Adolescent social anxiety is associated with diminished discrimination of anticipated threat and safety in the bed nucleus of the stria terminalis.

Social anxiety-which typically emerges in adolescence-lies on a continuum and, when extreme, can be devastating. Socially anxious individuals are prone to heightened fear, anxiety, and the avoidance of contexts associated with potential social scrutiny. Yet most neuroimaging research has focused on acute social threat. Much less attention has been devoted to understanding the neural systems recruited during the uncertain anticipation of potential encounters with social threat. Here we used a novel fMRI paradigm to probe the neural circuitry engaged during the anticipation and acute presentation of threatening faces and voices in a racially diverse sample of 66 adolescents selectively recruited to encompass a range of social anxiety and enriched for clinically significant levels of distress and impairment. Results demonstrated that adolescents with more severe social anxiety symptoms experience heightened distress when anticipating encounters with social threat, and reduced discrimination of uncertain social threat and safety in the bed nucleus of the stria terminalis (BST), a key division of the central extended amygdala (EAc). Although the EAc-including the BST and central nucleus of the amygdala-was robustly engaged by the acute presentation of threatening faces and voices, the degree of EAc engagement was unrelated to the severity of social anxiety. Together, these observations provide a neurobiologically grounded framework for conceptualizing adolescent social anxiety and set the stage for the kinds of prospective-longitudinal and mechanistic research that will be necessary to determine causation and, ultimately, to develop improved interventions for this often-debilitating illness.

Neuroticism/negative emotionality is associated with increased reactivity to uncertain threat in the bed nucleus of the stria terminalis, not the amygdala.

Neuroticism/Negative Emotionality (N/NE)-the tendency to experience anxiety, fear, and other negative emotions-is a fundamental dimension of temperament with profound consequences for health, wealth, and wellbeing. Elevated N/NE is associated with a panoply of adverse outcomes, from reduced socioeconomic attainment and divorce to mental illness and premature death. Work in animals suggests that N/NE reflects heightened reactivity to uncertain threat in the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce), but the relevance of these discoveries to the human brain and temperament have remained unclear. Here we used a combination of psychometric, psychophysiological, and neuroimaging approaches to rigorously test this hypothesis in an ethnoracially diverse sample of 220 emerging adults selectively recruited to encompass a broad spectrum of N/NE. Cross-validated robust-regression analyses demonstrated that N/NE is selectively associated with heightened BST activation during the uncertain anticipation of a genuinely distressing threat. In contrast, N/NE was unrelated to BST activation during certain-threat anticipation, Ce activation during either type of threat anticipation, or BST/Ce reactivity to 'threat-related' faces. Implicit in much of the neuroimaging literature is the assumption that different threat paradigms are statistically interchangeable probes of individual differences in neural function, yet our results revealed negligible evidence of convergence between popular threat-anticipation and emotional-face tasks. These observations provide a framework for conceptualizing emotional traits and disorders; for guiding the design and interpretation of biobank and other neuroimaging studies of psychiatric risk, disease, and treatment; and for informing the next generation of mechanistic research.

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Anxiety-Related Frontocortical Activity Is Associated With Dampened Stressor Reactivity in the Real World.

Negative affect is a fundamental dimension of human emotion. When extreme, it contributes to a variety of adverse outcomes, from physical and mental illness to divorce and premature death. Mechanistic work in animals and neuroimaging research in humans and monkeys have begun to reveal the broad contours of the neural circuits governing negative affect, but the relevance of these discoveries to everyday distress remains incompletely understood. Here, we used a combination of approaches-including neuroimaging assays of threat anticipation and emotional-face perception and more than 10,000 momentary assessments of emotional experience-to demonstrate that individuals who showed greater activation in a cingulo-opercular circuit during an anxiety-eliciting laboratory paradigm experienced lower levels of stressor-dependent distress in their daily lives (ns = 202-208 university students). Extended amygdala activation was not significantly related to momentary negative affect. These observations provide a framework for understanding the neurobiology of negative affect in the laboratory and in the real world.

Training the Next Generation of Clinical Psychological Scientists: A Data-Driven Call to Action.

The central goal of clinical psychology is to reduce the suffering caused by mental health conditions. Anxiety, mood, psychosis, substance use, personality, and other mental disorders impose an immense burden on global public health and the economy. Tackling this burden will require the development and dissemination of intervention strategies that are more effective, sustainable, and equitable. Clinical psychology is uniquely poised to serve as a transdisciplinary hub for this work. But rising to this challengerequires an honest reckoning with the strengths and weaknesses of current training practices. Building on new data, we identify the most important challenges to training the next generation of clinical scientists. We provide specific recommendations for the full spectrum of stakeholders-from funders, accreditors, and universities to program directors, faculty, and students-with an emphasis on sustainable solutions that promote scientific rigor and discovery and enhance the mental health of clinical scientists and the public alike.

Anxiety and the Neurobiology of Temporally Uncertain Threat Anticipation.

When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala-the two major subdivisions of the extended amygdala-play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety.SIGNIFICANCE STATEMENT Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.

The value of clinical and translational neuroscience approaches to psychiatric illness.

Borsboom et al. confuse biological approaches with extreme biological reductionism and common-cause models of psychopathology. In muddling these concepts, they mistakenly throw the baby out with the bathwater. Here, we highlight recent work underscoring the unique value of clinical and translational neuroscience approaches for understanding the nature and origins of psychopathology and for developing improved intervention strategies.

Intrinsic functional connectivity of the central extended amygdala.

The central extended amygdala (EAc)-including the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce)-plays a critical role in triggering fear and anxiety and is implicated in the development of a range of debilitating neuropsychiatric disorders. Although it is widely believed that these disorders reflect the coordinated activity of distributed neural circuits, the functional architecture of the EAc network and the degree to which the BST and the Ce show distinct patterns of functional connectivity is unclear. Here, we used a novel combination of imaging approaches to trace the connectivity of the BST and the Ce in 130 healthy, racially diverse, community-dwelling adults. Multiband imaging, high-precision registration techniques, and spatially unsmoothed data maximized anatomical specificity. Using newly developed seed regions, whole-brain regression analyses revealed robust functional connectivity between the BST and Ce via the sublenticular extended amygdala, the ribbon of subcortical gray matter encompassing the ventral amygdalofugal pathway. Both regions displayed coupling with the ventromedial prefrontal cortex (vmPFC), midcingulate cortex (MCC), insula, and anterior hippocampus. The BST showed stronger connectivity with the thalamus, striatum, periaqueductal gray, and several prefrontal territories. The only regions showing stronger functional connectivity with the Ce were neighboring regions of the dorsal amygdala, amygdalohippocampal area, and anterior hippocampus. These observations provide a baseline against which to compare a range of special populations, inform our understanding of the role of the EAc in normal and pathological fear and anxiety, and showcase image registration techniques that are likely to be useful for researchers working with "deidentified" neuroimaging data.

The neurobiology of dispositional negativity and attentional biases to threat: Implications for understanding anxiety disorders in adults and youth.

When extreme, anxiety can become debilitating. Anxiety disorders, which often first emerge early in development, are common and challenging to treat, yet the neurocognitive mechanisms that confer increased risk have only recently begun to come into focus. Here we review recent work highlighting the importance of neural circuits centered on the amygdala. We begin by describing dispositional negativity, a core dimension of childhood temperament and adult personality and an important risk factor for the development of anxiety disorders and other kinds of stress-sensitive psychopathology. Converging lines of epidemiological, neurophysiological, and mechanistic evidence indicate that the amygdala supports stable individual differences in dispositional negativity across the lifespan and contributes to the etiology of anxiety disorders in adults and youth. Hyper-vigilance and attentional biases to threat are prominent features of the anxious phenotype and there is growing evidence that they contribute to the development of psychopathology. Anatomical studies show that the amygdala is a hub, poised to govern attention to threat via projections to sensory cortex and ascending neuromodulatory systems. Imaging and lesion studies demonstrate that the amygdala plays a key role in selecting and prioritizing the processing of threat-related cues. Collectively, these observations provide a neurobiologically-grounded framework for understanding the development and maintenance of anxiety disorders in adults and youth and set the stage for developing improved intervention strategies.

Dispositional negativity: An integrative psychological and neurobiological perspective.

Dispositional negativity-the propensity to experience and express more frequent, intense, or enduring negative affect-is a fundamental dimension of childhood temperament and adult personality. Elevated levels of dispositional negativity can have profound consequences for health, wealth, and happiness, drawing the attention of clinicians, researchers, and policymakers. Here, we highlight recent advances in our understanding of the psychological and neurobiological processes linking stable individual differences in dispositional negativity to momentary emotional states. Self-report data suggest that 3 key pathways-increased stressor reactivity, tonic increases in negative affect, and increased stressor exposure-explain most of the heightened negative affect that characterizes individuals with a more negative disposition. Of these 3 pathways, tonically elevated, indiscriminate negative affect appears to be most central to daily life and most relevant to the development of psychopathology. New behavioral and biological data provide insights into the neural systems underlying these 3 pathways and motivate the hypothesis that seemingly "tonic" increases in negative affect may actually reflect increased reactivity to stressors that are remote, uncertain, or diffuse. Research focused on humans, monkeys, and rodents suggests that this indiscriminate negative affect reflects trait-like variation in the activity and connectivity of several key brain regions, including the central extended amygdala and parts of the prefrontal cortex. Collectively, these observations provide an integrative psychobiological framework for understanding the dynamic cascade of processes that bind emotional traits to emotional states and, ultimately, to emotional disorders and other kinds of adverse outcomes. (PsycINFO Database Record

Brain electrophysiology reveals intact processing of speech sounds in deformational plagiocephaly.

BACKGROUND: The prevalence of deformational plagiocephaly has risen dramatically in recent years, now affecting 15 percent or more of infants. Prior research using developmental scales suggests that these children may be at elevated risk for developmental delays. However, the low positive predictive value of such instruments in identifying long-term impairment, coupled with their poor reliability in infants, warrants the development of methods to more precisely measure brain function in craniofacial patients. Event-related potentials offer a direct measure of cortical activity that is highly applicable to young populations and has been implemented in other disorders to predict long-term cognitive functioning. The current study used event-related potentials to contrast neural correlates of auditory perception in infants with deformational plagiocephaly and typically developing children. METHODS: Event-related potentials were recorded while 16 infants with deformational plagiocephaly and 18 nonaffected controls passively listened to speech sounds. Given prior research suggesting their association with subsequent functioning, analyses focused on the P150 and N450 event-related potential components. RESULTS: Deformational plagiocephaly patients and normal controls showed comparable cortical responses to speech sounds at both auditory event-related potential components. CONCLUSIONS: Children with deformational plagiocephaly demonstrate neural responses to language that are consistent with normative expectations and comparable to those of typical children. These results indicate that head shape deformity secondary to supine sleep is not associated with impairments in auditory processing. The applicability of the current methods in early infancy suggests that electrophysiologic brain recordings represent a promising method of monitoring brain development in children with cranial disorders. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Normal rates of neuroradiological findings in children with high functioning autism.

Magnetic resonance imaging (MRI) has been used to analyze highly specific volumetric and morphological features of the brains of individuals with autism spectrum disorder (ASD). To date, there are few comprehensive studies examining the prevalence of neuroradiologic findings seen on routine MRI scans in children with ASD. This study examined the prevalence of neuroradiologic findings in children with high functioning ASD, and compared these rates to those in children with Attention-Deficit/Hyperactivity Disorder (ADHD) and children who are typically developing (TD). Results showed that approximately 90% of children had normal MRI scans. There was no significant effect of diagnosis on the total number of neuroradiological findings or the number of specific brain findings. Implications and future research directions are discussed.