Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release.

The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-ß-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation.

Psychometric properties of the GAD-7 and PROMIS-Anxiety-4a among youth with depression and suicidality: Results from the Texas youth depression and suicide research network.

There is a tremendous need for brief, valid, and free assessments of anxiety in child mental healthcare. The goal of this study was to determine the psychometric properties of two such measures, the GAD-7 and PROMIS-Anxiety-4a, in 1000 children, adolescents, and young adults (8-20 years-old) with depression and/or suicidality. The GAD-7, the PROMIS-Anxiety-4a, and other validated assessments of anxiety, physical functioning, and psychiatric diagnoses were completed. Confirmatory factor analyses showed an acceptable fit for a single factor in both measures via all indices but the RMSEA. They demonstrated measurement invariance across pre-adolescents (8-12 years-old) and adolescents and emerging adults (13-20 years-old), though scalar invariance was not observed for the GAD-7. Both measures showed strong convergent validity, GAD-7: r = 0.68; PROMIS-Anxiety-4a: r = 0.75, divergent validity with a measure of physical function, GAD-7: r = -0.24; PROMIS-Anxiety-4a: r = -0.28, good internal consistency, ω = 0.89 for both, and high test-retest reliability, GAD-7: r = 0.69; PROMIS-Anxiety-4a: r = 0.71. Both measures also showed acceptable sensitivity and specificity in detecting the presence of any anxiety disorder, GAD-7 cut-off score of 10: AUC = 0.75; PROMIS-Anxiety-4a cutoff score of 12: AUC = 0.79. The GAD-7 correlated similarly with the Screen for Child Anxiety Related Disorders total score and generalized anxiety subscale, and also showed similar diagnostic sensitivity and specificity when used to detect the presence of any anxiety disorder vs. generalized anxiety disorder specifically. Results suggest that both of these brief, publicly available instruments are valid and reliable assessments of anxiety among youth in treatment for depression and/or suicidality.

Clinical correlates of anxious depression in youth from the Texas Youth Depression and Suicide Research Network (TX-YDSRN).

BACKGROUND: Anxious depression is a prevalent subtype of depression associated with adverse outcomes such as higher depression severity and higher rates of suicidality. This study leveraged a state-wide research registry of depressed and/or suicidal youth to compare the prevalence, clinical correlates, and symptom patterns of those with versus without anxious depression. METHODS: We included baseline data from 797 participants (ages 8-20) with a diagnosis of a depressive disorder. A score on the Generalized Anxiety Disorder Scale (GAD-7) ≥ 10 was used to define individuals with and without anxious depression. A structured battery was used to capture psychiatric diagnostic status, depression/anxiety severity, suicide risk, history of trauma, functioning, and resilience. RESULTS: The prevalence of anxious depression among youth with depressive disorders was 59.5 % (n = 474). Youth with anxious depression had greater depression severity and anxiety symptoms, higher suicidality, and a higher prevalence of comorbid anxiety disorders than those without. Youth with anxious depression had greater impairment in functioning defined as worse pain interference, pain severity, fatigue, and social relationships compared to those without anxious depression. Youth with anxious depression also reported higher rates of depressive symptoms such as irritable mood, feelings of guilt, and psychomotor agitation compared to those without anxious depression. CONCLUSION: Anxious depression is associated with worse depression severity, higher suicidality, and lower functioning. Longitudinal work is needed to examine long-term courses of anxious depression to explore its stability as a diagnostic subcategory.

The clinical presentation of major depressive disorder in youth with co-occurring obsessive-compulsive disorder.

BACKGROUND: Major depressive disorder (MDD) is common in youth and among the most frequent comorbid disorders in pediatric obsessive-compulsive disorder (OCD), but it is unclear whether the presence of OCD affects the symptom presentation of MDD in youth. METHODS: A sample of youth with OCD and MDD (n = 124) and a sample of youth with MDD but no OCD (n = 673) completed the Patient Health Questionnaire for Adolescents (PHQ-A). The overall and symptom-level presentation of MDD were examined using group comparisons and network analysis. RESULTS: Youth with MDD and OCD, compared to those with MDD and no OCD, had more severe MDD (Cohen's d = 0.39) and more reported moderate to severe depression (75 % vs 61 %). When accounting for demographic variables and the overall severity of MDD, those with comorbid OCD reported lower levels of anhedonia and more severe difficulties with psychomotor retardation/agitation. No significant differences in the interconnections among symptoms emerged. LIMITATIONS: Data were cross-sectional and self-reported, gold standard diagnostic tools were not used to assess OCD, and the sample size for the group with MDD and OCD was relatively small yielding low statistical power for network analysis. CONCLUSIONS: Youth with MDD and OCD have more severe MDD than those with MDD and no OCD and they experience more psychomotor issues and less anhedonia, which may relate to the behavioral activation characteristic of OCD.

Development and pilot testing of internet-delivered, family-based cognitive behavioral therapy for anxiety and obsessive-compulsive disorders in autistic youth.

Cognitive behavioral therapy adapted for autistic youth with anxiety and/or OCD has a strong evidence base, but few have access. A 12-week family-based, Internet-delivered cognitive behavioral therapy (iCBT) program for 7-15 year-old autistic youth with anxiety and/or OCD was developed as a potential method to address this problem. Quantitative and qualitative feedback from stakeholders (parents, youth, clinicians) was gathered on an initial draft of content before conducting a pilot trial. This feedback suggested high quality, engagement, usability, and informativeness of the material. Suggestions were incorporated into the treatment program that was tested in a pilot trial. Eight families were randomized to the iCBT program with either 1) weekly email support or 2) weekly email support plus biweekly telehealth check-ins, and seven of these families completed pre- and post-treatment assessments. An average reduction of 39% in anxiety severity was found, with six of the seven being classified as responders. Preliminary evidence suggests that family-based iCBT is an acceptable and promising treatment for autistic youth with anxiety and/or obsessive-compulsive disorders that should be further modified and tested in future work.

Psychometric properties of Concise Associated Symptom Tracking (CAST) scale in youths and young adults: Findings from the Texas youth depression and suicide research network (TX-YDSRN).

Symptoms of irritability, anxiety, panic, and insomnia are common in patients with depression, and their worsening after antidepressant treatment initiation is associated with poorer long-term outcomes. The Concise Associated Symptom Tracking (CAST) scale was developed to measure these symptoms in adults with major depressive disorder (MDD). Here, we evaluate the psychometric properties of CAST in an ongoing community-based observational study involving children, adolescents, and young adults. Individuals from the ongoing Texas Youth Depression and Suicide Research Network (TX-YDSRN; N = 952) with CAST data available were included. Fit statistics [Goodness of Fit Index (GFI), Comparative Fit Index (CFI), and Root Mean Square Error of Approximation (RMSEA)] from confirmatory factor analyses were used to evaluate the five- and four-domain structure of CAST. Item response theory (IRT) analyses were also used. Individuals were grouped based on age (in years) as youths (8-17) and young adults (18-20). Correlations with other clinical measures were used to inform construct validity. Four-domain (irritability, anxiety, panic, and insomnia) 12-item structure of CAST (CAST-12) was optimal for youths (N = 709, GFI = 0.906, CFI = 0.919, RMSEA = 0.095) and young adults (N = 243, GFI = 0.921, CFI = 0.938, RMSEA = 0.0797) with Cronbach's alpha of 0.87 and 0.88, respectively. Slope of each item exceeded 1.0 on IRT analyses suggesting adequate discrimination for each item. Scores on irritability, anxiety, panic, and insomnia were significantly correlated with similar items on other scales. Together these findings suggest that CAST-12 is a valid self-report measure of irritability, anxiety, insomnia, and panic in youths and young adults.

Obsessive-compulsive disorder in youth and young adults with depression: Clinical characteristics of comorbid presentations.

Obsessive-compulsive disorder (OCD), anxiety disorders, and depressive disorders are highly comorbid, and each contribute to significant functional impairment for affected youth. Comorbid anxiety disorders in depressed youth have been associated with greater depressive symptom severity and impairment, but the impact of comorbid OCD in this population remains unclear. Accordingly, the present study examined the differential clinical characteristics of youth with depression and comorbid OCD relative to age/gender matched depressed youth with no such comorbidity and to those with depression and a comorbid (non-OCD) anxiety disorder. A sample of 797 youth and young adults ages 8-20 years who met diagnostic criteria for depression alone, depression with co-occurring OCD or any anxiety disorder were included in the present study. Rates of comorbid anxiety and OCD were very high (60.5% and 15.5%, respectively). Relative to youth with only depression, depressed youth with comorbid OCD or anxiety had greater severity of depression, suicidality, and overall impairment in social, physical, and emotional functioning. These results highlight the contribution of OCD or anxiety comorbidity in more complex clinical presentations for depressed youth.

A Case-Based Neuroanatomy Laboratory on the Neurobiology of Psychiatric Conditions for Second-Year Medical Students.

A case-based laboratory event integrating neuroanatomy, neuroscience, and psychiatry was implemented into a pre-clerkship psychiatry-based course for second-year medical students. Learners rotating through lab stations to work on different cases to make interdisciplinary connections among these fields is an innovative way for them to integrate foundational neurology, neuroanatomy, and psychiatry concepts. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40670-020-01171-0.

Are ratings in the eye of the beholder? A non-technical primer on many facet Rasch measurement to evaluate rater effects on teacher behavior rating scales.

Rater-mediated assessments, such as teacher behavior rating scales, measure student behavior indirectly through the lens of a rater. As a result, scores from rater-mediated assessments can be influenced by rater effects- individual differences in rater perspectives, attitudes, beliefs, and interpretation of rating scale items. Rater effects are a fundamental aspect of all rater-mediated assessments. However, traditional approaches to evaluate rater effects (i.e., classical test theory, generalizability theory, and multilevel modeling) merely estimate how much score variability is due to the rater. These approaches, while informative, do not offer a solution to the problem. In contrast, Many-facet Rasch measurement (MFRM) approaches estimate and control for rater effects in rater-mediated assessments so that scores are adjusted to account for rater variability. Thus, MFRM offers unique insights into individual- and group-level rater effects that can be used to inform a solution. The resultant purpose of this paper is to introduce MFRM, discuss its advantages for evaluating rater effects in rater-mediated assessments, and demonstrate its use through an applied example.

Early Identification of SARS-CoV-2 Emergence in the Department of Defense via Retrospective Analysis of 2019-2020 Upper Respiratory Illness Samples.

The first U.S. case of non-travel-related severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was detected in late February 2020 in California, but the prevailing delay in diagnostic testing and initial stringent testing criteria made it difficult to identify those who could have acquired the virus through community spread. The emergence of the virus in the western Pacific region in late 2019 and the global distribution of Department of Defense (DoD) personnel present the risk that DoD members may have been exposed and contracted the virus earlier then U.S. detections. Here, a retrospective study from residual samples collected from a global DoD Respiratory Surveillance Program was conducted to establish a tentative timeline of when this virus began circulating in the DoD population. Quantitative real-time reverse-transcription polymerase chain reaction testing for SARS-CoV-2 was performed and the specimen collection dates of positive results were compared to the dates of the first infections previously identified in respective states and counties. Twenty-four positive samples were identified out of approximately 7,000 tested. Although this retrospective testing found early cases in 8 locations, there were no results indicative of circulation before late February.

Variation in Streptococcus pyogenes NAD+ glycohydrolase is associated with tissue tropism.

Streptococcus pyogenes is an important pathogen that causes a variety of diseases. The most common infections involve the throat (pharyngitis) or skin (impetigo); however, the factors that determine tissue tropism and severity are incompletely understood. The S. pyogenes NAD(+) glycohydrolase (SPN) is a virulence factor that has been implicated in contributing to the pathogenesis of severe infections. However, the role of SPN in determining the bacterium's tissue tropism has not been evaluated. In this report, we examine the sequences of spn and its endogenous inhibitor ifs from a worldwide collection of S. pyogenes strains. Analysis of average pairwise nucleotide diversity, average number of nucleotide differences, and ratio of nonsynonymous to synonymous substitutions revealed significant diversity in spn and ifs. Application of established models of molecular evolution shows that SPN is evolving under positive selection and diverging into NAD(+) glycohydrolase (NADase)-active and -inactive subtypes. Additionally, the NADase-inactive SPN subtypes maintain the characteristics of a functional gene while ifs becomes a pseudogene. Thus, NADase-inactive SPN continues to evolve under functional constraint. Furthermore, NADase activity did not correlate with invasive disease in our collection but was associated with tissue tropism. The ability to cause infection at both the pharynx and the skin ("generalist" strains) is correlated with NADase-active SPN, while the preference for causing infection at either the throat or the skin ("specialist" strains) is associated with NADase-inactive SPN. These findings suggest that SPN has a NADase-independent function and prompt a reevaluation of the role of SPN in streptococcal pathogenesis.

Adult-onset deficiency in growth hormone and insulin-like growth factor-I alters oligodendrocyte turnover in the corpus callosum.

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) provide trophic support during development and also appear to influence cell structure, function and replacement in the adult brain. Recent studies demonstrated effects of the GH/IGF-I axis on adult neurogenesis, but it is unclear whether the GH/IGF-I axis influences glial turnover in the normal adult brain. In the current study, we used a selective model of adult-onset GH and IGF-I deficiency to evaluate the role of GH and IGF-I in regulating glial proliferation and survival in the adult corpus callosum. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete via twice daily injections of GH starting at postnatal day 28 (P28), approximately the age at which GH pulse amplitude increases in developing rodents. GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Quantitative analyses revealed that adult-onset GH/IGF-I deficiency decreased cell proliferation in the white matter and decreased the survival of newborn oligodendrocytes. These findings are consistent with the hypothesis that aging-related changes in the GH/IGF-I axis produce deficits in ongoing turnover of oligodendrocytes, which may contribute to aging-related cognitive changes and deficits in remyelination after injury.

Stability of local brain levels of insulin-like growth factor-I in two well-characterized models of decreased plasma IGF-I.

Insulin-like growth factor-I (IGF-I), a functionally important neurotrophic factor, impacts tissues throughout the body including the central nervous system. In addition to the significant proportion of IGF-I that is synthesized in the liver and released into the plasma, IGF-I is expressed locally in tissues. The present study investigated the relationship between plasma and local brain levels of IGF-I in two well-characterized models of decreased IGF-I. The first is an adult-onset growth hormone deficiency (AOGHD) model, and the second is a caloric restriction (CR) model. In the first cohort of animals from both models, the hippocampus was removed from the brain immediately following decapitation, and in the second cohort, the animals were perfused transcardially with phosphate buffered saline to remove cerebral blood prior to harvesting the hippocampus. Our results demonstrated that although the plasma IGF-I levels were decreased in the CR and AOGHD rats compared to controls, the hippocampal IGF-I levels did not differ among the groups. These data suggest that local brain IGF-I levels are regulated in a different manner than plasma IGF-I levels.

Trends in Clostridium difficile Disease: Epidemiology and Intervention.

Clostridium difficile is the most common cause of nosocomial infectious diarrhea. The incidence of C difficile infection (CDI) is increasing in both inpatients and outpatients, and outbreaks caused by a hypervirulent strain of C difficile are resulting in more severe disease. Moreover, community-associated CDI is occurring in persons who lack the traditional risk factors, which include antibiotic use, advanced age, and severe underlying disease. The clinical severity of CDI ranges from a mild, self-limited diarrheal illness to a fulminant, life-threatening colitis. Enzyme-linked immunosorbent assay is the most common laboratory method used for detection of C difficile toxins and can confirm the diagnosis within several hours. The choice of treatment should be based on disease severity. Oral metronidazole is generally regarded as the treatment of choice for mild to moderate CDI, while oral vancomycin is recommended for severe disease. Timely surgical intervention is important in patients who have severe complicated CDI.

TCR-MHC docking orientation: natural selection, or thymic selection?

T cell receptors (TCR) dock on their peptide-major histocompatibility complex (pMHC) targets in a conserved orientation. Since amino acid sidechains are the foundation of specific protein-protein interactions, a simple explanation for the conserved docking orientation is that key amino acids encoded by the TCR and MHC genes have been selected and maintained through evolution in order to preserve TCR/pMHC binding. Expectations that follow from the hypothesis that TCR and MHC evolved to interact are discussed in light of the data that both support and refute them. Finally, an alternative and equally simple explanation for the driving force behind the conserved docking orientation is described.

Aging-dependent changes in the radiation response of the adult rat brain.

PURPOSE: To assess the impact of aging on the radiation response in the adult rat brain. METHODS AND MATERIALS: Male rats 8, 18, or 28 months of age received a single 10-Gy dose of whole-brain irradiation (WBI). The hippocampal dentate gyrus was analyzed 1 and 10 weeks later for sensitive neurobiologic markers associated with radiation-induced damage: changes in density of proliferating cells, immature neurons, total microglia, and activated microglia. RESULTS: A significant decrease in basal levels of proliferating cells and immature neurons and increased microglial activation occurred with normal aging. The WBI induced a transient increase in proliferation that was greater in older animals. This proliferation response did not increase the number of immature neurons, which decreased after WBI in young rats, but not in old rats. Total microglial numbers decreased after WBI at all ages, but microglial activation increased markedly, particularly in older animals. CONCLUSIONS: Age is an important factor to consider when investigating the radiation response of the brain. In contrast to young adults, older rats show no sustained decrease in number of immature neurons after WBI, but have a greater inflammatory response. The latter may have an enhanced role in the development of radiation-induced cognitive dysfunction in older individuals.

Single MHC mutation eliminates enthalpy associated with T cell receptor binding.

The keystone of the adaptive immune response is T cell receptor (TCR) recognition of peptide presented by major histocompatibility complex (pMHC) molecules. The crystal structure of AHIII TCR bound to MHC, HLA-A2, showed a large interface with an atypical binding orientation. MHC mutations in the interface of the proteins were tested for changes in TCR recognition. From the range of responses observed, three representative HLA-A2 mutants, T163A, W167A, and K66A, were selected for further study. Binding constants and co-crystal structures of the AHIII TCR and the three mutants were determined. K66 in HLA-A2 makes contacts with both peptide and TCR, and has been identified as a critical residue for recognition by numerous TCR. The K66A mutation resulted in the lowest AHIII T cell response and the lowest binding affinity, which suggests that the T cell response may correlate with affinity. Importantly, the K66A mutation does not affect the conformation of the peptide. The change in affinity appears to be due to a loss in hydrogen bonds in the interface as a result of a conformational change in the TCR complementarity-determining region 3 (CDR3) loop. Isothermal titration calorimetry confirmed the loss of hydrogen bonding by a large loss in enthalpy. Our findings are inconsistent with the notion that the CDR1 and CDR2 loops of the TCR are responsible for MHC restriction, while the CDR3 loops interact solely with the peptide. Instead, we present here an MHC mutation that does not change the conformation of the peptide, yet results in an altered conformation of a CDR3.

Aging reduces hypoxia-induced microvascular growth in the rodent hippocampus.

The effect of aging on microvascular density and plasticity in the rodent hippocampus, a brain region critically important for learning and memory, was investigated in F344xBN rats. Capillary density and angiogenesis were measured in three regions of the hippocampus in young and old rats and in old rats administered growth hormone, a treatment that improves cognitive function in older animals. Animals were housed under control conditions or in hypoxic conditions (11% ambient oxygen levels) to stimulate vascular growth. Our results indicate that aging is not associated with a reduction in hippocampal capillary density. However, aged animals demonstrate a significant impairment in hypoxia-induced capillary angiogenesis compared to young animals. Growth hormone treatment to aged animals for 6 weeks did not alter hippocampal capillary density and did not ameliorate the age-related deficit in angiogenesis. We conclude that aging significantly reduces hippocampal microvascular plasticity, which is not improved with growth hormone therapy.

Clostridium difficile infection in solid organ transplant recipients.

PURPOSE OF REVIEW: To provide a general understanding of Clostridium difficile infection with a focus on recent publications that evaluate the disease in solid organ transplant recipients. RECENT FINDINGS: The incidence of C. difficile infection is increasing worldwide. Epidemics due to a hypervirulent C. difficile strain are associated with an escalating severity of disease. New evidence further supports basing initial treatment choice on disease severity. SUMMARY: C. difficile is a significant pathogen in solid organ transplant recipients. Multiple risk factors are found in this population that may result in more severe disease. A high index of suspicion is necessary for the early diagnosis and treatment of C. difficile infection in transplant recipients. Metronidazole and vancomycin show equivalent efficacy in the treatment for mild-to-moderate disease, but vancomycin has demonstrated superiority in the treatment of severe disease. Surgical intervention is also an important consideration in the treatment of solid organ transplant recipients with severe colitis. Rigorous infection control practices are essential for preventing the spread of C. difficile within the hospital environment.

PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3Kα Inhibitors.

Purpose: We describe herein a novel P447_L455 deletion in the C2 domain of PIK3CA in a patient with an ER+ breast cancer with an excellent response to the PI3Kα inhibitor alpelisib. Although PIK3CA deletions are relatively rare, a significant portion of deletions cluster within amino acids 446-460 of the C2 domain, suggesting these residues are critical for p110α function.Experimental Design: A computational structural model of PIK3CAdelP447-L455 in complex with the p85 regulatory subunit and MCF10A cells expressing PIK3CAdelP447-L455 and PIK3CAH450_P458del were used to understand the phenotype of C2 domain deletions.Results: Computational modeling revealed specific favorable inter-residue contacts that would be lost as a result of the deletion, predicting a significant decrease in binding energy. Coimmunoprecipitation experiments showed reduced binding of the C2 deletion mutants with p85 compared with wild-type p110α. The MCF10A cells expressing PIK3CA C2 deletions exhibited growth factor-independent growth, an invasive phenotype, and higher phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All these changes were ablated by alpelisib treatment.Conclusions: C2 domain deletions in PIK3CA generate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors. Clin Cancer Res; 24(6); 1426-35. ©2017 AACR.