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In recent years ample studies have reported that intranasal administration of the neuropeptide oxytocin can facilitate social motivation and cognition in healthy and clinical populations. However, it is still unclear how effects are mediated since intranasally administered oxytocin can both directly enter the brain (nose to brain) and increase peripheral vascular concentrations (nose to blood). The relative functional contributions of these routes are not established and have received insufficient attention in the field. The current study used vasoconstrictor pretreatment to prevent intranasal oxytocin (24 IU) from increasing peripheral concentrations and measured effects on both resting-state neural (electroencephalography) and physiological responses (electrocardiogram, electrogastrogram and skin conductance). Results demonstrated that intranasal oxytocin alone produced robust and widespread increases of delta-beta cross-frequency coupling (CFC) from 30 min post-treatment but did not influence peripheral physiological measures. As predicted, vasoconstrictor pretreatment greatly reduced the normal increase in peripheral oxytocin concentrations and, importantly, abolished the majority of intranasal oxytocin effects on delta-beta CFC. Furthermore, time-dependent positive correlations were found between increases in plasma oxytocin concentrations and corresponding increases in delta-beta CFC following oxytocin treatment alone. Our findings suggest a critical role of peripheral vasculature-mediated routes on neural effects of exogenous oxytocin administration with important translational implications for its use as an intervention in psychiatric disorders.

This study investigated heterogeneity in language skills of children with autism and their relationship with different autistic social subtypes. Data from 90 autistic and 30 typically developing children were analyzed. Results showed that autistic social subtypes varied in language skill problems (aloof passive active-but-odd). There was a negative association between aloof dimension scores and language performance but positive for the active-but-odd dimension and no association in the passive one. Moreover, aloof dimension score was the main contributor to language performance. A receiver operating characteristic analysis suggested language vocabulary as an additional component in differentiating autistic social subtypes. These findings demonstrate that variations in language skills in autistic children provide additional information for discriminating their social subtype.

The motivation to strive for and consume primary rewards such as palatable food is bound by devaluation mechanisms, yet secondary rewards such as money may not be bound by these regulatory mechanisms. The present study therefore aimed at determining diverging devaluation trajectories for primary (chocolate milk) and secondary (money) reinforcers on the behavioral and neural level. Devaluation procedures with repeated exposure to reward combined with a choice (Experiment 1) and an incentive delay (Experiment 2) paradigm consistently revealed decreasing hedonic value for the primary reward as reflected by decreasing hedonic evaluation and choice preference with repeated receipt, while hedonic value and preferences for the secondary reward increased. Concomitantly acquired functional near-infrared spectroscopy (fNIRS) data during the incentive delay paradigm revealed that increasing value of the secondary reward was accompanied by increasing anticipatory activation in the lateral orbitofrontal cortex, while during the consummatory phase the secondary reinforcer associated with higher medial orbitofrontal activity irrespective of devaluation stage. Overall, the findings suggest that—in contrast to primary reinforcers—secondary reinforcers, i.e. money, can acquire progressively enhanced incentive motivation with repeated receipt, suggesting a mechanism which could promote escalating striving to obtain secondary rewards.

Cognitive control regulates cognitive and emotional systems to facilitate goal-directed behavior in the context of task-irrelevant distractors. Cognitive control deficits contribute to residual functional impairments across psychiatric disorders and represent a promising novel treatment target. Translational evidence suggests that modafinil may enhance performance in executive functions; however, differential effects on regulatory control in cognitive and emotional domains have not been examined. The present pre-registered randomized-controlled pharmacological fMRI trial examined differential effects of modafinil (single-dose, 200 mg) on cognitive and emotional conflict processing. To further separate objective cognitive enhancing effects from subjective performance perception, a metacognitive paradigm was employed. Results indicated that modafinil specifically enhanced cognitive conflict performance and concomitantly increased activation in the inferior frontal gyrus and its functional communication with the dorsomedial prefrontal cortex. Exploratory analysis further revealed modafinil-enhanced basolateral amygdala reactivity to cognitive conflict, with stronger reactivity being associated with higher cognitive conflict performance. Whereas modafinil enhanced cognitive performance in the metacognitive paradigm, confidence indices remained unaffected. Overall, the present results suggest that modafinil has the potential to enhance cognitive conflict processing while leaving emotional conflict processing unaffected. On the neural level modafinil enhanced the recruitment of a network engaged in general conflict and regulatory control processes, whereas effects on the amygdala may reflect improved arousal-mediated attention processes for conflicting information. The pattern of cognitive enhancing effects in the absence of effects on affective processing suggests a promising potential to enhance cognitive control in clinical populations.

The specific neural systems underlying the subjective feeling of fear are debated in affective neuroscience. Here, we combine functional MRI with machine learning to identify and evaluate a sensitive and generalizable neural signature predictive of the momentary self-reported subjective fear experience across discovery (n = 67), validation (n = 20) and generalization (n = 31) cohorts. We systematically demonstrate that accurate fear prediction crucially requires distributed brain systems, with important contributions from cortical (e.g., prefrontal, midcingulate and insular cortices) and subcortical (e.g., thalamus, periaqueductal gray, basal forebrain and amygdala) regions. We further demonstrate that the neural representation of subjective fear is distinguishable from the representation of conditioned threat and general negative affect. Overall, our findings suggest that subjective fear, which exhibits distinct neural representation with some other aversive states, is encoded in distributed systems rather than isolated ‘fear centers’., The brain systems underlying fear experience are debated. Here the authors develop an fMRI-based neural signature for fear and show that fear is represented in distributed brain systems rather than isolated ‘fear centers’.

Jealousy is a complex social emotion combining the different primary emotions of anger, fear and sadness. Previous evidence has suggested the involvement of fronto-striatal dopaminergic circuitry in pathological jealousy, although little is known about overlaps with the neural representation of primary emotions involved in non-morbid jealousy and the utility of a dimensional neuroimaging approach. In the current study, 85 healthy subjects underwent fMRI during an emotional face recognition paradigm and resting state. A total of 150 faces (happy, angry, fearful, sad, neutral) were presented and subjects required to identify the expression and rate its intensity. Trait jealousy was assessed using the Multidimensional Jealousy Scale. Behavioral results showed that only intensity ratings of angry faces were positively associated with subjects' jealousy scores. During processing of angry versus neutral expression faces, subjects with elevated jealousy exhibited increased activation in the right thalamus, insula, fusiform gyrus and hippocampus, left dorsal striatum, superior parietal lobule and bilateral cerebellum and inferior frontal gyrus after controlling for trait aggression and sex. Functional connectivity between the inferior frontal gyrus and dorsal striatum was also increased. No associations with resting-state functional connectivity were found. Overall, the present study demonstrates an association between exaggerated jealousy and increased intensity ratings of angry faces as well as activity and functional connectivity of the dorsal striatal-inferior frontal circuitry. Thus, increased emotional responsivity to social threat and enhanced activity in limbic regions and dopaminergic fronto-striatal circuitry may be features of both non-morbid and pathological jealousy confirming the utility of a dimensional approach.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is characterized by inattention, hyperactivity, and impulsivity but also by negative emotionality. The aim of the present study was to investigate whether subclinical ADHD tendencies are associated with negative emotionality in healthy adult samples. The present study is of special interest since it investigated negative emotionality with a questionnaire anchored in Neuroscience Theory-the Affective Neuroscience Personality Scales (ANPS). Furthermore, through the investigation of samples in two countries, namely Germany and China, the study aims to replicate the results across different cultures. German (n = 377; age: M = 23.25, SD = 8.47; 117 males) and Chinese (n = 389; age: M = 20.74, SD = 2.47; 279 males) subjects completed ANPS (primary emotional traits) and ASRS (ADHD tendencies) questionnaires in an online survey. Principal component analysis of the ANPS revealed one factor for negative emotionality and one factor for positive emotionality. Partial correlations between ANPS and ASRS (controlled for age) were conducted separately for nation and gender. The same correlation patterns between ADHD tendencies and negative emotionality could be found in male and female German/Chinese participants (range r= .189 to r = .352). Higher negative emotionality was always significantly associated with more inattentive, hyperactive/impulsive, or combined tendencies. However, significant negative correlations between ADHD tendencies and positive emotionality could only be observed in Chinese males (range r = - .264 to r = - .296). The results are in line with former findings in children and show that also in healthy adults, associations between negative emotionality and ADHD tendencies are robustly visible. The results were independent of the cultural background, indicating a general association between ADHD tendencies and negative emotionality, even in healthy adults.

Language plays an important role in romantic attachment. However, it is unclear whether the structure and topic of language use might influence potential mate choice. We investigated 124 female students’ preference for compliments paid by males incorporating either literal or metaphoric (conventional/novel) language and targeting their appearance or possessions (house) throughout their menstrual cycle. Male faces paired with novel metaphorical compliments were rated as more attractive by women than those paired with literal ones. Compliments targeting appearance increased male attractiveness more than possessions. Interestingly, compliments on appearance using novel metaphors were preferred by women in a relationship during the fertile phase but by single women during the luteal phase. A similar pattern of altered face attraction ratings was subsequently shown by subjects in the absence of the verbal compliments and even though they were unable to recognize the faces. Thus the maintained attraction bias for faces previously associated with figurative language compliments appears to be unconscious. Overall this study provides the first evidence that women find men who typically use novel metaphorical language to compliment appearance more attractive than those using prosaic language or complimenting possessions. The evolutionary significance for such a language use bias in mate selection is discussed.

Social communication through touch and mutual grooming can convey highly salient socio-emotional signals and has been shown to involve the neuropeptide oxytocin (OXT) in several species. Less is known about the modulatory influence of OXT on the neural and emotional responses to human interpersonal touch. The present randomized placebo (PLC)-controlled within-subject pharmaco-functional magnetic resonance imaging (fMRI) study was designed to test the hypothesis that a single intranasal dose of synthetic OXT (24 IU) would facilitate both neural and emotional responses to interpersonal touch in a context- (female vs male touch) and trait- (autistic trait load) specific manner. Specifically, the experimental rationale was to manipulate the reward value of interpersonal touch independent of the intensity and type of actual cutaneous stimulation administered. Thus, 40 heterosexual males believed that they were touched by either a man or a woman, although in fact an identical pattern of touch was always given by the same female experimenter blind to condition type. Our results show that OXT increased the perceived pleasantness of female, but not male touch, and associated neural responses in insula, precuneus, orbitofrontal, and pregenual anterior cingulate cortex. Moreover, the behavioral and neural effects of OXT were negatively correlated with autistic-like traits. Taken together, this is the first study to show that the perceived hedonic value of human heterosexual interpersonal touch is facilitated by OXT in men, but that its behavioral and neural effects in this context are blunted in individuals with autistic traits.

It has been well documented that cognitive conflict is sensitive to the relative proportion of congruent and incongruent trials. However, few studies have examined whether affective conflict processing is modulated as a function of proportion congruency (PC). To address this question we recorded event-related potentials (ERP) while subjects performed both cognitive and affective face-word Stroop tasks. By varying the proportion of congruent and incongruent trials in each block, we examined the extent to which PC impacts both cognitive and affective conflict control at different temporal stages. Results showed that in the cognitive task an anteriorly localized early N2 component occurred predominantly in the low proportion congruency context, whereas in the affective task it was found to occur in the high proportion congruency one. The N2 effects across the two tasks were localized to the dorsolateral prefrontal cortex, where responses were increased in the cognitive task but decreased in the affective one. Furthermore, high proportions of congruent items produced both larger amplitude of a posteriorly localized sustained potential component and a larger behavioral Stroop effect in cognitive and affective tasks. Our findings suggest that cognitive and affective conflicts engage early dissociable attentional control mechanisms and a later common conflict response system.

We investigated the effect of restraint on the release of dopamine, GABA and glutamate in the medial prefrontal cortex (mPFC) of lactating compared with virgin Wistar female rats; besides the expression of D1, neuropeptide Y Y2, GABA receptors and corticotropin-releasing factor (CRF). Results from microdialysis experiments showed that basal dopamine and GABA, but not glutamate, concentrations were higher in lactating rats. In virgin animals, immobilization caused significant increase in dopamine, whereas GABA was unchanged and glutamate reduced. In lactating animals, restrain significantly decreased dopamine concentrations and, in contrast to virgin animals, GABA and glutamate concentrations increased. We found a higher expression of CRF, as well as the D1 and neuropeptide Y Y2 receptors in the left mPFC of virgin stressed rats; also, only stressed lactating animals showed a significant increase in immunopositive cells to GABA in the left cingulate cortex; meanwhile, a significant decrease was measured in virgin rats after stress in the left prelimbic region. The increased inhibition of the mPFC dopamine cells during stress and the down-regulated expression of the neuropeptide Y Y2 receptor may explain the lower CRF and hyporesponse to stress measured in lactating animals. Interestingly, participation of mPFC in stress regulation seems to be lateralized.

The more times people fail the more likely they are to give up, however little is known about the neural mechanisms underlying this impact of repeated failure on decision making. Here we have used a visual shape discrimination task with computer-controlled feedback combined with functional magnetic resonance imaging (fMRI) to investigate the neural circuits involved. The behavioral task confirmed that the more times subjects experienced failure the more likely they were to give up, with three successive failures being the key threshold and the majority of subjects reaching the point where they decided to quit and try a new stimulus set after three or four failures. The fMRI analysis revealed activity changes in frontal, parietal, temporal, limbic and striatal regions, especially anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and temporal parietal junction (TPJ) associated with the number of previous failures experienced. Furthermore, their parameter estimates were predictive of subjects’ quitting rate. Thus, subjects reach the point where they decide to quit after three/four failures and this is associated with differential changes in brain regions involved in error monitoring and reward which regulate both failure detection and changes in decision-making strategy.

It is increasingly recognized that we need a better understanding of how mental disorders such as depression alter the brain's functional connections to improve both early diagnosis and therapy. A new holistic approach has been used to investigate functional connectivity changes in the brains of patients suffering from major depression using resting-state functional magnetic resonance imaging (fMRI) data. A canonical template of connectivity in 90 different brain regions was constructed from healthy control subjects and this identified a six-community structure with each network corresponding to a different functional system. This template was compared with functional networks derived from fMRI scans of both first-episode and longer-term, drug resistant, patients suffering from severe depression. The greatest change in both groups of depressed patients was uncoupling of the so-called ‘hate circuit’ involving the superior frontal gyrus, insula and putamen. Other major changes occurred in circuits related to risk and action responses, reward and emotion, attention and memory processing. A voxel-based morphometry analysis was also carried out but this revealed no evidence in the depressed patients for altered gray or white matter densities in the regions showing altered functional connectivity. This is the first evidence for the involvement of the ‘hate circuit’ in depression and suggests a potential reappraisal of the key neural circuitry involved. We have hypothesized that this may reflect reduced cognitive control over negative feelings toward both self and others.

Sheep learn to recognize the odours of their lambs within two hours of giving birth, and this learning involves synaptic changes within the olfactory bulb. Specifically, mitral cells become increasingly responsive to the learned odour, which stimulates release of both glutamate and GABA (gamma-aminobutyric acid) neurotransmitters from the reciprocal synapses between the excitatory mitral cells and inhibitory granule cells. Nitric oxide (NO) has been implicated in synaptic plasticity in other regions of the brain as a result of its modulation of cyclic GMP levels. Here we investigate the possible role of NO in olfactory learning. We find that the neuronal enzyme nitric oxide synthase (nNOS) is expressed in both mitral and granule cells, whereas the guanylyl cyclase subunits that are required for NO stimulation of cGMP formation are expressed only in mitral cells. Immediately after birth, glutamate levels rise, inducing formation of NO and cGMP, which potentiate glutamate release at the mitral-to-granule cell synapses. Inhibition of nNOS or guanylyl cyclase activity prevents both the potentiation of glutamate release and formation of the olfactory memory. The effects of nNOS inhibition can be reversed by infusion of NO into the olfactory bulb. Once memory has formed, however, inhibition of nNOS or guanylyl cyclase activity cannot impair either its recall or the neurochemical release evoked by the learned lamb odour. Nitric oxide therefore seems to act as a retrograde and/or intracellular messenger, being released from both mitral and granule cells to potentiate glutamate release from mitral cells by modulating cGMP concentrations. We propose that the resulting changes in the functional circuitry of the olfactory bulb underlie the formation of olfactory memories.

Background How oscillatory brain rhythms alone, or in combination, influence cortical information processing to support learning has yet to be fully established. Local field potential and multi-unit neuronal activity recordings were made from 64-electrode arrays in the inferotemporal cortex of conscious sheep during and after visual discrimination learning of face or object pairs. A neural network model has been developed to simulate and aid functional interpretation of learning-evoked changes. Results Following learning the amplitude of theta (4-8 Hz), but not gamma (30-70 Hz) oscillations was increased, as was the ratio of theta to gamma. Over 75% of electrodes showed significant coupling between theta phase and gamma amplitude (theta-nested gamma). The strength of this coupling was also increased following learning and this was not simply a consequence of increased theta amplitude. Actual discrimination performance was significantly correlated with theta and theta-gamma coupling changes. Neuronal activity was phase-locked with theta but learning had no effect on firing rates or the magnitude or latencies of visual evoked potentials during stimuli. The neural network model developed showed that a combination of fast and slow inhibitory interneurons could generate theta-nested gamma. By increasing N-methyl-D-aspartate receptor sensitivity in the model similar changes were produced as in inferotemporal cortex after learning. The model showed that these changes could potentiate the firing of downstream neurons by a temporal desynchronization of excitatory neuron output without increasing the firing frequencies of the latter. This desynchronization effect was confirmed in IT neuronal activity following learning and its magnitude was correlated with discrimination performance. Conclusions Face discrimination learning produces significant increases in both theta amplitude and the strength of theta-gamma coupling in the inferotemporal cortex which are correlated with behavioral performance. A network model which can reproduce these changes suggests that a key function of such learning-evoked alterations in theta and theta-nested gamma activity may be increased temporal desynchronization in neuronal firing leading to optimal timing of inputs to downstream neural networks potentiating their responses. In this way learning can produce potentiation in neural networks simply through altering the temporal pattern of their inputs.

How coupled brain rhythms influence cortical information processing to support learning is unresolved. Local field potential and neuronal activity recordings from 64- electrode arrays in sheep inferotemporal cortex showed that visual discrimination learning increased the amplitude of theta oscillations during stimulus presentation. Coupling between theta and gamma oscillations, the theta/gamma ratio and the regularity of theta phase were also increased, but not neuronal firing rates. A neural network model with fast and slow inhibitory interneurons was developed which generated theta nested gamma. By increasing N-methyl-D-aspartate receptor sensitivity similar learning-evoked changes could be produced. The model revealed that altered theta nested gamma could potentiate downstream neuron responses by temporal desynchronization of excitatory neuron output independent of changes in overall firing frequency. This learning-associated desynchronization was also exhibited by inferotemporal cortex neurons. Changes in theta nested gamma may therefore facilitate learning-associated potentiation by temporal modulation of neuronal firing.

Nature 414, 165–166 (2001) In Fig. 1b of this Brief Communication, the legend and text did not make it clear that two different groups of ten sheep were used in the study to give overall n = 20. A reanalysis of the data using a post-hoc Tukey test (rather than a paired t-test, as originally stated) revealed some small errors that altered the significance values slightly; however, there is no overall change in the results.

The extent to which behaviour is determined by ‘nurture’ as opposed to ‘nature’ in mammals is controversial, although most recent interest has focused on genetic determinants. Here we investigate maternal influences on behavioural development by using the approach of cross-fostering between sheep and goats, which, like ourselves, form close individual attachment bonds with their offspring. We show that the emotional bond between a mother and her male offspring, rather than other social or genetic factors, may irreversibly determine these species' social and sexual preferences. Maternal influences on female offspring are weaker and totally reversible. In both sexes, visual cues from the face are important for determining attraction.

Measurements of male and female copulatory behavior in pairs of common marmosets were made during 30-min mating tests (n = 170). For the male,both frequencies and latencies of mounting, pelvic thrusting, and ejaculatory behaviors were analyzed. For the female, frequencies of proceptive displays (tongue-flicking) and of sexual receptivity were measured. The sexual and associated behavior of the marmoset is compared to that of other primates and the suitability of this species for laboratory studies of neurohumoral mechanisms and sexual behavior is assessed.

Absolute refractory periods of a subpopulation of corticomedial amygdala (CMA) neurones which project to the medial preoptic/anterior hypothalamic junction (MPH) via the stria terminalis were recorded in the female rat. Previous experiments have shown that this sub-population of CMA neurones is testosterone-sensitive in the male rat. In the ovariectomised female testosterone propionate (TP, 200 microgram/day for 18-22 days) significantly reduced the mean absolute refractory period of these CMA neurones compared to oil treated controls (from 1.34 ms to 0.87 ms). In a second experiment the absolute refractory periods of these CMA neurones were measured during the pro-oestrus and di-oestrus stages of the oestrous cycle as well as in ovariectomised controls. The mean absolute refractory period of these neurones was significantly shortened at pro-oestrus (0.99 ms) compared both to animals in di-oestrus 1 (1.45 ms) and ovariectomised controls (1.42 ms). The median firing rate of these CMA neurones was also significantly increased at pro-oestrus (1.24 Hz) compared to di-oestrus 1 (0.13 Hz) and ovariectomised controls (0.09 Hz). No firing rate increase was observed after TP treatment ov ovariectomised animals in the first experiment. Results show that the testosterone-sensitive CMA neurones sensitivity in the female rat. They also show that the refractory periods of these neurones are shortened at pro-oestrus. Further, these same neurones also show firing rate increases at this time, although such an increase has not been observed in gonadally intact male rats when compared to castrated ones. Results are interpreted in terms of a possible functional sexual dimorphism in the output of these CMA neurones.

Testosterone is aromatized to oestradiol in the brain, and it has been suggested that its effects on the brain are produced by this metabolite. Oestradiol does indeed restore sexual behaviour in castrated rats, but is is much more effective if combined with a second metabolite, dihydrotestosterone. This may be because the two hormones have a synergistic effect on the brain; or because the central effect of oestradiol synergises with the peripheral effects of dihydrotestosterone (which include stimulation of penile development). Evidence that the corticomedial amygdala (CMA) and the preoptic area of the rat brain are both involved in the control of sexual behaviour led us to examine the neurones of the stria terminalis that connect the two. These neurones are hormone-sensitive; their absolute refractory period is lengthened by castration and reduced again by testosterone. So we have investigated the aromatization hypothesis further by examining the effect of oestradiol and dihydrotestosterone on these testosterone-sensitive neurones. Oestradiol has exactly the same effect as testosterone; dihydrotestosterone has no effect, whether it is given alone or in combination with oestradiol.