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.

Effects of acute stress and depression on functional connectivity between prefrontal cortex and the amygdala.

Stress is known to be a significant risk factor for the development of Major Depressive Disorder (MDD), yet the neural mechanisms that underlie this risk are poorly understood. Prior work has heavily implicated the corticolimbic system in the pathophysiology of MDD. In particular, the prefrontal cortex (PFC) and amygdala play a central role in regulating the response to stress, with dorsal PFC and ventral PFC exhibiting reciprocal excitatory and inhibitory influences on amygdala subregions. However, it remains unclear how best to disentangle the impact of stress from the impact of current MDD symptoms on this system. Here, we examined stress-induced changes in resting state functional connectivity (rsFC) within an a priori corticolimbic network in MDD patients and healthy controls (total n = 80) before and after an acute stressor or a "no stress" control condition. Using graph theoretic analysis, we found that connectivity between basolateral amygdala and dorsal prefrontal nodes of the corticolimbic network had a negative association with individual differences in chronic perceived stress at baseline. Following the acute stressor, healthy individuals showed a reduction of the amygdala node strength, while MDD patients exhibited little change. Finally, dorsal PFC-particularly dorsomedial PFC- connectivity to the basolateral amygdala was associated with the strength of the basolateral amygdala responses to loss feedback during a reinforcement learning task. These findings highlight attenuated connectivity between basolateral amygdala and prefrontal cortex in patients with MDD. In healthy individuals, acute stress exposure was found to push the corticolimbic network to a "stress-phenotype" that may be chronically present in patients with current depression and high levels of perceived stress. In sum, these results help to identify circuit mechanisms underlying the effects of acute stress and their role in mood disorders.

The Brain Activation-Based Sexual Image Classifier (BASIC): A Sensitive and Specific fMRI Activity Pattern for Sexual Image Processing.

Previous studies suggest there is a complex relationship between sexual and general affective stimulus processing, which varies across individuals and situations. We examined whether sexual and general affective processing can be distinguished at the brain level. In addition, we explored to what degree possible distinctions are generalizable across individuals and different types of sexual stimuli, and whether they are limited to the engagement of lower-level processes, such as the detection of visual features. Data on sexual images, nonsexual positive and negative images, and neutral images from Wehrum et al. (2013) (N = 100) were reanalyzed using multivariate support vector machine models to create the brain activation-based sexual image classifier (BASIC) model. This model was tested for sensitivity, specificity, and generalizability in cross-validation (N = 100) and an independent test cohort (N = 18; Kragel et al. 2019). The BASIC model showed highly accurate performance (94-100%) in classifying sexual versus neutral or nonsexual affective images in both datasets with forced choice tests. Virtual lesions and tests of individual large-scale networks (e.g., visual or attention networks) show that individual networks are neither necessary nor sufficient to classify sexual versus nonsexual stimulus processing. Thus, responses to sexual images are distributed across brain systems.

The Temporal Dynamics of Spontaneous Emotional Brain States and Their Implications for Mental Health.

Temporal processes play an important role in elaborating and regulating emotional responding during routine mind wandering. However, it is unknown whether the human brain reliably transitions among multiple emotional states at rest and how psychopathology alters these affect dynamics. Here, we combined pattern classification and stochastic process modeling to investigate the chronometry of spontaneous brain activity indicative of six emotions (anger, contentment, fear, happiness, sadness, and surprise) and a neutral state. We modeled the dynamic emergence of these brain states during resting-state fMRI and validated the results across two population cohorts-the Duke Neurogenetics Study and the Nathan Kline Institute Rockland Sample. Our findings indicate that intrinsic emotional brain dynamics are effectively characterized as a discrete-time Markov process, with affective states organized around a neutral hub. The centrality of this network hub is disrupted in individuals with psychopathology, whose brain state transitions exhibit greater inertia and less frequent resetting from emotional to neutral states. These results yield novel insights into how the brain signals spontaneous emotions and how alterations in their temporal dynamics contribute to compromised mental health.

Functional Involvement of Human Periaqueductal Gray and Other Midbrain Nuclei in Cognitive Control.

Recent theoretical advances have motivated the hypothesis that the periaqueductal gray (PAG) participates in behaviors that involve changes in the autonomic control of visceromotor activity, including during cognitively demanding tasks. We used ultra-high-field (7 tesla) fMRI to measure human brain activity at 1.1 mm resolution while participants completed a working memory task. Consistent with prior work, participants were less accurate and responded more slowly with increasing memory load-signs of increasing task difficulty. Whole-brain fMRI analysis revealed increased activity in multiple cortical areas with increasing working memory load, including frontal and parietal cortex, dorsal cingulate, supplementary motor area, and anterior insula. Several dopamine-rich midbrain nuclei, such as the substantia nigra and ventral tegmental area, also exhibited load-dependent increases in activation. To investigate PAG involvement during cognitive engagement, we developed an automated method for segmenting and spatially normalizing the PAG. Analyses using cross-validated linear support vector machines showed that the PAG discriminated high versus low working memory load conditions with 95% accuracy in individual subjects based on activity increases in lateral and ventrolateral PAG. Effect sizes in the PAG were comparable in magnitude to those in many of the cortical areas. These findings suggest that cognitive control is not only associated with cortical activity in the frontal and parietal lobes, but also with increased activity in the subcortical PAG and other midbrain regions involved in the regulation of autonomic nervous system function.SIGNIFICANCE STATEMENT Functional neuroimaging in humans has shown that cognitive control engages multiple corticostriatal networks and brainstem nuclei, but theoretical advances suggest that the periaqueductal gray (PAG) should also be engaged during cognitively demanding tasks. Recent advances in ultra-high-field fMRI provided an opportunity to obtain the first evidence that increased activation of intermediate and rostral portions of lateral and ventrolateral PAG columns in humans is modulated by cognitive load. These findings suggest that cognitive control is not solely mediated by activity in the cortex, but that midbrain structures important for autonomic regulation also play a crucial role in higher-order cognition.

Decoding Spontaneous Emotional States in the Human Brain.

Pattern classification of human brain activity provides unique insight into the neural underpinnings of diverse mental states. These multivariate tools have recently been used within the field of affective neuroscience to classify distributed patterns of brain activation evoked during emotion induction procedures. Here we assess whether neural models developed to discriminate among distinct emotion categories exhibit predictive validity in the absence of exteroceptive emotional stimulation. In two experiments, we show that spontaneous fluctuations in human resting-state brain activity can be decoded into categories of experience delineating unique emotional states that exhibit spatiotemporal coherence, covary with individual differences in mood and personality traits, and predict on-line, self-reported feelings. These findings validate objective, brain-based models of emotion and show how emotional states dynamically emerge from the activity of separable neural systems.

Taking tests in the magnet: Brain mapping standardized tests.

Standardized psychometric tests are sophisticated, well-developed, and consequential instruments; test outcomes are taken as facts about people that impact their lives in important ways. As part of an initial demonstration that human brain mapping techniques can add converging neural-level evidence to understanding standardized tests, our participants completed items from standardized tests during an fMRI scan. We compared tests for diagnosing posttraumatic stress disorder (PTSD) and the correlated measures of Neuroticism, Attachment, and Centrality of Event to a general-knowledge baseline test. Twenty-three trauma-exposed participants answered 20 items for each of our five tests in each of the three runs for a total of 60 items per test. The tests engaged different neural processes; which test a participant was taking was accurately predicted from other participants' brain activity. The novelty of the application precluded specific anatomical predictions; however, the interpretation of activated regions using meta-analyses produced encouraging results. For instance, items on the Attachment test engaged regions shown to be more active for tasks involving judgments of others than judgments of the self. The results are an initial demonstration of a theoretically and practically important test-taking neuroimaging paradigm and suggest specific neural processes in answering PTSD-related tests. Hum Brain Mapp 38:5706-5725, 2017. © 2017 Wiley Periodicals, Inc.

The Clinical Significance of Posterior Insular Volume in Adolescent Anorexia Nervosa.

OBJECTIVE: The diagnostic criterion disturbance in the experience of the body remains a poorly understood and persistent feature of anorexia nervosa (AN). Increased sophistication in understanding the structure of the insular cortex-a neural structure that receives and integrates visceral sensations with action and meaning-may elucidate the nature of this disturbance. We explored age, weight status, illness severity, and self-reported body dissatisfaction associations with insular cortex volume. METHODS: Structural magnetic resonance imaging data were collected from 21 adolescents with a history of AN and 20 age-, sex-, and body mass index-matched controls. Insular cortical volumes (bilateral anterior and posterior regions) were identified using manual tracing. RESULTS: Volumes of the right posterior insula demonstrated the following: (a) a significant age by clinical status interaction (ß = -0.018 [0.008]; t = 2.32, p = .02) and (b) larger volumes were associated with longer duration of illness (r = 0.48, p < .04). In contrast, smaller volumes of the right anterior insula were associated with longer duration of illness (r = -0.50, p < .03). The associations of insular volume with body dissatisfaction were of moderate effect size and also of opposite direction, but a statistical trend in right posterior (r = 0.40, p < .10 in right posterior; r = -0.49, p < .04 in right anterior). CONCLUSIONS: In this exploratory study, findings of atypical structure of the right posterior insular cortex point to the importance of future work investigating the role of visceral afferent signaling in understanding disturbance in body experience in AN.

Adolescent development of insula-dependent interoceptive regulation.

Adolescence is hypothesized to be a critical period for the maturation of self-regulatory capacities, including those that depend on interoceptive sensitivity, but the neural basis of interoceptive regulation in adolescence is unknown. We used functional magnetic resonance imaging and psychophysiology to study interoceptive regulation in healthy adolescent females. Participants regulated their gut activities in response to a virtual roller coaster by deep breathing aided by visually monitoring their online electrogastrogram (EGG) activity through a virtual thermometer (i.e. gut biofeedback), or without biofeedback. Analyses focused on the insula, given its putative role in interoception. The bilateral posterior insula showed increased activation in the no-biofeedback compared to biofeedback condition, suggesting that the participants relied more on interoceptive input when exteroceptive feedback was unavailable. The bilateral dorsal anterior insula showed activation linearly associated with age during both induction and regulation, and its activation during regulation correlated positively with change of EGG in the tachygastria frequency band from induction to regulation. Induction-related activation in the bilateral ventral anterior insula was nonlinearly associated with age and peaked at mid-adolescence. These results implicate different developmental trajectories of distinct sub-regions of the insula in interoceptive processes, with implications for competing neurobiological theories of female adolescent development.

Medial prefrontal pathways for the contextual regulation of extinguished fear in humans.

The maintenance of anxiety disorders is thought to depend, in part, on deficits in extinction memory, possibly due to reduced contextual control of extinction that leads to fear renewal. Animal studies suggest that the neural circuitry responsible fear renewal includes the hippocampus, amygdala, and dorsomedial (dmPFC) and ventromedial (vmPFC) prefrontal cortex. However, the neural mechanisms of context-dependent fear renewal in humans remain poorly understood. We used functional magnetic resonance imaging (fMRI), combined with psychophysiology and immersive virtual reality, to elucidate how the hippocampus, amygdala, and dmPFC and vmPFC interact to drive the context-dependent renewal of extinguished fear. Healthy human participants encountered dynamic fear-relevant conditioned stimuli (CSs) while navigating through 3-D virtual reality environments in the MRI scanner. Conditioning and extinction were performed in two different virtual contexts. Twenty-four hours later, participants were exposed to the CSs without reinforcement while navigating through both contexts in the MRI scanner. Participants showed enhanced skin conductance responses (SCRs) to the previously-reinforced CS+ in the acquisition context on Day 2, consistent with fear renewal, and sustained responses in the dmPFC. In contrast, participants showed low SCRs to the CSs in the extinction context on Day 2, consistent with extinction recall, and enhanced vmPFC activation to the non-reinforced CS-. Structural equation modeling revealed that the dmPFC fully mediated the effect of the hippocampus on right amygdala activity during fear renewal, whereas the vmPFC partially mediated the effect of the hippocampus on right amygdala activity during extinction recall. These results indicate dissociable contextual influences of the hippocampus on prefrontal pathways, which, in turn, determine the level of reactivation of fear associations.

Aversive learning modulates cortical representations of object categories.

Experimental studies of conditioned learning reveal activity changes in the amygdala and unimodal sensory cortex underlying fear acquisition to simple stimuli. However, real-world fears typically involve complex stimuli represented at the category level. A consequence of category-level representations of threat is that aversive experiences with particular category members may lead one to infer that related exemplars likewise pose a threat, despite variations in physical form. Here, we examined the effect of category-level representations of threat on human brain activation using 2 superordinate categories (animals and tools) as conditioned stimuli. Hemodynamic activity in the amygdala and category-selective cortex was modulated by the reinforcement contingency, leading to widespread fear of different exemplars from the reinforced category. Multivariate representational similarity analyses revealed that activity patterns in the amygdala and object-selective cortex were more similar among exemplars from the threat versus safe category. Learning to fear animate objects was additionally characterized by enhanced functional coupling between the amygdala and fusiform gyrus. Finally, hippocampal activity co-varied with object typicality and amygdala activation early during training. These findings provide novel evidence that aversive learning can modulate category-level representations of object concepts, thereby enabling individuals to express fear to a range of related stimuli.

Visual looming is a primitive for human emotion.

Looming objects afford threat of collision across the animal kingdom. Defensive responses to looming and neural computations for looming detection are strikingly conserved across species. In mammals, information about rapidly approaching threats is conveyed from the retina to the midbrain superior colliculus, where variables that indicate the position and velocity of approach are computed to enable defensive behavior. Although neuroscientific theories posit that midbrain representations contribute to emotion through connectivity with distributed brain systems, it remains unknown whether a computational system for looming detection can predict both defensive behavior and phenomenal experience in humans. Here, we show that a shallow convolutional neural network based on the Drosophila visual system predicts defensive blinking to looming objects in infants and superior colliculus responses to optical expansion in adults. Further, the responses of the convolutional network to a broad array of naturalistic video clips predict self-reported emotion largely on the basis of subjective arousal. Our findings illustrate how motor and experiential components of human emotion relate to species-general systems for survival in unpredictable environments.

Visual looming is a primitive for human emotion.

The neural computations for looming detection are strikingly similar across species. In mammals, information about approaching threats is conveyed from the retina to the midbrain superior colliculus, where approach variables are computed to enable defensive behavior. Although neuroscientific theories posit that midbrain representations contribute to emotion through connectivity with distributed brain systems, it remains unknown whether a computational system for looming detection can predict both defensive behavior and phenomenal experience in humans. Here, we show that a shallow convolutional neural network based on the Drosophila visual system predicts defensive blinking to looming objects in infants and superior colliculus responses to optical expansion in adults. Further, the neural network's responses to naturalistic video clips predict self-reported emotion largely by way of subjective arousal. These findings illustrate how a simple neural network architecture optimized for a species-general task relevant for survival explains motor and experiential components of human emotion.

A multimodal fMRI dataset unifying naturalistic processes with a rich array of experimental tasks.

Cognitive neuroscience has advanced significantly due to the availability of openly shared datasets. Large sample sizes, large amounts of data per person, and diversity in tasks and data types are all desirable, but are difficult to achieve in a single dataset. Here, we present an open dataset with N = 101 participants and 6 hours of scanning per participant, with 6 multifaceted cognitive tasks including 2 hours of naturalistic movie viewing. This datasets' combination of ample sample size, extensive data per participant, more than 600 hours worth of data, and a wide range of experimental conditions - including cognitive, affective, social, and somatic/interoceptive tasks - positions it uniquely for probing important questions in cognitive neuroscience.

Neural networks supporting autobiographical memory retrieval in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) affects the functional recruitment and connectivity between neural regions during autobiographical memory (AM) retrieval that overlap with default and control networks. Whether such univariate changes relate to potential differences in the contributions of the large-scale neural networks supporting cognition in PTSD is unknown. In the present functional MRI study, we employed independent-component analysis to examine the influence of the engagement of neural networks during the recall of personal memories in a PTSD group (15 participants) as compared to non-trauma-exposed healthy controls (14 participants). We found that the PTSD group recruited similar neural networks when compared to the controls during AM recall, including default-network subsystems and control networks, but group differences emerged in the spatial and temporal characteristics of these networks. First, we found spatial differences in the contributions of the anterior and posterior midline across the networks, and of the amygdala in particular, for the medial temporal subsystem of the default network. Second, we found temporal differences within the medial prefrontal subsystem of the default network, with less temporal coupling of this network during AM retrieval in PTSD relative to controls. These findings suggest that the spatial and temporal characteristics of the default and control networks potentially differ in a PTSD group versus healthy controls and contribute to altered recall of personal memory.

A mesocorticolimbic signature of pleasure in the human brain.

Pleasure is a fundamental driver of human behaviour, yet its neural basis remains largely unknown. Rodent studies highlight opioidergic neural circuits connecting the nucleus accumbens, ventral pallidum, insula and orbitofrontal cortex as critical for the initiation and regulation of pleasure, and human neuroimaging studies exhibit some translational parity. However, whether activation in these regions conveys a generalizable representation of pleasure regulated by opioidergic mechanisms remains unclear. Here we use pattern recognition techniques to develop a human functional magnetic resonance imaging signature of mesocorticolimbic activity unique to states of pleasure. In independent validation tests, this signature is sensitive to pleasant tastes and affect evoked by humour. The signature is spatially co-extensive with mu-opioid receptor gene expression, and its response is attenuated by the opioid antagonist naloxone. These findings provide evidence for a basis of pleasure in humans that is distributed across brain systems.

Inferring the Genetic Influences on Psychological Traits Using MRI Connectivity Predictive Models: Demonstration with Cognition.

Introduction: Genetic correlations between brain and behavioral phenotypes in analyses from major genetic consortia have been weak and mostly nonsignificant. fMRI models of systems-level brain patterns may help improve our ability to link genes, brains, and behavior by identifying reliable and reproducible endophenotypes. Work using connectivity-based predictive modeling has generated brain-based proxies of behavioral and neuropsychological variables. If such models capture activity in inherited brain systems, they may offer a more powerful link between genes and behavior. Method: As a proof of concept, we develop models predicting intelligence (IQ) based on fMRI connectivity and test their effectiveness as endophenotypes. We link brain and IQ in a model development dataset of N = 3,000 individuals and test the genetic correlations between brain models and measured IQ in a genetic validation sample of N = 13,092 individuals from the UK Biobank. We compare an additive connectivity-based model to multivariate LASSO and ridge models phenotypically and genetically. We also compare these approaches to single "candidate" brain areas. Results: We found that predictive brain models were significantly phenotypically correlated with IQ and showed much stronger correlations than individual edges. Further, brain models were more heritable (h2 = 0.155-0.181) than single brain regions (h2 = 0.038-0.118) and captured about half of the genetic variance in IQ (rG = 0.422-0.576), while rGs with single brain measures were smaller and nonsignificant. For the different approaches, LASSO and ridge were similarly predictive, with slightly weaker performance of the additive model. LASSO model weights were highly theoretically interpretable and replicated known brain IQ associations. Finally, functional connectivity models trained in midlife showed genetic correlations with early life correlates of IQ, suggesting some stability in the prediction of fMRI models. Conclusion: Multisystem predictive models hold promise as imaging endophenotypes that offer complex and theoretically relevant conclusions for future imaging genetics research.

Brain mediators of negative affect-induced physical symptom reporting in patients with functional somatic syndromes.

Functional somatic syndromes (FSS) include fibromyalgia, irritable bowel syndrome (IBS), and others. In FSS patients, merely viewing negative affective pictures can elicit increased physical symptoms. Our aim was to investigate the neural mechanisms underlying such negative affect-induced physical symptoms in FSS patients. Thirty patients with fibromyalgia and/or IBS and 30 healthy controls (all women) watched neutral, positive and negative affective picture blocks during functional MRI scanning and rated negative affect and physical symptoms after every block. We compared brain-wide activation during negative versus neutral picture viewing in FSS patients versus controls using robust general linear model analysis. Further, we compared neurologic pain signature (NPS), stimulus intensity-independent pain signature (SIIPS) and picture-induced negative emotion signature (PINES) responses to the negative versus neutral affect contrast and investigated whether they mediated between-group differences in affective picture-induced physical symptom reporting. More physical symptoms were reported after viewing negative compared to neutral pictures, and this effect was larger in patients than controls (p = 0.025). Accordingly, patients showed stronger activation in somatosensory regions during negative versus neutral picture viewing. NPS, but not SIIPS nor PINES, responses were higher in patients than controls during negative versus neutral pictures (p = 0.026). These differential NPS responses partially mediated between-group differences in physical symptoms. In conclusion, picture-induced negative affect elicits physical symptoms in FSS patients as a result of activation of somatosensory and nociceptive brain patterns, supporting the idea that affect-driven alterations in processing of somatic signals is a critical mechanism underlying FSS.

The nature and neurobiology of fear and anxiety: State of the science and opportunities for accelerating discovery.

Fear and anxiety play a central role in mammalian life, and there is considerable interest in clarifying their nature, identifying their biological underpinnings, and determining their consequences for health and disease. Here we provide a roundtable discussion on the nature and biological bases of fear- and anxiety-related states, traits, and disorders. The discussants include scientists familiar with a wide variety of populations and a broad spectrum of techniques. The goal of the roundtable was to take stock of the state of the science and provide a roadmap to the next generation of fear and anxiety research. Much of the discussion centered on the key challenges facing the field, the most fruitful avenues for future research, and emerging opportunities for accelerating discovery, with implications for scientists, funders, and other stakeholders. Understanding fear and anxiety is a matter of practical importance. Anxiety disorders are a leading burden on public health and existing treatments are far from curative, underscoring the urgency of developing a deeper understanding of the factors governing threat-related emotions.