Jennifer Urbano Blackford

Behavioral Inhibition and Risk for Developing Social Anxiety Disorder: A Meta-Analytic Study.

OBJECTIVE Behavioral inhibition (BI) has been associated with increased risk for developing social anxiety disorder (SAD); however, the degree of risk associated with BI has yet to be systematically examined and quantified. The goal of the present study was to quantify the association between childhood BI and risk for developing SAD. METHOD A comprehensive literature search was conducted to identify studies that assessed both BI and SAD. Meta-analyses were performed to estimate the odds ratio (OR) of the association between BI and SAD in children. RESULTS Seven studies met inclusion criteria. BI was associated with a greater than sevenfold increase in risk for developing SAD (odds ratio = 7.59, p < .00002). This association remained significant even after considering study differences in temperament assessment, control group, parental risk, age at temperament assessment, and age at anxiety diagnosis. CONCLUSIONS Identifying early developmental risk factors is critical for preventing psychiatric illness. Given that 15% of all children show extreme BI, and that almost half of these inhibited children will eventually develop SAD, we propose that BI is one of the largest single risk factors for developing SAD.

A unique role for the human amygdala in novelty detection

Previous research indicates that the amygdala and hippocampus are sensitive to novelty; however, two types of novelty can be distinguished - stimuli that are ordinary, but novel in the current context, and stimuli that are unusual. Using functional magnetic resonance imaging, we examined blood oxygen dependent level (BOLD) response of the human amygdala and hippocampus to novel, commonly seen objects versus novel unusual objects. When presented with the novel common stimuli, the BOLD signal increased significantly in both the amygdala and hippocampus. However, for the novel unusual stimuli, only the amygdala showed an increased response compared to the novel common stimuli. These findings suggest that the amygdala is distinctly responsive to novel unusual stimuli, making a unique contribution to the novelty detection circuit.

Neural substrates of childhood anxiety disorders: a review of neuroimaging findings.

The development of fear is a normative process, and significant progress has been made in identifying fear neurocircuitry. The normal development of fear goes awry in children who develop anxiety disorders, and dysfunction in fear circuitry is likely. In this article, the authors present current knowledge about the neural basis of normal fear development and reviews findings from structural and functional neuroimaging studies of childhood anxiety disorders.

BNST neurocircuitry in humans.

Anxiety and addiction disorders are two of the most common mental disorders in the United States, and are typically chronic, disabling, and comorbid. Emerging evidence suggests the bed nucleus of the stria terminalis (BNST) mediates both anxiety and addiction through connections with other brain regions, including the amygdala and nucleus accumbens. Although BNST structural connections have been identified in rodents and a limited number of structural connections have been verified in non-human primates, BNST connections have yet to be described in humans. Neuroimaging is a powerful tool for identifying structural and functional circuits in vivo. In this study, we examined BNST structural and functional connectivity in a large sample of humans. The BNST showed structural and functional connections with multiple subcortical regions, including limbic, thalamic, and basal ganglia structures, confirming structural findings in rodents. We describe two novel connections in the human brain that have not been previously reported in rodents or non-human primates, including a structural connection with the temporal pole, and a functional connection with the paracingulate gyrus. The findings of this study provide a map of the BNSTs structural and functional connectivity across the brain in healthy humans. In large part, the BNST neurocircuitry in humans is similar to the findings from rodents and non-human primates; however, several connections are unique to humans. Future explorations of BNST neurocircuitry in anxiety and addiction disorders have the potential to reveal novel mechanisms underlying these disabling psychiatric illnesses.

The Human BNST: Functional Role in Anxiety and Addiction

The consequences of chronic stress on brain structure and function are far reaching. Whereas stress can produce short-term adaptive changes in the brain, chronic stress leads to long-term maladaptive changes that increase vulnerability to psychiatric disorders, such as anxiety and addiction. These two disorders are the most prevalent psychiatric disorders in the United States, and are typically chronic, disabling, and highly comorbid. Emerging evidence implicates a tiny brain region—the bed nucleus of the stria terminalis (BNST)—in the body’s stress response and in anxiety and addiction. Rodent studies provide compelling evidence that the BNST plays a central role in sustained threat monitoring, a form of adaptive anxiety, and in the withdrawal and relapse stages of addiction; however, little is known about the role of BNST in humans. Here, we review current evidence for BNST function in humans, including evidence for a role in the production of both adaptive and maladaptive anxiety. We also review preliminary evidence of the role of BNST in addiction in humans. Together, these studies provide a foundation of knowledge about the role of BNST in adaptive anxiety and stress-related disorders. Although the field is in its infancy, future investigations of human BNST function have tremendous potential to illuminate mechanisms underlying stress-related disorders and identify novel neural targets for treatment.

Amygdala and hippocampus fail to habituate to faces in individuals with an inhibited temperament

Habituation is a basic form of learning that reflects the adaptive reduction in responses to a stimulus that is neither threatening nor rewarding. Extremely shy, or inhibited individuals, are typically slow to acclimate to new people, a behavioral pattern that may reflect slower habituation to novelty. To test this hypothesis, we used functional magnetic resonance imaging to examine habituation to neutral faces in 39 young adults with either an extreme inhibited or extreme uninhibited temperament. Our investigation focused on two key brain regions involved in response to novelty—the amygdala and the hippocampus. Habituation to neutral faces in the amygdala and hippocampus differed significantly by temperament group. Individuals with an uninhibited temperament demonstrated habituation in both the amygdala and hippocampus, as expected. In contrast, in individuals with an inhibited temperament, the amygdala and hippocampus failed to habituate across repeated presentations of faces. The failure of the amygdala and hippocampus to habituate to faces represents a novel neural substrate mediating the behavioral differences seen in individuals with an inhibited temperament. We propose that this failure to habituate reflects a social learning deficit in individuals with an inhibited temperament and provides a possible mechanism for increased risk for social anxiety.

Multivariate permutation analysis associates multiple polymorphisms with subphenotypes of major depression.

Unipolar major depressive disorder (MDD) is a prevalent, disabling condition with multiple genetic and environmental factors impacting disease risk. The diagnosis of MDD relies on a cumulative measure derived from multiple trait dimensions and alone is limited in elucidating MDD genetic determinants. We and others have proposed that MDD may be better dissected using paradigms that assess how specific genes associate with component features of MDD. This within‐disease design requires both a well‐phenotyped cohort and a robust statistical approach that retains power with multiple tests of genetic association. In the present study, common polymorphic variants of genes related to central monoaminergic and cholinergic pathways that previous studies align with functional change in vitro or depression associations in vivo were genotyped in 110 individuals with unipolar MDD. Subphenotypic characteristics were examined using responses to individual items assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM IV), the 17‐item Hamilton Rating Scale for Depression (HAM‐D) and the NEO Five Factor Inventory. Multivariate Permutation Testing (MPT) was used to infer genotype–phenotype relationships underlying dimensional findings within clinical categories. MPT analyses show significant associations of the norepinephrine transporter (NET, SLC6A2) ‐182 T/C (rs2242446) with recurrent depression [odds ratio, OR = 4.15 (1.91–9.02)], NET ‐3081 A/T (rs28386840) with increase in appetite [OR = 3.58 (1.53–8.39)] and the presynaptic choline transporter (CHT, SLC5A7) Ile89Val (rs1013940) with HAM‐D‐17 total score {i.e. overall depression severity [OR = 2.74 (1.05–7.18)]}. These relationships illustrate an approach to the elucidation of gene influences on trait components of MDD and with replication, may help identify MDD subpopulations that can benefit from more targeted pharmacotherapy.

Relationship between patient complaints and surgical complications

Background: Patient complaints are associated with increased malpractice risk but it is unclear if complaints might be associated with medical complications. The purpose of this study was to determine whether an association exists between patient complaints and surgical complications. Methods: A retrospective analysis of 16 713 surgical admissions was conducted over a 54 month period at a single academic medical center. Surgical complications were identified using administrative data. The primary outcome measure was unsolicited patient complaints. Results: During the study period 0.9% of surgical admissions were associated with a patient complaint. 19% of admissions associated with a patient complaint included a postoperative complication compared with 12.5% of admissions without a patient complaint (p = 0.01). After adjusting for surgical specialty, co-morbid illnesses and length of stay, admissions with complications had an odds ratio of 1.74 (95% confidence interval 1.01 to 2.98) of being associated with a complaint compared with admissions without complications. Conclusions: Admissions with surgical complications are more likely to be associated with a complaint than surgical admissions without complications. Further research is necessary to determine if patient complaints might serve as markers for poor clinical outcomes.

Sustained amygdala response to both novel and newly familiar faces characterizes inhibited temperament.

Previous theories have proposed that the amygdala is hyper-responsive to novel stimuli in persons with an inhibited temperament-a biologically based predisposition to respond to novelty with wariness or avoidance behavior. In the current study, we used functional magnetic resonance imaging (fMRI) to assess amygdala blood oxygenation level-dependent (BOLD) response when viewing novel or recently familiarized faces in persons with an extreme inhibited or uninhibited temperament. In persons with an inhibited temperament, the amygdala showed increased BOLD response when viewing both novel and recently familiarized faces. In contrast, in persons with an uninhibited temperament, BOLD response in the amygdala was increased only when viewing novel faces. These findings suggest that inhibited temperament is characterized not by a simple exaggerated response to novel faces, but rather by a sustained increase in amygdala response to faces even after the faces have become familiarized. In individuals with an inhibited temperament, this sustained response may be related to the wariness of social situations that persists beyond initial exposure.

Amygdala temporal dynamics: temperamental differences in the timing of amygdala response to familiar and novel faces

BackgroundInhibited temperament - the predisposition to respond to new people, places or things with wariness or avoidance behaviors - is associated with increased risk for social anxiety disorder and major depression. Although the magnitude of the amygdalas response to novelty has been identified as a neural substrate of inhibited temperament, there may also be differences in temporal dynamics (latency, duration, and peak). We hypothesized that persons with inhibited temperament would have faster responses to novel relative to familiar neutral faces compared to persons with uninhibited temperament. We used event-related functional magnetic resonance imaging to measure the temporal dynamics of the blood oxygen level dependent (BOLD) response to both novel and familiar neutral faces in participants with inhibited or uninhibited temperament.ResultsInhibited participants had faster amygdala responses to novel compared with familiar faces, and both longer and greater amygdala response to all faces. There were no differences in peak response.ConclusionFaster amygdala response to novelty may reflect a computational bias that leads to greater neophobic responses and represents a mechanism for the development of social anxiety.