Ca 2+ are required for neuronal DCV exocytosis, including which VGCCs, if specific channels are organized at specialized release sites, or if differences exist depending on the fusion location. ...
Regulated secretion typically depends on activity-induced Ca2+ influx. However, in invertebrates, the endoplasmic reticulum (ER) plays a distinct role, particularly in the release of neuromodulators from dense-core vesicles (DCVs). Here, we investigated the role of the neuronal ER as a Ca2+ source for neuromodulator secretion in primary mouse neurons by directly monitoring ER and cytosolic Ca2+ dynamics, along with DCV exocytosis at single vesicle resolution. During neuronal activity, neurons with a low initial [Ca2+]ER took up Ca2+ into the ER, while those with a high initial [Ca2+]ER released ER Ca2+. These latter neurons showed more DCV exocytosis. Acute ER Ca2+ release by caffeine or thapsigargin application, resulted in minute increases in bulk cytosolic free Ca2+ that did not trigger DCV exocytosis. Remarkably, following ER Ca2+ depletion levels, activity-dependent Ca2+ influx and DCV exocytosis were reduced by 50-90%, while synaptic vesicle (SV) exocytosis was unaffected. L-type Ca2+-channel inhibition by nimodipine reduced DCV exocytosis and Ca2+ influx by 80-90 % without affecting SV exocytosis, a phenocopy of ER store depletion. In addition, introducing L-type channels lacking STIM1 interaction sites restored DCV fusion following ER store depletion. We conclude that the ER functions as a dynamic Ca2+ store serving both as a Ca2+ source or sink. Moreover, ER depletion activates a feedback loop that controls L-type Ca2+ channel activity, essential for DCV exocytosis.
... In addition to its well-established actions in reproductive and cardiovascular regulation, OT has been shown to play a role in the processing of emotional and social cues, having overall anxiolytic and antidepressant effects (Meyer-Lindenberg et al., 2011;Neumann & Slattery, 2016). These OT actions are mediated particularly within the central nucleus of the amygdala (CeA) (Huber et al., 2005), where OT modulates a powerful local GABAergic circuit (Knobloch et al., 2012;Viviani et al., 2011). ...
Heart failure (HF) patients suffer from cognitive decline and mood impairments, but the molecular signals and brain circuits underlying these effects remain elusive. The hypothalamic neuropeptide oxytocin (OT) is critically involved in regulating mood, and OTergic signalling in the central amygdala (CeA) is a key mechanism that controls emotional responses including anxiety‐like behaviours. Still, whether an altered OTergic signalling contributes to mood disorders in HF remains unknown. To address this, we used an ischaemic rat HF model, along with a highly multidisciplinary approach, to mechanistically study multiple levels of the hypothalamus‐to‐CeA OTergic circuit in male rats with HF. We aimed to test the hypothesis that sustained activation of the OT system following an infarct leads to depletion of OT content in this pathway, with subsequent changes in OT receptor expression and blunted modulation of local GABAergic circuits. We found that most of OTergic innervation of the CeA originated from the supraoptic nucleus (SON). While no differences in the numbers of SON→CeA OTergic neurons was observed between sham and HF rats, we observed a blunted content and release of OT from axonal terminals within the CeA. Moreover, we report downregulation of neuronal and astrocytic OT receptors, and impaired OTR‐driven GABAergic synaptic activity within the CeA microcircuit of HF rats. We provide the first evidence that male HF rats display perturbations in the hypothalamus‐to‐amygdala OTergic circuit, laying the foundation for future translational studies targeting either the OT system or GABAergic amygdalar microcircuit to ameliorate mood impairments in rats or patients with chronic HF. image
Key points
Heart failure patients suffer from cognitive decline, depression and mood impairments, but the underlying mechanisms remain elusive.
Acting within the central amygdala, the neuropeptide oxytocin regulates emotional responses, including anxiety‐like behaviours. However, whether changes in oxytocin signalling occurs during heart failure is unknown.
In this study, we used an ischaemic rat heart failure model to mechanistically study multiple levels of the hypothalamus‐to‐amygdala oxytocinergic circuit in this disease.
We report an overall blunted oxytocinergic signalling pathway in rats with heart failure, including blunted content and release of oxytocin from axonal terminals, downregulation of neuronal and astrocytic oxytocin receptors, and impaired oxytocin‐driven GABAergic synaptic activity within the central amygdala microcircuit of HF rats.
These studies shed light on mechanisms that contribute to mood disorders in cardiovascular disease states and help to identify potential molecular targets for their improved treatment.
... Among these structures, the prefrontal cortex (PFC), and the caudate putamen (CPU) and nucleus accumbens (NAC) of the striatum are interconnected and play a key role in both motor behaviors and social interaction and reward [31][32][33][34][35]. Disruptions in these regions are associated with core autism-like features in mice. There is emerging evidence suggesting a potential link between dysregulation of the OT system and the etiology of ASD (for reviews [36][37][38][39]), particularly the association with pathogenic variants in oxytocin (OXT), oxytocin receptor (OXTR), and vasopressin receptor 1A (AVPR1A) genes (SFARI Gene). Additionally, OXT mRNAs are particularly susceptible to deadenylation and degradation [19] and both OXT and its receptor, OXTR, show reduced levels in the brains of individuals with ASD or related conditions [40,41] and mouse models displaying autism-like behaviors [39,42]. ...
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.
... 108 Recent research has also found that OXT plays a significant role in neuropsychiatric disorders, such as addiction and autism. 89,109 PVN OXT neurons, which are large cell-type neurons in the PVN, primarily function in regulating stress and social behaviors. 110,111 This regulation may be achieved through the local release of OXT within the PVN, modulating the excitability of PVN CRF neurons. ...
Background
Drug addiction, characterized by compulsive drug use and high relapse rates, arises from complex interactions between reward and aversion systems in the brain. The paraventricular nucleus (PVN), located in the anterior hypothalamus, serves as a neuroendocrine center and is a key component of the hypothalamic–pituitary–adrenal axis.
Objective
This review aimed to explore how the PVN impacts reward and aversion in drug addiction through stress responses and emotional regulation and to evaluate the potential of PVN as a therapeutic target for drug addiction.
Methods
We review the current literature, focusing on three main neuron types in the PVN—corticotropin‐releasing factor, oxytocin, and arginine vasopressin neurons—as well as other related neurons, to understand their roles in modulating addiction.
Results
Existing studies highlight the PVN as a key mediator in addiction, playing a dual role in reward and aversion systems. These findings are crucial for understanding addiction mechanisms and developing targeted therapies.
Conclusion
The role of PVN in stress response and emotional regulation suggests its potential as a therapeutic target in drug addiction, offering new insights for addiction treatment.
... Hipotalamusun paraventriküler ve supraoptik çekirdeği tarafından üretilen ve vücudun merkezi işlevlerinde bir nörotransmitter olarak da görev yapan, bir peptit hormon türüdür (54). Hipotalamus tarafından üretilen ve hipofiz bezi aracılığıyla salınan bir hormondur (55). Oksitosin, özellikle doğum sırasında ve emzirme sırasında annelerde salınarak doğum sürecini kolaylaştırır ve anne-bebek bağını güçlendirir (56). ...
... Hipotalamusun paraventriküler ve supraoptik çekirdeği tarafından üretilen ve vücudun merkezi işlevlerinde bir nörotransmitter olarak da görev yapan, bir peptit hormon türüdür (54). Hipotalamus tarafından üretilen ve hipofiz bezi aracılığıyla salınan bir hormondur (55). Oksitosin, özellikle doğum sırasında ve emzirme sırasında annelerde salınarak doğum sürecini kolaylaştırır ve anne-bebek bağını güçlendirir (56). ...
... Mirror neuron system facilitates empathy and emotional resonance [15]. ...
The Leadership Competency Model Drenica, developed by Çitaku and Ramadani in 2020, offers a comprehensive framework encompassing essential competencies crucial for effective leadership. However, validating the efficacy of these competencies necessitates exploring their neuroscientific underpinnings. This study conducted an extensive literature review to elucidate the neural mechanisms associated with each competency outlined in the Drenica model. The findings reveal a robust neuroscientific basis supporting these competencies, ranging from decision-making to communication and collaboration. Key neuroscientific validations include the role of prefrontal cortex activity and neurotransmitter balance in decision-making, the involvement of neural circuits in language processing and empathy for communication skills, and the contribution of neuroplasticity mechanisms to continuous learning and adaptability. Furthermore, the analysis underscores the importance of neurotransmitter systems such as dopamine, serotonin, and oxytocin in shaping leadership behaviors across various competencies. Understanding the neural substrates of effective leadership allows organizations to tailor leadership development programs to enhance organizational outcomes and foster a culture of innovation and inclusivity. Integrating neuroscience into leadership studies holds promise for advancing the understanding of leadership effectiveness and facilitating evidence-based practices in leadership development. In essence, this study underscores the significance of the Drenica model as a versatile tool for leadership development, enriched by neuroscientific insights, thus paving the way for Neuoleadership-a paradigm that leverages neuroscientific principles to cultivate effective leadership behaviors and drive organizational success.
... During the 1990s, studies revealed that social and anxiety-like behaviors in rats were found to be affected by intracerebroventricular and intraseptal injections of V1a-specific antagonists [15][16][17] , as well as by the administration of V1a antisense oligodeoxynucleotide into the septal region 18 , suggesting an association between V1a receptor and these behaviors. Subsequent research has further explored the role of V1a in social cognition and behavior [19][20][21] , and its potential implications for autism spectrum disorder (ASD) [22][23][24][25][26] , a complex neurodevelopmental condition characterized by impaired social interaction, communication challenges, and repetitive behaviors. Despite ongoing investigations into the detailed mechanisms, the V1a receptor has emerged as a potential therapeutic target in ASD [27][28][29][30][31][32] . ...
The arginine-vasopressin (AVP) hormone plays a pivotal role in regulating various physiological processes, such as hormone secretion, cardiovascular modulation, and social behavior. Recent studies have highlighted the V1a receptor as a promising therapeutic target. In-depth insights into V1a receptor-related pathologies, attained through in vivo imaging and quantification in both peripheral organs and the central nervous system (CNS), could significantly advance the development of effective V1a inhibitors. To address this need, we develop a novel V1a-targeted positron emission tomography (PET) ligand, [¹⁸F]V1A-2303 ([¹⁸F]8), which demonstrates favorable in vitro binding affinity and selectivity for the V1a receptor. Specific tracer binding in peripheral tissues was also confirmed through rigorous cell uptake studies, autoradiography, biodistribution assessments. Furthermore, [¹⁸F]8 was employed in PET imaging and arterial blood sampling studies in healthy rhesus monkeys to assess its brain permeability and specificity, whole-body distribution, and kinetic properties. Our research indicated [¹⁸F]8 as a valuable tool for noninvasively studying V1a receptors in peripheral organs, and as a foundational element for the development of next-generation, brain-penetrant ligands specifically designed for the CNS.
... These neuropeptides are predominantly synthesized in neurons of the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus [13][14][15][16] and project extensively to brain structures involved in emotional and social circuit, such as the prefrontal cortex and striatum, where their receptors are expressed, or the pituitary [17][18][19]. There is emerging evidence suggesting a potential link between dysregulation of the oxytocin system and the etiology of ASD (for reviews [20][21][22][23]), particularly the association with pathogenic variants in oxytocin (OXT), oxytocin receptor (OXTR), and vasopressin receptor 1A (AVPR1A) genes (SFARI Gene). Additionally, decreased OXT and OXTR mRNA levels have been reported in the brains of individuals with ASD or related conditions [24,25] and mouse models of ASD [23,26]. ...
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction, communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous ASD mouse models, each exhibiting unique behavioral features along the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes in social plasticity in the four models. Through integrative analysis, we identified Egr1 , Foxp1, Homer1a , Oxt and Oxtr as five robust and discriminant molecular markers that allowed successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.
... Higher oxytocin levels may be of explanatory value for differences between exclusive and mixed breastfeeding. The quality of mother-child interrelations and maternal oxytocin levels appear to be positively correlated [87][88][89][90] . Oxytocin has also been found to be lower in patients with major depression 91 and with higher depression symptoms postpartum 47,92 . ...
Associations between depressive symptoms and breastfeeding are well documented. However, evidence is lacking for subdivisions of feeding styles, namely exclusive breastfeeding, exclusive formula feeding and a mixed feeding style (breastfeeding and formula feeding). In addition, studies examining associations between mother-child-bonding and breastfeeding have yielded mixed results. The aim of this study is to provide a more profound understanding of the different feeding styles and their associations with maternal mental health and mother-child-bonding. Data from 307 women were collected longitudinally in person (prenatally) and by telephone (3 months postnatally) using validated self-report measures, and analyzed using correlational analyses, unpaired group comparisons and regression analyses. Our results from a multinomial regression analysis revealed that impaired mother-child-bonding was positively associated with mixed feeding style (p = .003) and depressive symptoms prenatal were positively associated with exclusive formula feeding (p = .013). Further studies could investigate whether information about the underlying reasons we found for mixed feeding, such as insufficient weight gain of the child or the feeling that the child is unsatiated, could help prevent impaired mother-child-bonding. Overall, the results of this study have promising new implications for research and practice, regarding at-risk populations and implications for preventive measures regarding postpartum depression and an impaired mother-child-bonding.
... The encouraging behavioral effects of oxytocin in animals have captured widespread interest. Many are intrigued by the clinical potential of oxytocin as a treatment for psychopathologies related to socio-emotional dysfunction, including autism spectrum disorders, anxiety disorders, social phobia, and schizophrenia [99][100][101]. Human research relies on non-invasive approaches like observational studies on oxytocin and social behavior, translational studies on patients with social behavior disorders, and intervention studies with peripheral oxytocin administration. Clinical trials exploring the administration of oxytocin have yielded mixed results, and the effectiveness of oxytocin in various contexts is still an area of ongoing research [102][103][104]. ...
Purpose of Review
Oxytocin plays many diverse roles in physiological and behavioral processes, including social activity, parental nurturing, stress responses, and sexual function. In this narrative review, we provide an update on the most noteworthy recent findings in this fascinating field.
Recent Findings
The development of techniques such as serial two-photon tomography and fiber photometry have provided a window into oxytocin neuroanatomy and real-time neuronal activity during social interactions. fMRI and complementary mapping techniques offer new insights into oxytocin's influence on brain activity and connectivity. Indeed, oxytocin has recently been found to influence the acquisition of maternal care behaviors and to mediate the influence of social touch on brain development and social interaction. Additionally, oxytocin plays a crucial role in male sexual function, affecting erectile activity and ejaculation, while its role in females remains controversial. Recent studies also highlight oxytocin's interaction with other neuropeptides, such as melanin-concentrating hormone, serotonin, and arginine vasopressin, influencing social and affective behaviors. Finally, an update is provided on the status of clinical trials involving oxytocin as a therapeutic intervention.
Summary
The exploration of oxytocin's complexities and its interplay with other neuropeptides holds promise for targeted treatment in various health and disease contexts. Overall, these findings contribute to the discovery of new and specific pathways to allow therapeutic targeting of oxytocin to treat disorders.
... Research in the past two decades from animal models on oxytocinergic transmission reconstructed neuronal connectivity, demonstrating that most magnocellular neurons project collaterals from the hypothalamic-posterior pituitary axons to more than 50 forebrain regions [67][68][69] . Together with associated limbic networks, these complex central circuits regulate contextual socio-emotional behaviour in mammals, including in-group favouritism and protection against social threats, emotional transfer between conspecifics, fostering trust and attachment, as well as promoting empathy and emotion recognition [70][71][72][73] . Circuits of smaller parvocellular oxytocinergic neurons that project to the midbrain, brainstem and spinal cord are suggested to be involved in autonomic functions including regulation of food intake, cardiovascular reflexes, erection and pain processing [74][75][76][77][78] . ...
Polyuria-polydipsia syndrome can be caused by central diabetes insipidus, nephrogenic diabetes insipidus or primary polydipsia. To avoid confusion with diabetes mellitus, the name 'central diabetes insipidus' was changed in 2022 to arginine vasopressin (AVP) deficiency and 'nephrogenic diabetes insipidus' was renamed as AVP resistance. To differentiate the three entities, various osmotic and non-osmotic copeptin-based stimulation tests have been introduced in the past decade. The hypertonic saline test plus plasma copeptin measurement emerged as the test with highest diagnostic accuracy, replacing the water deprivation test as the gold standard in differential diagnosis of the polyuria-polydipsia syndrome. The mainstay of treatment for AVP deficiency is AVP replacement with desmopressin, a synthetic analogue of AVP specific for AVP receptor 2 (AVPR2), which usually leads to rapid improvements in polyuria and polydipsia. The main adverse effect of desmopressin is dilutional hyponatraemia, which can be reduced by regularly performing the so-called desmopressin escape method. Evidence from the past few years suggests an additional oxytocin deficiency in patients with AVP deficiency. This potential deficiency should be further evaluated in future studies, including feasible provocation tests for clinical practice and interventional trials with oxytocin substitution.
This book served as a growing place for my developing ideas on consciousness. The first version was published in 2017. Those ideas were updated in the 2020 version. This is the 2023 update. Major edition changes are summarized in the Introduction.
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Consciousness has a neurological basis and yet it results in subjective feelings of self. Minding Consciousness brings these aspects of mind together. It explains that life urges, adaptive neural dispositions in the brainstem, have extensive links to the vertebrate attention network. Features linked with stronger life urges are more likely to gain attention. And when features gain conscious attention, the life urges that gain attention are experienced as feelings. In effect, life urges both guide attention and become subjective feelings during conscious attention.
Feelings are an essential part of conscious experience. Descartes missed this point when he proclaimed "I think; therefore, I am." We are not simply detached thinkers. Our sense of self is determined by how we feel as we perceive and think. But how does this sense of self develop? Minding Consciousness argues that perceptions provide evidence of external events, the world. Feelings and actions provide evidence of an internal agency, the self. Conscious agents are literally growing storms of attention that learn about their world and about their own reactions to that world. In principle, we can build conscious agents that have feeling-bound attention and who can develop similar feelings of self and world.
Background
Oxytocin is being evaluated as potential treatment for psychostimulant use disorders. It is unknown what effect oxytocin has on dopamine signaling in response to psychostimulants in brain regions such as the striatum where oxytocin and dopamine interact to process natural rewards. We investigated the effect of oxytocin on striatal dopamine release stimulated by methylphenidate whose mechanism of action is analogous to that of cocaine.
Method
We conducted an [11C] raclopride positron emission tomography study to assess striatal dopamine release in male rhesus macaques treated with oxytocin (80 IU) [administered via the intranasal (N=5) and intravenous (N=6) routes] followed by methylphenidate/[11C] raclopride.
Results
Oxytocin delivered by both routes significantly reduced methylphenidate-stimulated dopamine release in the dorsal striatum (caudate/putamen). These effects were, in part, evidenced by a reduction in dorsal striatal [11C] raclopride binding potential (increased dopamine release) following oxytocin administration.
Conclusion
The results provide translational and mechanistic evidence for the potential role of oxytocin as a treatment for psychostimulant use disorders.
Borderline personality disorder constitutes a significant medical challenge. Despite the fact that its occurrence among adolescents is currently attracting increasing interest from both clinicians and researchers, there is still insufficient data on this phenomenon. The etiology and maintenance of borderline personality disorder are not yet fully comprehended. Neuropeptides, including oxytocin and vasopressin, are considered to be involved in the development of this condition. The mechanism behind the actions of these neurohormones requires further investigation. Our work aims to collect and analyze the available research and existing hypotheses on the role of oxytocin and vasopressin in people with borderline personality disorder, with special attention drawn to adolescents suffering from this condition.
Oxytocin (OXT) is a neurohypophysial nonapeptide that exerts its effects mainly through the oxytocin receptor (OXTR). Several studies have pointed out the role of OXT in the modulation of stem cell (SC) fate and properties. SCs are undifferentiated cells characterized by a remarkable ability to self-renew and differentiate into various cell types of the body. In this review, we focused on the role of OXT in SC differentiation. Specifically, we summarize and discuss the scientific research examining the effects of OXT on mesodermal SC-derived lineages, including cardiac, myogenic, adipogenic, osteogenic, and chondrogenic differentiation. The available studies related to the effects of OXT on SC differentiation provide little insights about the molecular mechanism mediated by the OXT–OXTR pathway. Further research is needed to fully elucidate these pathways to effectively modulate SC differentiation and develop potential therapeutic applications in regenerative medicine.
The use and misuse of opioids are a growing global problem. Although the effects of these drugs on the human endocrine system have been studied for decades, attention on their related clinical consequences, particularly on the hypothalamic-pituitary system and bone health, has intensified over recent years. This Statement appraises research data related to the impact of opioids on the gonadal and adrenal function. Whereas hypogonadism is well recognized as a side effect of opioids, the significance of their inhibitory actions on the hypothalamic-pituitary-adrenal system and the occurrence of clinically relevant adrenal insufficiency is not fully elucidated. The often-inconsistent results of studies investigating how opioids affect the secretion of GH, prolactin, arginine vasopressin, and oxytocin are assessed. The accumulating evidence of opioid actions on bone metabolism and their negative sequelae on bone mineral density and risk of fracture are also reviewed. In each section, available data on diagnostic and management approaches for opioid endocrine sequelae are described. This Statement highlights a plethora of gaps in research associated with the effects and clinical consequences of opioids on the endocrine system. It is anticipated that addressing these gaps will improve the care of people using or misusing opioids worldwide. The Statement is not intended to serve as a guideline or dictate treatment decisions.
The abundance of molecules on early Earth likely enabled a wide range of prebiotic chemistry, with peptides playing a key role in the development of early life forms and the evolution of metabolic pathways. Among peptides, those with enzyme-like activities occupy a unique position between peptides and enzymes, combining both structural flexibility and catalytic functionality. However, their full potential remains largely untapped. Further exploration of these enzyme-like peptides at the nanoscale could provide valuable insights into modern nanotechnology, biomedicine, and even the origins of life. Hence, this review introduces the groundbreaking concept of “peptide nanozymes (PepNzymes)”, which includes single peptides exhibiting enzyme-like activities, peptide-based nanostructures with enzyme-like activities, and peptide-based nanozymes, thus enabling the investigation of biological phenomena at nanoscale dimensions. Through the rational design of enzyme-like peptides or their assembly with nanostructures and nanozymes, researchers have found or created PepNzymes capable of catalyzing a wide range of reactions. By scrutinizing the interactions between the structures and enzyme-like activities of PepNzymes, we have gained valuable insights into the underlying mechanisms governing enzyme-like activities. Generally, PepNzymes play a crucial role in biological processes by facilitating small-scale enzyme-like reactions, speeding up molecular oxidation-reduction, cleavage, and synthesis reactions, leveraging the functional properties of peptides, and creating a stable microenvironment, among other functions. These discoveries make PepNzymes useful for diagnostics, cellular imaging, antimicrobial therapy, tissue engineering, anti-tumor treatments, and more while pointing out opportunities. Overall, this research provides a significant journey of PepNzymes’ potential in various biomedical applications, pushing them towards new advancements.
The Default Mode Network (DMN) is a network of brain regions responsible for active or passive narration and the sharing of experiences. The ability to simulate experiences and use memories to construct hypothetical tales about how people might behave is a fundamental skill in building a social aggregate as it allows us to foreshadow the consequences of our actions and reflect on the intentions of others, simulating their experiences to anticipate their behavior. We can process imaginary situations whose accuracy is a measure of our social skills since the closer the imagination approaches social reality, the better we negotiate our social worlds. The DMN is responsible for these activities that encompass the frontal and parietal structures of the brain along the midline, the lateral and medial temporal lobes, and the lateral parietal cortex. This work reviews the DMN in all its aspects, both in the construction of narrative plots and in the preparation of believable and immersive emotional scenarios, including endocrine outcomes (oxytocin and cortisol).
The present study offers the comprehension data on three types of ambiguous possessive structures in Mandarin, including compound possessives (e.g., " xuēshéng zhuō" or "student desk"), two-level possessives (e.g., "Xiǎomíng de xuēshén zhuō" or "Xiaoming’s student desk"), and three-level possessives (e.g., " Xiǎomíng de xuēshéng de xuēshéng zhuō" or "Xiaoming’s student’s student desk"). Each of these structures has both a generic and a regular possessive interpretation. The findings indicate that children of all ages can identify the difference in generic regular possessives in each type of ambiguous structures. As regards the two-level and three-level possessives, the results reveal that children are more inclined to adopt a recursive analysis compared to young adults, who tend to adopt a generic analysis. These findings suggest that the reluctance to use recursive possessives is intervened by prelinguistic representations (such as generic interpretations).
Although dysregulated stress biology is becoming increasingly recognized as a key driver of lifelong disparities in chronic disease, we presently have no validated biomarkers of toxic stress physiology; no biological, behavioral, or cognitive treatments specifically focused on normalizing toxic stress processes; and no agreed-upon guidelines for treating stress in the clinic or evaluating the efficacy of interventions that seek to reduce toxic stress and improve human functioning. We address these critical issues by (a) systematically describing key systems and mechanisms that are dysregulated by stress; (b) summarizing indicators, biomarkers, and instruments for assessing stress response systems; and (c) highlighting therapeutic approaches that can be used to normalize stress-related biopsychosocial functioning. We also present a novel multidisciplinary Stress Phenotyping Framework that can bring stress researchers and clinicians one step closer to realizing the goal of using precision medicine-based approaches to prevent and treat stress-associated health problems.
Adeno-associated virus (AAV) vectors are potential tools for cell-type-selective gene delivery to the central nervous system. Although cell-type-specific enhancers and promoters have been identified for AAV systems, there is limited information regarding the effects of AAV genomic components on the selectivity and efficiency of gene expression. Here, we offer an alternative strategy to provide specific and efficient gene delivery to a targeted neuronal population by optimizing recombinant AAV genomic components, named TAREGET (TransActivator-Regulated Enhanced Gene Expression within Targeted neuronal populations). We established this strategy in oxytocinergic neurons and showed that the TAREGET enabled sufficient gene expression to label long-projecting axons in wild-type mice. Its application to other cell types, including serotonergic and dopaminergic neurons, was also demonstrated. These results demonstrate that optimization of AAV expression cassettes can improve the specificity and efficiency of cell-type-specific gene expression and that TAREGET can renew previously established cell-type-specific promoters with improved performance.
Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.
Neurobiological factors contributing to violence in humans remain poorly understood. One approach to this question is examining allelic variation in the X-linked monoamine oxidase A (MAOA) gene, previously associated with impulsive aggression in animals and humans. Here, we have studied the impact of a common functional polymorphism in MAOA on brain structure and function assessed with MRI in a large sample of healthy human volunteers. We show that the low expression variant, associated with increased risk of violent behavior, predicted pronounced limbic volume reductions and hyperresponsive amygdala during emotional arousal, with diminished reactivity of regulatory prefrontal regions, compared with the high expression allele. In men, the low expression allele is also associated with changes in orbitofrontal volume, amygdala and hippocampus hyperreactivity during aversive recall, and impaired cingulate activation during cognitive inhibition. Our data identify differences in limbic circuitry for emotion regulation and cognitive control that may be involved in the association of MAOA with impulsive aggression, suggest neural systems-level effects of X-inactivation in human brain, and point toward potential targets for a biological approach toward violence.
The nanopeptide oxytocin has physiological functions during labour and lactation. In addition, oxytocin is known to modulate aggression, anxiety, social behaviour and cognition. Little is known about its effects on memory for emotional stimuli. In the present single-blind, placebo-controlled, randomised study we have investigated the short- and long-term effects of a single post-learning dose (20 IU) of intranasal oxytocin on memory for facial identity and expression in 36 healthy young females and males using a face portrait recognition test. In the acquisition phase of the test, 60 different male faces with happy, angry or neutral expressions were presented to the volunteers. Thirty minutes and 24h after oxytocin administration, recognition memory tests were performed using portraits with neutral facial expressions, only. Oxytocin improved identity recognition memory independently of participant's gender, for neutral and angry faces, whereas this effect was not present for happy faces. Oxytocin-treated subjects had a lower bias to judge not previously seen faces as being previously seen. Oxytocin had no effect on facial expression memory. In conclusion, oxytocin has distinct effects on memory performance for facial identity and may contribute to the modulation of social behaviour.
The neuropeptide vasopressin is a key molecular mediator of social behavior in animals and humans, implicated in anxiety and autism. Social recognition, the ability to assess the familiarity of others, is essential for appropriate social interactions and enhanced by vasopressin; however, the neural mechanisms mediating this effect in humans are unknown. Using functional magnetic resonance imaging (fMRI) and an implicit social recognition matching task, we employed a double-blinded procedure in which 20 healthy male volunteers self-administered 40 UI of vasopressin or placebo intranasally, 45 min before performing the matching task in the scanner. In a random-effects fMRI analysis, we show that vasopressin induces a regionally specific alteration in a key node of the theory of mind network, the left temporoparietal junction, identifying a neurobiological mechanism for prosocial neuropeptide effects in humans that suggests novel treatment strategies.
Instrumental conditioning studies how animals and humans choose actions appropriate to the affective structure of an environment.
According to recent reinforcement learning models, two distinct components are involved: a “critic,” which learns to predict
future reward, and an “actor,” which maintains information about the rewarding outcomes of actions to enable better ones to
be chosen more frequently. We scanned human participants with functional magnetic resonance imaging while they engaged in
instrumental conditioning. Our results suggest partly dissociable contributions of the ventral and dorsal striatum, with the
former corresponding to the critic and the latter corresponding to the actor.
To explore genetic and environmental influences on individual differences in autistic traits in early adulthood and to test if there is assortative mating (nonrandom partner choice) for autistic traits in the general population.
Twin family study using structural equation modeling.
Population-based twin family sample from the Netherlands.
Twins aged 18 years (n = 370) and their siblings (n = 94); parents of twins (128 couples). Main Outcome Measure Self-reported Autism-Spectrum Quotient (AQ) scores, a quantitative measure of autistic traits.
Autistic traits were continuously distributed in the population. Twins and siblings did not significantly differ in AQ scores; men obtained significantly higher AQ scores than women (in twin-sibling sample, P<.001; twin-parent sample, P = .02). Individual differences in endorsement on autistic traits show substantial heritability (57%). No significant shared environmental influences were detected. The genes affecting autistic traits appear to be the same across the sexes. The correlation in AQ score between spouses was low and not significant (Pearson r = .05; P = .59).
Previous general population twin studies reported high heritability for autistic traits in childhood and early adolescence. This study extends these findings to late adolescence and yields no evidence for sex-specific genetic influences on autistic traits in later stages of development. As autistic traits show substantial variation in the general population, future genetic studies may be facilitated by measuring autistic traits on a continuous scale like the AQ. No evidence for assortative mating for autistic traits was found, suggesting that, in the general population, there is no passive or active partner selection for autistic traits.
This study explored the effects of oxytocin on Compassion Focused Imagery (CFI), that is, imagining another "mind" being deeply compassionate to oneself, and the interaction of these effects with self-criticism and feeling socially safe with others. Forty-four healthy participants (29 men and 15 women) completed self-report measures of self-criticism, attachment style, and social safeness before taking part in a double-blind randomized placebo controlled study. They attended two imagery sessions, receiving oxytocin in one and a placebo in the other. Positive affect was measured before and after each imagery session, and "imagery experience" was assessed after each session. Overall, oxytocin increased the ease of imagining compassionate qualities but there were important individual differences in how CFI was experienced. Participants higher in self-criticism, lower in self-reassurance, social safeness, and attachment security had less positive experiences of CFI under oxytocin than placebo, indicating that the effects of oxytocin on affiliation may depend on attachment and self-evaluative styles.
More than half of the world's population now lives in cities, making the creation of a healthy urban environment a major policy priority. Cities have both health risks and benefits, but mental health is negatively affected: mood and anxiety disorders are more prevalent in city dwellers and the incidence of schizophrenia is strongly increased in people born and raised in cities. Although these findings have been widely attributed to the urban social environment, the neural processes that could mediate such associations are unknown. Here we show, using functional magnetic resonance imaging in three independent experiments, that urban upbringing and city living have dissociable impacts on social evaluative stress processing in humans. Current city living was associated with increased amygdala activity, whereas urban upbringing affected the perigenual anterior cingulate cortex, a key region for regulation of amygdala activity, negative affect and stress. These findings were regionally and behaviourally specific, as no other brain structures were affected and no urbanicity effect was seen during control experiments invoking cognitive processing without stress. Our results identify distinct neural mechanisms for an established environmental risk factor, link the urban environment for the first time to social stress processing, suggest that brain regions differ in vulnerability to this risk factor across the lifespan, and indicate that experimental interrogation of epidemiological associations is a promising strategy in social neuroscience.
Hyponatremia and dexamethasone resistance in polydipsic schizophrenic patients are attributable to changes in hippocampal-modulated antidiuretic and stress hormone activity, respectively. The relationship of the neuroendocrine findings to the psychiatric illness, however, is unknown. An impaired ability to identify facial emotions has been linked to core features of schizophrenia and to diminished levels of the closely related hormone, oxytocin, in the polydipsic subset. Intranasal oxytocin enhances facial affect discrimination in healthy subjects.
The aim of this study is to explore if oxytocin reverses impaired facial affect discrimination in schizophrenic patients with, relative to that in patients without, polydipsia.
Intranasal oxytocin (10 or 20 IU) and placebo were administered on three occasions to five polydipsic schizophrenic patients, eight nonpolydipsic patients, and 11 healthy controls. Subsequently, subjects rated the presence and intensity of six facial emotions.
Emotion recognition fell in both patient groups following 10 IU of oxytocin due to an increased propensity to identify all emotions regardless of whether they were displayed. By contrast, emotion recognition improved following 20 IU in polydipsic relative to nonpolydipsic patients due primarily to divergent effects on the bias to identify fear in nonfearful faces.
The effects of 20 IU oxytocin support the hypothesis that altered neuroendocrine function in polydipsic patients contributes to their psychiatric illness. Further studies are warranted to confirm these findings and assess if oxytocin treatment improves social functioning in this subset. This is the first psychopharmacologic study to compare different doses of oxytocin in the same subject, thus the significance of the opposing responses is unclear.
Although the infant-caregiver attachment bond is critical to survival, little is known about the biological mechanisms supporting attachment representations in humans. Oxytocin plays a key role in attachment bond formation and maintenance in animals and thus could be expected to affect attachment representations in humans. To investigate this possibility, we administered 24 IU intranasal oxytocin to healthy male adults in a double-blind, placebo-controlled, crossover designed study and then assessed memories of childhood maternal care and closeness--two features of the attachment bond. We found that the effects of oxytocin were moderated by the attachment representations people possess, with less anxiously attached individuals remembering their mother as more caring and close after oxytocin (vs. placebo) but more anxiously attached individuals remembering their mother as less caring and close after oxytocin (vs. placebo). These data contrast with the popular notion that oxytocin has broad positive effects on social perception and are more consistent with the animal literature, which emphasizes oxytocin's role in encoding social memories and linking those memories to the reward value of the social stimulus.
We investigated the effects of intranasal oxytocin (OXT) on trust and cooperation in borderline personality disorder (BPD), a disorder marked by interpersonal instability and difficulties with cooperation. Although studies in healthy adults show that intranasal OXT increases trust, individuals with BPD may show an altered response to exogenous OXT because the effects of OXT on trust and pro-social behavior may vary depending on the relationship representations and expectations people possess and/or altered OXT system functioning in BPD. BPD and control participants received intranasal OXT and played a social dilemma game with a partner. Results showed that OXT produced divergent effects in BPD participants, decreasing trust and the likelihood of cooperative responses. Additional analyses focusing on individual differences in attachment anxiety and avoidance across BPD and control participants indicate that these divergent effects were driven by the anxiously attached, rejection-sensitive participants. These data suggest that OXT does not uniformly facilitate trust and pro-social behavior in humans; indeed, OXT may impede trust and pro-social behavior depending on chronic interpersonal insecurities, and/or possible neurochemical differences in the OXT system. Although popularly dubbed the 'hormone of love', these data suggest a more circumspect answer to the question of who will benefit from OXT.
Decision making in the face of conflicting ethical demands has intrigued mankind for millennia. A long philosophical tradition has placed emphasis on reasoning, about utilitarian outcomes, for example, in such decisions (1). However, recent work in social neuroscience (2, 3) has identified brain circuits active during moral judgment that have been linked to prosocial emotions such as empathy, guilt, and pity. Using an innovative combination of behavioral research and pharmacological intervention, a study in this issue of PNAS (4) suggests a role for the neurotransmitter serotonin in the neural substrate of ethical decision making.
Social and financial considerations are often integrated when real life decisions are made, and recent studies have provided evidence that similar brain networks are engaged when either social or financial information is integrated. Other studies, however, have suggested that the neuropeptide oxytocin can specifically affect social behaviors, which would suggest separable mechanisms at the pharmacological level. Thus, we examined the hypothesis that oxytocin would specifically affect social and not financial information in a decision making task, in which participants learned which of the two faces, one smiling and the other angry or sad, was most often being rewarded. We found that oxytocin specifically decreased aversion to angry faces, without affecting integration of positive or negative financial feedback or choices related to happy vs sad faces.
The distribution, pharmacology and function of the arginine vasopressin (Avp) 1b receptor subtype (Avpr1b) has proved more challenging to investigate compared to other members of the Avp receptor family. Avp is increasingly recognised as an important modulator of the hypothalamic-pituitary-adrenal (HPA) axis, an action mediated by the Avpr1b present on anterior pituitary corticotrophs. The Avpr1b is also expressed in some peripheral tissues including pancreas and adrenal, and in the hippocampus (HIP), paraventricular nucleus and olfactory bulb of the rodent brain where its function is unknown. The central distribution of Avpr1bs is far more restricted than that of the Avpr1a, the main Avp receptor subtype found in the brain. Whether Avpr1b expression in rodent tissues is dependent on differences in the length of microsatellite dinucleotide repeats present in the 5' promoter region of the Avpr1b gene remains to be determined. One difficulty of functional studies on the Avpr1b, especially its involvement in the HPA axis response to stress, which prompted the generation of Avpr1b knockout (KO) mouse models, was the shortage of commercially available Avpr1b ligands, particularly antagonists. Research on mice lacking functional Avpr1bs has highlighted behavioural deficits in social memory and aggression. The Avpr1b KO also appears to be an excellent model to study the contribution of the Avpr1b in the HPA axis response to acute and perhaps some chronic (repeated) stressors where corticotrophin-releasing hormone and other genes involved in the HPA axis response to stress do not appear to compensate for the loss of the Avpr1b.
Patients with generalized social anxiety disorder (GSAD) exhibit heightened activation of the amygdala in response to social cues conveying threat (eg, fearful/angry faces). The neuropeptide oxytocin (OXT) decreases anxiety and stress, facilitates social encounters, and attenuates amygdala reactivity to threatening faces in healthy subjects. The goal of this study was to examine the effects of OXT on fear-related amygdala reactivity in GSAD and matched healthy control (CON) subjects. In a functional magnetic resonance imaging study utilizing a double-blind placebo-controlled within-subjects design, we measured amygdala activation to an emotional face matching task of fearful, angry, and happy faces following acute intranasal administration of OXT (24 IU or 40.32 μg) and placebo in 18 GSAD and 18 CON subjects. Both the CON and GSAD groups activated bilateral amygdala to all emotional faces during placebo, with the GSAD group exhibiting hyperactivity specifically to fearful faces in bilateral amygdala compared with the CON group. OXT had no effect on amygdala activity to emotional faces in the CON group, but attenuated the heightened amygdala reactivity to fearful faces in the GSAD group, such that the hyperactivity observed during the placebo session was no longer evident following OXT (ie, normalization). These findings suggest that OXT has a specific effect on fear-related amygdala activity, particularly when the amygdala is hyperactive, such as in GSAD, thereby providing a brain-based mechanism of the impact of OXT in modulating the exaggerated processing of social signals of threat in patients with pathological anxiety.
The hormone and neuropeptide oxytocin is believed to buffer against social stress and reduce social-threat perception. We employed a widely used ostracism paradigm, Cyberball, to investigate whether oxytocin ameliorated the acute behavioral and affective consequences of social rejection. In a double-blind, randomized, between-subjects design, 74 healthy male and female participants were administered intranasal oxytocin or placebo and subsequently ostracized or included during this virtual ball-tossing game. Ostracized participants reported negative affective and attachment-related reactions, as well as a significant motivational change in increased desire to be involved in the game; these effects were not influenced by oxytocin. Intranasal oxytocin did, however, increase included participants' desire to play again with the same participants, suggesting oxytocin enhanced desire for future social engagement following inclusion. These findings are argued to provide evidence that the effects of oxytocin in promoting social approach behavior may be context specific and sensitive to positive social cues. The results suggest that in an explicitly aversive context, oxytocin does not buffer against the immediate impact of blunt social rejection.
The evolutionarily highly conserved neuropeptide oxytocin is a key mediator of social and emotional behavior in mammals, including humans. A common variant (rs53576) in the oxytocin receptor gene (OXTR) has been implicated in social-behavioral phenotypes, such as maternal sensitivity and empathy, and with neuropsychiatric disorders associated with social impairment, but the intermediate neural mechanisms are unknown. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to identify structural and functional alterations in OXTR risk allele carriers and their link to temperament. Activation and interregional coupling of the amygdala during the processing of emotionally salient social cues was significantly affected by genotype. In addition, evidence for structural alterations in key oxytocinergic regions emerged, particularly in the hypothalamus. These neural characteristics predicted lower levels of reward dependence, specifically in male risk allele carriers. Our findings identify sex-dependent mechanisms impacting the structure and function of hypothalamic-limbic circuits that are of potential clinical and translational significance.
Oxytocin (OXT) has been implicated in a suite of complex social behaviors including observed choices in economic laboratory experiments. However, actual studies of associations between oxytocin receptor (OXTR) gene variants and experimentally elicited social preferences are rare.
We test hypotheses of associations between social preferences, as measured by behavior in two economic games, and 9 single nucleotide polymorphisms (SNPs) of the OXTR gene in a sample of Swedish twins (n = 684). Two standard economic games, the dictator game and the trust game, both involving real monetary consequences, were used to elicit such preferences. After correction for multiple hypothesis testing, we found no significant associations between any of the 9 single nucleotide polymorphisms (SNPs) and behavior in either of the games.
We were unable to replicate the most significant association reported in previous research between the amount donated in a dictator game and an OXTR genetic variant.
Social relations between humans critically depend on our affective experiences of others. Oxytocin enhances prosocial behavior, but its effect on humans’ affective experience of others is not known. We tested whether oxytocin influences affective ratings, and underlying
brain activity, of faces that have been aversively conditioned. Using a standard conditioning procedure, we induced differential negative affective ratings in faces exposed to an aversive conditioning compared with nonconditioning manipulation. This differential negative
evaluative effect was abolished by treatment with oxytocin, an effect associated with an attenuation of activity in anterior medial temporal and anterior cingulate cortices. In amygdala and fusiform gyrus, this modulation was stronger for faces with direct gaze, relative to
averted gaze, consistent with a relative specificity for socially relevant cues. The data suggest that oxytocin modulates the expression of evaluative conditioning for socially relevant faces via influences on amygdala and fusiform gyrus, an effect that may explain its prosocial
effects.
Vasopressin (AVP) actions on vascular tone and blood pressure are mainly mediated by the V1-vascular receptor (V1R). We recently reported the structure and functional expression of the human V1R cDNA and described the genomic characteristics, tissue expression, chromosomal localization, and regional mapping of the human V1R gene, AVPR1A. To test whether the V1R is a marker for human essential hypertension, we sequenced the human AVPR1A gene and its 5' upstream region and found several DNA microsatellite motifs. One (GT)14-(GA)13-(A)8 microsatellite is located 2983 bp downstream of the transcription start site, within a 2.2 kbp intron interrupting the coding sequence of the receptor. Three other microsatellites are present in the 5' flanking DNA of the AVPR1A gene: a (GT)25 dinucleotide repeat, a complex (CT)4-TT-(CT)8-(GT)24 motif and a (GATA)14 tetranucleotide repeat located respectively 3956 bp, 3625 bp and 553 bp upstream of the transcription start site. Analysis of these polymorphisms in 79 hypertensive and 86 normotensive subjects for the (GT)14-(GA)13-(A)8 and the (GT)25 motifs revealed a high percentage of heterozygosity but no difference in alleles frequencies between the two groups. A linkage study using the affected sib pair method and the (GT)25 repeat in 446 hypertensive sib pairs from 282 French Caucasian pedigrees showed no excess of alleles sharing at the AVPR1A locus. No linkage was found in the subgroups of patients with early onset hypertension (diagnosis before age 40) or severe hypertension (diastolic blood pressure ≥ 100mmHg or requirement for ≥ two medications). These findings suggest that molecular variants of the V1R gene are not involved in unselected forms of essential hypertension.
Arginine vasopressin (AVP) and arginine vasotocin (AVT) influence social behaviors in a number of species from diverse taxonomic groups, therefore suggesting a conservation of social functions for these homologous neuropeptides during vertebrate evolution. However, whether or not AVP has the ability to directly influence social behavior in humans has not yet been determined. Because influences of AVT/AVP on behaviors related to social communication, particularly in aggressive contexts, are among the most consistently observed across species from diverse vertebrate groups, the present study was designed to determine if AVP administration would influence cognitive, autonomic and/or somatic responses to species-specific social stimuli important for agonistic communication in humans. Specifically, we tested the effects of intranasal AVP administration on attention towards emotionally expressive facial expressions, as well as on heart rate (HR), skin conductance (SC) and corrugator supercilii electromyograms (corrugator EMG) in response to these social stimuli. AVP did not affect attention toward, nor autonomic arousal in response to, emotionally neutral, happy or angry facial expressions, but it did selectively enhance the corrugator EMG responses evoked by emotionally neutral facial expressions, making them similar in magnitude to responses evoked by angry facial expressions in control subjects. Because this muscle group is involved in agonistic communication, these results suggest that AVP may influence aggression in human males by biasing individuals to respond to emotionally ambiguous social stimuli as if they were threatening/aggressive.
Increasing evidence suggests that two nonapeptides, arginine vasopressin and oxytocin, shape human social behavior in both nonclinical and clinical subjects. Evidence is discussed that in autism spectrum disorders genetic polymorphisms in the vasopressin–oxytocin pathway, notably the arginine vasopressin receptor 1a (AVPR1a), the oxytocin receptor (OXTR), neurophysin I and II, and CD38 (recently shown to be critical for social behavior by mediating oxytocin secretion) contribute to deficits in socialization skills in this group of patients. We also present first evidence that CD38 expression in lymphoblastoid cells derived from subjects diagnosed with autism is correlated with social skill phenotype inventoried by the Vineland Adaptive Behavioral Scales. Additionally, we discuss molecular genetic evidence that in nonclinical subjects both AVPR1a and OXTR genes contribute to prosocial or altruistic behavior inventoried by two experimental paradigms, the dictator game and social values orientation. The role of the AVPR1a is also analyzed in prepulse inhibition. Prepulse inhibition of the startle response to auditory stimuli is a largely autonomic response that resonates with social cognition in both animal models and humans. First results are presented showing that intranasal administration of arginine vasopressin increases salivary cortisol levels in the Trier Social Stress test. To summarize, accumulating studies employing a broad array of cutting-edge tools in psychology, neuroeconomics, molecular genetics, pharmacology, electrophysiology, and brain imaging are beginning to elaborate the intriguing role of oxytocin and arginine vasopressin in human social behavior. We expect that future studies will continue this advance and deepen our understanding of these complex events.
A classical task of experimental psychology, the retention of lists of words, was given twice to three groups of subjects treated with lysine vasopressin (LVP), oxytocin or saline. From a baseline session (no treatment) to a second session with treatment, the LVP and placebo groups showed an enhancement of the number of words remembered correctly, whereas the oxytocin group did not. Rather, oxytocin impaired memory performance. However, we cannot claim a memory enhancing effect of LVP, because placebo treatment enhanced memory performance to the same extent.
Oxytocin and vasopressin are key effectors of social behaviour (Insel, T. R. and Fernald, R. D. (2004). Annu. Rev. Neurosci., 27: 697-722). Oxytocin effects in humans were recently demonstrated by a behavioural study showing selectively increased trust after hormone administration (Kosfeld, M., et al. (2005). Nature, 435: 673-676). Since this suggested involvement of the amygdala, which is linked to trust (Winston, J. S., et al. (2002). Nat. Neurosci., 5: 277-283) - presumably because of its role in danger monitoring - and highly expresses oxytocin receptors (Huber, D., et al. (2005). Science, 308: 245-248), we studied amygdala circuitry after double-blind crossover intranasal application of placebo or oxytocin (Kirsch, P., et al. (2005). J. Neurosci., 25: 11489-11493). Oxytocin potently reduced amygdala activation and decreased coupling to brainstem regions implicated in autonomic and behavioural manifestations of fear, indicating a neural mechanism for the effects of oxytocin in social cognition in humans and providing a potential therapeutic approach to social anxiety currently being tested in social phobia and autism. Furthermore, these data suggested a translational genetic approach. Preliminary findings (data not presented) from our laboratory using imaging genetics indeed implicate genetic variants for both AVPR1A, encoding the primary receptor of vasopressin in brain, and the oxytocin receptor, OXTR, in amygdala regulation and activation. Taken together, our results indicate neural mechanisms for human social behaviour mediating genetic risk for autism through an impact on amygdala signalling and provide a rationale for exploring therapeutic strategies aimed at abnormal amygdala function in this disorder and in social dysfunction in general.
Autism is a developmental disorder characterized by three core symptom domains: speech and communication abnormalities, social functioning impairments and repetitive behaviours and restricted interests. Oxytocin (OXT) is a nine-amino-acid peptide that is synthesized in the paraventricular and supraoptic nucleus of the hypothalamus and released into the bloodstream by axon terminals in the posterior pituitary where it plays an important role in facilitating uterine contractions during parturition and in milk let-down. In addition, OXT and the structurally similar peptide arginine vasopressin (AVP) are released within the brain where they play a key role in regulating affiliative behaviours, including sexual behaviour, mother-infant and adult-adult pair-bond formation and social memory/recognition. Finally, OXT has been implicated in repetitive behaviours and stress reactivity. Given that OXT is involved in the regulation of repetitive and affiliative behaviours, and that these are key features of autism, it is believed that OXT may play a role in autism and that OXT may be an effective treatment for these two core symptom domains. In this chapter we review evidence to date supporting a relationship between OXT and autism; we then discuss research looking at the functional role of OXT in autism, as well as a pilot study investigating the therapeutic efficacy of OXT in treating core autism symptom domains. Finally, we conclude with a discussion of directions for future research.
The fundamental ability to form attachment is indispensable for human social relationships. Impairments in social behaviour are associated with decreased quality of life and psychopathological states. In non-human mammals, the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are key mediators of complex social behaviours, including attachment, social recognition and aggression. In particular, OXT reduces behavioural and neuroendocrine responses to social stress and seems both to enable animals to overcome their natural avoidance of proximity and to inhibit defensive behaviour, thereby facilitating approach behaviour. AVP has primarily been implicated in male-typical social behaviours, including aggression and pair-bond formation, and mediates anxiogenic effects. Initial studies in humans suggest behavioural, neural, and endocrine effects of both neuropeptides, similar to those found in animal studies. This review focuses on advances made to date in the effort to understand the role of OXT and AVP in human social behaviour. First, the literature on OXT and AVP and their involvement in social stress and anxiety, social cognition, social approach, and aggression is reviewed. Second, we discuss clinical implications for mental disorders that are associated with social deficits (e.g. autism spectrum disorder, borderline personality disorder). Finally, a model of the interactions of anxiety and stress, social approach behaviour, and the oxytocinergic system is presented, which integrates the novel approach of a psychobiological therapy in psychopathological states.
Sex differences in vasopressin and oxytocin expression are helpful in studying the anatomy and function of vasopressin innervation of the brain. They also provide insight in the function of neural sex differences in general. This paper will discuss nature, cause and possible significance of these sex differences, focusing on vasopressin projections from the bed nucleus of the stria terminalis and the medial amygdaloid nucleus, which show some of the most consistently found sex differences among vertebrates.
The evolutionarily highly conserved neuropeptide oxytocin seems to be involved in the regulation of complex forms of social behavior. It enhances the processing of positive social stimuli, reduces behavioral and neuroendocrine stress responses and modulates amygdala activity in humans. Moreover, it has been proposed that oxytocin dampens sympathetic nervous system activity. This hypothesis was tested in a double-blind, placebo-controlled study with 38 men either receiving 24 IU oxytocin intranasally or a placebo spray. While accomplishing an emotion classification task, electrodermal responses were measured as an index of sympathetic activity. Moreover, heart rate changes were recorded that are additionally mediated by the parasympathetic nervous system. Oxytocin enhanced differential heart rate responses to facial expressions as a function of the emotional valence, but had no effect on electrodermal activity or tonic measures of physiological arousal. These results indicate that oxytocin specifically modulates phasic activity of the parasympathetic nervous system which potentially reflects an increased motivational value of facial expressions following oxytocin treatment. Findings suggest that anxiolytic effects of oxytocin are not reflected in short-term sympathetic responses and may even be a consequence of rather than a prerequisite for improved social information processing.
Oxytocin (OT) is known to be involved in anxiety, as well as cardiovascular and hormonal regulation. The objective of this study was to assess the acute effect of intranasally administered OT on subjective states, as well as cardiovascular and endocrine parameters, in healthy volunteers (n = 14) performing a simulated public speaking test. OT or placebo was administered intranasally 50 min before the test. Assessments were made across time during the experimental session: (1) baseline (-30 min); (2) pre-test (-15 min); (3) anticipation of the speech (50 min); (4) during the speech (1:03 h), post-test time 1 (1:26 h), and post-test time 2 (1:46 h). Subjective states were evaluated by self-assessment scales. Cortisol serum and plasma adrenocorticotropic hormone (ACTH) were measured. Additionally, heart rate, blood pressure, skin conductance, and the number of spontaneous fluctuations in skin conductance were measured. Compared with placebo, OT reduced the Visual Analogue Mood Scale (VAMS) anxiety index during the pre-test phase only, while increasing sedation at the pre-test, anticipation, and speech phases. OT also lowered the skin conductance level at the pre-test, anticipation, speech, and post-test 2 phases. Other parameters evaluated were not significantly affected by OT. The present results show that OT reduces anticipatory anxiety, but does not affect public speaking fear, suggesting that this hormone has anxiolytic properties.
The nonapeptide arginine vasopressin (AVP) plays an important role in hypothalamus-pituitary-adrenal axis regulation and also functions as a social hormone in a wide variety of species, from voles to humans. In the current report we use a variety of stress inducing tasks, including the Trier Social Stress Test (TSST) and intranasal administration of AVP to show that intranasal administration of this neuropeptide leads to a significant increase in salivary cortisol and pulse rate, specifically in conditions where subjects perform tasks in the presence of a social evaluative threat (task performance could be negatively judged by others). In contrast, in conditions without a social evaluative threat (no task condition, modified TSST without audience and bike ergometry), subjects receiving AVP did not differ from subjects receiving placebo. Thus exogenous AVP's influence is contingent upon a circumscribed set of initial conditions that constitute a direct threat to the maintenance of our social selves. Stress evoked by social threat is an integral part of social life and is related to self-esteem and in extreme forms, to poor mental health (e.g., social phobia). Our findings suggest that AVP is a key component in the circuit that interlaces stress and social threat and findings offer inroads to our understanding of individual differences in sociability and in stress response elicited in threatening social situations.
Oxytocin has known stress-reducing and attachment-enhancing effects. We thus hypothesized that oxytocin would attenuate emotional and hormonal responses to stress in borderline personality disorder (BPD). Fourteen BPD and 13 healthy control (HC) adults received 40 IU intranasal oxytocin or placebo in double-blind randomized order followed by the Trier Social Stress Test. Subjective dysphoria (Profile of Mood Changes) and plasma cortisol levels were measured. Childhood trauma history, attachment style, and self-esteem were also rated. A significant "Group × Drug × Time" interaction effect for dysphoria (p=.04) reflected a proportionately greater attenuation of stress-induced dysphoria in the BPD group after oxytocin administration. Additionally, a marginally significant "Group × Drug" interaction effect for cortisol (p=.10) reflected a tendency toward greater attenuation of the stress-induced cortisol surge in the BPD group after oxytocin administration. In the combined sample, the oxytocin-placebo difference in the emotional stress reactivity was significantly predicted by childhood trauma alone (p=.037) and combined with self-esteem (p=.030), whereas the oxytocin-placebo difference in cortisol stress reactivity was predicted only by insecure attachment (p=.013). Results suggest that oxytocin may have a beneficial impact on emotional regulation in BPD, which merits further investigation and could have important treatment implications.
The neuropeptide oxytocin has been shown to improve many aspects of social cognitive functioning, including facial emotion recognition, and to promote social approach behaviour. In the present study, we investigated the modulatory effects of oxytocin on the recognition of briefly presented facial expressions. In order to diversify the degree of visual awareness for the facial stimuli, presentation duration was systematically varied. Fifty-six participants were administered intranasal oxytocin or a placebo in a double-blind, randomized, between-subjects design. Participants viewed angry and happy target faces or neutral distractors for 18, 35, or 53 ms subsequently masked by neutral faces. Participants had to indicate the presence or absence of the briefly presented target face. Discrimination indices (d') showed that oxytocin generally enhanced detection accuracy of emotional stimuli. This effect was more pronounced for the recognition of happy faces. We provide evidence that a single dose of intranasally administered oxytocin enhances detection of briefly presented emotional stimuli. The possible role of stimulus valence and recognition difficulty is discussed.
Recent discoveries of single-gene influences on social behaviour have generated a great deal of interest in the proximate mechanisms underlying the expression of complex behaviours. Length polymorphism in a microsatellite in the regulatory region of the gene encoding the vasopressin 1a receptor (avpr1a) has been associated with both inter- and intra-specific variation in socially monogamous behaviour in voles (genus Microtus) under laboratory conditions. Here, we evaluate the relationship between avpr1a length polymorphism and social associations, genetic monogamy, and reproductive success in free-living prairie vole (M. ochrogaster) populations. We found no evidence of a relationship between avpr1a microsatellite length and any of our correlates of either social or genetic monogamy in the field. Our results, especially when taken in conjunction with those of recent experimental studies in semi-natural enclosures, suggest that avpr1a polymorphism is unlikely to have been a major influence in the evolution or maintenance of social monogamy in prairie voles under natural conditions.
De Dreu et al. (1) presented a set of experiments exploring the effects of the neuropeptide oxytocin on implicit associations and moral reasoning about in-group and out-group members. Although their experiments were cleverly designed, their data did not clearly support their interpretation that oxytocin promotes human “ethnocentrism” (1).
Human ethnocentrism--the tendency to view one's group as centrally important and superior to other groups--creates intergroup bias that fuels prejudice, xenophobia, and intergroup violence. Grounded in the idea that ethnocentrism also facilitates within-group trust, cooperation, and coordination, we conjecture that ethnocentrism may be modulated by brain oxytocin, a peptide shown to promote cooperation among in-group members. In double-blind, placebo-controlled designs, males self-administered oxytocin or placebo and privately performed computer-guided tasks to gauge different manifestations of ethnocentric in-group favoritism as well as out-group derogation. Experiments 1 and 2 used the Implicit Association Test to assess in-group favoritism and out-group derogation. Experiment 3 used the infrahumanization task to assess the extent to which humans ascribe secondary, uniquely human emotions to their in-group and to an out-group. Experiments 4 and 5 confronted participants with the option to save the life of a larger collective by sacrificing one individual, nominated as in-group or as out-group. Results show that oxytocin creates intergroup bias because oxytocin motivates in-group favoritism and, to a lesser extent, out-group derogation. These findings call into question the view of oxytocin as an indiscriminate "love drug" or "cuddle chemical" and suggest that oxytocin has a role in the emergence of intergroup conflict and violence.
Oxytocin facilitates stress regulation but little is known about individual differences in this effect. The present study investigates whether the effect of intranasal oxytocin on stress-contingent cortisol release differs between individuals with high vs. low emotional regulation abilities (ERA). In a double-blind study thirty-six healthy male students with either high or low ERA were randomly assigned to receive intranasally 24 IU oxytocin or placebo. Cortisol was measured at several times before and after a social stressor (public speaking). Individuals with impaired ERA showed a reduced cortisol response to stress after oxytocin but an increased cortisol response after placebo application. The results suggest that healthy individuals with low ERA benefit from intranasal oxytocin application. Neurobiological mechanisms potentially underlying the link between oxytocin, cortsiol and ERA are discussed against the background of a neuroendocrinological perspective on personality.
Pharmacological studies indicate a functional interaction between the serotonergic and oxytocinergic system.
This study tested for an interaction of the prominent serotonin transporter polymorphism (SLC6A4) and an oxytocin receptor gene variation on individual differences in negative emotionality in healthy Caucasians (n = 750).
Participants carrying both the homozygous LL-variant of the serotonin transporter polymorphism and the TT variant of the single nucleotide polymorphism rs2268498 on the oxytocin receptor gene showed lowest scores on the personality dimensions Fear and Sadness of the Affective Neuroscience Personality Scales, as well as on an underlying factor Negative Emotionality.
The observed interaction effect provides converging evidence from human molecular genetics that serotonergic and oxytocinergic neurotransmission are entwined and play a crucial role for human personality with implications for affective disorders.
Impairments in social processes characterize one of the core deficits in autism spectrum disorders (ASD) and accumulating evidence suggests that oxytocin neurotransmission is implicated in mediating social adaptation in ASD. Using a mouse model, CD38, a transmembrane protein expressed in immune cells but also in brain, was found to be critical for social behavior via regulation of oxytocin secretion. This prompted us to both examine CD38 expression in human lymphoblastoid cell lines (LBC) as well as to test association between SNPs across the CD38 gene and ASD.
LBC’s were derived from 44 ASD lines and 40 "unaffected" parents. Family-based association (UNPHASED) was examined by genotyping 11 tagging SNPs spanning the CD38 gene identified using HapMap data in 170 trios. An additional SNP (rs3796863) associated in a study by Munesue et al. with ASD was also genotyped.
A highly significant reduction in CD38 expression was observed in immortalized lymphocytes derived from ASD subjects compared to their "unaffected" parents (F517.2, P50.00024, df51). Haplotype analysis showed significant association (permutation corrected) between three and seven locus haplotypes and DSM IV ASD in low functioning (IQ < 70) subjects.
The current report supports a role for CD38 in conferring risk for ASD. Notably, our study shows that this gene is not only associated with low functioning ASD but that CD38 expression is markedly reduced in LBC derived from ASD subjects compared to "unaffected" parents, strengthening the connection between oxytocin and ASD.
The current study examined the role of perceived social isolation in moderating the effects of oxytocin on cardiac autonomic control in humans. Intranasal administration of 20 IU oxytocin resulted in a significant increase in autonomic (parasympathetic and sympathetic) cardiac control. Specifically, oxytocin increased high frequency heart rate variability, a relatively pure measure of parasympathetic cardiac control, and decreased pre-ejection period, a well-validated marker of enhanced sympathetic cardiac control. Derived metrics of autonomic co-activity and reciprocity revealed that oxytocin significantly increased overall autonomic cardiac control. Furthermore, the effects of oxytocin on cardiac autonomic control were significantly associated with loneliness ratings. Higher levels of loneliness were associated with diminished parasympathetic cardiac reactivity to intranasal oxytocin. The effects of OT on autonomic cardiac control were independent of any effects on circulating pro-inflammatory cytokine or stress hormone levels. Thus, lonely individuals may be less responsive to the salubrious effects of oxytocin on cardiovascular responsivity.
Recent studies have suggested that oxytocin affects social cognition and behavior mediated by the oxytocin receptor (OXTR) in amygdala in humans as well as in experimental animals. Genetic studies have revealed a link between the OXTR gene and the susceptibility to autism spectrum disorders (ASD), especially in the social dysfunctional feature of ASD.
We examined the relationship between amygdala volume measured with manual tracing methodology and seven single nucleotide polymorphisms and one haplotype-block in OXTR, which were previously reported to be associated with ASD, in 208 socially intact Japanese adults with no neuropsychiatric history or current diagnosis.
The rs2254298A allele of OXTR was significantly associated with larger bilateral amygdala volume. The rs2254298A allele effect on amygdala volume varied in proportion to the dose of this allele. The larger the number of rs2254298A alleles an individual had, the larger their amygdala volume. Such an association was not observed with hippocampal volume or with global brain volumes, including whole gray, white matter, and cerebrospinal-fluid space. Furthermore, two three-single nucleotide polymorphism haplotypes, including rs2254298G allele, showed significant associations with the smaller bilateral amygdala volume.
The present results suggest that OXTR might be associated with the susceptibility to ASD, especially in its aspects of social interaction and communication mediated by a modulation of amygdala development, one of the most distributed brain regions with high density of OXTR. Furthermore, amygdala volume measured with magnetic resonance imaging could be a useful intermediate phenotype to uncover the complex link between OXTR and social dysfunction in ASD.
Arginine Vasopressin modulates complex social and sexual behavior by enhancing social recognition, pair bonding, and aggression in non-human mammals. The influence of Arginine Vasopressin in human social and sexual behavior is, however, yet to be fully understood. We evaluated whether Arginine Vasopressin nasal spray facilitated recognition of positive and negative social and sexual stimuli over non-social stimuli. We used a recognition task that has already been shown to be sensitive to the influence of Oxytocin nasal spray (Unkelbach et al., 2008). In a double-blind, randomized, placebo-controlled, between-subjects design, 41 healthy male volunteers were administered Arginine Vasopressin (20 IU) or a placebo nasal spray after a 45 min wait period and then completed the recognition task. Results showed that the participants administered Arginine Vasopressin nasal spray were faster to detect sexual words over other types of words. This effect appeared for both positively and negatively valenced words. Results demonstrate for the first time that Arginine Vasopressin selectively enhances human cognition for sexual stimuli, regardless of valence. They further extend animal and human genetic studies linking Arginine Vasopressin to sexual behavior in males. Findings suggest an important cognitive mechanism that could enhance sexual behaviors in humans.
The nonapeptide oxytocin and its receptor have been implicated in the regulation of mammalian social behavior and stress physiology. Evidence is accumulating that the quality of the parental environment is associated with oxytocin biology in children. The present study was designed to examine the interaction of the single nucleotide polymorphism (SNP) rs2254298 within the oxytocin receptor (OXTR) gene and quality of parental environment in predicting children's psychosocial functioning. More specifically, in a sample of 92 Caucasian adolescent girls (9-14 years old), we examined whether adverse parental environment, operationalized as mothers' history of recurrent major depressive disorder, interacts with the rs2254298 SNP on the OXTR gene to predict daughters' symptoms of depression and anxiety. Caucasian girls who both were heterozygous for the OXTR rs2254298 polymorphism and had high early adversity reported the highest levels of symptoms of depression, physical anxiety, and social anxiety. These findings highlight the potential importance of this OXTR gene polymorphism in the etiology of depression and anxiety disorders.
Both human and animal studies suggest oxytocin may have antipsychotic properties. Therefore, we conducted a clinical trial to directly test this notion.
Nineteen schizophrenia patients with residual symptoms despite being on a stable dose of at least one antipsychotic were enrolled in a randomized, double-blind, crossover study. They received 3 weeks of daily intranasal oxytocin (titrated to 40 IU twice a day) and placebo adjunctive to their antipsychotics. Order of intranasal treatment was randomly assigned and there was a 1-week washout between treatments.
Analysis of the 15 subjects who completed all the study visits revealed that oxytocin significantly reduced scores on the Positive and Negative Symptom Scale (p < .001) and Clinical Global Impression-Improvement Scale (p < .001) compared with placebo at the 3-week end point. No benefit was seen at the early time points. Oxytocin was well tolerated and produced no adverse effects based upon patient reports or laboratory analysis.
The results support the hypothesis that oxytocin has antipsychotic properties and is well tolerated. Higher doses and longer duration of treatment may produce larger benefits and should be evaluated in future studies.