Steady-state approximations for Hodgkin-Huxley cell models: Reduction of order for uterine smooth muscle cell model.

Multi-scale mathematical bioelectrical models of organs such as the uterus, stomach or heart present challenges both for accuracy and computational tractability. These multi-scale models are typically founded on models of biological cells derived from the classic Hodkgin-Huxley (HH) formalism. Ion channel behaviour is tracked with dynamical variables representing activation or inactivation of currents that relax to steady-state dependencies on cellular membrane voltage. Timescales for relaxation may be orders of magnitude faster than companion ion channel variables or phenomena of physiological interest for the entire cell (such as bursting sequences of action potentials) or the entire organ (such as electromechanical coordination). Exploiting these time scales with steady-state approximations for relatively fast-acting systems is a well-known but often overlooked approach as evidenced by recent published models. We thus investigate feasibility of an extensive reduction of order for an HH-type cell model with steady-state approximations to the full dynamical activation and inactivation ion channel variables. Our effort utilises a published comprehensive uterine smooth muscle cell model that encompasses 19 ordinary differential equations and 105 formulations overall. The numerous ion channel submodels in the published model exhibit relaxation times ranging from order 10-1 to 105 milliseconds. Substitution of the faster dynamic variables with steady-state formulations demonstrates both an accurate reproduction of the full model and substantial improvements in time-to-solve, for test cases performed. Our demonstration here of an effective and relatively straightforward reduction method underlines the particular importance of considering time scales for model simplification before embarking on large-scale computations or parameter sweeps. As a preliminary complement to more intensive reduction of order methods such as parameter sensitivity and bifurcation analysis, this approach can rapidly and accurately improve computational tractability for challenging multi-scale organ modelling efforts.

Towards assessing subcortical "deep brain" biomarkers of PTSD with functional near-infrared spectroscopy.

Assessment of brain function with functional near-infrared spectroscopy (fNIRS) is limited to the outer regions of the cortex. Previously, we demonstrated the feasibility of inferring activity in subcortical "deep brain" regions using cortical functional magnetic resonance imaging (fMRI) and fNIRS activity in healthy adults. Access to subcortical regions subserving emotion and arousal using affordable and portable fNIRS is likely to be transformative for clinical diagnostic and treatment planning. Here, we validate the feasibility of inferring activity in subcortical regions that are central to the pathophysiology of posttraumatic stress disorder (PTSD; i.e. amygdala and hippocampus) using cortical fMRI and simulated fNIRS activity in a sample of adolescents diagnosed with PTSD (N = 20, mean age = 15.3 ± 1.9 years) and age-matched healthy controls (N = 20, mean age = 14.5 ± 2.0 years) as they performed a facial expression task. We tested different prediction models, including linear regression, a multilayer perceptron neural network, and a k-nearest neighbors model. Inference of subcortical fMRI activity with cortical fMRI showed high prediction performance for the amygdala (r > 0.91) and hippocampus (r > 0.95) in both groups. Using fNIRS simulated data, relatively high prediction performance for deep brain regions was maintained in healthy controls (r > 0.79), as well as in youths with PTSD (r > 0.75). The linear regression and neural network models provided the best predictions.

Comparing diagnostic criteria for posttraumatic stress disorder in a diverse sample of trauma-exposed youth.

Divergent conceptualization of posttraumatic stress disorder (PTSD) within the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) and International Statistical Classification of Diseases and Related Health Problems (11th ed..; ICD-11) significantly confounds both research and practice. Using a diverse sample of trauma-exposed youth (N = 1,542, age range: 8-20 years), we compared these two diagnostic approaches along with an expanded version of the ICD-11 PTSD criteria that included three additional reexperiencing symptoms (ICD-11+). Within the sample, PTSD was more prevalent using the DSM-5 criteria (25.7%) compared to the ICD-11 criteria (16.0%), with moderate agreement between these diagnostic systems, κ = .57. The inclusion of additional reexperiencing symptoms (i.e., ICD-11+) reduced this discrepancy in prevalence (24.7%) and increased concordance with DSM-5 criteria, κ = .73. All three PTSD classification systems exhibited similar comorbidity rates with major depressive episode (MDE) or generalized anxiety disorder (GAD; 78.0%-83.6%). Most youths who met the DSM-5 PTSD criteria also met the criteria for ICD-11 PTSD, MDE, or GAD (88.4%), and this proportion increased when applying the ICD-11+ criteria (95.5%). Symptom-level analyses identified reexperiencing/intrusions and negative alterations in cognition and mood symptoms as primary sources of discrepancy between the DSM-5 and ICD-11 PTSD diagnostic systems. Overall, these results challenge assertions that nonspecific distress and diagnostically overlapping symptoms within DSM-5 PTSD inflate comorbidity with depressive and anxiety disorders. Further, they support the argument that the DSM-5 PTSD criteria can be refined and simplified without reducing the overall prevalence of psychiatric diagnoses in youth.

Isolated cardiac muscle contracting against a real-time model of systemic and pulmonary cardiovascular loads.

Isolated cardiac tissues allow a direct assessment of cardiac muscle function and enable precise control of experimental loading conditions. However, current experimental methods do not expose isolated tissues to the same contraction pattern and cardiovascular loads naturally experienced by the heart. In this study, we implement a computational model of systemic-pulmonary impedance that is solved in real time and imposed on contracting isolated rat muscle tissues. This systemic-pulmonary model represents the cardiovascular system as a lumped-parameter, closed-loop circuit. The tissues performed force-length work-loop contractions where the model output informed both the shortening and restretch phases of each work-loop. We compared the muscle mechanics and energetics associated with work-loops driven by the systemic-pulmonary model with that of a model-based loading method that only accounts for shortening. We obtained results that show simultaneous changes of afterload and preload or end-diastolic length of the muscle, as compared with the static, user-defined preload as in the conventional loading method. This feature allows assessment of muscle work output, heat output, and efficiency of contraction as functions of end-diastolic length. The results reveal the behavior of cardiac muscle as a pump source to achieve load-dependent work and efficiency outputs over a wider range of loads. This study offers potential applications of the model to investigate cardiac muscle response to hemodynamic coupling between systemic and pulmonary circulations in an in vitro setting.NEW & NOTEWORTHY We present the use of a "closed-loop" model of systemic and pulmonary circulations to apply, for the first time, real-time model-calculated preload and afterload to isolated cardiac muscle preparations. This method extends current experimental protocols where only afterload has been considered. The extension to include preload provides the opportunity to investigate ventricular muscle response to hemodynamic coupling and as a pump source across a wider range of cardiovascular loads.

Slower shortening kinetics of cardiac muscle performing Windkessel work-loops increase mechanical efficiency.

Conventional experimental methods for studying cardiac muscle in vitro often do not expose the tissue preparations to a mechanical impedance that resembles the in vivo hemodynamic impedance dictated by the arterial system. That is, the afterload in work-loop contraction is conventionally simplified to be constant throughout muscle shortening, and at a magnitude arbitrarily defined. This conventional afterload does not capture the time-varying interaction between the left ventricle and the arterial system. We have developed a contraction protocol for isolated tissue experiments that allows the afterload to be described within a Windkessel framework that captures the mechanics of the large arteries. We aim to compare the energy expenditure of cardiac muscle undergoing the two contraction protocols: conventional versus Windkessel loading. Isolated rat left-ventricular trabeculae were subjected to the two force-length work-loop contractions. Mechanical work and heat liberation were assessed, and mechanical efficiency quantified, over wide ranges of afterloads or peripheral resistances. Both extent of shortening and heat output were unchanged between protocols, but peak shortening velocity was 39.0% lower and peak work output was 21.8% greater when muscles contracted against the Windkessel afterload than against the conventional isotonic afterload. The greater work led to a 25.2% greater mechanical efficiency. Our findings demonstrate that the mechanoenergetic performance of cardiac muscles in vitro may have been previously constrained by the conventional, arbitrary, loading method. A Windkessel loading protocol, by contrast, unleashes more cardiac muscle mechanoenergetic potential, where the slower shortening increases efficiency in performing mechanical work.NEW & NOTEWORTHY Cardiac muscle samples were allowed to describe their natural shortening dynamics while performing force-length work and liberating heat. The muscle shortened more slowly and produced greater force and work output against a time-varying "Windkessel" load than during conventional constant-force shortening, thereby yielding greater mechanical efficiency. A key finding is that the slower shortening kinetics developed in the face of a time-varying load enhances the mechanical efficiency of cardiac muscle during work-loop contractions.

Heat production in quiescent cardiac muscle is length, velocity and muscle dependent: Implications for active heat measurement.

NEW FINDINGS: What is the central question of this study? Intracellular energetic processes in quiescent cardiac muscle release 'basal' heat; during contraction, a much larger amount of 'active' heat is also produced. Previously, measurement challenges have constrained researchers to assume that basal heat rate remains constant during contraction and shortening. Is this assumption correct? What is the main finding and its importance? We show that basal heat rate is modulated by the extent and velocity of muscle shortening. Their relative contributions are muscle specific. We apply a method with which researchers can now disentangle, for each experiment, changes in basal heat from active heat production, providing more precise measures of the individual energetic processes underlying cardiac muscle contraction. ABSTRACT: Separating the variations in cardiac basal heat rate from variations in active heat rate is necessary to determine cardiac muscle energy consumption accurately during the performance of active work. By developing a model of cardiac muscle basal heat rate, we aimed to investigate changes in basal heat rate when cardiac muscle performs work. Experiments were conducted on 10 isolated rat cardiac trabeculae subjected to both active (work-loops) and quiescent (length-change and velocity) interventions. Muscle force, length and heat output rate were measured simultaneously in a flow-through work-loop calorimeter. Quiescent muscle characteristics were used to parameterize muscle-specific models of change in basal heat rate, thereby to predict dynamic changes in basal heat rate during active work-loop contraction. Our data showed that the quiescent heat characteristics of cardiac muscle varied between samples, displaying dependence on both the extent and the rate of change in muscle length. We found a moderate correlation between muscle dimensions (cross-sectional area and volume) and the length-dependent basal heat parameter (P = 0.0330 and P = 0.0242, respectively), but no correlation with the velocity-dependent parameter. These findings lead us to conclude that the heat output of cardiac muscle at quiescence varies with both the extent and the velocity of shortening, to an extent that is muscle specific, and that this variation must be measured and accounted for in each specimen when assessing active energetics.

Neural changes in youth at high risk for bipolar disorder undergoing family-focused therapy or psychoeducation.

BACKGROUND: Patients with mood disorders may benefit from psychosocial interventions through changes in brain networks underlying emotion processing. In this study, we used functional magnetic resonance imaging (fMRI) to investigate treatment-related changes in emotion processing networks in youth at familial high risk for bipolar disorder (BD). METHODS: Youth, ages 9-17, were randomly assigned to family-focused therapy for high-risk youth (FFT-HR) or an active comparison treatment, Enhanced Care (EC). Before and after these 4-month treatments, participants underwent fMRI while viewing happy, fearful, and calm facial expressions. Twenty youth in FFT-HR and 20 in EC were included in analyses of pre- to post-treatment changes in activation across the whole brain. Significant clusters were assessed for correlation with mood symptom improvement. RESULTS: In the dorsolateral prefrontal cortex (DLPFC), activation increased from pre- to post-treatment in the FFT-HR group and decreased in the EC group. Insula activation decreased in the FFT-HR group and did not change in the EC group. Across both treatments, decreasing activation in the hippocampus and amygdala was correlated with pre- to post-treatment improvement in hypomania, while increasing activation in the DLPFC was correlated with pre- to post-treatment improvement in depression. DISCUSSION: Psychosocial treatment addresses abnormalities in emotion regulation networks in youth at high risk for BD. Increased prefrontal cortex activation suggests enhanced emotion regulation from pre- to post-treatment with FFT-HR. Improvements in family interactions may facilitate the development of prefrontal resources that provide protection against future mood episodes.

Changes in Brain Volume Associated with Trauma-Focused Cognitive Behavioral Therapy Among Youth with Posttraumatic Stress Disorder.

This study investigated group differences and longitudinal changes in brain volume before and after trauma-focused cognitive behavioral therapy (TF-CBT) in 20 unmedicated youth with maltreatment-related posttraumatic stress disorder (PTSD) and 20 non-trauma-exposed healthy control (HC) participants. We collected MRI scans of brain anatomy before and after 5 months of TF-CBT or the same time interval for the HC group. FreeSurfer software was used to segment brain images into 95 cortical and subcortical volumes, which were submitted to optimal scaling regression with lasso variable selection. The resulting model of group differences at baseline included larger right medial orbital frontal and left posterior cingulate corticies and smaller right midcingulate and right precuneus corticies in the PTSD relative to the HC group, R2 = .67. The model of group differences in pre- to posttreatment change included greater longitudinal changes in right rostral middle frontal, left pars triangularis, right entorhinal, and left cuneus corticies in the PTSD relative to the HC group, R2 = .69. Within the PTSD group, pre- to posttreatment symptom improvement was modeled by longitudinal decreases in the left posterior cingulate cortex, R2 = .45, and predicted by baseline measures of a smaller right isthmus (retrosplenial) cingulate and larger left caudate, R2 = .77. In sum, treatment was associated with longitudinal changes in brain regions that support executive functioning but not those that discriminated PTSD from HC participants at baseline. Additionally, results confirm a role for the posterior/retrosplenial cingulate as a correlate of PTSD symptom improvement and predictor of treatment outcome.

The metabolic syndrome in pregnancy and its association with child telomere length.

AIMS/HYPOTHESIS: The aim of this study was to determine whether presence of the metabolic syndrome in pregnancy associates with child telomere length or child anthropometry (weight, BMI) and BP, measured at 10 years of age. METHODS: The Screening for Pregnancy Endpoints study (SCOPE) was a multicentre, international prospective cohort of nulliparous pregnant women recruited from Australia, New Zealand, Ireland and the UK (N = 5628). The current analysis is a 10 year follow-up of SCOPE pregnant women and their children, from the Australian cohort. Clinical data collected at 14-16 weeks' gestation during the SCOPE study were used to diagnose the metabolic syndrome using IDF criteria. Telomere length, a biomarker of ageing, was assessed by quantitative PCR from children's saliva collected at 10 years of age. RESULTS: In women who completed follow-up (n = 255), 20% had the metabolic syndrome in pregnancy. After adjusting for a range of confounders, children of mothers who had the metabolic syndrome in pregnancy had 14% shorter telomeres than children of mothers without the metabolic syndrome in pregnancy (mean difference -0.36 [95% CI -0.74, 0.01]). Height- and weight-for-age, and BMI z scores were similar in children of mothers who did and did not have the metabolic syndrome during pregnancy. CONCLUSIONS/INTERPRETATION: Children of mothers who had the metabolic syndrome in pregnancy have shorter telomeres, a biomarker of accelerated ageing. These findings warrant further studies in larger cohorts of children, as well as investigations into whether telomere length measured in cord blood associates with telomere length in childhood.

Examination and prognostic implications of the unique microenvironment of breast cancer brain metastases.

PURPOSE: Brain metastases (BM) are a complication of advanced breast cancer (BC). Histology of melanoma BM offers prognostic value; however, understanding the microenvironment of breast cancer brain metastases (BCBM) is less characterized. This study reports on four histological biomarkers, gliosis, immune infiltrate, hemorrhage, necrosis, and their prognostic significance in BCBM. METHODS: A biobank of 203 human tissues from patients who underwent craniotomy for BCBM was created across four academic institutions. Degree of gliosis, immune infiltrate, hemorrhage, and necrosis were identified and scored via representative H&E stain (0-3+). Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards regression evaluated prognostic value of the biomarkers in the context of standard clinical characteristics. RESULTS: BCBM subtype (available for n = 158) was 36% Her2+, 26% hormone receptor (HR)+/Her2- 38% HR-/Her2- (triple negative, TN). Gliosis was observed in 82% (116/141) of BCBM, with immune infiltrate 44% (90/201), hemorrhage 82% (166/141), and necrosis 87% (176/201). Necrosis was significantly higher in TNBC (p < 0.01). Presence of gliosis, immune infiltrate, and hemorrhage correlated with improved OS (p = 0.03, p = 0.03, p = 0.1), while necrosis correlated with inferior OS (p = 0.01). Improved OS was associated with gliosis in TN (p = 0.02), and immune infiltrate (p = 0.001) and hemorrhage (p = 0.07) in HER2+. In a multivariable model for OS, incorporating these biomarkers with traditional clinical variables improved the model fit (p < 0.001). CONCLUSION: Gliosis confers superior prognosis in TNBC BM; immune infiltrate and hemorrhage correlate with superior prognosis in HER2+ BCBM. Understanding the metastatic microenvironment of BCBM refines prognostic considerations and may unveil novel therapeutic strategies.

Neural correlates of emotion processing predict resilience in youth at familial risk for mood disorders.

Aberrant face emotion processing has been demonstrated in youth with and at a familial risk for bipolar and major depressive disorders. However, the neurobiological factors related to emotion processing that underlie resilience from youth-onset mood disorders are not well understood. Functional magnetic resonance imaging data during an implicit emotion processing task were collected at baseline from a sample of 50 youth, ages 8-17, who were healthy but also familially at high risk for either bipolar disorder or major depressive disorder, and 24 healthy controls with no family history of psychopathology (HCL). Participants were reevaluated 3 years later and classified into three groups for analysis: high-risk youth who converted to a psychiatric diagnosis (CVT; N = 23), high-risk youth who were resilient from developing any psychopathology (RES; N = 27), and HCL youth (N = 24) who remained healthy at follow-up. For happy > calm faces, the CVT and RES groups had significantly lower activation in the left inferior parietal lobe (IPL), while the RES group had lower activation in the right supramarginal gyrus. For fear > calm faces, the RES group had lower activation in the right precuneus and inferior frontal gyrus (IFG) compared to the CVT group. Connectivity analyses revealed the RES group exhibited higher left IPL connectivity with visual cortical regions for happy > calm faces, and higher IFG connectivity with frontal, temporal, and limbic regions for fear > calm faces. These connectivities were correlated with improvements in prosocial behaviors and global functioning. Our findings suggest that differential activation and connectivity in the IPL, IFG, and precuneus in response to emotional stimuli may represent distinct resilience and risk markers for youth-onset mood disorders.

Unresolved-Disorganized Attachment is Associated With Smaller Hippocampus and Increased Functional Connectivity Beyond Psychopathology.

Loss and abuse in children can lead to unresolved-disorganized (UD) attachment. How this condition relates to brain structure and functional connectivity (FC) is unknown. We therefore aimed to investigate gray matter volume (GMV) and resting state functional connectivity (RSFC) correlates of UD attachment in adolescents. Based on previous neuroimaging studies of trauma effects, we hypothesized that the structure of the amygdala and hippocampus and the FC of the latter would be linked to UD attachment. Anatomical and RSFC data were collected from a mixed group of adolescents (N = 74) with symptoms of posttraumatic stress disorder (PTSD) related to childhood sexual abuse (CSA), anxiety/depressive symptoms, and without psychiatric disorder as part of the Emotional Pathways' Imaging Study in Clinical Adolescents (EPISCA). Bilateral volumes of the amygdala and hippocampus were measured using the FMRIB Software Library, and RSFC of the hippocampus was assessed using seed-based correlation. UD attachment was measured using the Adult Attachment Interview. Hierarchical regression and correlation were used to assess the associations between UD status (continuous and categorical), brain structure, and FC, adjusting for a general psychopathology factor, puberty stage, gender, age, and IQ. UD attachment was associated with a smaller left hippocampal volume, R2 = .23, and a higher level of FC between the hippocampus and the middle temporal gyrus and lateral occipital cortex. The associations among UD attachment, specific brain structure, and FC across psychopathological classifications shows promise for dimensional complements to the dominant classificatory approach in clinical research and practice.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) El apego desorganizado no resuelto asociado con un menor hipocampo y un incremento de la conectividad funcional más allá de la psicopatología APEGO, HIPOCAMPO Y CONECTIVIDAD FUNCIONAL. Las pérdidas y el abuso en niños pueden conllevar a un apego desorganizado no resuelto (DN). La forma en que esta condición se relaciona con la estructura cerebral y conectividad funcional (CF) es desconocida. Por lo tanto, nuestro objetivo fue investigar el volumen de materia gris (VMG) y los correlatos de la conectividad funcional en estado de reposo (CFER) de DN en adolescentes. Basado en estudios previos de neuroimágenes sobre los efectos del trauma, hipotetizamos que la estructura de la amígdala e hipocampo y la CF de este último podría estar relacionado con DN. Los datos anatómicos y de CFER fueron recolectados de un grupo mixto de adolescentes (N = 74) con síntomas de trastorno de estrés postraumático (TEPT) relacionado con abuso sexual infantil (ASI), síntomas de ansiedad/depresión, y sin trastornos psiquiátricos, como parte del Estudio de Imágenes de Vías Emocionales en Clínica Adolescente (EPISCA en su sigla en inglés). Volúmenes bilaterales de la amígdala e hipocampo fueron evaluados usando el software de biblioteca FMRIB, y la CFER del hipocampo fue evaluada usando la correlación basada en semillas. La DN fue medido utilizando la Entrevista de Apego Adulto. Regresiones jerárquicas y correlaciones fueron utilizadas para evaluar las asociaciones entre DN (continuo y categórico), estructura cerebral, y CF, ajustando un factor general de psicopatología, etapa de pubertad, género, edad y CI. DN fue asociado con un menor volumen del hipocampo izquierdo, R2 = .23, y altos niveles de CF entre el hipocampo y giro temporal medio y la corteza occipital lateral. La asociación de DN con una estructura cerebral especifica y CF a través de clasificaciones psicopatológicas es prometedora como complementos dimensionales al enfoque clasificatorio dominante en la investigación y práctica clínica.

A Multidisciplinary Breast Cancer Brain Metastases Clinic: The University of North Carolina Experience.

BACKGROUND: Breast cancer brain metastasis (BCBM) confers a poor prognosis and is unusual in requiring multidisciplinary care in the metastatic setting. The University of North Carolina at Chapel Hill (UNC-CH) has created a BCBM clinic to provide medical and radiation oncology, neurosurgical, and supportive services to this complex patient population. We describe organization and design of the clinic as well as characteristics, treatments, and outcomes of the patients seen in its first 3 years. METHODS: Clinical and demographic data were collected from patients in a prospectively maintained database. Descriptive statistics are reported as percentages and means. The Kaplan-Meier method was used to estimate time-to-event outcomes. RESULTS: Sixty-five patients were seen between January 2012 and January 2015. At the time of presentation to the BCBM clinic, most patients (74%) had multiple (≥2) brain metastases and had received prior systemic (77%) and whole-brain radiation therapy and/or central nervous system stereotactic radiosurgery (65%) in the metastatic setting. Seventy-eight percent returned for a follow-up visit; 32% were enrolled in a clinical trial. Median time from diagnosis of brain metastasis to death was 2.11 years (95% confidence interval [CI] 1.31-2.47) for all patients, 1.15 years (95% CI 0.4-2.43) for triple-negative breast cancer, 1.31 years (95% CI 0.51-2.52) for hormone receptor-positive/HER2- breast cancer, and 3.03 years (95% CI lower limit 1.94, upper limit not estimable) for HER2+ breast cancer (p = .0037). CONCLUSION: Patients with BCBM have unique and complex needs that require input from several oncologic disciplines. The development of the UNC-CH multidisciplinary BCBM clinic is a model that can be adapted at other centers to provide coordinated care for patients with a challenging and complex disease. IMPLICATIONS FOR PRACTICE: Patients with breast cancer brain metastases often require unique multidisciplinary care to meet the numerous and uncommon challenges associated with their conditions. Here, the development and characteristics of a clinic designed specifically to provide for the multidisciplinary needs of patients with breast cancer brain metastases are described. This clinic may serve as a model for other institutions interested in creating specialty clinics with similar objectives.

Association Between Prediagnostic Serum 25-Hydroxyvitamin D Concentration and Glioma.

There are no previous studies of the association between prediagnostic serum vitamin D concentration and glioma. Vitamin D has immunosuppressive properties; as does glioma. It was, therefore, our hypothesis that elevated vitamin D concentration would increase glioma risk. We conducted a nested case-control study using specimens from the Janus Serum Bank cohort in Norway. Blood donors who were subsequently diagnosed with glioma (n = 592), between 1974 and 2007, were matched to donors without glioma (n = 1112) on date and age at blood collection and sex. We measured 25-hydroxyvitamin D [25(OH)D], an indicator of vitamin D availability, using liquid chromatography coupled with mass spectrometry. Seasonally adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for each control quintile of 25(OH)D using conditional logistic regression. Among men diagnosed with high grade glioma >56, we found a negative trend (P = .04). Men diagnosed ≤ 56 showed a borderline positive trend (P = .08). High levels (>66 nmol/L) of 25(OH)D in men >56 were inversely related to high grade glioma from ≥2 yr before diagnosis (OR = 0.59; 95% CI = 0.38, 0.91) to ≥15 yr before diagnosis (OR = 0.61; 95% CI = 0.38,0.96). Our findings are consistent long before glioma diagnosis and are therefore unlikely to reflect preclinical disease.

Using neuroimaging to evaluate and guide pharmacological and psychotherapeutic treatments for mood disorders in children.

Mood disorders are increasing in childhood, and often require multimodal and comprehensive treatment plans to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for treatment and stabilization. Current evidence supports the use of a number of interventions in children and adolescents diagnosed with DSM-5 mood spectrum disorders, which are associated with impairments in prefrontal-striatal-limbic networks, which are key for emotional functioning and regulation. Yet, little is known about the neurobiological effects of interventions on the developing brain. This chapter provides a synopsis of the literature demonstrating the neural effects of psychotropic medications and psychotherapy in youth with depressive or bipolar spectrum disorders. Additional longitudinal and biological studies are warranted to characterize the effects of these interventions on all phases and stages of mood illness development in children and adolescents.

Multichannel mapping of in vivo rat uterine myometrium exhibits both high and low frequency electrical activity in non-pregnancy.

The uterus exhibits intermittent electrophysiological activity in vivo. Although most active during labor, the non-pregnant uterus can exhibit activity of comparable magnitude to the early stages of labor. In this study, two types of flexible electrodes were utilized to measure the electrical activity of uterine smooth muscle in vivo in anesthetized, non-pregnant rats. Flexible printed circuit electrodes were placed on the serosal surface of the uterine horn of six anesthetized rats. Electrical activity was recorded for a duration of 20-30 min. Activity contained two components: high frequency activity (bursts) and an underlying low frequency 'slow wave' which occurred concurrently. These components had dominant frequencies of 6.82 ± 0.63 Hz for the burst frequency and 0.032 ± 0.0055 Hz for the slow wave frequency. There was a mean burst occurrence rate of 0.76 ± 0.23 bursts per minute and mean burst duration of 20.1 ± 6.5 s. The use of multiple high-resolution electrodes enabled 2D mapping of the initiation and propagation of activity along the uterine horn. This in vivo approach has the potential to provide the organ level detail to help interpret non-invasive body surface recordings.

The role of resilience in the development of depression, anxiety, and post-traumatic stress disorder after trauma in children and adolescents.

This investigation, conducted within the Texas Childhood Trauma Research Network, investigated the prospective relationships between resiliency and emergent internalizing symptoms among trauma-exposed youth. The cohort encompassed 1262 youth, aged 8-20, from twelve health-related institutions across Texas, who completed assessments at baseline and one- and six-month follow-ups for resiliency, symptoms of depression, generalized anxiety, posttraumatic stress disorder (PTSD), and other demographic and clinical characteristics. At baseline, greater resilience was positively associated with older age, male (vs female) sex assigned at birth, and history of mental health treatment. Unadjusted for covariates, higher baseline resilience was associated with greater prospective depression and PTSD symptoms but not anxiety symptoms. Upon adjusting for demographic and clinical factors, higher baseline resilience was no longer associated with depression, PTSD, or anxiety symptoms. Our analyses demonstrate that the predictive value of resilience on psychopathology is relatively small compared to more readily observable clinical and demographic factors. These data suggest a relatively minor prospective role of resilience in protecting against internalizing symptoms among trauma-exposed youth and highlight the importance of controlling for relevant youth characteristics when investigating a protective effect of resilience on internalizing symptoms.

Deformations of amygdala morphology in familial pediatric bipolar disorder.

OBJECTIVE: Smaller amygdalar volumes have been consistently observed in pediatric bipolar disorder subjects compared to healthy control subjects. Whether smaller amygdalar volume is a consequence or antecedent of the first episode of mania is not known. Additionally, smaller volume has not been localized to specific amygdala subregions. METHODS: We compared surface contour maps of the amygdala between 22 youths at high risk for bipolar disorder, 26 youths meeting full diagnostic criteria for pediatric familial bipolar disorder, and 24 healthy control subjects matched for age, gender, and intelligence quotient. Amygdalae were manually delineated on three-dimensional spoiled gradient echo images by a blinded rater using established tracing protocols. Statistical surface mesh modeling algorithms supported by permutation statistics were used to identify regional surface differences between the groups. RESULTS: When compared to high-risk subjects and controls, youth with bipolar disorder showed surface deformations in specific amygdalar subregions, suggesting smaller volume of the basolateral nuclei. The high-risk subjects did not differ from controls in any subregion. CONCLUSIONS: These findings support previous reports of smaller amygdala volume in pediatric bipolar disorder and map the location of abnormality to specific amygdala subregions. These subregions have been associated with fear conditioning and emotion-enhanced memory. The absence of amygdala size abnormalities in youth at high risk for bipolar disorder suggests that reductions might occur after the onset of mania.

Early Family Intervention for Youth at Risk for Bipolar Disorder: Psychosocial and Neural Mediators of Outcome.

BACKGROUND: The impairing neurodevelopmental course of bipolar disorder (BD) suggests the importance of early intervention for youth in the beginning phases of the illness. OBJECTIVE: We report the results of a 3-site randomized trial of family-focused therapy for youth at high-risk (FFT-HR) for BD, and explore psychosocial and neuroimaging variables as mediators of treatment effects. METHODS: High-risk youth (<18 years) with major depressive disorder or other specified BD, active mood symptoms, and a family history of BD were randomly assigned to 4 months of FFT-HR (psychoeducation, communication and problem-solving skills training) or 4 months of enhanced care psychoeducation. Adjunctive pharmacotherapy was provided by study psychiatrists. Neuroimaging scans were conducted before and after psychosocial treatments in eligible participants. Independent evaluators interviewed participants every 4-6 months over 1-4 years regarding symptomatic outcomes. RESULTS: Among 127 youth (mean 13.2 ± 2.6 years) over a median of 98 weeks, FFT-HR was associated with longer intervals prior to new mood episodes and lower levels of suicidal ideation than enhanced care. Reductions in perceived family conflict mediated the effects of psychosocial interventions on the course of mood symptoms. Among 34 participants with pre-/post-treatment fMRI scans, youth in FFT-HR had (a) stronger resting state connectivity between ventrolateral PFC and anterior default mode network, and (b) increased activity of dorsolateral and medial PFC in emotion processing and problem-solving tasks, compared to youth in enhanced care. CONCLUSION: FFT-HR may delay new mood episodes in symptomatic youth with familial liability to BD. Putative treatment mechanisms include neural adaptations suggestive of improved emotion regulation.

Structural equation modeling of treatment-related changes in neural connectivity for youth with PTSD.

BACKGROUND: Previous studies suggest that improvement in symptoms of posttraumatic stress disorder (PTSD) is accompanied by changes in neural connectivity, however, few studies have investigated directional (effective) connectivity. The current study assesses treatment-related changes in effective connectivity in youth with PTSD undergoing Trauma-Focused Cognitive Behavioral Therapy (TF-CBT). METHODS: Functional MRI scans before and after 16 weeks of TF-CBT for 20 youth with PTSD, or the same time interval for 20 healthy controls (HC) were included in the analysis. Structural equation modeling was used to model group differences in directional connectivity at baseline, and changes in connectivity from pre- to post-treatment. RESULTS: At baseline, the PTSD group, relative to the HC group, had significantly greater connectivity in the path from dorsal cingulate to anterior cingulate and from dorsal cingulate to posterior cingulate corticies. From pre- to post-treatment, connectivity in these paths decreased significantly in the PTSD group, as did connectivity from right hippocampus to left superior temporal gyrus. Connectivity from the left amygdala to the lateral orbital frontal cortex was significantly lower in PTSD vs HC at baseline, but did not change from pre- to post-treatment. CONCLUSION: Although based on a small sample, these results converge with previous studies in suggesting a central role for the dorsal cingulate cortex in PTSD symptoms. The direction of this connectivity suggests that the dorsal cingulate is the source of modulation of anterior and posterior cingulate cortex during trauma-focused cognitive behavioral therapy.