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The editors of this unique volume asked some of the world's leading emotion researchers to address 14 fundamental questions about the nature and origins of emotion. Each chapter addresses one of these questions, with often divergent answers from the more than 100 experts represented here. At the end of each chapter, the editors highlight key areas of agreement and disagreement. In the final chapter, they outline the most important challenges facing the field and the most fruitful avenues for future research. Not a textbook offering a single viewpoint, 'The Nature of Emotion' reveals the central issues in emotion research and theory in the words of the leading scientists working in the field today, providing a unique and highly accessible guide for students, researchers, and clinicians.

Key Points The rostral cingulate cortex occupies a central position in models of emotion, pain and cognitive control. Work in these domains has strongly influenced recent models of social behaviour and psychopathology. The segregationist view: it has been argued that the rostral cingulate cortex is functionally segregated into affective and cognitive divisions. Although this view remains influential, new data suggest that it is no longer tenable. Robust links have been forged between the anterior subdivision of the midcingulate cortex (aMCC) and negative affect (as with the anticipation and delivery of pain), leading some to speculate that aMCC implements a 'domain-general' process that is integral to negative affect, pain and cognitive control. Physiological evidence: a meta-analysis of activation foci from functional imaging studies of negative affect, pain and cognitive control revealed that aMCC is consistently activated by all three domains, refuting claims that cognition and emotion are strictly segregated in the cingulate. Anatomical evidence: aMCC is characterized by substantial connections with subcortical regions involved in negative affect and pain (the spinothalamic system, periaqueductal grey, amygdala, nucleus accumbens and substantia nigra). Unlike other cortical 'hot spots' for emotion, aMCC harbours the rostral cingulate zone (RCZ) — a premotor area that is heavily interconnected with other motor centres (including the facial nucleus). Functional evidence: measures of negative affect, pain and cognitive control exhibit convergent functional properties. These measures covary with one another and are amplified in similar ways by uncertainty about responses and outcomes. The adaptive control hypothesis: the core function common to negative affect, pain and cognitive control is the need to determine an optimal course of action in the face of uncertainty — that is, to exert 'adaptive control'. We suggest that aMCC implements adaptive control by using information about punishment to bias responding in situations where the optimal course of action is uncertain or entails response competition. Further evidence: pain-responsive MCC neurons are activated by the anticipation of pain, activated during instrumental escape from pain and are sensitive to manipulations of certainty and conflict. Lesions of aMCC alter how threat modulates instrumental behaviour. aMCC activity during aversively motivated learning is predicted by computational models of control and reinforcement learning. These data encourage a broader perspective on the functional significance of cingulate activity, one that recognizes that aMCC did not evolve to optimize performance on laboratory measures of 'cold' cognition. The data that we have surveyed are consistent with the possibility that the contribution of aMCC to measures of cognitive control stems from its older role in regulating 'hot' behaviours. The adaptive control hypothesis provides a clear roadmap to the most profitable avenues for understanding the contribution of aMCC to negative affect and pain. In this Review, Shackman and colleagues challenge claims that emotion and cognition are functionally segregated in the cingulate cortex. They show that negative affect, pain and cognitive control activate a common subdivision of the cingulate cortex, and propose that this region uses punishment-related information to optimize goal-directed behaviour. It has been argued that emotion, pain and cognitive control are functionally segregated in distinct subdivisions of the cingulate cortex. However, recent observations encourage a fundamentally different view. Imaging studies demonstrate that negative affect, pain and cognitive control activate an overlapping region of the dorsal cingulate — the anterior midcingulate cortex (aMCC). Anatomical studies reveal that the aMCC constitutes a hub where information about reinforcers can be linked to motor centres responsible for expressing affect and executing goal-directed behaviour. Computational modelling and other kinds of evidence suggest that this intimacy reflects control processes that are common to all three domains. These observations compel a reconsideration of the dorsal cingulate's contribution to negative affect and pain.

Compassion is a key motivator of altruistic behavior, but little is known about individuals’ capacity to cultivate compassion through training. We examined whether compassion may be systematically trained by testing whether (a) short-term compassion training increases altruistic behavior and (b) individual differences in altruism are associated with training-induced changes in neural responses to suffering. In healthy adults, we found that compassion training increased altruistic redistribution of funds to a victim encountered outside of the training context. Furthermore, increased altruistic behavior after compassion training was associated with altered activation in brain regions implicated in social cognition and emotion regulation, including the inferior parietal cortex and dorsolateral prefrontal cortex (DLPFC), and in DLPFC connectivity with the nucleus accumbens. These results suggest that compassion can be cultivated with training and that greater altruistic behavior may emerge from increased engagement of neural systems implicated in understanding the suffering of other people, executive and emotional control, and reward processing.

Delivering genes to and across the brain vasculature efficiently and specifically across species remains a critical challenge for addressing neurological diseases. We have evolved adeno-associated virus (AAV9) capsids into vectors that transduce brain endothelial cells specifically and efficiently following systemic administration in wild-type mice with diverse genetic backgrounds, and in rats. These AAVs also exhibit superior transduction of the CNS across non-human primates (marmosets and rhesus macaques), and in ex vivo human brain slices, although the endothelial tropism is not conserved across species. The capsid modifications translate from AAV9 to other serotypes such as AAV1 and AAV-DJ, enabling serotype switching for sequential AAV administration in mice. We demonstrate that the endothelial-specific mouse capsids can be used to genetically engineer the blood-brain barrier by transforming the mouse brain vasculature into a functional biofactory. We apply this approach to Hevin knockout mice, where AAV-X1-mediated ectopic expression of the synaptogenic protein Sparcl1/Hevin in brain endothelial cells rescued synaptic deficits. Delivering genes to and across the brain vasculature efficiently and specifically across species remains challenging. Here, the authors show that endothelial-specific AAVs with serotype flexibility enable redosing and transform the brain vasculature into an in vivo biofactory in genetically diverse rodents. In primates, these vectors cross the blood-brain-barrier and show broad tropism.

Brain extraction (a.k.a. skull stripping) is a fundamental step in the neuroimaging pipeline as it can affect the accuracy of downstream preprocess such as image registration, tissue classification, etc. Most brain extraction tools have been designed for and applied to human data and are often challenged by non-human primates (NHP) data. Amongst recent attempts to improve performance on NHP data, deep learning models appear to outperform the traditional tools. However, given the minimal sample size of most NHP studies and notable variations in data quality, the deep learning models are very rarely applied to multi-site samples in NHP imaging. To overcome this challenge, we used a transfer-learning framework that leverages a large human imaging dataset to pretrain a convolutional neural network (i.e. U-Net Model), and then transferred this to NHP data using a small NHP training sample. The resulting transfer-learning model converged faster and achieved more accurate performance than a similar U-Net Model trained exclusively on NHP samples. We improved the generalizability of the model by upgrading the transfer-learned model using additional training datasets from multiple research sites in the Primate Data-Exchange (PRIME-DE) consortium. Our final model outperformed brain extraction routines from popular MRI packages (AFNI, FSL, and FreeSurfer) across a heterogeneous sample from multiple sites in the PRIME-DE with less computational cost (20 s~10 min). We also demonstrated the transfer-learning process enables the macaque model to be updated for use with scans from chimpanzees, marmosets, and other mammals (e.g. pig). Our model, code, and the skull-stripped mask repository of 136 macaque monkeys are publicly available for unrestricted use by the neuroimaging community at https://github.com/HumanBrainED/NHP-BrainExtraction.

Compassion, the emotional response of caring for another who is suffering and that results in motivation to relieve suffering, is thought to be an emotional antecedent to altruistic behavior. However, it remains unclear whether compassion enhances altruistic behavior in a uniform way or is specific to sub-types of behavior such as altruistic helping of a victim or altruistic punishment of a transgressor. We investigated the relationship between compassion and subtypes of altruistic behavior using third-party paradigms where participants (1) witnessed an unfair economic exchange between a transgressor and a victim, and (2) had the opportunity to either spend personal funds to either economically (a) help the victim or (b) punish the transgressor. In Study 1, we examined whether individual differences in self-reported empathic concern (the emotional component of compassion) was associated with greater altruistic helping or punishment behavior in two independent samples. For participants who witnessed an unfair transaction, trait empathic concern was associated with greater helping of a victim and had no relationship to punishment. However, in those who decided to punish the transgressor, participants who reported greater empathic concern decided to punish less. In Study 2, we directly enhanced compassion using short-term online compassion meditation training to examine whether altruistic helping and punishment were increased after two weeks of training. Compared to an active reappraisal training control group, the compassion training group gave more to help the victim and did not differ in punishment of the transgressor. Together, these two studies suggest that compassion is related to greater altruistic helping of victims and is not associated with or may mitigate altruistic punishment of transgressors.

According to the World Health Organization, anxiety and depressive disorders are a leading source of disability, affecting hundreds of millions of people. Children can inherit an extremely anxious temperament, which is a prominent risk factor for the later development of anxiety, depression, and comorbid substance abuse. This study uses high-resolution functional and structural imaging in our well-established developmental nonhuman primate model to identify the heritable neural substrate that underlies extreme childhood anxious temperament. Using a large multigenerational family pedigree, genetic correlation analyses revealed a tripartite neural circuit where metabolism likely shares a genetic substrate with early-life dispositional anxiety. Interestingly, we found that brain function—not structure—is the critical intermediary between genetics and the childhood risk to develop stress-related psychopathology. Understanding the heritability of neural systems linked to psychopathology is not sufficient to implicate them as intergenerational neural mediators. By closely examining how individual differences in neural phenotypes and psychopathology cosegregate as they fall through the family tree, we can identify the brain systems that underlie the parent-to-child transmission of psychopathology. Although research has identified genes and neural circuits that contribute to the risk of developing anxiety and depression, the specific neural systems that mediate the inborn risk for these debilitating disorders remain unknown. In a sample of 592 young rhesus monkeys that are part of an extended multigenerational pedigree, we demonstrate that metabolism within a tripartite prefrontal-limbic-midbrain circuit mediates some of the inborn risk for developing anxiety and depression. Importantly, although brain volume is highly heritable early in life, it is brain metabolism—not brain structure—that is the critical intermediary between genetics and the childhood risk to develop stress-related psychopathology.

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Mechanistic work in animals implicates the central extended amygdala (EAc)—including the central nucleus of the amygdala and the neighboring bed nucleus of the stria terminalis—but the translational relevance of these discoveries remains unexplored. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

Children with an anxious temperament (AT) are at risk for developing psychiatric disorders along the internalizing spectrum, including anxiety and depression. Like these disorders, AT is a multidimensional phenotype and children with extreme anxiety show varying mixtures of physiological, behavioral, and other symptoms. Using a well-validated juvenile monkey model of AT, we addressed the degree to which this phenotypic heterogeneity reflects fundamental differences or similarities in the underlying neurobiology. The rhesus macaque is optimal for studying AT because children and young monkeys express the anxious phenotype in similar ways and have similar neurobiology. Fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET) in 238 freely behaving monkeys identified brain regions where metabolism predicted variation in three dimensions of the AT phenotype: hypothalamic-pituitary-adrenal (HPA) activity, freezing behavior, and expressive vocalizations. We distinguished brain regions that predicted all three dimensions of the phenotype from those that selectively predicted a single dimension. Elevated activity in the central nucleus of the amygdala and the anterior hippocampus was consistently found across individuals with different presentations of AT. In contrast, elevated activity in the lateral anterior hippocampus was selective to individuals with high levels of HPA activity, and decreased activity in the motor cortex (M1) was selective to those with high levels of freezing behavior. Furthermore, activity in these phenotype-selective regions mediated relations between amygdala metabolism and different expressions of anxiety. These findings provide a framework for understanding the mechanisms that lead to heterogeneity in the clinical presentation of internalizing disorders and set the stage for developing improved interventions.

•Data sharing of primate neuroimaging offers new opportunities.•The potential of metadata to enrich primate neuroimaging is described.•Illustration of how meta-data can be shared in the BIDS format is provided. Sharing and pooling large amounts of non-human primate neuroimaging data offer new exciting opportunities to understand the primate brain. The potential of big data in non-human primate neuroimaging could however be tremendously enhanced by combining such neuroimaging data with other types of information. Here we describe metadata that have been identified as particularly valuable by the non-human primate neuroimaging community, including behavioural, genetic, physiological and phylogenetic data.