Seven Tesla Evidence for Columnar and Rostral-Caudal Organization of the Human Periaqueductal Gray Response in the Absence of Threat: A Working Memory Study.

The periaqueductal gray (PAG) is a small midbrain structure that surrounds the cerebral aqueduct, regulates brain-body communication, and is often studied for its role in "fight-or-flight" and "freezing" responses to threat. We used ultra-high-field 7 T fMRI to resolve the PAG in humans and distinguish it from the cerebral aqueduct, examining its in vivo function during a working memory task (N = 87). Both mild and moderate cognitive demands elicited spatially similar patterns of whole-brain blood oxygenation level-dependent (BOLD) response, and moderate cognitive demand elicited widespread BOLD increases above baseline in the brainstem. Notably, these brainstem increases were not significantly greater than those in the mild demand condition, suggesting that a subthreshold brainstem BOLD increase occurred for mild cognitive demand as well. Subject-specific masks were group aligned to examine PAG response. In PAG, both mild and moderate demands elicited a well-defined response in ventrolateral PAG, a region thought to be functionally related to anticipated painful threat in humans and nonhuman animals-yet, the present task posed only the most minimal (if any) "threat," with the cognitive tasks used being approximately as challenging as remembering a phone number. These findings suggest that the PAG may play a more general role in visceromotor regulation, even in the absence of threat.

A new science of emotion: implications for functional neurological disorder.

Functional neurological disorder reflects impairments in brain networks leading to distressing motor, sensory and/or cognitive symptoms that demonstrate positive clinical signs on examination incongruent with other conditions. A central issue in historical and contemporary formulations of functional neurological disorder has been the mechanistic and aetiological role of emotions. However, the debate has mostly omitted fundamental questions about the nature of emotions in the first place. In this perspective article, we first outline a set of relevant working principles of the brain (e.g. allostasis, predictive processing, interoception and affect), followed by a focused review of the theory of constructed emotion to introduce a new understanding of what emotions are. Building on this theoretical framework, we formulate how altered emotion category construction can be an integral component of the pathophysiology of functional neurological disorder and related functional somatic symptoms. In doing so, we address several themes for the functional neurological disorder field including: (i) how energy regulation and the process of emotion category construction relate to symptom generation, including revisiting alexithymia, 'panic attack without panic', dissociation, insecure attachment and the influential role of life experiences; (ii) re-interpret select neurobiological research findings in functional neurological disorder cohorts through the lens of the theory of constructed emotion to illustrate its potential mechanistic relevance; and (iii) discuss therapeutic implications. While we continue to support that functional neurological disorder is mechanistically and aetiologically heterogenous, consideration of how the theory of constructed emotion relates to the generation and maintenance of functional neurological and functional somatic symptoms offers an integrated viewpoint that cuts across neurology, psychiatry, psychology and cognitive-affective neuroscience.

Heightened fearfulness in infants is not adaptive.

Grossmann proposes the "fearful ape hypothesis," suggesting that heightened fearfulness in early life is evolutionarily adaptive. We question this claim with evidence that (1) perceived fearfulness in children is associated with negative, not positive long-term outcomes; (2) caregivers are responsive to all affective behaviors, not just those perceived as fearful; and (3) caregiver responsiveness serves to reduce perceived fearfulness.

Greater Neural Differentiation in the Ventral Visual Cortex Is Associated with Youthful Memory in Superaging.

Superagers are older adults who maintain youthful memory despite advanced age. Previous studies showed that superagers exhibit greater structural and intrinsic functional brain integrity, which contribute to their youthful memory. However, no studies, to date, have examined brain activity as superagers learn and remember novel information. Here, we analyzed functional magnetic resonance imaging data collected from 41 young and 40 older adults while they performed a paired associate visual recognition memory task. Superaging was defined as youthful performance on the long delay free recall of the California Verbal Learning Test. We assessed the fidelity of neural representations as participants encoded and later retrieved a series of word stimuli paired with a face or a scene image. Superagers, like young adults, exhibited more distinct neural representations in the fusiform gyrus and parahippocampal gyrus while viewing visual stimuli belonging to different categories (greater neural differentiation) and more similar category representations between encoding and retrieval (greater neural reinstatement), compared with typical older adults. Greater neural differentiation and reinstatement were associated with superior memory performance in all older adults. Given that the fidelity of cortical sensory processing depends on neural plasticity and is trainable, these mechanisms may be potential biomarkers for future interventions to promote successful aging.

Allostasis, Action, and Affect in Depression: Insights from the Theory of Constructed Emotion.

The theory of constructed emotion is a systems neuroscience approach to understanding the nature of emotion. It is also a general theoretical framework to guide hypothesis generation for how actions and experiences are constructed as the brain continually anticipates metabolic needs and attempts to meet those needs before they arise (termed allostasis). In this review, we introduce this framework and hypothesize that allostatic dysregulation is a trans-disorder vulnerability for mental and physical illness. We then review published findings consistent with the hypothesis that several symptoms in major depressive disorder (MDD), such as fatigue, distress, context insensitivity, reward insensitivity, and motor retardation, are associated with persistent problems in energy regulation. Our approach transforms the current understanding of MDD as resulting from enhanced emotional reactivity combined with reduced cognitive control and, in doing so, offers novel hypotheses regarding the development, progression, treatment, and prevention of MDD.

Neural effects of antidepressant medication and psychological treatments: a quantitative synthesis across three meta-analyses.

BACKGROUND: Influential theories predict that antidepressant medication and psychological therapies evoke distinct neural changes. AIMS: To test the convergence and divergence of antidepressant- and psychotherapy-evoked neural changes, and their overlap with the brain's affect network. METHOD: We employed a quantitative synthesis of three meta-analyses (n = 4206). First, we assessed the common and distinct neural changes evoked by antidepressant medication and psychotherapy, by contrasting two comparable meta-analyses reporting the neural effects of these treatments. Both meta-analyses included patients with affective disorders, including major depressive disorder, generalised anxiety disorder and panic disorder. The majority were assessed using negative-valence tasks during neuroimaging. Next, we assessed whether the neural changes evoked by antidepressants and psychotherapy overlapped with the brain's affect network, using data from a third meta-analysis of affect-based neural activation. RESULTS: Neural changes from psychotherapy and antidepressant medication did not significantly converge on any region. Antidepressants evoked neural changes in the amygdala, whereas psychotherapy evoked anatomically distinct changes in the medial prefrontal cortex. Both psychotherapy- and antidepressant-related changes separately converged on regions of the affect network. CONCLUSIONS: This supports the notion of treatment-specific brain effects of antidepressants and psychotherapy. Both treatments induce changes in the affect network, but our results suggest that their effects on affect processing occur via distinct proximal neurocognitive mechanisms of action.

Stronger Functional Connectivity in the Default Mode and Salience Networks Is Associated With Youthful Memory in Superaging.

"Superagers" are older adults who, despite their advanced age, maintain youthful memory. Previous morphometry studies revealed multiple default mode network (DMN) and salience network (SN) regions whose cortical thickness is greater in superagers and correlates with memory performance. In this study, we examined the intrinsic functional connectivity within DMN and SN in 41 young (24.5 ± 3.6 years old) and 40 older adults (66.9 ± 5.5 years old). Superaging was defined as youthful performance on a memory recall task, the California Verbal Learning Test (CVLT). Participants underwent a resting-state functional magnetic resonance imaging (fMRI) scan and performed a separate visual-verbal recognition memory task. As predicted, within both DMN and SN, superagers had stronger connectivity compared with typical older adults and similar connectivity compared with young adults. Superagers also performed similarly to young adults and better than typical older adults on the recognition task, demonstrating youthful episodic memory that generalized across memory tasks. Stronger connectivity within each network independently predicted better performance on both the CVLT and recognition task in older adults. Variation in intrinsic connectivity explained unique variance in memory performance, above and beyond youthful neuroanatomy. These results extend our understanding of the neural basis of superaging as a model of successful aging.

Topography Impacts Topology: Anatomically Central Areas Exhibit a "High-Level Connector" Profile in the Human Cortex.

Degree centrality is a widely used measure in complex networks. Within the brain, degree relates to other topological features, with high-degree nodes (i.e., hubs) exhibiting high betweenness centrality, participation coefficient, and within-module z-score. However, increasing evidence from neuroanatomical and predictive processing literature suggests that topological properties of a brain network may also be impacted by topography, that is, anatomical (spatial) distribution. More specifically, cortical limbic areas (agranular and dysgranular cortices), which occupy an anatomically central position, have been proposed to be topologically central and well suited to initiate predictions in the cerebral cortex. We estimated anatomical centrality and showed that it positively correlated with betweenness centrality, participation coefficient, and communicability, analogously to degree. In contrast to degree, however, anatomical centrality negatively correlated with within-module z-score. Our data suggest that degree centrality and anatomical centrality reflect distinct contributions to cortical organization. Whereas degree would be more related to the amount of information integration performed by an area, anatomical centrality would be more related to an area's position in the predictive hierarchy. Highly anatomically central areas may function as "high-level connectors," integrating already highly integrated information across modules. These results are consistent with a high-level, domain-general limbic workspace, integrated by highly anatomically central cortical areas.

Interoceptive predictions in the brain.

Intuition suggests that perception follows sensation and therefore bodily feelings originate in the body. However, recent evidence goes against this logic: interoceptive experience may largely reflect limbic predictions about the expected state of the body that are constrained by ascending visceral sensations. In this Opinion article, we introduce the Embodied Predictive Interoception Coding model, which integrates an anatomical model of corticocortical connections with Bayesian active inference principles, to propose that agranular visceromotor cortices contribute to interoception by issuing interoceptive predictions. We then discuss how disruptions in interoceptive predictions could function as a common vulnerability for mental and physical illness.

Biological Characteristics of Connection-Wise Resting-State Functional Connectivity Strength.

Functional connectivity is defined as the statistical dependency of neurophysiological activity between 2 separate brain areas. To investigate the biological characteristics of resting-state functional connectivity (rsFC)-and in particular the significance of connection-wise variation in time-series correlations-rsFC was compared with strychnine-based connectivity measured in the macaque. Strychnine neuronography is a historical technique that induces activity in cortical areas through means of local administration of the substance strychnine. Strychnine causes local disinhibition through GABA suppression and leads to subsequent activation of functional pathways. Multiple resting-state fMRI recordings were acquired in 4 macaques (examining in total 299 imaging runs) from which a group-averaged rsFC matrix was constructed. rsFC was observed to be higher (P < 0.0001) between region-pairs with a strychnine-based connection as compared with region-pairs with no strychnine-based connection present. In particular, higher resting-state connectivity was observed in connections that were relatively stronger (weak < moderate < strong; P < 0.01) and in connections that were bidirectional (P < 0.0001) instead of unidirectional in strychnine-based connectivity. Our results imply that the level of correlation between brain areas as extracted from resting-state fMRI relates to the strength of underlying interregional functional pathways.

Dopamine in the medial amygdala network mediates human bonding.

Research in humans and nonhuman animals indicates that social affiliation, and particularly maternal bonding, depends on reward circuitry. Although numerous mechanistic studies in rodents demonstrated that maternal bonding depends on striatal dopamine transmission, the neurochemistry supporting maternal behavior in humans has not been described so far. In this study, we tested the role of central dopamine in human bonding. We applied a combined functional MRI-PET scanner to simultaneously probe mothers' dopamine responses to their infants and the connectivity between the nucleus accumbens (NAcc), the amygdala, and the medial prefrontal cortex (mPFC), which form an intrinsic network (referred to as the "medial amygdala network") that supports social functioning. We also measured the mothers' behavioral synchrony with their infants and plasma oxytocin. The results of this study suggest that synchronous maternal behavior is associated with increased dopamine responses to the mother's infant and stronger intrinsic connectivity within the medial amygdala network. Moreover, stronger network connectivity is associated with increased dopamine responses within the network and decreased plasma oxytocin. Together, these data indicate that dopamine is involved in human bonding. Compared with other mammals, humans have an unusually complex social life. The complexity of human bonding cannot be fully captured in nonhuman animal models, particularly in pathological bonding, such as that in autistic spectrum disorder or postpartum depression. Thus, investigations of the neurochemistry of social bonding in humans, for which this study provides initial evidence, are warranted.

Beginning with biology: "Aspects of cognition" exist in the service of the brain's overall function as a resource-regulator.

Lieder and Griffiths rightly urge that computational cognitive models be constrained by resource usage, but they should go further. The brain's primary function is to regulate resource usage. As a consequence, resource usage should not simply select among algorithmic models of "aspects of cognition." Rather, "aspects of cognition" should be understood as existing in the service of resource management.

Primary Interoceptive Cortex Activity during Simulated Experiences of the Body.

Studies of the classic exteroceptive sensory systems (e.g., vision, touch) consistently demonstrate that vividly imagining a sensory experience of the world-simulating it-is associated with increased activity in the corresponding primary sensory cortex. We hypothesized, analogously, that simulating internal bodily sensations would be associated with increased neural activity in primary interoceptive cortex. An immersive, language-based mental imagery paradigm was used to test this hypothesis (e.g., imagine your heart pounding during a roller coaster ride, your face drenched in sweat during a workout). During two neuroimaging experiments, participants listened to vividly described situations and imagined "being there" in each scenario. In Study 1, we observed significantly heightened activity in primary interoceptive cortex (of dorsal posterior insula) during imagined experiences involving vivid internal sensations. This effect was specific to interoceptive simulation: It was not observed during a separate affect focus condition in Study 1 nor during an independent Study 2 that did not involve detailed simulation of internal sensations (instead involving simulation of other sensory experiences). These findings underscore the large-scale predictive architecture of the brain and reveal that words can be powerful drivers of bodily experiences.

Vegetarians' and omnivores' affective and physiological responses to images of food.

Many vegetarians report that meat is unpleasant, but little else is known about their affective responses to meat and non-meat foods. Here we explored affective responses to food images in vegetarians and omnivores and tested the hypothesis that vegetarians have global differences in affective processing (e.g., increased disgust sensitivity). We presented pictures of different food items and recorded participants' affective experience while we recorded peripheral physiology. We found that vegetarians' self-reported experience of meat meal images was less pleasant than omnivores', but that other food images were equally pleasant across the two groups. Moreover, vegetarians and omnivores had strikingly similar physiological responses to all food images - including meat meals. We interpret these results from a psychological constructionist perspective, which posits that individuals conceptualize changes in their bodily states in ways that match their beliefs, such that increased sympathetic nervous system activity may be conceptualized as an experience of excitement about a delicious meat meal for omnivores but as an experience of displeasure for a vegetarian who believes meat is cruel, wasteful, impure, or unhealthy. This interpretation is consistent with emerging neuroscience evidence that the brain constructs experience by predicting and making meaning of internal sensations based on past experience and knowledge.

Seeing What You Feel: Affect Drives Visual Perception of Structurally Neutral Faces.

Affective realism, the phenomenon whereby affect is integrated into an individual's experience of the world, is a normal consequence of how the brain processes sensory information from the external world in the context of sensations from the body. In the present investigation, we provided compelling empirical evidence that affective realism involves changes in visual perception (i.e., affect changes how participants see neutral stimuli). In two studies, we used an interocular suppression technique, continuous flash suppression, to present affective images outside of participants' conscious awareness. We demonstrated that seen neutral faces are perceived as more smiling when paired with unseen affectively positive stimuli. Study 2 also demonstrated that seen neutral faces are perceived as more scowling when paired with unseen affectively negative stimuli. These findings have implications for real-world situations and challenge beliefs that affect is a distinct psychological phenomenon that can be separated from cognition and perception.

Spatial Bayesian latent factor regression modeling of coordinate-based meta-analysis data.

Now over 20 years old, functional MRI (fMRI) has a large and growing literature that is best synthesised with meta-analytic tools. As most authors do not share image data, only the peak activation coordinates (foci) reported in the article are available for Coordinate-Based Meta-Analysis (CBMA). Neuroimaging meta-analysis is used to (i) identify areas of consistent activation; and (ii) build a predictive model of task type or cognitive process for new studies (reverse inference). To simultaneously address these aims, we propose a Bayesian point process hierarchical model for CBMA. We model the foci from each study as a doubly stochastic Poisson process, where the study-specific log intensity function is characterized as a linear combination of a high-dimensional basis set. A sparse representation of the intensities is guaranteed through latent factor modeling of the basis coefficients. Within our framework, it is also possible to account for the effect of study-level covariates (meta-regression), significantly expanding the capabilities of the current neuroimaging meta-analysis methods available. We apply our methodology to synthetic data and neuroimaging meta-analysis datasets.

Multivoxel Pattern Analysis Does Not Provide Evidence to Support the Existence of Basic Emotions.

Saarimaki et al. (2015) published a paper claiming to find the neural "fingerprints" for anger, fear, disgust, happiness, sadness, and surprise using multivariate pattern analysis. There are 2 ways in which Saarimaki et al.'s interpretation mischaracterizes their actual findings. The first is statistical: a pattern that successfully distinguishes the members of one category from the members of another (with an accuracy greater than that which might be expected by chance) is not a "fingerprint" (i.e., an essence); it is an abstract, statistical summary of a variable population of instances. The second way in which Saarimaki et al.'s interpretation mischaracterizes their results is conceptual: their findings do not actually meet the specific criteria for basic emotion theory. Instead, their findings are more consistent with a theory of constructed emotion. In our view, Saarimaki et al. is elegant in method and important in that it demonstrates empirical support for a theory of emotion that relies on population thinking; it is also an example of how essentialism-the belief that all instances of a category possesses necessary features that define what is, and what is not, a category member-contributes to a fundamental misunderstanding of the neural basis of emotion.

Youthful Brains in Older Adults: Preserved Neuroanatomy in the Default Mode and Salience Networks Contributes to Youthful Memory in Superaging.

UNLABELLED: Decline in cognitive skills, especially in memory, is often viewed as part of "normal" aging. Yet some individuals "age better" than others. Building on prior research showing that cortical thickness in one brain region, the anterior midcingulate cortex, is preserved in older adults with memory performance abilities equal to or better than those of people 20-30 years younger (i.e., "superagers"), we examined the structural integrity of two large-scale intrinsic brain networks in superaging: the default mode network, typically engaged during memory encoding and retrieval tasks, and the salience network, typically engaged during attention, motivation, and executive function tasks. We predicted that superagers would have preserved cortical thickness in critical nodes in these networks. We defined superagers (60-80 years old) based on their performance compared to young adults (18-32 years old) on the California Verbal Learning Test Long Delay Free Recall test. We found regions within the networks of interest where the cerebral cortex of superagers was thicker than that of typical older adults, and where superagers were anatomically indistinguishable from young adults; hippocampal volume was also preserved in superagers. Within the full group of older adults, thickness of a number of regions, including the anterior temporal cortex, rostral medial prefrontal cortex, and anterior midcingulate cortex, correlated with memory performance, as did the volume of the hippocampus. These results indicate older adults with youthful memory abilities have youthful brain regions in key paralimbic and limbic nodes of the default mode and salience networks that support attentional, executive, and mnemonic processes subserving memory function. SIGNIFICANCE STATEMENT: Memory performance typically declines with age, as does cortical structural integrity, yet some older adults maintain youthful memory. We tested the hypothesis that superagers (older individuals with youthful memory performance) would exhibit preserved neuroanatomy in key brain networks subserving memory. We found that superagers not only perform similarly to young adults on memory testing, they also do not show the typical patterns of brain atrophy in certain regions. These regions are contained largely within two major intrinsic brain networks: the default mode network, implicated in memory encoding, storage, and retrieval, and the salience network, associated with attention and executive processes involved in encoding and retrieval. Preserved neuroanatomical integrity in these networks is associated with better memory performance among older adults.

The Brain Basis of Positive and Negative Affect: Evidence from a Meta-Analysis of the Human Neuroimaging Literature.

The ability to experience pleasant or unpleasant feelings or to represent objects as "positive" or "negative" is known as representing hedonic "valence." Although scientists overwhelmingly agree that valence is a basic psychological phenomenon, debate continues about how to best conceptualize it scientifically. We used a meta-analysis of 397 functional magnetic resonance imaging (fMRI) and positron emission tomography studies (containing 914 experimental contrasts and 6827 participants) to test 3 competing hypotheses about the brain basis of valence: the bipolarity hypothesis that positive and negative affect are supported by a brain system that monotonically increases and/or decreases along the valence dimension, the bivalent hypothesis that positive and negative affect are supported by independent brain systems, and the affective workspace hypothesis that positive and negative affect are supported by a flexible set of valence-general regions. We found little evidence for the bipolar or bivalent hypotheses. Findings instead supported the hypothesis that, at the level of brain activity measurable by fMRI, valence is flexibly implemented across instances by a set of valence-general limbic and paralimbic brain regions.

Heightened sensitivity to emotional expressions in generalised anxiety disorder, compared to social anxiety disorder, and controls.

Few studies have examined potential differences between social anxiety disorder (SAD) and generalised anxiety disorder (GAD) in the sensitivity to detect emotional expressions. The present study aims to compare the detection of emotional expressions in SAD and GAD. Participants with a primary diagnosis of GAD (n = 46), SAD (n = 70), and controls (n = 118) completed a morph movies task. The task presented faces expressing increasing degrees of emotional intensity, slowly changing from a neutral to a full-intensity happy, sad, or angry expressions. Participants used a slide bar to view the movie frames from left to right, and to stop at the first frame where they perceived an emotion. The frame selected thus indicated the intensity of emotion required to identify the facial expression. Participants with GAD detected the onset of facial emotions at lower intensity of emotion than participants with SAD (p = 0.002) and controls (p = 0.039). In a multiple regression analysis controlling for age, race, and depressive symptom severity, lower frame at which the emotion was detected was independently associated and GAD diagnosis (B = -5.73, SE = 1.74, p < 0.01). Our findings suggest that individuals with GAD exhibit enhanced detection of facial emotions compared to those with SAD or controls.