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.

Neural correlates of out-group bias predict social impairment in patients with schizophrenia.

BACKGROUND: Social impairments are a hallmark feature of schizophrenia and are a key predictor of functional disability. Deficits in social information processing likely underlie social impairment; however, this relationship is understudied. We previously demonstrated that patients with schizophrenia fail to habituate to neutral faces, providing evidence for an alteration in basic social information processing. It remains unknown whether patients with schizophrenia also show deficits in processing of more complex social information. Out-group bias provides an excellent opportunity to test complex social information processing because the bias requires basic face processing skills, the ability to discriminate between groups, as well as the ability to categorize oneself into a salient social group. METHODS: Study participants were 23 patients with schizophrenia and 21 controls. Using functional magnetic resonance imaging, habituation of response to 120 s of repeated presentations of faces was assessed in participants who viewed either same-gender faces or opposite-gender faces. The interaction between face gender (same/opposite) and group was examined in three key regions: amygdala, hippocampus, and visual cortex. Social impairment was measured using the PANSS and correlations between social impairment and out-group effect (main effect of face type) were performed in patients. RESULTS: Patients with schizophrenia had aberrant neural responses to opposite-gender faces (interaction, p<.05 corrected). Healthy controls showed an immediate heightened response to opposite-gender faces relative to same-gender faces; but in patients this effect was substantially delayed (~70s). In patients with schizophrenia, the out-group bias was significantly correlated with social impairment. Patients with no social impairment showed a heightened neural response to opposite-gender faces after 30s, whereas patients with mild-moderate social impairment failed to ever show a heightened response. CONCLUSION: Alterations in neural responses during out-group processing predicted degree of social impairment in patients with schizophrenia; thus, neural responses to opposite-gender faces may provide a novel measure for studies of treatment response and disease outcome.

The nature of individual differences in inhibited temperament and risk for psychiatric disease: A review and meta-analysis.

What makes us different from one another? Why does one person jump out of airplanes for fun while another prefers to stay home and read? Why are some babies born with a predisposition to become anxious? Questions about individual differences in temperament have engaged the minds of scientists, psychologists, and philosophers for centuries. Recent technological advances in neuroimaging and genetics provide an unprecedented opportunity to answer these questions. Here we review the literature on the neurobiology of one of the most basic individual differences-the tendency to approach or avoid novelty. This trait, called inhibited temperament, is innate, heritable, and observed across species. Importantly, inhibited temperament also confers risk for psychiatric disease. Here, we provide a comprehensive review of inhibited temperament, including neuroimaging and genetic studies in human and non-human primates. We conducted a meta-analysis of neuroimaging findings in inhibited humans that points to alterations in a fronto-limbic-basal ganglia circuit; these findings provide the basis of a model of inhibited temperament neurocircuitry. Lesion and neuroimaging studies in non-human primate models of inhibited temperament highlight roles for the amygdala, hippocampus, orbitofrontal cortex, and dorsal prefrontal cortex. Genetic studies highlight a role for genes that regulate neurotransmitter function, such as the serotonin transporter polymorphisms (5-HTTLPR), as well as genes that regulate stress response, such as corticotropin-releasing hormone (CRH). Together these studies provide a foundation of knowledge about the genetic and neural substrates of this most basic of temperament traits. Future studies using novel imaging methods and genetic approaches promise to expand upon these biological bases of inhibited temperament and inform our understanding of risk for psychiatric disease.

Processing speed impairment in schizophrenia is mediated by white matter integrity.

BACKGROUND: Processing speed predicts functional outcome and is a potential endophenotype for schizophrenia. Establishing the neural basis of processing speed impairment may inform the treatment and etiology of schizophrenia. Neuroimaging investigations in healthy subjects have linked processing speed to brain anatomical connectivity. However, the relationship between processing speed impairment and white matter (WM) integrity in schizophrenia is unclear. METHOD: Individuals with schizophrenia and healthy subjects underwent diffusion tensor imaging (DTI) and completed a brief neuropsychological assessment that included measures of processing speed, verbal learning, working memory and executive functioning. Group differences in WM integrity, inferred from fractional anisotropy (FA), were examined throughout the brain and the hypothesis that processing speed impairment in schizophrenia is mediated by diminished WM integrity was tested. RESULTS: WM integrity of the corpus callosum, cingulum, superior and inferior frontal gyri, and precuneus was reduced in schizophrenia. Average FA in these regions mediated group differences in processing speed but not in other cognitive domains. Diminished WM integrity in schizophrenia was accounted for, in large part, by individual differences in processing speed. CONCLUSIONS: Cognitive impairment in schizophrenia was mediated by reduced WM integrity. This relationship was strongest for processing speed because deficits in working memory, verbal learning and executive functioning were not mediated by WM integrity. Larger sample sizes may be required to detect more subtle mediation effects in these domains. Interventions that preserve WM integrity or ameliorate WM disruption may enhance processing speed and functional outcome in schizophrenia.

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.

Community fluoridation status and caries experience in children.

OBJECTIVE: This study compares dental caries experience in fluoridated and nonfluoridated communities. METHODS: A dental health survey designed to collect data on caries experience and treatment needs for community-specific public health planning purposes was conducted in public elementary schools during the 1996-97 school year. Oral examinations of 17,256 children were completed, representing 93 percent of children residing in 62 East Tennessee communities. RESULTS: The analysis showed that water fluoridation was significantly related to caries experience in the primary (dfs) and permanent (DMFS) dentitions and to the proportion of caries-free children in the primary and permanent dentitions. When the data were adjusted for socioeconomic status, race, and age, caries levels were 21 percent lower in the primary dentition and 25 percent lower in the permanent dentition in fluoridated communities than in nonfluoridated communities. In addition, the proportion of children who were caries free was larger in fluoridated as compared with nonfluoridated communities by 19 percent in the primary dentition and 6 percent in the permanent dentition. CONCLUSION: Although the design of the study prevented the collection of individual fluoride and residency histories, findings suggest there was substantially lower caries experience in fluoridated communities than in nonfluoridated communities.

Successful implementation of community water fluoridation via the community diagnosis process.

OBJECTIVES: This paper describes the community diagnosis process and how it was used to implement community water fluoridation in Tennessee. METHODS: Public health dental staff developed a survey instrument to collect community-specific data on the oral health status of schoolchildren. Key survey findings were presented to county health councils who were determining and prioritizing the health needs of their communities. RESULTS: Community-specific data showed higher caries levels in children without access to an optimally fluoridated community water supply. Presentation of local survey findings to county health councils resulted in fluoridation being a high-priority health issue in several counties. With health council support, opposition to fluoridation by utility district officials was overcome when decision makers were challenged with local survey findings. The community diagnosis process resulted in the successful fluoridation of six community water systems serving a total of 33,000 residents. CONCLUSIONS: The community diagnosis approach was successful in implementing community water fluoridation in geographic areas historically opposed to this public health measure. The success of these fluoridation initiatives was attributed to: (1) current, community-specific assessments of children's oral health; (2) identification of communities with disparate oral health needs, problems, and resources; and (3) effective presentation of community-specific oral health survey data to community leaders, stakeholders, and decision makers.

Community socioeconomic status and children's dental health.

BACKGROUND: Although a substantial decline in dental caries has occurred among U.S. children, not everyone has benefited equally. The first-ever surgeon general's report on oral health in America indicates that the burden of oral diseases is found in poor Americans. This study investigates the relationship between community socioeconomic status, or SES, and dental health of children. METHODS: An oral health survey of 17,256 children, representing 93 percent of children residing in 62 Tennessee communities, was conducted in public elementary schools during the 1996-1997 school year. Portable dental equipment was used for examinations, and data from each examination were entered directly into a laptop computer. The authors performed analyses of covariance to examine the relationship between community SES (low/medium/high) and dental health, controlling for community fluoridation. RESULTS: Community SES was significantly related to caries experience in the primary teeth, the proportion of untreated caries in the primary and permanent teeth, dental treatment needs, dental sealants and incisor trauma. Overall, dental health was significantly worse for low-SES communities than for medium- and high-SES communities. CONCLUSION: The authors conclude that all specific dental indexes used to measure children's dental health in this study, with the exceptions of caries experience in the permanent teeth and sealant presence, were inversely related to the communities' SES. The percentage of children with dental sealants was directly related to the community's SES. PRACTICE IMPLICATIONS: Further improvements in oral health will necessitate that community-based preventive programs and access to quality dental care be made available to children who are identified as being at highest risk of experiencing oral disease.

Differences in social signals produced by children with developmental delays of differing etiologies.

Clarity of referential looks (either a focus on parent's face or other focus) produced by preschool children with delays of differing etiologies and children without delays was examined. Adults (with and without experience with children with delays) viewed videotaped segments in which children's looks did or did not occur. Adults judged whether a look occurred and rated their confidence in each judgment; latency to respond was measured. Adults' experience with children with delays did not influence outcome measures. When viewing looks focusing on parents' faces, participants were more accurate and more confident judging looks by children with typical development, less accurate when viewing face-directed looks of children with developmental delays, and least accurate when viewing children with Down syndrome. Discriminability of social looks differed by etiological group, and judges' decision criteria, confidence, and speed of responding also differed.