One and Done Epinephrine in Out-of-Hospital Cardiac Arrest? Outcomes in a Multiagency United States Study.

BACKGROUND: Cardiac arrest guidelines recommend epinephrine every 3-5 minutes during cardiac arrest resuscitation. However, it is unclear if multiple epinephrine doses are associated with improved outcomes. The objective of this study was to determine if a single-dose epinephrine protocol was associated with improved survival compared to traditional multidose protocols. METHODS: We conducted a pre-post study across five North Carolina EMS agencies from 11/1/2016 to 10/29/2019. Patients ≥18 years old with attempted resuscitation for non-traumatic prehospital cardiac arrest were included. Data were collected 1 year before and after implementation of the single-dose epinephrine protocol. Prior to implementation, all agencies used a multidose epinephrine protocol. The Cardiac Arrest Registry to Enhance Survival (CARES) was used to obtain patient outcomes. Study outcomes were survival to hospital discharge (primary) and return of spontaneous circulation (ROSC). Analysis was by intention to treat. Outcomes were compared pre- vs. post-implementation using generalized estimating equations to account for clustering within EMS agencies. Adjusted analyses included age, sex, race, shockable vs. non-shockable rhythm, witnessed arrest, automatic external defibrillator availability, EMS response interval, and bystander cardiopulmonary resuscitation. RESULTS: During the study period there were 1,690 encounters (899 pre- and 791 post-implementation). The population was 74.7% white, 61.1% male, and had a median age of 65 (IQR 53-76) years. Survival to hospital discharge was similar pre- vs. post-implementation [13.6% (122/899) vs. 15.4% (122/791); OR 1.19, 95%CI 0.89-1.59]. However, ROSC was more common post-implementation [42.3% (380/899) vs. 32.5% (257/791); OR 0.66, 95%CI 0.54-0.81]. After adjusting for covariates, the single-dose protocol was associated with similar survival to discharge rates (aOR 0.88, 95%CI 0.77-1.29), but with decreased ROSC rates (aOR 0.58, 95%CI 0.47-0.72). CONCLUSION: A prehospital single-dose epinephrine protocol was associated with similar survival to hospital discharge, but decreased ROSC rates compared to the traditional multidose epinephrine protocol.

The behavioral neuroendocrinology of dopamine systems in differently reared juvenile male rhesus monkeys (Macaca mulatta).

Dopamine (DA) is a critical neuromodulator of behavior. With propensities for addiction, hyper-activity, cognitive impairment, aggression, and social subordinance, monkeys enduring early maternal deprivation evoke human disorders involving dopaminergic dysfunction. To examine whether DA system alterations shape the behavioral correlates of adverse rearing, male monkeys (Macaca mulatta) were either mother-reared (MR: N = 6), or separated from their mothers at birth and nursery-reared (NR: N = 6). Behavior was assessed during 20-minute observations of subjects interacting with same- or differently-reared peers. Cerebrospinal fluid (CSF) biogenic amines, and serum testosterone (T), cortisol (CORT), and prolactin (PRL) were collected before and after pharmacologic challenge with saline or the DA receptor-2 (DRD2) antagonist Raclopride (RAC). Neuropeptide correlations observed in MR were non-existent in NR monkeys. Compared to MR, NR showed reduced DA tone; higher basal serum T; and lower CSF serotonin (5-HT). RAC increased PRL, T and CORT, but the magnitude of responses varied as a function of rearing. Levels of PRL significantly increased following RAC in MR, but not NR. Elevations in T following RAC were only significant among MR. Contrastingly, the net change (RAC CORT - saline CORT) in CORT was greater in NR than MR. Finally, observations conducted during the juvenile phase in a novel play-arena revealed more aggressive, self-injurious, and repetitive behaviors, which negatively correlated with indexes of dopaminergic tone in NR monkeys. In conclusion, early maternal deprivation alters brain DA systems, and thus may be associated with characteristic cognitive, social, and addiction outcomes.

One-Year Mortality and Associated Factors in Patients Receiving Out-of-Hospital Naloxone for Presumed Opioid Overdose.

STUDY OBJECTIVE: Out-of-hospital naloxone has been championed as a lifesaving solution during the opioid epidemic. However, the long-term outcomes of out-of-hospital naloxone recipients are unknown. The objectives of this study are to describe the 1-year mortality of presumed opioid overdose victims identified by receiving out-of-hospital naloxone and to determine which patient factors are associated with subsequent mortality. METHODS: This was a regional retrospective cohort study of out-of-hospital records from 7 North Carolina counties from January 1, 2015 to February 28, 2017. Patients who received out-of-hospital naloxone were included. Out-of-hospital providers subjectively assessed patients for improvement after administering naloxone. Naloxone recipients were cross-referenced with the North Carolina death index to examine mortality at days 0, 1, 30, and 365. Naloxone recipient mortality was compared with the age-adjusted, at-large population's mortality rate in 2017. Generalized estimating equations and Cox proportional hazards models were used to assess for mortality-associated factors. RESULTS: Of 3,085 out-of-hospital naloxone encounters, 72.7% of patients (n=2,244) improved, whereas 27.3% (n=841) had no improvement with naloxone. At day 365, 12.0% (n=269) of the improved subgroup, 22.6% (n=190) of the no improvement subgroup, and 14.9% (n=459) of the whole population were dead. Naloxone recipients who improved were 13.2 times (95% confidence interval 13.0 to 13.3) more likely to be dead at 1 year than a member of the general populace after age adjusting of the at-large population to match this study population. Older age and being black were associated with 1-year mortality, whereas sex and multiple overdoses were not. CONCLUSION: Opioid overdose identified by receiving out-of-hospital naloxone with clinical improvement carries a 13-fold increase in mortality compared to the general population. This suggests that this is a high-risk population that deserves attention from public health officials, policymakers, and health care providers in regard to the development of long-term solutions.

Fluoxetine administered to juvenile monkeys: effects on the serotonin transporter and behavior.

OBJECTIVE: This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth-an animal model of human childhood stress-were also studied. METHOD: At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N=8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration. RESULTS: Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures. CONCLUSIONS: Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo.

Early life stress affects cerebral glucose metabolism in adult rhesus monkeys (Macaca mulatta).

Early life stress (ELS) is a risk factor for anxiety, mood disorders and alterations in stress responses. Less is known about the long-term neurobiological impact of ELS. We used [(18)F]-fluorodeoxyglucose Positron Emission Tomography (FDG-PET) to assess neural responses to a moderate stress test in adult monkeys that experienced ELS as infants. Both groups of monkeys showed hypothalamic-pituitary-adrenal (HPA) axis stress-induced activations and cardiac arousal in response to the stressor. A whole brain analysis detected significantly greater regional cerebral glucose metabolism (rCGM) in superior temporal sulcus, putamen, thalamus, and inferotemporal cortex of ELS animals compared to controls. Region of interest (ROI) analyses performed in areas identified as vulnerable to ELS showed greater activity in the orbitofrontal cortex of ELS compared to control monkeys, but greater hippocampal activity in the control compared to ELS monkeys. Together, these results suggest hyperactivity in emotional and sensory processing regions of adult monkeys with ELS, and greater activity in stress-regulatory areas in the controls. Despite these neural responses, no group differences were detected in neuroendocrine, autonomic or behavioral responses, except for a trend towards increased stillness in the ELS monkeys. Together, these data suggest hypervigilance in the ELS monkeys in the absence of immediate danger.

Amygdala volume predicts patterns of eye fixation in rhesus monkeys.

In both human and nonhuman primates the eyes are a highly salient feature of the face, conveying identity, emotion and attentional direction of conspecifics. Studies have indicated that the amygdala plays an important role in eye contact, and amygdala dysfunction may underlie social deficits in disorders such as autism through effects on eye contact. In the present study we compared the volume of the amygdala in 32 juvenile rhesus monkeys to visual fixation patterns in a social memory paradigm. Amygdala volume was determined from manual traces of structural MRIs and fixation patterns were assessed using eyetracking methodology. A significant positive relationship was found between amygdala volume and fixation on both the face and the eye region. Amygdala volume was also found to relate to habituation across multiple presentations of different photographs of the same individual monkeys indicating a role in social memory. These data provide an important linkage between structural variation of amygdala and previous demonstrations of function in a nonhuman primate model.

The effect of gonadectomy on prepulse inhibition and fear-potentiated startle in adolescent rhesus macaques.

Sex steroids, such as testosterone, can regulate brain development, cognition and modify psychiatric conditions. However, the role of adolescent testosterone in the emergence of cognitive deficits relevant to psychiatric illness has not been directly studied in primates. We examined whether removing testosterone during adolescence in rhesus macaques would affect prepulse inhibition (PPI) and fear-potentiated startle (FPS), which are translational tests of cognition affected in psychiatric disorders. Prepubertal macaques (30 months old) were castrated (n=6) or sham operated (n=6), and PPI and (FPS) were tested before the onset of puberty (34 months old) and after the pubertal surge in sex hormones 16 months later (50 months old). As expected there were no differences between the gonadectomized and intact groups' level of startle amplitude, PPI or (FPS) before puberty. After puberty, the intact group displayed substantially less PPI than the gonadectomized group, consistent with evidence that PPI is attenuated by endogenous increases in sex hormones. At the end of the study, testosterone among the intact monkeys was also correlated with tyrosine hydroxylase levels in the putamen, suggesting the attenuation of PPI by gonadal sex hormones may be influenced by subcortical dopamine. Thus, puberty involves significant increases in sex hormones, which in turn may modulate subcortical dopamine synthesis and affect cognitive functions impaired in psychiatric illnesses such as schizophrenia.

Adverse rearing experiences enhance responding to both aversive and rewarding stimuli in juvenile rhesus monkeys.

BACKGROUND: While adverse rearing is thought to alter threat responding, the effects on appetitive behavior remains minimally explored. This study examines the effects that early life emotional adversity has on response to both threatening and appetitive stimuli in juvenile rhesus monkeys. METHODS: Twenty-four, 2-year-old monkeys with differential rearing histories were tested for fear-potentiated startle responding and consumption of an artificially sweetened solution. RESULTS: Relative to monkeys reared under typical conditions, monkeys removed from their mothers at birth and reared with peers demonstrated both increases in reward responding, as evidenced by greater consumption of a palatable solution in a free choice test, and increased threat responding, as evidenced by enhanced fear-potentiated startle responding. CONCLUSIONS: Findings suggest that early rearing impacts juvenile manifestations of both appetitive and aversive emotional systems. Results are discussed in the context of development, anxiety, depression, and substance abuse.

Gonadectomy negatively impacts social behavior of adolescent male primates.

Social behavior changes dramatically during primate adolescence. However, the extent to which testosterone and other gonadal hormones are necessary for adolescent social behavioral development is unknown. In this study, we determined that gonadectomy significantly impairs social dominance in naturalistic settings and changes reactions to social stimuli in experimental settings. Rhesus macaques were castrated (n= 6) or sham operated (n=6) at age 2.4 years, group-housed for 2 years, and ethograms were collected weekly. During adolescence the gonadally intact monkeys displayed a decrease in subordinate behaviors and an increase in dominant behaviors, which ultimately related to a rise in social status and rank in the dominance hierarchy. We measured monkey's reactions to emotional faces (fear, threat, neutral) of conspecifics of three ages (adult, peer, infant). Intact monkeys were faster to retrieve a treat in front of a threatening or infant face, while castrated monkeys did not show a differential response to different emotional faces or ages. No group difference in reaction to an innate fear-eliciting object (snake) was found. Approach and proximity responses to familiar vs unfamiliar conspecifics were tested, and intact monkeys spent more time proximal to a novel conspecific as compared to castrates who tended to spend more time with a familiar conspecific. No group differences in time spent with novel or familiar objects were found. Thus, gonadectomy resulted in the emergence of significantly different responses to social stimuli, but not non-social stimuli. Our work suggests that intact gonads, which are needed to produce adolescent increases in circulating testosterone, impact social behavior during adolescences in primates.

Early adverse rearing experiences alter sleep-wake patterns and plasma cortisol levels in juvenile rhesus monkeys.

Monkeys separated from their mothers soon after birth and raised with peers display many disturbances in emotional behavior that are similar to human mood and anxiety disorders. In addition to emotional disturbances, both mood and anxiety disorders are often characterized by disruptions in normal sleep-wake cycles, a behavior that has not been well characterized in adversely reared non-human primates. Because polysomnographic measures are difficult to obtain in unrestrained monkeys we used 24-h actigraphy measures to assess probable sleep-wake patterns in juvenile nursery- and mother-reared rhesus macaques (Macaca mulatta, N=16) over several days in the home cage. In addition we assayed plasma cortisol in the morning, afternoon, and evening. Relative to mother-reared (MR) monkeys, actigraphic algorithms indicated that nursery-reared (NR) animals had shorter durations of nocturnal sleep, earlier morning waking, and longer periods of sleep during the active period, specifically in the mid morning. No shift in diurnal patterns of cortisol was observed, but NR animals displayed an overall elevation in cortisol. Finally a significant interaction was found between cortisol and actigraphic determination of sleep efficiency in the two groups. A strong positive relationship (r(2)>0.8) was found between mean cortisol levels and sleep efficiency for the MR monkeys, but a significant negative relationship was found between these same variables for the NR monkeys, indicating a fundamentally different relationship between waking cortisol and actigraphy patterns in these two groups.

Non-human primates: model animals for developmental psychopathology.

Non-human primates have been used to model psychiatric disease for several decades. The success of this paradigm has issued from comparable cognitive skills, brain morphology, and social complexity in adult monkeys and humans. Recently, interest in biological psychiatry has focused on similar brain, social, and emotional developmental processes in monkeys. In part, this is related to evidence that early postnatal experiences in human development may have profound implications for subsequent mental health. Non-human primate studies of postnatal phenomenon have generally fallen into three basic categories: experiential manipulation (largely manipulations of rearing), pharmacological manipulation (eg drug-induced psychosis), and anatomical localization (defined by strategic surgical damage). Although these efforts have been very informative each of them has certain limitations. In this review we highlight general findings from the non-human primate postnatal developmental literature and their implications for primate models in psychiatry. We argue that primates are uniquely capable of uncovering interactions between genes, environmental challenges, and development resulting in altered risk for psychopathology.

The nonhuman primate amygdala is necessary for the acquisition but not the retention of fear-potentiated startle.

BACKGROUND: In a previous study, we found that rhesus monkeys prepared with bilateral lesions of the amygdala failed to acquire fear-potentiated startle to a visual cue. However, a second group of monkeys, which received the lesion after training, successfully demonstrated fear-potentiated startle learned prior to the lesion. METHODS: In the current experiment, the eight monkeys used in the second part of the original study, four of which had bilateral amygdala lesions and the four control animals, were trained using an auditory cue and tested in the fear-potentiated startle paradigm. This test was performed to determine whether they could acquire fear-potentiated startle to a new cue. RESULTS: Monkeys with essentially complete damage to the amygdala (based on histological analysis) that had retained and expressed fear-potentiated startle to a visual cue learned before the lesion failed to acquire fear-potentiated startle to an auditory cue when training occurred after the lesion. CONCLUSIONS: The results suggest that while the nonhuman primate amygdala is essential for the initial acquisition of fear conditioning, it does not appear to be necessary for the memory and expression of conditioned fear. These findings are discussed in relation to a network of connections between the amygdala and the orbitofrontal cortex that may subserve different component processes of fear conditioning.

Acoustic startle reflex in rhesus monkeys: a review.

Modulation of the acoustic startle response is a simple and objective indicator of emotionality and attention in rodents and humans. This finding has proven extremely valuable for the analysis of neural systems associated with fear and anxiety. Until recently, there have been few efforts to develop acoustic startle measurement in non-human primates. Here we review recent work in which whole body acoustic startle amplitude has been measured in rhesus monkeys. Initial studies revealed that the amplitude of whole body startle in monkeys, as in rodents and humans, is directly proportional to acoustic stimulus intensity and gradually habituates with repeated exposures. Presentation of a weak acoustic stimulus 25-5,000 msec before a startle stimulus reduces startle amplitude by 40-50% depending on inter-stimulus interval length (prepulse inhibition). We have also measured significant fear-potentiated startle in the presence of a visual stimulus after pairing it with an inescapable pulse of pressurized air (fear-potentiated startle). This effect was reduced by diazepam and morphine, but not by buspirone. Ibotenic acid-induced lesions of the amygdala prevented the acquisition of fear-potentiated startle but, remarkably, did not prevent the expression of fear-potentiated startle when fear conditioning was carried out prior to the lesion. Finally, we have developed an objective measure of fear inhibition in monkeys using a novel conditioned inhibition procedure identical to one used in rats and humans. Our data demonstrate that acoustic startle in non-human primates successfully bridges rodent and human research. The opportunity now emerges to link concepts developed in rodents to the more complex neuroanatomical and cognitive processes common to monkeys and humans.

AX+/BX- discrimination learning in the fear-potentiated startle paradigm in monkeys.

Individuals with anxiety disorders often do not respond to safety signals and hence continue to be afraid and anxious. Consequently, it is important to develop paradigms in animals that can directly study brain systems involved in learning about, and responding to, safety signals. We previously developed a discrimination procedure in rats of the form AX+/BX-, where cues A and X presented together are paired with an aversive stimulus and cues B and X presented together predict the absence of an aversive stimulus. The present experiment adapted this procedure to the fear-potentiated startle paradigm in rhesus monkeys.

Role of the primate amygdala in fear-potentiated startle: effects of chronic lesions in the rhesus monkey.

In experiment 1, we assessed the role of the primate amygdala and hippocampus in the acquisition of learned fear measured with fear-potentiated startle. Three groups of six rhesus monkeys were prepared with bilateral ibotenic acid lesions of the amygdaloid complex and the hippocampus or were sham operated. Selective ibotenic acid lesions of the amygdala, but not the hippocampus, blocked the acquisition of fear-potentiated startle. In experiment 2, we assessed the role of the primate amygdala in the expression of fear-potentiated startle. Surprisingly, animals that sustained amygdala damage after they successfully learned fear-potentiated startle expressed normal fear-potentiated startle, despite a complete amygdala lesion based on magnetic resonance imaging assessments. These results suggest that although the amygdala is necessary for the initial acquisition of fear-potentiated startle, it is not necessary for the retention and expression of fear-potentiated startle. These findings are discussed in relation to the role of the amygdala in emotional learning and in cross-species comparisons of emotional behavior.

Modulation of fear-potentiated startle and vocalizations in juvenile rhesus monkeys by morphine, diazepam, and buspirone.

BACKGROUND: Modulation of the acoustic startle response by aversive sensory stimulation is a simple and objective indicator of emotionality in rodents and human beings that has been extremely valuable for the analysis of neural systems associated with fear and anxiety. We have described a paradigm for measuring fear-potentiated, whole-body acoustic startle in nonhuman primates and have developed a protocol for maintaining fear-potentiated startle over repeated sessions with minimal extinction to allow measurement of pharmacological effects on fear-potentiated startle by using within-subjects designs in relatively small groups of monkeys. METHODS: A novel, within-subjects testing protocol was used to examine the effects of three compounds in rhesus monkeys that have anxiolytic effects in rodents on fear-potentiated startle but that differ in their mechanism of action. Spontaneous vocalizations during testing also were recorded. Juvenile monkeys that were trained to associate a visual stimulus with a fear-inducing air blast to the face were tested after acute administration of different doses of buspirone diazepam, morphine, or vehicle. RESULTS: Monkeys rapidly developed a robust and persistent elevation of startle response in the presence of the CS during repeated testing sessions. Diazepam and morphine produced dose-related reductions of fear-potentiated startle. Buspirone did not significantly reduce fear-potentiated startle at the doses tested, although a trend was evident at the highest dose. All drugs reduced rates of coo vocalizations during startle testing. CONCLUSIONS: These fear-potentiated startle results suggest that rhesus monkeys have a pharmacological profile with respect to these compounds that is closer to humans than to rats. This demonstrates the value of examining the effects of drugs on fear-potentiated startle in nonhuman primates.

Social buffering: relief from stress and anxiety.

Communication is essential to members of a society not only for the expression of personal information, but also for the protection from environmental threats. Highly social mammals have a distinct characteristic: when conspecific animals are together, they show a better recovery from experiences of distress. This phenomenon, termed 'social buffering', has been found in rodents, birds, non-human primates and also in humans. This paper reviews classical findings on social buffering and focuses, in particular, on social buffering effects in relation to neuroendocrine stress responses. The social cues that transmit social buffering signals, the neural mechanisms of social buffering and a partner's efficacy with respect to social buffering are also detailed. Social contact appears to have a very positive influence on the psychological and the physiological aspects of social animals, including human beings. Research leading towards further understanding of the mechanisms of social buffering could provide alternative medical treatments based on the natural, individual characteristics of social animals, which could improve the quality of life.

Neuropeptides and non-human primate social deficits associated with pathogenic rearing experience.

There is a persuasive evidence that autism is highly heritable and likely to be substantially determined by polygenic mechanisms. Nevertheless, some intriguing findings in children raised in conditions of extreme social deprivation suggest that an autistic-like syndrome may occur as a consequence of environmental conditions. A particularly close model of this human syndrome has been studied in rhesus monkeys for almost half a century. Monkeys reared in pathogenic rearing conditions manifest considerable deficits in social interaction and increased self-directed behaviors. We have been interested in the possibility that disruptions in normal social development in non-human primates might be expressed in neuropeptide systems which have emerged in rodent studies as important candidates for a unique social biology. In recent studies, we have described persistently reduced CSF OT levels in male rhesus monkeys with significant social deficits. We also found that OT levels were positively related to the expression of affiliative social behaviors. Alterations were also detected in both CRH and AVP receptor binding patterns in limbic structures likely to influence social and emotional development. Taken together, these data suggest that abnormal rearing influences the development of brain systems critical to normal social and emotional competence in rhesus monkeys and may contribute to the development of autistic-like symptomatology associated with pathogenic rearing histories.

Alterations in diurnal cortisol rhythm and acoustic startle response in nonhuman primates with adverse rearing.

BACKGROUND: Early adverse experiences represent risk factors for the development of anxiety and mood disorders. Studies in nonhuman primates have largely focused on the impact of protracted maternal and social deprivation, but such intense manipulations also result in severe social and emotional deficits very difficult to remediate. This study attempts to model more subtle developmental perturbations that may increase the vulnerability for anxiety/mood disorders but lack the severe deficits associated with motherless rearing. METHODS: We investigated the consequences of repeated maternal separations between 3 to 6 months of age on rhesus monkeys' hypothalamic-pituitary-adrenal (HPA) axis function and acoustic startle reactivity. RESULTS: Repetitive maternal separation led to increased cortisol reactivity to the separation protocol in female infants and alterations in mother-infant interaction. It also resulted in a flattened diurnal rhythm of cortisol secretion and increased acoustic startle reactivity at later ages. CONCLUSIONS: Macaques with adverse rearing exhibited short-term and long-term alterations in HPA axis function and increased acoustic startle response comparable with changes associated with mood/anxiety disorders. The magnitude of HPA axis reactivity to the separations and the alterations in mother-infant relationship detected during the separation protocol predicted some of the alterations in HPA axis and emotionality exhibited later in life.

The neural correlates of mate competition in dominant male rhesus macaques.

BACKGROUND: Male sexual jealousy provoked by threatened exclusive access to a female mate is a frequently reported motive in cases involving spousal abuse. Dominant male rhesus macaques also respond aggressively to threats to mating exclusivity. METHODS: Nine dominant male monkeys were injected with [(18)F]-fluorodeoxyglucose ([(18)F]-FDG) and then exposed to one of two conditions: a "challenge" condition in which they witnessed a potential sexual interaction between their female consort and a rival male, and a control condition in which the consort was present without the rival male. After the brain uptake period for [(18)F]-FDG, dominant males were sedated, blood samples were drawn, and regional cerebral glucose metabolism was measured with positron emission tomographic imaging. RESULTS: Males that showed larger increases in plasma testosterone in the challenge condition showed more aggression and greater activation in the central gray matter of the midbrain, a brain area rich in androgen receptors. The challenge condition was associated with activation in both right superior temporal sulcus and right amygdala, which might relate to increased social vigilance and anxiety, respectively. CONCLUSIONS: Sexual jealousy in male humans is also often accompanied by vigilance behavior and anxiety and might recruit a similar neural network to that described here.